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Heart Failure Diagnostic Alerts to Prompt Pharmacist Evaluation and Medication Optimization
Heart Failure Diagnostic Alerts to Prompt Pharmacist Evaluation and Medication Optimization
Heart failure (HF) is a prevalent disease in the United States affecting > 6.5 million adults and contributing to significant morbidity and mortality.1 The disease course associated with HF includes potential symptom improvement with intermittent periods of decompensation and possible clinical deterioration. Multiple therapies have been developed to improve outcomes in people with HF—to palliate HF symptoms, prevent hospitalizations, and reduce mortality.2 However, the risks of decompensation and hospitalization remain. HF decompensation development may precede clear actionable symptoms such as worsening dyspnea, noticeable edema, or weight gain. Tools to identify patient deterioration and trigger interventions to prevent HF admissions are clinically attractive compared with reliance on subjective factors alone.
Cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator (ICD) devices made by Boston Scientific include the HeartLogic monitoring feature. Five main sensors produce an index risk score; an index score > 16 warns clinicians that the patient is at an increased risk for a HF event.3 The 5 sensors are thoracic impedance, first (S1) and third heart sounds (S3), night heart rate (NHR), respiratory rate (RR), and activity. Each sensor can draw attention to the primary driver of the alert and guide health care practitioners (HCPs) to the appropriate interventions.3 A HeartLogic alert example is shown in Figure 1.
The S3 occurs during the early diastolic phase when blood moves into the ventricles. As HF worsens, with a combination of elevated filling pressures and reduced cardiac muscle compliance, S3 can become more pronounced.4 The S1 is correlated with the contractility of the left ventricle and will be reduced in patients at risk for HF events.5 Physical activity is a long-term prognostic marker in patients with HF; reduced activity is associated with mortality and increased risk of an HF event.6 Thoracic impedance is a sensor used to identify pulmonary congestion, pocket infections, pleural/pericardial effusion, and respiratory infections. The accumulation of intrathoracic fluid during pulmonary congestion increases conductance, causing a decrease in impedance.7 RR will increase as patients experience dyspnea with a more rapid, shallow breath and may trigger alerts closer to the actual HF event than other sensors. Nearly 90% of patients hospitalized for HF experience shortness of breath.8,9 NHR is used as a surrogate for resting heart rate (HR). A high resting HR is correlated with the progression of coronary atherosclerosis, harmful effects on left ventricular function, and increased risk of myocardial ischemia and ventricular arrhythmias.10
One of the challenges with preventing hospitalizations may be the lack of patient reported symptoms leading up to the event. The purpose of the sensors and HeartLogic index is to identify patients a median of 34 days before an HF event (HF admission or unscheduled intervention with intravenous treatment) with a sensitivity rate of 70%.3 According to real-word experience data, alerts have been found to precede HF symptoms by a median of 12 days and HF events such as hospitalizations by a median of 38 days, with an overall 67% reduction in HF hospitalizations when integrated into clinical care.11,12
MANAGE-HF evaluated 191 patients with HF with reduced ejection fraction (HFrEF) (< 35%), New York Heart Association class II-III symptoms, and who had an implanted CRT and/or ICD to develop an alert management guide to optimize medical treatment.12 It aimed to adjust patient regimen within 6 days of an elevated Heart- Logic index by either initiation, escalation, or maintenance of HF treatment depending on the index trend after the initial alert. This trial found that by focusing on such optimization, HF treatment was augmented during 74% of the 585 alert cases and during 54% of 3290 weekly alerts.
Initiation and uptitration of the 4 primary components of guideline-directed medical therapy (GDMT) are recommended by the 2022 Heart Failure Guidelines to reduce mortality and morbidity in patients with HFrEF.2 The 4 pillars of GDMT consist of -blockers (BB), sodium-glucose cotransporter type 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRA), and renin-angiotensin-system inhibitors (RASi) including angiotensin II receptor blocker/neprilysin inhibitors (ARNi), angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) (Appendix 1). Obtaining and titrating to target doses wherever possible is recommended, as those were the doses that established safety and efficacy in patients with HFrEF in clinical trials.2 Pharmacists are adequately equipped to optimize HF GDMT and appropriately monitor drug response.
Through the use of HeartLogic in clinical practice, patients with HF have been shown to have improved clinical outcomes and are more likely to receive effective care; 80% of alerts were shown to provide new information to clinicians.13 This project sought to quantify the total number and types of pharmacist interventions driven by integration of HeartLogic index monitoring into practice.
Methods
The West Palm Beach Veterans Affairs Medical Center (WPBVAMC) Research Program Office approved this project and determined it was exempt from institutional review board oversight. Patients were screened retrospectively and prospectively from May 26, 2022, through December 31, 2022, by a cardiology clinical pharmacist practitioner (CPP) and a cardiology pharmacy resident using the local monitoring suite for the HeartLogic-compatible device, LATITUDE NXT. Read-only access to the local monitoring suit was granted by the National Cardiac Device Surveillance Program. Training for HeartLogic was completed through continuing education courses provided by Boston Scientific. Additional information was provided by Boston Scientific representative presentations and collaboration with WPBVAMC pacemaker clinic HCPs.
Individuals included were patients with HeartLogic-capable ICDs. A HeartLogic alert had to be present at initial patient contact. Patients were also contacted as part of routine clinical practice, but no formal number or frequency of calls to patients was required. The initial contact must be with a pharmacist for the patient to be included, but subsequent contact by other HCPs was included. Patients in the cardiology clinic are required to meet with a cardiologist at least annually; however, interim visits can be completed by advanced practice registered nurse practitioners, physicians assistants, or CPPs.
Patients in alert status were contacted by telephone and appropriate modifications of HF therapy were made by the CPP based on score metrics, medical record review, and patient interview. Information surrounding the initial alert, baseline patient data, medication and monitoring interventions made, and clinical outcomes such as hospitalization, symptom improvement, follow-up, and mortality were collected. Information for each encounter was collected until 42 days from the initial date of pharmacist contact.
Clinically successful tolerability of intervention implementation was defined as tolerability, adherence, and lack of adverse effects (AEs) per patient report at follow-up or within 42 days from initial alert (Appendix 2). A decrease in dose was not counted as intolerance. A single patient may have been counted as multiple encounters if the original intervention resulted in treatment intolerance and the patient remained in alert or if an additional alert occurred after 42 days of the initial alert. There were no specific time criteria for follow-up, which occurred at the CPP’s discretion.
There was no mandated algorithm used to alter medications based on the Heart- Logic score, nor were there required minimum or maximum numbers of interventions after an alert. Patient contact by telephone initiated an encounter. The types of interventions included medication increases, decreases, initiation, discontinuation, or no medication change. Each medication change and rationale, if applicable, was recorded for the encounter ≤ 42 days after the initial contact date. If a medication with required monitoring parameters was augmented, the pharmacist was responsible for ordering laboratory testing and follow-up. Most interventions were completed by telephone; however, some patients had in-person visits in the HF CPP clinic.
Outcomes
The primary outcome was the number of pharmacist interventions made to optimize GDMT, defined as either an initiation or dose increase. Key intervention analysis included the use and dosing of the 4 primary components of HF GDMT: BB, SGLT2i, MRA, and ARNi/ARB/ACEi. In addition to the 4 primary components of GDMT, loop diuretic changes were also recorded and analyzed. Secondary endpoints were the number of HF hospitalizations ≤ 42 days after the initial alert, and the effect of medication interventions on device metrics, patient symptoms, and tolerability. Successful tolerability was defined as continued use of augmented GDMT without intolerance or discontinuation. The primary analysis was analyzed through descriptive statistics. Median changes in HeartLogic scores and metrics from baseline were analyzed using a paired, 2-sided t test with an α of .05 to detect significance.
Results
There were 39 WPBVAMC patients with a HeartLogic-capable device. Twenty-one alert encounters were analyzed in 16 patients (41%) over 31 weeks of data collection. The 16 patients at baseline had a mean age of 74 years, all were male, and 12 (75%) were White. Eight patients (50%) had a recent ejection fraction (EF) between 30% and 40%. Three patients had an EF ≥ 40%. At the time of alert, 15 patients used BB (94%), 10 used loop diuretics (63%), and 9 used ARNi (56%) (Table 1).
There were 23 medication changes made during initial contact. The most common change was starting an SGLT2i (30%; n = 7), followed by starting an MRA (22%; n = 5), and increasing the ARNi dose (22%; n = 5). At the initial contact, ≥ 1 medication optimization occurred in 95% (n = 20) of encounters. The CPP contacted patients a mean of 4.8 days after the initial alert.
Patients were taking a mean of 2.6 primary GDMT medications at baseline and 3.0 at 42 days. CPP encounters led to a mean of 1.8 medication changes over the 6-week period (range, 0-5). Seventeen medications were started, 13 medications were increased, 3 medications were decreased, and 4 medications were stopped (Table 2). One ACEi and 1 ARB were switched as a therapy escalation to an ARNi. One patient was on 1 of 4 primary GDMTs at baseline, which increased to 4 GDMT agents at 42 days.
SGLT2 inhibitors were added most often at initial contact (54%) and throughout the 42-day period (41%). The most common successfully tolerated optimizations were RASi, followed by MRA, SGLT2 inhibitors, BB, and loop diuretics with 11, 6, 5, 3, and 2 patients, respectively. Interventions were tolerated by 90% of patients, and no HF hospitalization occurred during follow-up. All possible rationales for patients with the same or reduced number of GDMT at 42 days compared with baseline are shown in Appendix 2.
Device Metrics
During initial contact, the most common HeartLogic metric category that was predominantly worsening were heart sounds (S1, S3, and S3/S1 ratio), followed by compensatory mechanism sensors (NHR and RR) and congestion (impedance) at rates of 61.9%, 23.8%, and 14.3%, respectively (Figure 2).
The median HeartLogic index score was 18 at baseline and 5 at the end of the follow-up period (P < .001). The changes in score and metrics were compared with the type of successfully tolerated GDMT optimization made (Table 3). The GDMT optimization analysis included SGLT2i, RASi, MRA, BB, and loop diuretics. All interventions reduced the overall HeartLogic index score, ranging from a 9.5-point reduction (loop diuretics) to a 16-point reduction (SGLT2i and BB). Optimization of SGLT2i, RASi, and loop diuretics had a positive impact on S1 score. For S3 score, SGLT2i, MRA, and BB had a positive impact. All medications, except for SGLT2i therapy, reduced the NHR score. Optimization of MRA, SGLT2i, and BB had positive impacts on the impedance score. All medications reduced RR from baseline. Only SGLT2i and loop diuretics had positive impacts on the activity score.
Clinical Outcomes and Adverse Effects
Within 42 days of contact, 17 encounters (81%) had ≥ 1 follow-up appointment with a CPP and all 21 patients had ≥ 1 follow-up health care team member. One patient had a HF-related hospitalization within 42 days of contact; however, that individual refused the recommended medication intervention. There were 13 encounters (62%) with reported symptoms at the time of the initial alert and 10 (77%) had subjective symptom improvement at 42 days (Appendix 3).
Of 30 medication optimizations, 27 primary GDMT medications were tolerated. Two medication intolerances led to discontinuation (1 SGLT2i and 1 loop diuretic) and 1 patient never started the SGLT2i (Table 4). There was only 1 known patient who did not follow the directions to adjust their medications. That individual was included because the patient agreed to the change during the CPP visit but later reported that he had never started the SGLT2i.
Discussion
The HeartLogic tool created a bridge for patients with HF to work with CPPs as soon as possible to optimize medication therapy to reduce HF events. This study highlights an additional area of expertise and service that CPPs may offer to their specialty HF clinic team. Over 31 weeks, 21 encounters and 30 medication optimizations were completed. These interventions led to significant reductions in HeartLogic scores, improvements in symptoms, and optimization of HF care, most of which were well tolerated.
Additional hemodynamic monitoring devices are available. Similar to HeartLogic, OptiVol is a tool embedded in select Medtronic implantable devices that monitors fluid status. 14 CardioMEMS is an implantable pulmonary artery pressure sensor used as a presymptomatic data point to alert clinicians when HF is worsening. In the CHAMPION trial, the use of CardioMEMS showed a 28% reduction in HF-related hospitalization at 6 months.15 Conversely, in the GUIDE-HF trial, monitoring with CardioMEMS did not significantly reduce the composite endpoint of mortality and total HF events.16 Therefore, remote hemodynamic monitoring has variable results and the use of these tools remains uncertain per the clinical guidelines.2
The MANAGE-HF study that contributed to the validation of the HeartLogic tool may provide a comparison with this smaller single-center project. The time to follow-up within 7 days of alert was noted in only 54% of the patients in MANAGE-HF.12 In this study, 86% of patients received follow-up within 7 days, with a mean of 4.8 days. The quick turnaround from the time of alert to intervention portrays pharmacists as readily available HCPs.
In MANAGE-HF, 89% of medication augmentation involved loop diuretics or thiazides; in our project, loop diuretics were the least frequently changed medication. Most optimizations in this project included ARNi, SGLT2i, BB, and MRA, which have been shown to reduce morbidity and mortality.2 Our project included use of SGLT2i therapy to affect HeartLogic metrics, which has not been evaluated previously. SGLT2i were the most commonly initiated medication after an alert. Of the 5 tolerated SGLT2i optimization encounters, 4 were out of alert at 42 days.
SGLT2i resulted in a significant decrease in HeartLogic index score from baseline and were the only class of medication that did not produce a negative change in any metric. In this study, CPPs utilizing and acting on HeartLogic alerts led to 1 (4.8%) hospitalization with HF as the primary reason for admission and no hospitalizations as a secondary cause in 42 days, compared to 37% and 7.9% in the MANAGE-HF in 1 year, respectively. An additional screening 1 year after the initial alert found that 2 (12.5%) of 12 patients had been admitted with 1 HF hospitalization each.
A strength of this study was the ability to use HeartLogic to identify high-risk patients, provide a source of patient contact and monitoring, interpret 5 cardiac sensors, and optimize all HF GDMT, not just volume management. By focusing efforts on making patient contact and pharmacotherapy interventions with morbidity and mortality benefit, remote hemodynamic monitoring may show a clear clinical benefit and become a vital part of HF care.
Limitations
Checking for adherence and tolerance to medications were mainly patient reported if there was a CPP follow-up within 42 days, or potentially through refill history when unclear. However, this limitation is reflective of current practice where patients may have multiple clinicians working to optimize HF care and where there is reliance on patients in order to guide continued therapy. Although unable to explicitly show a reduction in HF events given lack of comparator group, the interventions made are associated with improved outcomes and thus would be expected to improve patient outcomes. Changes in vital signs were not tracked as part of this project, however the main rationale for changes made were to optimize GDMT therapy, not specifically to impact vital sign measures.
HeartLogic alerts prompted identification of high-risk patients with HF, pharmacist evaluation and outreach, patient-focused pharmacotherapy care, and beneficial patient outcomes. With only 2 cardiology CPPs checking alerts once weekly, future studies may be needed with larger samples to create algorithms and protocols to increase the clinical utility of this tool on a greater scale.
Conclusions
Cardiology CPP-led HF interventions triggered by HeartLogic alerts lead to effective patient identification, increased access to care, reductions in HeartLogic scores, improvements in symptoms, and optimization of HF care. This project demonstrates the practical utility of the HeartLogic suite in conjunction with CPP care to prioritize treatment for highrisk patients with HF in an efficient manner. The data highlight the potential value of the HeartLogic tool and a CPP in HF care to facilitate initiation and optimization of GDMT to ultimately improve the morbidity and mortality in patients with HF.
- Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2023 update: a report from the American Heart Association. Circulation. 2023;147:e93-e621. doi:10.1161/CIR.0000000000001123
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/ American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e895-e1032. doi:10.1161/CIR.0000000000001063
- Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE study. J Am Coll Cardiol HF. 2017;5:216-225. doi:10.1016/j.jchf.2016.12.011
- Cao M, Gardner RS, Hariharan R, et al. Ambulatory monitoring of heart sounds via an implanted device is superior to auscultation for prediction of heart failure events. J Card Fail. 2020;26:151-159. doi:10.1016/j.cardfail.2019.10.006
- Calò L, Capucci A, Santini L, et al. ICD-measured heart sounds and their correlation with echocardiographic indexes of systolic and diastolic function. J Interv Card Electrophysiol. 2020;58:95-101. doi:10.1007/s10840-019-00668
- Del Buono MG, Arena R, Borlaug BA, et al. Exercise intolerance in patients with heart failure: JACC state-of-the- art review. J Am Coll Cardiol. 2019;73:2209-2225. doi:10.1016/j.jacc.2019.01.072
- Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation. 2005;112:841-848. doi:10.1161/CIRCULATIONAHA.104.492207
- Rials S, Aktas M, An Q, et al. Continuous respiratory rate is superior to routine outpatient dyspnea assessment for predicting heart failure events. J Card Fail. 2018;24:S45.
- Fonarow GC, ADHERE Scientific Advisory Committee. The Acute Decompensated Heart Failure National Registry (ADHERE): opportunities to improve care of patients hospitalized with acute decompensated heart failure. Rev Cardiovasc Med. 2003;4(suppl 7):S21-S30. doi:10.1016/j.cardfail.2018.07.130
- Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823-830. doi:10.1016/j.jacc.2007.04.079
- De Ruvo E, Capucci A, Ammirati F, et al. Preliminary experience of remote management of heart failure patients with a multisensor ICD alert [abstract P1536]. Eur J Heart Fail. 2019;21(suppl S1):370.
- Hernandez AF, Albert NM, Allen LA, et al. Multiple cardiac sensors for management of heart failure (MANAGE- HF) - phase I evaluation of the integration and safety of the HeartLogic multisensor algorithm in patients with heart failure. J Card Fail. 2022;28:1245-1254. doi:10.1016/j.cardfail.2022.03.349
- Santini L, D’Onofrio A, Dello Russo A, et al. Prospective evaluation of the multisensor HeartLogic algorithm for heart failure monitoring. Clin Cardiol. 2020;43:691-697. doi:10.1002/clc.23366
- Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation. 2005;112:841-848. doi:10.1161/CIRCULATIONAHA.104.492207
- Adamson PB, Abraham WT, Stevenson LW, et al. Pulmonary artery pressure-guided heart failure management reduces 30-day readmissions. Circ Heart Fail. 2016;9:e002600. doi:10.1161/CIRCHEARTFAILURE.115.002600
- Lindenfeld J, Zile MR, Desai AS, et al. Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial. Lancet. 2021;398:991-1001. doi:10.1016/S0140-6736(21)01754-2
Heart failure (HF) is a prevalent disease in the United States affecting > 6.5 million adults and contributing to significant morbidity and mortality.1 The disease course associated with HF includes potential symptom improvement with intermittent periods of decompensation and possible clinical deterioration. Multiple therapies have been developed to improve outcomes in people with HF—to palliate HF symptoms, prevent hospitalizations, and reduce mortality.2 However, the risks of decompensation and hospitalization remain. HF decompensation development may precede clear actionable symptoms such as worsening dyspnea, noticeable edema, or weight gain. Tools to identify patient deterioration and trigger interventions to prevent HF admissions are clinically attractive compared with reliance on subjective factors alone.
Cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator (ICD) devices made by Boston Scientific include the HeartLogic monitoring feature. Five main sensors produce an index risk score; an index score > 16 warns clinicians that the patient is at an increased risk for a HF event.3 The 5 sensors are thoracic impedance, first (S1) and third heart sounds (S3), night heart rate (NHR), respiratory rate (RR), and activity. Each sensor can draw attention to the primary driver of the alert and guide health care practitioners (HCPs) to the appropriate interventions.3 A HeartLogic alert example is shown in Figure 1.
The S3 occurs during the early diastolic phase when blood moves into the ventricles. As HF worsens, with a combination of elevated filling pressures and reduced cardiac muscle compliance, S3 can become more pronounced.4 The S1 is correlated with the contractility of the left ventricle and will be reduced in patients at risk for HF events.5 Physical activity is a long-term prognostic marker in patients with HF; reduced activity is associated with mortality and increased risk of an HF event.6 Thoracic impedance is a sensor used to identify pulmonary congestion, pocket infections, pleural/pericardial effusion, and respiratory infections. The accumulation of intrathoracic fluid during pulmonary congestion increases conductance, causing a decrease in impedance.7 RR will increase as patients experience dyspnea with a more rapid, shallow breath and may trigger alerts closer to the actual HF event than other sensors. Nearly 90% of patients hospitalized for HF experience shortness of breath.8,9 NHR is used as a surrogate for resting heart rate (HR). A high resting HR is correlated with the progression of coronary atherosclerosis, harmful effects on left ventricular function, and increased risk of myocardial ischemia and ventricular arrhythmias.10
One of the challenges with preventing hospitalizations may be the lack of patient reported symptoms leading up to the event. The purpose of the sensors and HeartLogic index is to identify patients a median of 34 days before an HF event (HF admission or unscheduled intervention with intravenous treatment) with a sensitivity rate of 70%.3 According to real-word experience data, alerts have been found to precede HF symptoms by a median of 12 days and HF events such as hospitalizations by a median of 38 days, with an overall 67% reduction in HF hospitalizations when integrated into clinical care.11,12
MANAGE-HF evaluated 191 patients with HF with reduced ejection fraction (HFrEF) (< 35%), New York Heart Association class II-III symptoms, and who had an implanted CRT and/or ICD to develop an alert management guide to optimize medical treatment.12 It aimed to adjust patient regimen within 6 days of an elevated Heart- Logic index by either initiation, escalation, or maintenance of HF treatment depending on the index trend after the initial alert. This trial found that by focusing on such optimization, HF treatment was augmented during 74% of the 585 alert cases and during 54% of 3290 weekly alerts.
Initiation and uptitration of the 4 primary components of guideline-directed medical therapy (GDMT) are recommended by the 2022 Heart Failure Guidelines to reduce mortality and morbidity in patients with HFrEF.2 The 4 pillars of GDMT consist of -blockers (BB), sodium-glucose cotransporter type 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRA), and renin-angiotensin-system inhibitors (RASi) including angiotensin II receptor blocker/neprilysin inhibitors (ARNi), angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) (Appendix 1). Obtaining and titrating to target doses wherever possible is recommended, as those were the doses that established safety and efficacy in patients with HFrEF in clinical trials.2 Pharmacists are adequately equipped to optimize HF GDMT and appropriately monitor drug response.
Through the use of HeartLogic in clinical practice, patients with HF have been shown to have improved clinical outcomes and are more likely to receive effective care; 80% of alerts were shown to provide new information to clinicians.13 This project sought to quantify the total number and types of pharmacist interventions driven by integration of HeartLogic index monitoring into practice.
Methods
The West Palm Beach Veterans Affairs Medical Center (WPBVAMC) Research Program Office approved this project and determined it was exempt from institutional review board oversight. Patients were screened retrospectively and prospectively from May 26, 2022, through December 31, 2022, by a cardiology clinical pharmacist practitioner (CPP) and a cardiology pharmacy resident using the local monitoring suite for the HeartLogic-compatible device, LATITUDE NXT. Read-only access to the local monitoring suit was granted by the National Cardiac Device Surveillance Program. Training for HeartLogic was completed through continuing education courses provided by Boston Scientific. Additional information was provided by Boston Scientific representative presentations and collaboration with WPBVAMC pacemaker clinic HCPs.
Individuals included were patients with HeartLogic-capable ICDs. A HeartLogic alert had to be present at initial patient contact. Patients were also contacted as part of routine clinical practice, but no formal number or frequency of calls to patients was required. The initial contact must be with a pharmacist for the patient to be included, but subsequent contact by other HCPs was included. Patients in the cardiology clinic are required to meet with a cardiologist at least annually; however, interim visits can be completed by advanced practice registered nurse practitioners, physicians assistants, or CPPs.
Patients in alert status were contacted by telephone and appropriate modifications of HF therapy were made by the CPP based on score metrics, medical record review, and patient interview. Information surrounding the initial alert, baseline patient data, medication and monitoring interventions made, and clinical outcomes such as hospitalization, symptom improvement, follow-up, and mortality were collected. Information for each encounter was collected until 42 days from the initial date of pharmacist contact.
Clinically successful tolerability of intervention implementation was defined as tolerability, adherence, and lack of adverse effects (AEs) per patient report at follow-up or within 42 days from initial alert (Appendix 2). A decrease in dose was not counted as intolerance. A single patient may have been counted as multiple encounters if the original intervention resulted in treatment intolerance and the patient remained in alert or if an additional alert occurred after 42 days of the initial alert. There were no specific time criteria for follow-up, which occurred at the CPP’s discretion.
There was no mandated algorithm used to alter medications based on the Heart- Logic score, nor were there required minimum or maximum numbers of interventions after an alert. Patient contact by telephone initiated an encounter. The types of interventions included medication increases, decreases, initiation, discontinuation, or no medication change. Each medication change and rationale, if applicable, was recorded for the encounter ≤ 42 days after the initial contact date. If a medication with required monitoring parameters was augmented, the pharmacist was responsible for ordering laboratory testing and follow-up. Most interventions were completed by telephone; however, some patients had in-person visits in the HF CPP clinic.
Outcomes
The primary outcome was the number of pharmacist interventions made to optimize GDMT, defined as either an initiation or dose increase. Key intervention analysis included the use and dosing of the 4 primary components of HF GDMT: BB, SGLT2i, MRA, and ARNi/ARB/ACEi. In addition to the 4 primary components of GDMT, loop diuretic changes were also recorded and analyzed. Secondary endpoints were the number of HF hospitalizations ≤ 42 days after the initial alert, and the effect of medication interventions on device metrics, patient symptoms, and tolerability. Successful tolerability was defined as continued use of augmented GDMT without intolerance or discontinuation. The primary analysis was analyzed through descriptive statistics. Median changes in HeartLogic scores and metrics from baseline were analyzed using a paired, 2-sided t test with an α of .05 to detect significance.
Results
There were 39 WPBVAMC patients with a HeartLogic-capable device. Twenty-one alert encounters were analyzed in 16 patients (41%) over 31 weeks of data collection. The 16 patients at baseline had a mean age of 74 years, all were male, and 12 (75%) were White. Eight patients (50%) had a recent ejection fraction (EF) between 30% and 40%. Three patients had an EF ≥ 40%. At the time of alert, 15 patients used BB (94%), 10 used loop diuretics (63%), and 9 used ARNi (56%) (Table 1).
There were 23 medication changes made during initial contact. The most common change was starting an SGLT2i (30%; n = 7), followed by starting an MRA (22%; n = 5), and increasing the ARNi dose (22%; n = 5). At the initial contact, ≥ 1 medication optimization occurred in 95% (n = 20) of encounters. The CPP contacted patients a mean of 4.8 days after the initial alert.
Patients were taking a mean of 2.6 primary GDMT medications at baseline and 3.0 at 42 days. CPP encounters led to a mean of 1.8 medication changes over the 6-week period (range, 0-5). Seventeen medications were started, 13 medications were increased, 3 medications were decreased, and 4 medications were stopped (Table 2). One ACEi and 1 ARB were switched as a therapy escalation to an ARNi. One patient was on 1 of 4 primary GDMTs at baseline, which increased to 4 GDMT agents at 42 days.
SGLT2 inhibitors were added most often at initial contact (54%) and throughout the 42-day period (41%). The most common successfully tolerated optimizations were RASi, followed by MRA, SGLT2 inhibitors, BB, and loop diuretics with 11, 6, 5, 3, and 2 patients, respectively. Interventions were tolerated by 90% of patients, and no HF hospitalization occurred during follow-up. All possible rationales for patients with the same or reduced number of GDMT at 42 days compared with baseline are shown in Appendix 2.
Device Metrics
During initial contact, the most common HeartLogic metric category that was predominantly worsening were heart sounds (S1, S3, and S3/S1 ratio), followed by compensatory mechanism sensors (NHR and RR) and congestion (impedance) at rates of 61.9%, 23.8%, and 14.3%, respectively (Figure 2).
The median HeartLogic index score was 18 at baseline and 5 at the end of the follow-up period (P < .001). The changes in score and metrics were compared with the type of successfully tolerated GDMT optimization made (Table 3). The GDMT optimization analysis included SGLT2i, RASi, MRA, BB, and loop diuretics. All interventions reduced the overall HeartLogic index score, ranging from a 9.5-point reduction (loop diuretics) to a 16-point reduction (SGLT2i and BB). Optimization of SGLT2i, RASi, and loop diuretics had a positive impact on S1 score. For S3 score, SGLT2i, MRA, and BB had a positive impact. All medications, except for SGLT2i therapy, reduced the NHR score. Optimization of MRA, SGLT2i, and BB had positive impacts on the impedance score. All medications reduced RR from baseline. Only SGLT2i and loop diuretics had positive impacts on the activity score.
Clinical Outcomes and Adverse Effects
Within 42 days of contact, 17 encounters (81%) had ≥ 1 follow-up appointment with a CPP and all 21 patients had ≥ 1 follow-up health care team member. One patient had a HF-related hospitalization within 42 days of contact; however, that individual refused the recommended medication intervention. There were 13 encounters (62%) with reported symptoms at the time of the initial alert and 10 (77%) had subjective symptom improvement at 42 days (Appendix 3).
Of 30 medication optimizations, 27 primary GDMT medications were tolerated. Two medication intolerances led to discontinuation (1 SGLT2i and 1 loop diuretic) and 1 patient never started the SGLT2i (Table 4). There was only 1 known patient who did not follow the directions to adjust their medications. That individual was included because the patient agreed to the change during the CPP visit but later reported that he had never started the SGLT2i.
Discussion
The HeartLogic tool created a bridge for patients with HF to work with CPPs as soon as possible to optimize medication therapy to reduce HF events. This study highlights an additional area of expertise and service that CPPs may offer to their specialty HF clinic team. Over 31 weeks, 21 encounters and 30 medication optimizations were completed. These interventions led to significant reductions in HeartLogic scores, improvements in symptoms, and optimization of HF care, most of which were well tolerated.
Additional hemodynamic monitoring devices are available. Similar to HeartLogic, OptiVol is a tool embedded in select Medtronic implantable devices that monitors fluid status. 14 CardioMEMS is an implantable pulmonary artery pressure sensor used as a presymptomatic data point to alert clinicians when HF is worsening. In the CHAMPION trial, the use of CardioMEMS showed a 28% reduction in HF-related hospitalization at 6 months.15 Conversely, in the GUIDE-HF trial, monitoring with CardioMEMS did not significantly reduce the composite endpoint of mortality and total HF events.16 Therefore, remote hemodynamic monitoring has variable results and the use of these tools remains uncertain per the clinical guidelines.2
The MANAGE-HF study that contributed to the validation of the HeartLogic tool may provide a comparison with this smaller single-center project. The time to follow-up within 7 days of alert was noted in only 54% of the patients in MANAGE-HF.12 In this study, 86% of patients received follow-up within 7 days, with a mean of 4.8 days. The quick turnaround from the time of alert to intervention portrays pharmacists as readily available HCPs.
In MANAGE-HF, 89% of medication augmentation involved loop diuretics or thiazides; in our project, loop diuretics were the least frequently changed medication. Most optimizations in this project included ARNi, SGLT2i, BB, and MRA, which have been shown to reduce morbidity and mortality.2 Our project included use of SGLT2i therapy to affect HeartLogic metrics, which has not been evaluated previously. SGLT2i were the most commonly initiated medication after an alert. Of the 5 tolerated SGLT2i optimization encounters, 4 were out of alert at 42 days.
SGLT2i resulted in a significant decrease in HeartLogic index score from baseline and were the only class of medication that did not produce a negative change in any metric. In this study, CPPs utilizing and acting on HeartLogic alerts led to 1 (4.8%) hospitalization with HF as the primary reason for admission and no hospitalizations as a secondary cause in 42 days, compared to 37% and 7.9% in the MANAGE-HF in 1 year, respectively. An additional screening 1 year after the initial alert found that 2 (12.5%) of 12 patients had been admitted with 1 HF hospitalization each.
A strength of this study was the ability to use HeartLogic to identify high-risk patients, provide a source of patient contact and monitoring, interpret 5 cardiac sensors, and optimize all HF GDMT, not just volume management. By focusing efforts on making patient contact and pharmacotherapy interventions with morbidity and mortality benefit, remote hemodynamic monitoring may show a clear clinical benefit and become a vital part of HF care.
Limitations
Checking for adherence and tolerance to medications were mainly patient reported if there was a CPP follow-up within 42 days, or potentially through refill history when unclear. However, this limitation is reflective of current practice where patients may have multiple clinicians working to optimize HF care and where there is reliance on patients in order to guide continued therapy. Although unable to explicitly show a reduction in HF events given lack of comparator group, the interventions made are associated with improved outcomes and thus would be expected to improve patient outcomes. Changes in vital signs were not tracked as part of this project, however the main rationale for changes made were to optimize GDMT therapy, not specifically to impact vital sign measures.
HeartLogic alerts prompted identification of high-risk patients with HF, pharmacist evaluation and outreach, patient-focused pharmacotherapy care, and beneficial patient outcomes. With only 2 cardiology CPPs checking alerts once weekly, future studies may be needed with larger samples to create algorithms and protocols to increase the clinical utility of this tool on a greater scale.
Conclusions
Cardiology CPP-led HF interventions triggered by HeartLogic alerts lead to effective patient identification, increased access to care, reductions in HeartLogic scores, improvements in symptoms, and optimization of HF care. This project demonstrates the practical utility of the HeartLogic suite in conjunction with CPP care to prioritize treatment for highrisk patients with HF in an efficient manner. The data highlight the potential value of the HeartLogic tool and a CPP in HF care to facilitate initiation and optimization of GDMT to ultimately improve the morbidity and mortality in patients with HF.
Heart failure (HF) is a prevalent disease in the United States affecting > 6.5 million adults and contributing to significant morbidity and mortality.1 The disease course associated with HF includes potential symptom improvement with intermittent periods of decompensation and possible clinical deterioration. Multiple therapies have been developed to improve outcomes in people with HF—to palliate HF symptoms, prevent hospitalizations, and reduce mortality.2 However, the risks of decompensation and hospitalization remain. HF decompensation development may precede clear actionable symptoms such as worsening dyspnea, noticeable edema, or weight gain. Tools to identify patient deterioration and trigger interventions to prevent HF admissions are clinically attractive compared with reliance on subjective factors alone.
Cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator (ICD) devices made by Boston Scientific include the HeartLogic monitoring feature. Five main sensors produce an index risk score; an index score > 16 warns clinicians that the patient is at an increased risk for a HF event.3 The 5 sensors are thoracic impedance, first (S1) and third heart sounds (S3), night heart rate (NHR), respiratory rate (RR), and activity. Each sensor can draw attention to the primary driver of the alert and guide health care practitioners (HCPs) to the appropriate interventions.3 A HeartLogic alert example is shown in Figure 1.
The S3 occurs during the early diastolic phase when blood moves into the ventricles. As HF worsens, with a combination of elevated filling pressures and reduced cardiac muscle compliance, S3 can become more pronounced.4 The S1 is correlated with the contractility of the left ventricle and will be reduced in patients at risk for HF events.5 Physical activity is a long-term prognostic marker in patients with HF; reduced activity is associated with mortality and increased risk of an HF event.6 Thoracic impedance is a sensor used to identify pulmonary congestion, pocket infections, pleural/pericardial effusion, and respiratory infections. The accumulation of intrathoracic fluid during pulmonary congestion increases conductance, causing a decrease in impedance.7 RR will increase as patients experience dyspnea with a more rapid, shallow breath and may trigger alerts closer to the actual HF event than other sensors. Nearly 90% of patients hospitalized for HF experience shortness of breath.8,9 NHR is used as a surrogate for resting heart rate (HR). A high resting HR is correlated with the progression of coronary atherosclerosis, harmful effects on left ventricular function, and increased risk of myocardial ischemia and ventricular arrhythmias.10
One of the challenges with preventing hospitalizations may be the lack of patient reported symptoms leading up to the event. The purpose of the sensors and HeartLogic index is to identify patients a median of 34 days before an HF event (HF admission or unscheduled intervention with intravenous treatment) with a sensitivity rate of 70%.3 According to real-word experience data, alerts have been found to precede HF symptoms by a median of 12 days and HF events such as hospitalizations by a median of 38 days, with an overall 67% reduction in HF hospitalizations when integrated into clinical care.11,12
MANAGE-HF evaluated 191 patients with HF with reduced ejection fraction (HFrEF) (< 35%), New York Heart Association class II-III symptoms, and who had an implanted CRT and/or ICD to develop an alert management guide to optimize medical treatment.12 It aimed to adjust patient regimen within 6 days of an elevated Heart- Logic index by either initiation, escalation, or maintenance of HF treatment depending on the index trend after the initial alert. This trial found that by focusing on such optimization, HF treatment was augmented during 74% of the 585 alert cases and during 54% of 3290 weekly alerts.
Initiation and uptitration of the 4 primary components of guideline-directed medical therapy (GDMT) are recommended by the 2022 Heart Failure Guidelines to reduce mortality and morbidity in patients with HFrEF.2 The 4 pillars of GDMT consist of -blockers (BB), sodium-glucose cotransporter type 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRA), and renin-angiotensin-system inhibitors (RASi) including angiotensin II receptor blocker/neprilysin inhibitors (ARNi), angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) (Appendix 1). Obtaining and titrating to target doses wherever possible is recommended, as those were the doses that established safety and efficacy in patients with HFrEF in clinical trials.2 Pharmacists are adequately equipped to optimize HF GDMT and appropriately monitor drug response.
Through the use of HeartLogic in clinical practice, patients with HF have been shown to have improved clinical outcomes and are more likely to receive effective care; 80% of alerts were shown to provide new information to clinicians.13 This project sought to quantify the total number and types of pharmacist interventions driven by integration of HeartLogic index monitoring into practice.
Methods
The West Palm Beach Veterans Affairs Medical Center (WPBVAMC) Research Program Office approved this project and determined it was exempt from institutional review board oversight. Patients were screened retrospectively and prospectively from May 26, 2022, through December 31, 2022, by a cardiology clinical pharmacist practitioner (CPP) and a cardiology pharmacy resident using the local monitoring suite for the HeartLogic-compatible device, LATITUDE NXT. Read-only access to the local monitoring suit was granted by the National Cardiac Device Surveillance Program. Training for HeartLogic was completed through continuing education courses provided by Boston Scientific. Additional information was provided by Boston Scientific representative presentations and collaboration with WPBVAMC pacemaker clinic HCPs.
Individuals included were patients with HeartLogic-capable ICDs. A HeartLogic alert had to be present at initial patient contact. Patients were also contacted as part of routine clinical practice, but no formal number or frequency of calls to patients was required. The initial contact must be with a pharmacist for the patient to be included, but subsequent contact by other HCPs was included. Patients in the cardiology clinic are required to meet with a cardiologist at least annually; however, interim visits can be completed by advanced practice registered nurse practitioners, physicians assistants, or CPPs.
Patients in alert status were contacted by telephone and appropriate modifications of HF therapy were made by the CPP based on score metrics, medical record review, and patient interview. Information surrounding the initial alert, baseline patient data, medication and monitoring interventions made, and clinical outcomes such as hospitalization, symptom improvement, follow-up, and mortality were collected. Information for each encounter was collected until 42 days from the initial date of pharmacist contact.
Clinically successful tolerability of intervention implementation was defined as tolerability, adherence, and lack of adverse effects (AEs) per patient report at follow-up or within 42 days from initial alert (Appendix 2). A decrease in dose was not counted as intolerance. A single patient may have been counted as multiple encounters if the original intervention resulted in treatment intolerance and the patient remained in alert or if an additional alert occurred after 42 days of the initial alert. There were no specific time criteria for follow-up, which occurred at the CPP’s discretion.
There was no mandated algorithm used to alter medications based on the Heart- Logic score, nor were there required minimum or maximum numbers of interventions after an alert. Patient contact by telephone initiated an encounter. The types of interventions included medication increases, decreases, initiation, discontinuation, or no medication change. Each medication change and rationale, if applicable, was recorded for the encounter ≤ 42 days after the initial contact date. If a medication with required monitoring parameters was augmented, the pharmacist was responsible for ordering laboratory testing and follow-up. Most interventions were completed by telephone; however, some patients had in-person visits in the HF CPP clinic.
Outcomes
The primary outcome was the number of pharmacist interventions made to optimize GDMT, defined as either an initiation or dose increase. Key intervention analysis included the use and dosing of the 4 primary components of HF GDMT: BB, SGLT2i, MRA, and ARNi/ARB/ACEi. In addition to the 4 primary components of GDMT, loop diuretic changes were also recorded and analyzed. Secondary endpoints were the number of HF hospitalizations ≤ 42 days after the initial alert, and the effect of medication interventions on device metrics, patient symptoms, and tolerability. Successful tolerability was defined as continued use of augmented GDMT without intolerance or discontinuation. The primary analysis was analyzed through descriptive statistics. Median changes in HeartLogic scores and metrics from baseline were analyzed using a paired, 2-sided t test with an α of .05 to detect significance.
Results
There were 39 WPBVAMC patients with a HeartLogic-capable device. Twenty-one alert encounters were analyzed in 16 patients (41%) over 31 weeks of data collection. The 16 patients at baseline had a mean age of 74 years, all were male, and 12 (75%) were White. Eight patients (50%) had a recent ejection fraction (EF) between 30% and 40%. Three patients had an EF ≥ 40%. At the time of alert, 15 patients used BB (94%), 10 used loop diuretics (63%), and 9 used ARNi (56%) (Table 1).
There were 23 medication changes made during initial contact. The most common change was starting an SGLT2i (30%; n = 7), followed by starting an MRA (22%; n = 5), and increasing the ARNi dose (22%; n = 5). At the initial contact, ≥ 1 medication optimization occurred in 95% (n = 20) of encounters. The CPP contacted patients a mean of 4.8 days after the initial alert.
Patients were taking a mean of 2.6 primary GDMT medications at baseline and 3.0 at 42 days. CPP encounters led to a mean of 1.8 medication changes over the 6-week period (range, 0-5). Seventeen medications were started, 13 medications were increased, 3 medications were decreased, and 4 medications were stopped (Table 2). One ACEi and 1 ARB were switched as a therapy escalation to an ARNi. One patient was on 1 of 4 primary GDMTs at baseline, which increased to 4 GDMT agents at 42 days.
SGLT2 inhibitors were added most often at initial contact (54%) and throughout the 42-day period (41%). The most common successfully tolerated optimizations were RASi, followed by MRA, SGLT2 inhibitors, BB, and loop diuretics with 11, 6, 5, 3, and 2 patients, respectively. Interventions were tolerated by 90% of patients, and no HF hospitalization occurred during follow-up. All possible rationales for patients with the same or reduced number of GDMT at 42 days compared with baseline are shown in Appendix 2.
Device Metrics
During initial contact, the most common HeartLogic metric category that was predominantly worsening were heart sounds (S1, S3, and S3/S1 ratio), followed by compensatory mechanism sensors (NHR and RR) and congestion (impedance) at rates of 61.9%, 23.8%, and 14.3%, respectively (Figure 2).
The median HeartLogic index score was 18 at baseline and 5 at the end of the follow-up period (P < .001). The changes in score and metrics were compared with the type of successfully tolerated GDMT optimization made (Table 3). The GDMT optimization analysis included SGLT2i, RASi, MRA, BB, and loop diuretics. All interventions reduced the overall HeartLogic index score, ranging from a 9.5-point reduction (loop diuretics) to a 16-point reduction (SGLT2i and BB). Optimization of SGLT2i, RASi, and loop diuretics had a positive impact on S1 score. For S3 score, SGLT2i, MRA, and BB had a positive impact. All medications, except for SGLT2i therapy, reduced the NHR score. Optimization of MRA, SGLT2i, and BB had positive impacts on the impedance score. All medications reduced RR from baseline. Only SGLT2i and loop diuretics had positive impacts on the activity score.
Clinical Outcomes and Adverse Effects
Within 42 days of contact, 17 encounters (81%) had ≥ 1 follow-up appointment with a CPP and all 21 patients had ≥ 1 follow-up health care team member. One patient had a HF-related hospitalization within 42 days of contact; however, that individual refused the recommended medication intervention. There were 13 encounters (62%) with reported symptoms at the time of the initial alert and 10 (77%) had subjective symptom improvement at 42 days (Appendix 3).
Of 30 medication optimizations, 27 primary GDMT medications were tolerated. Two medication intolerances led to discontinuation (1 SGLT2i and 1 loop diuretic) and 1 patient never started the SGLT2i (Table 4). There was only 1 known patient who did not follow the directions to adjust their medications. That individual was included because the patient agreed to the change during the CPP visit but later reported that he had never started the SGLT2i.
Discussion
The HeartLogic tool created a bridge for patients with HF to work with CPPs as soon as possible to optimize medication therapy to reduce HF events. This study highlights an additional area of expertise and service that CPPs may offer to their specialty HF clinic team. Over 31 weeks, 21 encounters and 30 medication optimizations were completed. These interventions led to significant reductions in HeartLogic scores, improvements in symptoms, and optimization of HF care, most of which were well tolerated.
Additional hemodynamic monitoring devices are available. Similar to HeartLogic, OptiVol is a tool embedded in select Medtronic implantable devices that monitors fluid status. 14 CardioMEMS is an implantable pulmonary artery pressure sensor used as a presymptomatic data point to alert clinicians when HF is worsening. In the CHAMPION trial, the use of CardioMEMS showed a 28% reduction in HF-related hospitalization at 6 months.15 Conversely, in the GUIDE-HF trial, monitoring with CardioMEMS did not significantly reduce the composite endpoint of mortality and total HF events.16 Therefore, remote hemodynamic monitoring has variable results and the use of these tools remains uncertain per the clinical guidelines.2
The MANAGE-HF study that contributed to the validation of the HeartLogic tool may provide a comparison with this smaller single-center project. The time to follow-up within 7 days of alert was noted in only 54% of the patients in MANAGE-HF.12 In this study, 86% of patients received follow-up within 7 days, with a mean of 4.8 days. The quick turnaround from the time of alert to intervention portrays pharmacists as readily available HCPs.
In MANAGE-HF, 89% of medication augmentation involved loop diuretics or thiazides; in our project, loop diuretics were the least frequently changed medication. Most optimizations in this project included ARNi, SGLT2i, BB, and MRA, which have been shown to reduce morbidity and mortality.2 Our project included use of SGLT2i therapy to affect HeartLogic metrics, which has not been evaluated previously. SGLT2i were the most commonly initiated medication after an alert. Of the 5 tolerated SGLT2i optimization encounters, 4 were out of alert at 42 days.
SGLT2i resulted in a significant decrease in HeartLogic index score from baseline and were the only class of medication that did not produce a negative change in any metric. In this study, CPPs utilizing and acting on HeartLogic alerts led to 1 (4.8%) hospitalization with HF as the primary reason for admission and no hospitalizations as a secondary cause in 42 days, compared to 37% and 7.9% in the MANAGE-HF in 1 year, respectively. An additional screening 1 year after the initial alert found that 2 (12.5%) of 12 patients had been admitted with 1 HF hospitalization each.
A strength of this study was the ability to use HeartLogic to identify high-risk patients, provide a source of patient contact and monitoring, interpret 5 cardiac sensors, and optimize all HF GDMT, not just volume management. By focusing efforts on making patient contact and pharmacotherapy interventions with morbidity and mortality benefit, remote hemodynamic monitoring may show a clear clinical benefit and become a vital part of HF care.
Limitations
Checking for adherence and tolerance to medications were mainly patient reported if there was a CPP follow-up within 42 days, or potentially through refill history when unclear. However, this limitation is reflective of current practice where patients may have multiple clinicians working to optimize HF care and where there is reliance on patients in order to guide continued therapy. Although unable to explicitly show a reduction in HF events given lack of comparator group, the interventions made are associated with improved outcomes and thus would be expected to improve patient outcomes. Changes in vital signs were not tracked as part of this project, however the main rationale for changes made were to optimize GDMT therapy, not specifically to impact vital sign measures.
HeartLogic alerts prompted identification of high-risk patients with HF, pharmacist evaluation and outreach, patient-focused pharmacotherapy care, and beneficial patient outcomes. With only 2 cardiology CPPs checking alerts once weekly, future studies may be needed with larger samples to create algorithms and protocols to increase the clinical utility of this tool on a greater scale.
Conclusions
Cardiology CPP-led HF interventions triggered by HeartLogic alerts lead to effective patient identification, increased access to care, reductions in HeartLogic scores, improvements in symptoms, and optimization of HF care. This project demonstrates the practical utility of the HeartLogic suite in conjunction with CPP care to prioritize treatment for highrisk patients with HF in an efficient manner. The data highlight the potential value of the HeartLogic tool and a CPP in HF care to facilitate initiation and optimization of GDMT to ultimately improve the morbidity and mortality in patients with HF.
- Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2023 update: a report from the American Heart Association. Circulation. 2023;147:e93-e621. doi:10.1161/CIR.0000000000001123
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/ American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e895-e1032. doi:10.1161/CIR.0000000000001063
- Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE study. J Am Coll Cardiol HF. 2017;5:216-225. doi:10.1016/j.jchf.2016.12.011
- Cao M, Gardner RS, Hariharan R, et al. Ambulatory monitoring of heart sounds via an implanted device is superior to auscultation for prediction of heart failure events. J Card Fail. 2020;26:151-159. doi:10.1016/j.cardfail.2019.10.006
- Calò L, Capucci A, Santini L, et al. ICD-measured heart sounds and their correlation with echocardiographic indexes of systolic and diastolic function. J Interv Card Electrophysiol. 2020;58:95-101. doi:10.1007/s10840-019-00668
- Del Buono MG, Arena R, Borlaug BA, et al. Exercise intolerance in patients with heart failure: JACC state-of-the- art review. J Am Coll Cardiol. 2019;73:2209-2225. doi:10.1016/j.jacc.2019.01.072
- Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation. 2005;112:841-848. doi:10.1161/CIRCULATIONAHA.104.492207
- Rials S, Aktas M, An Q, et al. Continuous respiratory rate is superior to routine outpatient dyspnea assessment for predicting heart failure events. J Card Fail. 2018;24:S45.
- Fonarow GC, ADHERE Scientific Advisory Committee. The Acute Decompensated Heart Failure National Registry (ADHERE): opportunities to improve care of patients hospitalized with acute decompensated heart failure. Rev Cardiovasc Med. 2003;4(suppl 7):S21-S30. doi:10.1016/j.cardfail.2018.07.130
- Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823-830. doi:10.1016/j.jacc.2007.04.079
- De Ruvo E, Capucci A, Ammirati F, et al. Preliminary experience of remote management of heart failure patients with a multisensor ICD alert [abstract P1536]. Eur J Heart Fail. 2019;21(suppl S1):370.
- Hernandez AF, Albert NM, Allen LA, et al. Multiple cardiac sensors for management of heart failure (MANAGE- HF) - phase I evaluation of the integration and safety of the HeartLogic multisensor algorithm in patients with heart failure. J Card Fail. 2022;28:1245-1254. doi:10.1016/j.cardfail.2022.03.349
- Santini L, D’Onofrio A, Dello Russo A, et al. Prospective evaluation of the multisensor HeartLogic algorithm for heart failure monitoring. Clin Cardiol. 2020;43:691-697. doi:10.1002/clc.23366
- Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation. 2005;112:841-848. doi:10.1161/CIRCULATIONAHA.104.492207
- Adamson PB, Abraham WT, Stevenson LW, et al. Pulmonary artery pressure-guided heart failure management reduces 30-day readmissions. Circ Heart Fail. 2016;9:e002600. doi:10.1161/CIRCHEARTFAILURE.115.002600
- Lindenfeld J, Zile MR, Desai AS, et al. Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial. Lancet. 2021;398:991-1001. doi:10.1016/S0140-6736(21)01754-2
- Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2023 update: a report from the American Heart Association. Circulation. 2023;147:e93-e621. doi:10.1161/CIR.0000000000001123
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/ American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e895-e1032. doi:10.1161/CIR.0000000000001063
- Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE study. J Am Coll Cardiol HF. 2017;5:216-225. doi:10.1016/j.jchf.2016.12.011
- Cao M, Gardner RS, Hariharan R, et al. Ambulatory monitoring of heart sounds via an implanted device is superior to auscultation for prediction of heart failure events. J Card Fail. 2020;26:151-159. doi:10.1016/j.cardfail.2019.10.006
- Calò L, Capucci A, Santini L, et al. ICD-measured heart sounds and their correlation with echocardiographic indexes of systolic and diastolic function. J Interv Card Electrophysiol. 2020;58:95-101. doi:10.1007/s10840-019-00668
- Del Buono MG, Arena R, Borlaug BA, et al. Exercise intolerance in patients with heart failure: JACC state-of-the- art review. J Am Coll Cardiol. 2019;73:2209-2225. doi:10.1016/j.jacc.2019.01.072
- Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation. 2005;112:841-848. doi:10.1161/CIRCULATIONAHA.104.492207
- Rials S, Aktas M, An Q, et al. Continuous respiratory rate is superior to routine outpatient dyspnea assessment for predicting heart failure events. J Card Fail. 2018;24:S45.
- Fonarow GC, ADHERE Scientific Advisory Committee. The Acute Decompensated Heart Failure National Registry (ADHERE): opportunities to improve care of patients hospitalized with acute decompensated heart failure. Rev Cardiovasc Med. 2003;4(suppl 7):S21-S30. doi:10.1016/j.cardfail.2018.07.130
- Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823-830. doi:10.1016/j.jacc.2007.04.079
- De Ruvo E, Capucci A, Ammirati F, et al. Preliminary experience of remote management of heart failure patients with a multisensor ICD alert [abstract P1536]. Eur J Heart Fail. 2019;21(suppl S1):370.
- Hernandez AF, Albert NM, Allen LA, et al. Multiple cardiac sensors for management of heart failure (MANAGE- HF) - phase I evaluation of the integration and safety of the HeartLogic multisensor algorithm in patients with heart failure. J Card Fail. 2022;28:1245-1254. doi:10.1016/j.cardfail.2022.03.349
- Santini L, D’Onofrio A, Dello Russo A, et al. Prospective evaluation of the multisensor HeartLogic algorithm for heart failure monitoring. Clin Cardiol. 2020;43:691-697. doi:10.1002/clc.23366
- Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation. 2005;112:841-848. doi:10.1161/CIRCULATIONAHA.104.492207
- Adamson PB, Abraham WT, Stevenson LW, et al. Pulmonary artery pressure-guided heart failure management reduces 30-day readmissions. Circ Heart Fail. 2016;9:e002600. doi:10.1161/CIRCHEARTFAILURE.115.002600
- Lindenfeld J, Zile MR, Desai AS, et al. Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial. Lancet. 2021;398:991-1001. doi:10.1016/S0140-6736(21)01754-2
Heart Failure Diagnostic Alerts to Prompt Pharmacist Evaluation and Medication Optimization
Heart Failure Diagnostic Alerts to Prompt Pharmacist Evaluation and Medication Optimization
Codes, Contracts, and Commitments: Who Defines What is a Profession?
Codes, Contracts, and Commitments: Who Defines What is a Profession?
A professional is someone who can do his best work when he doesn’t feel like it.
Alistair Cooke
When I was a young person with no idea about growing up to be something, my father used to tell me there were 4 learned professions: medicine to heal the body, law to protect the body politic, teaching to nurture the mind, and the clergy to care for the soul.1 That adage, or some version of it, is attributed to a variety of sources, likely because it captures something essential and timeless about the learned professions. I write this as a much older person, and it has been my privilege to have worked in some capacity in all 4 of these venerable vocations.
There are many more recognized professions now than in my father’s time with new ones still emerging as the world becomes more complicated and specialized. In November 2025, however, the growth of the professions was dealt a serious blow when the US Department of Education (DOE) redefined what constitutes a profession for the purpose of federal funding of graduate degrees.2 The internet is understandably abuzz with opinions across the political spectrum. What is missing from many of these discussions is an understanding of the criteria for a profession and, even more importantly, who has the authority to decide when an individual or a group has met that standard.
But first, what and why did the DOE make this change? The One Big Beautiful Bill Act charged the DOE with reducing what it claims is massive overspending on graduate education by limiting the programs that meet the definition of a “professional degree” eligible for higher funding. Of my father’s 4, medicine (including dentistry) and law made the cut with students in those professions able to borrow up to $200,000 in direct unsubsidized student loans while those in other programs would be limited to $100,000.2
As one of the oldest and most respected professions in America, nursing has received the most media attention, yet there are also other important and valued professions that are missing from the DOE list.3 The excluded professions also include: physician assistants, physical therapists, audiologists, architects, accountants, educators, and social workers. The proposed regulatory changes are not yet finalized and Congressional representatives, health care experts, and a myriad of professional associations have rightly objected the reclassification will only worsen the critical shortage of nurses, teachers, and other helping professions the country is already facing.4
There are thousands of federal health care professionals who worked long and hard to achieve their goals whom this Act undervalues. Moreover, the regulatory change leaves many students enrolled in education and training programs under federal practice auspices confused and overwhelmed. Perhaps they can take some hope and inspiration from the recognition that historically and philosophically, no agency or administration can unilaterally define what is a profession.
The literature on professionalism is voluminous, in large part because it has been surprisingly difficult to reach a consensus definition. A proposed definition from scholars captures most of the key aspects of a profession. While it is drawn from the medical literature, it applies to most of the caring professions the DOE disqualified. For pedagogic purposes, the definition is parsed into discrete criteria in the Table.5
Even this simple summary makes it obvious that a government agency alone could not possibly have the competence to determine who meets these complex technical and moral criteria. The members of the profession must assume a primary role in that determination. The complicated history of the professions shows that the locus of these decisions has resided in various combinations of educational institutions, such as nursing schools,6 professional societies (eg, National Association of Social Workers),7 and certifying boards (eg, National Commission on Certification of Physician Assistants).8 States, not the federal government, have long played a key part in defining professions in the US, through their authority to grant licenses to practice.9
In response to criticism, the DOE has stated that “the definition of a ‘professional degree’ is an internal definition used by the Department of Education to distinguish among programs that qualify for higher loan limits, not a value judgment about the importance of programs. It has no bearing on whether a program is professional in nature or not.”2 Given the ancient compact between society and the professions in which the government subsidizes the training of professionals dedicated to public service, it is hard to see how these changes can be dismissed as merely semantic and not a promissory breach.10
I recognize that this abstract editorial is little comfort to beleaguered and demoralized professionals and students. Still, it offers a voice of support for each federal practitioner or trainee who fulfills the epigraph’s description of a professional day after day. The nurse who works the extra shift without complaint or resentment so that veterans receive the care they deserve, the social worker who responds on a weekend night to an active duty family without food so they do not spend another night hungry, and the physician assistant who makes it into the isolated public health clinic despite the terrible weather so there is someone ready to take care for patients in need. The proposed policy shift cannot in any meaningful sense rob them of their identity as individuals committed to a code of caring. However, without an intact social compact, it may well remove their practical ability to remain and enter the helping professions to the detriment of us all.
- Wade JW. Public responsibilities of the learned professions. Louisiana Law Rev. 1960;21:130-148
- US Department of Education. Myth vs. fact: the definition of professional degrees. Press Release. November 24, 2025. Accessed December 22, 2025. https://www.ed.gov/about/news/press-release/myth-vs-fact-definition-of-professional-degrees
- Laws J. Full list of degrees not classed as “professional” by Trump admin. Newsweek. Updated November 26, 2025. Accessed December 22, 2025. https://www.newsweek.com/full-list-degrees-professional-trump-administration-11085695
- New York Academy of Medicine. Response to stripping “professional status” as proposed by the Department of Education. New York Academy of Medicine. November 24, 2025. Accessed December 22, 2025. https://nyam.org/article/response-to-stripping-professional-status-as-proposed-by-the-department-of-education
- Cruess SR, Johnston S, Cruess RL. “Profession”: a working definition for medical educators. Teach Learn Med. 2004;16:74-76. doi:10.1207/s15328015tlm1601_15
- American Association of Colleges of Nursing. Nursing is a professional degree. American Association of Colleges of Nursing. Accessed December 20, 2025. https://www.aacnnursing.org/policy-advocacy/take-action/nursing-is-a-professional-degree
- National Association of Social Workers. Social work is a profession. Social Workers. Accessed December 20, 2025. https://www.socialworkers.org
- National Commission on Certification of Physician Assistants. Accessed December 20, 2025. https://www.nccpa.net/about-nccpa/#who-we-are
- The Federation of State Boards of Physical Therapy. Accessed December 20, 2025. https://www.fsbpt.org/About-Us/Staff-Home
- Cruess SR, Cruess RL. Professionalism and medicine’s contract with social contract with society. Virtual Mentor. 2004;6:185-188. doi:10.1001/virtualmentor.2004.6.4.msoc1-040
A professional is someone who can do his best work when he doesn’t feel like it.
Alistair Cooke
When I was a young person with no idea about growing up to be something, my father used to tell me there were 4 learned professions: medicine to heal the body, law to protect the body politic, teaching to nurture the mind, and the clergy to care for the soul.1 That adage, or some version of it, is attributed to a variety of sources, likely because it captures something essential and timeless about the learned professions. I write this as a much older person, and it has been my privilege to have worked in some capacity in all 4 of these venerable vocations.
There are many more recognized professions now than in my father’s time with new ones still emerging as the world becomes more complicated and specialized. In November 2025, however, the growth of the professions was dealt a serious blow when the US Department of Education (DOE) redefined what constitutes a profession for the purpose of federal funding of graduate degrees.2 The internet is understandably abuzz with opinions across the political spectrum. What is missing from many of these discussions is an understanding of the criteria for a profession and, even more importantly, who has the authority to decide when an individual or a group has met that standard.
But first, what and why did the DOE make this change? The One Big Beautiful Bill Act charged the DOE with reducing what it claims is massive overspending on graduate education by limiting the programs that meet the definition of a “professional degree” eligible for higher funding. Of my father’s 4, medicine (including dentistry) and law made the cut with students in those professions able to borrow up to $200,000 in direct unsubsidized student loans while those in other programs would be limited to $100,000.2
As one of the oldest and most respected professions in America, nursing has received the most media attention, yet there are also other important and valued professions that are missing from the DOE list.3 The excluded professions also include: physician assistants, physical therapists, audiologists, architects, accountants, educators, and social workers. The proposed regulatory changes are not yet finalized and Congressional representatives, health care experts, and a myriad of professional associations have rightly objected the reclassification will only worsen the critical shortage of nurses, teachers, and other helping professions the country is already facing.4
There are thousands of federal health care professionals who worked long and hard to achieve their goals whom this Act undervalues. Moreover, the regulatory change leaves many students enrolled in education and training programs under federal practice auspices confused and overwhelmed. Perhaps they can take some hope and inspiration from the recognition that historically and philosophically, no agency or administration can unilaterally define what is a profession.
The literature on professionalism is voluminous, in large part because it has been surprisingly difficult to reach a consensus definition. A proposed definition from scholars captures most of the key aspects of a profession. While it is drawn from the medical literature, it applies to most of the caring professions the DOE disqualified. For pedagogic purposes, the definition is parsed into discrete criteria in the Table.5
Even this simple summary makes it obvious that a government agency alone could not possibly have the competence to determine who meets these complex technical and moral criteria. The members of the profession must assume a primary role in that determination. The complicated history of the professions shows that the locus of these decisions has resided in various combinations of educational institutions, such as nursing schools,6 professional societies (eg, National Association of Social Workers),7 and certifying boards (eg, National Commission on Certification of Physician Assistants).8 States, not the federal government, have long played a key part in defining professions in the US, through their authority to grant licenses to practice.9
In response to criticism, the DOE has stated that “the definition of a ‘professional degree’ is an internal definition used by the Department of Education to distinguish among programs that qualify for higher loan limits, not a value judgment about the importance of programs. It has no bearing on whether a program is professional in nature or not.”2 Given the ancient compact between society and the professions in which the government subsidizes the training of professionals dedicated to public service, it is hard to see how these changes can be dismissed as merely semantic and not a promissory breach.10
I recognize that this abstract editorial is little comfort to beleaguered and demoralized professionals and students. Still, it offers a voice of support for each federal practitioner or trainee who fulfills the epigraph’s description of a professional day after day. The nurse who works the extra shift without complaint or resentment so that veterans receive the care they deserve, the social worker who responds on a weekend night to an active duty family without food so they do not spend another night hungry, and the physician assistant who makes it into the isolated public health clinic despite the terrible weather so there is someone ready to take care for patients in need. The proposed policy shift cannot in any meaningful sense rob them of their identity as individuals committed to a code of caring. However, without an intact social compact, it may well remove their practical ability to remain and enter the helping professions to the detriment of us all.
A professional is someone who can do his best work when he doesn’t feel like it.
Alistair Cooke
When I was a young person with no idea about growing up to be something, my father used to tell me there were 4 learned professions: medicine to heal the body, law to protect the body politic, teaching to nurture the mind, and the clergy to care for the soul.1 That adage, or some version of it, is attributed to a variety of sources, likely because it captures something essential and timeless about the learned professions. I write this as a much older person, and it has been my privilege to have worked in some capacity in all 4 of these venerable vocations.
There are many more recognized professions now than in my father’s time with new ones still emerging as the world becomes more complicated and specialized. In November 2025, however, the growth of the professions was dealt a serious blow when the US Department of Education (DOE) redefined what constitutes a profession for the purpose of federal funding of graduate degrees.2 The internet is understandably abuzz with opinions across the political spectrum. What is missing from many of these discussions is an understanding of the criteria for a profession and, even more importantly, who has the authority to decide when an individual or a group has met that standard.
But first, what and why did the DOE make this change? The One Big Beautiful Bill Act charged the DOE with reducing what it claims is massive overspending on graduate education by limiting the programs that meet the definition of a “professional degree” eligible for higher funding. Of my father’s 4, medicine (including dentistry) and law made the cut with students in those professions able to borrow up to $200,000 in direct unsubsidized student loans while those in other programs would be limited to $100,000.2
As one of the oldest and most respected professions in America, nursing has received the most media attention, yet there are also other important and valued professions that are missing from the DOE list.3 The excluded professions also include: physician assistants, physical therapists, audiologists, architects, accountants, educators, and social workers. The proposed regulatory changes are not yet finalized and Congressional representatives, health care experts, and a myriad of professional associations have rightly objected the reclassification will only worsen the critical shortage of nurses, teachers, and other helping professions the country is already facing.4
There are thousands of federal health care professionals who worked long and hard to achieve their goals whom this Act undervalues. Moreover, the regulatory change leaves many students enrolled in education and training programs under federal practice auspices confused and overwhelmed. Perhaps they can take some hope and inspiration from the recognition that historically and philosophically, no agency or administration can unilaterally define what is a profession.
The literature on professionalism is voluminous, in large part because it has been surprisingly difficult to reach a consensus definition. A proposed definition from scholars captures most of the key aspects of a profession. While it is drawn from the medical literature, it applies to most of the caring professions the DOE disqualified. For pedagogic purposes, the definition is parsed into discrete criteria in the Table.5
Even this simple summary makes it obvious that a government agency alone could not possibly have the competence to determine who meets these complex technical and moral criteria. The members of the profession must assume a primary role in that determination. The complicated history of the professions shows that the locus of these decisions has resided in various combinations of educational institutions, such as nursing schools,6 professional societies (eg, National Association of Social Workers),7 and certifying boards (eg, National Commission on Certification of Physician Assistants).8 States, not the federal government, have long played a key part in defining professions in the US, through their authority to grant licenses to practice.9
In response to criticism, the DOE has stated that “the definition of a ‘professional degree’ is an internal definition used by the Department of Education to distinguish among programs that qualify for higher loan limits, not a value judgment about the importance of programs. It has no bearing on whether a program is professional in nature or not.”2 Given the ancient compact between society and the professions in which the government subsidizes the training of professionals dedicated to public service, it is hard to see how these changes can be dismissed as merely semantic and not a promissory breach.10
I recognize that this abstract editorial is little comfort to beleaguered and demoralized professionals and students. Still, it offers a voice of support for each federal practitioner or trainee who fulfills the epigraph’s description of a professional day after day. The nurse who works the extra shift without complaint or resentment so that veterans receive the care they deserve, the social worker who responds on a weekend night to an active duty family without food so they do not spend another night hungry, and the physician assistant who makes it into the isolated public health clinic despite the terrible weather so there is someone ready to take care for patients in need. The proposed policy shift cannot in any meaningful sense rob them of their identity as individuals committed to a code of caring. However, without an intact social compact, it may well remove their practical ability to remain and enter the helping professions to the detriment of us all.
- Wade JW. Public responsibilities of the learned professions. Louisiana Law Rev. 1960;21:130-148
- US Department of Education. Myth vs. fact: the definition of professional degrees. Press Release. November 24, 2025. Accessed December 22, 2025. https://www.ed.gov/about/news/press-release/myth-vs-fact-definition-of-professional-degrees
- Laws J. Full list of degrees not classed as “professional” by Trump admin. Newsweek. Updated November 26, 2025. Accessed December 22, 2025. https://www.newsweek.com/full-list-degrees-professional-trump-administration-11085695
- New York Academy of Medicine. Response to stripping “professional status” as proposed by the Department of Education. New York Academy of Medicine. November 24, 2025. Accessed December 22, 2025. https://nyam.org/article/response-to-stripping-professional-status-as-proposed-by-the-department-of-education
- Cruess SR, Johnston S, Cruess RL. “Profession”: a working definition for medical educators. Teach Learn Med. 2004;16:74-76. doi:10.1207/s15328015tlm1601_15
- American Association of Colleges of Nursing. Nursing is a professional degree. American Association of Colleges of Nursing. Accessed December 20, 2025. https://www.aacnnursing.org/policy-advocacy/take-action/nursing-is-a-professional-degree
- National Association of Social Workers. Social work is a profession. Social Workers. Accessed December 20, 2025. https://www.socialworkers.org
- National Commission on Certification of Physician Assistants. Accessed December 20, 2025. https://www.nccpa.net/about-nccpa/#who-we-are
- The Federation of State Boards of Physical Therapy. Accessed December 20, 2025. https://www.fsbpt.org/About-Us/Staff-Home
- Cruess SR, Cruess RL. Professionalism and medicine’s contract with social contract with society. Virtual Mentor. 2004;6:185-188. doi:10.1001/virtualmentor.2004.6.4.msoc1-040
- Wade JW. Public responsibilities of the learned professions. Louisiana Law Rev. 1960;21:130-148
- US Department of Education. Myth vs. fact: the definition of professional degrees. Press Release. November 24, 2025. Accessed December 22, 2025. https://www.ed.gov/about/news/press-release/myth-vs-fact-definition-of-professional-degrees
- Laws J. Full list of degrees not classed as “professional” by Trump admin. Newsweek. Updated November 26, 2025. Accessed December 22, 2025. https://www.newsweek.com/full-list-degrees-professional-trump-administration-11085695
- New York Academy of Medicine. Response to stripping “professional status” as proposed by the Department of Education. New York Academy of Medicine. November 24, 2025. Accessed December 22, 2025. https://nyam.org/article/response-to-stripping-professional-status-as-proposed-by-the-department-of-education
- Cruess SR, Johnston S, Cruess RL. “Profession”: a working definition for medical educators. Teach Learn Med. 2004;16:74-76. doi:10.1207/s15328015tlm1601_15
- American Association of Colleges of Nursing. Nursing is a professional degree. American Association of Colleges of Nursing. Accessed December 20, 2025. https://www.aacnnursing.org/policy-advocacy/take-action/nursing-is-a-professional-degree
- National Association of Social Workers. Social work is a profession. Social Workers. Accessed December 20, 2025. https://www.socialworkers.org
- National Commission on Certification of Physician Assistants. Accessed December 20, 2025. https://www.nccpa.net/about-nccpa/#who-we-are
- The Federation of State Boards of Physical Therapy. Accessed December 20, 2025. https://www.fsbpt.org/About-Us/Staff-Home
- Cruess SR, Cruess RL. Professionalism and medicine’s contract with social contract with society. Virtual Mentor. 2004;6:185-188. doi:10.1001/virtualmentor.2004.6.4.msoc1-040
Codes, Contracts, and Commitments: Who Defines What is a Profession?
Codes, Contracts, and Commitments: Who Defines What is a Profession?
Impact of a Pharmacist ICS Deprescribing Intervention on COPD Exacerbations and Adverse Events
Impact of a Pharmacist ICS Deprescribing Intervention on COPD Exacerbations and Adverse Events
Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV1), and an increase in COPD mortality rate vs nonsmokers.3 Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.4
According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.3 Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β2-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.3
While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.5 Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.
The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.6 It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.
The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.7 Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.7
Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.
Methods
This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV1/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV1 improvement.
The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.
Statistical Analysis
The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.
Results
Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).
Discussion
This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.6
There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.7 A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV1.8 Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.8
Strengths and Limitations
The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.
The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.
Conclusions
This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.
- Li HY, Gao TY, Fang W, et al. Global, regional and national burden of chronic obstructive pulmonary disease over a 30-year period: estimates from the 1990 to 2019 Global Burden of Disease Study. Respirology. 2023;28:29-36. doi:10.1111/resp.14349/
- Anderson E, Wiener RS, Resnick K, et al. Care coordination for veterans with COPD: a positive deviance study. Am J Manag Care. 2020;26:63-68. doi:10.37765/ajmc.2020.42394
- Global Initiative for Chronic Obstructive Lung Disease. 2024 GOLD Report. November 12, 2023. Accessed April 1, 2026. https://goldcopd.org/2023-gold-report-2/
- US Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of chronic obstructive pulmonary disease. April 2021. Accessed April 1, 2026. https://www.healthquality.va.gov /guidelines/cd/copd/
- Gruffydd-Jones K. GOLD guidelines 2011: what are the implications for primary care? Prim Care Respir J. 2012;21:437-441. doi:10.4104/pcrj.2012.00058
- Chapman KR, Hurst JR, Frent SM, et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198:329-339. doi:10.1164/rccm.201803-0405OC
- Hahn NM, Nagy MW. Implementation of a targeted inhaled corticosteroid de-escalation process in patients with chronic obstructive pulmonary disease in the primary care setting. Innov Pharm. 2022;13:10.24926/iip.v13i1.4349. doi:10.24926/iip.v13i1.4349
- Georgiou A, Ramesh R, Schofield P, et al. Withdrawal of inhaled corticosteroids from patients with COPD; effect on exacerbation frequency and lung function: a systematic review. Int J Chron Obstruct Pulmon Dis. 2024;19:1403- 1419. doi:10.2147/COPD.S436525
Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV1), and an increase in COPD mortality rate vs nonsmokers.3 Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.4
According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.3 Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β2-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.3
While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.5 Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.
The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.6 It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.
The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.7 Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.7
Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.
Methods
This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV1/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV1 improvement.
The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.
Statistical Analysis
The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.
Results
Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).
Discussion
This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.6
There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.7 A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV1.8 Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.8
Strengths and Limitations
The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.
The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.
Conclusions
This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.
Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV1), and an increase in COPD mortality rate vs nonsmokers.3 Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.4
According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.3 Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β2-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.3
While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.5 Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.
The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.6 It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.
The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.7 Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.7
Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.
Methods
This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV1/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV1 improvement.
The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.
Statistical Analysis
The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.
Results
Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).
Discussion
This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.6
There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.7 A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV1.8 Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.8
Strengths and Limitations
The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.
The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.
Conclusions
This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.
- Li HY, Gao TY, Fang W, et al. Global, regional and national burden of chronic obstructive pulmonary disease over a 30-year period: estimates from the 1990 to 2019 Global Burden of Disease Study. Respirology. 2023;28:29-36. doi:10.1111/resp.14349/
- Anderson E, Wiener RS, Resnick K, et al. Care coordination for veterans with COPD: a positive deviance study. Am J Manag Care. 2020;26:63-68. doi:10.37765/ajmc.2020.42394
- Global Initiative for Chronic Obstructive Lung Disease. 2024 GOLD Report. November 12, 2023. Accessed April 1, 2026. https://goldcopd.org/2023-gold-report-2/
- US Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of chronic obstructive pulmonary disease. April 2021. Accessed April 1, 2026. https://www.healthquality.va.gov /guidelines/cd/copd/
- Gruffydd-Jones K. GOLD guidelines 2011: what are the implications for primary care? Prim Care Respir J. 2012;21:437-441. doi:10.4104/pcrj.2012.00058
- Chapman KR, Hurst JR, Frent SM, et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198:329-339. doi:10.1164/rccm.201803-0405OC
- Hahn NM, Nagy MW. Implementation of a targeted inhaled corticosteroid de-escalation process in patients with chronic obstructive pulmonary disease in the primary care setting. Innov Pharm. 2022;13:10.24926/iip.v13i1.4349. doi:10.24926/iip.v13i1.4349
- Georgiou A, Ramesh R, Schofield P, et al. Withdrawal of inhaled corticosteroids from patients with COPD; effect on exacerbation frequency and lung function: a systematic review. Int J Chron Obstruct Pulmon Dis. 2024;19:1403- 1419. doi:10.2147/COPD.S436525
- Li HY, Gao TY, Fang W, et al. Global, regional and national burden of chronic obstructive pulmonary disease over a 30-year period: estimates from the 1990 to 2019 Global Burden of Disease Study. Respirology. 2023;28:29-36. doi:10.1111/resp.14349/
- Anderson E, Wiener RS, Resnick K, et al. Care coordination for veterans with COPD: a positive deviance study. Am J Manag Care. 2020;26:63-68. doi:10.37765/ajmc.2020.42394
- Global Initiative for Chronic Obstructive Lung Disease. 2024 GOLD Report. November 12, 2023. Accessed April 1, 2026. https://goldcopd.org/2023-gold-report-2/
- US Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of chronic obstructive pulmonary disease. April 2021. Accessed April 1, 2026. https://www.healthquality.va.gov /guidelines/cd/copd/
- Gruffydd-Jones K. GOLD guidelines 2011: what are the implications for primary care? Prim Care Respir J. 2012;21:437-441. doi:10.4104/pcrj.2012.00058
- Chapman KR, Hurst JR, Frent SM, et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198:329-339. doi:10.1164/rccm.201803-0405OC
- Hahn NM, Nagy MW. Implementation of a targeted inhaled corticosteroid de-escalation process in patients with chronic obstructive pulmonary disease in the primary care setting. Innov Pharm. 2022;13:10.24926/iip.v13i1.4349. doi:10.24926/iip.v13i1.4349
- Georgiou A, Ramesh R, Schofield P, et al. Withdrawal of inhaled corticosteroids from patients with COPD; effect on exacerbation frequency and lung function: a systematic review. Int J Chron Obstruct Pulmon Dis. 2024;19:1403- 1419. doi:10.2147/COPD.S436525
Impact of a Pharmacist ICS Deprescribing Intervention on COPD Exacerbations and Adverse Events
Impact of a Pharmacist ICS Deprescribing Intervention on COPD Exacerbations and Adverse Events
Pharmacist Interventions Pay Off in Veterans' COPD Care
A pharmacist-driven Veterans Health Administration (VHA) care program for veterans recovering from hospital visits for chronic obstructive pulmonary disease (COPD) is helping reduce symptom burden, a new retrospective cohort study finds.
Of 286 patients with COPD who participated in the program and reported outcomes, 62.6% said their symptoms improved, 28.7% said they had no change, and 8.7% reported worsening symptoms, according to Edward Portillo, PharmD, and colleagues in Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation. Patients whose medications were changed by VHA pharmacists with prescribing authority were more likely to experience clinically meaningful improvement in symptoms compared to those without this medication change (66.3% vs. 46.6%, respectively, P < .001).
“If you had a debilitating lung disease that was affecting your ability to breathe all day, affected your ability to go to the grocery store, made it hard for you to see your grandkids, and all of a sudden you had this visit and a month to 2 months later reported feeling a heck of a lot better—that’s a really big deal,” Portillo said in an interview with Federal Practitioner.
COPD, a progressive and irreversible lung disease that encompasses emphysema and chronic bronchitis, is the fifth-leading cause of death in the US according to the most recently available data. Research has suggested that many patients do not receive guidance-concordant care.
“The prevalence of COPD among our veteran population is threefold greater than in the civilian population, and 1 in 4 veterans have a COPD diagnosis,” noted Portillo a pharmacist at the William S. Middleton Veterans Affairs (VA) Hospital and an associate professor at the University of Wisconsin, Madison School of Pharmacy.
In 2015, Portillo developed a program called COPD Coordinated Access to Reduce Exacerbations (COPD CARE). The program, now operating at 50 VA medical centers, allows pharmacists to optimize medication, order spirometry, assess symptoms, place referrals for pulmonary rehabilitation, and support inhaler adherence and tobacco cessation. The pharmacists work with other members of the patient care teams such as primary care physicians and nurses.
“It's integrated within the teams themselves that serve our veterans, which is very unique for a service like this,” Portillo said.
The program is especially beneficial for patients within their first 30 to 90 days posthospitalization when they may not normally be seen in the clinic, Portillo said.
“We use a national dashboard to identify patients who left the [emergency department] or hospital, and then we assess if they’d be appropriate candidates for the program,” he said. “Our goal is to see patients as fast as 30 days and as late as 90 days, but ideally within 30 to 60 days of discharge.”
An initial in-person visit of ≤ 30 minutes is followed by a 15-minute follow-up phone call in 30 days to see if interventions have been continued, he said.
The study analyzed data from September 2020 to February 2024 from 28 VA medical centers that administer the COPD CARE program. All patients had an initial wellness visit within 90 days of hospitalization and 2 COPD Assessment Test (CAT) scores. Among 326 patients, the average age was 73.2 years; 95.7% were male; 77.9% were White, 15.6% were Black, and 2.1% had Hispanic ethnicity.
At the time of the wellness visit, patients mean CAT score was 18.4. It improved to 15.2 by follow-up, with especially large improvements in limitations (2.5 to 2.0), tightness (1.7 to 1.2), cough (2.5 to 2.1), energy (2.9 to 2.5), phlegm (2.4 to 2.0), and sleep (1.9 to 1.5).
Pharmacists created 236 COPD action plans, changed 208 medications, provided 151 service referrals, identified 117 nonadherent patients, and identified 62 incorrect techniques.
But only 1 intervention – medication change – was linked to clinically meaningful improvements in symptoms.
“This is not a disease that's easy to change symptomatically,” Portillo said. “My hope is that over time, and with multiple visits, those patients shift into a mode of ‘I am actually feeling much better now.’”
Suzanne Bollmeier, PharmD, professor of Pharmacy Practice at the University of Health Sciences and Pharmacy in St. Louis, who is familiar with the study but did not take part in it, told Federal Practitioner that the results align with previous research.
Bollmeier mentioned several studies that link pharmacist interventions to better health outcomes, including inhalation technique and medication adherence.
“Pharmacists are well-positioned within the health care team to help care for patients with COPD,” she said. “Pharmacists can help with patient adherence, inhaler education, and reduction in disease risk but also identify drug-related problems and modify respiratory regimens to better optimize patient outcomes.”
Moving forward, she said, “it would be interesting to see what specific medication regimen changes were made in this present study that led to improvement in symptoms.”
The study was funded by the VA Office of Rural Health and the University of Wisconsin Institute for Clinical and Translational Research, which is supported by the National Center for Advancing Translational Sciences. The study authors and Bollmeier had no disclosures.
A pharmacist-driven Veterans Health Administration (VHA) care program for veterans recovering from hospital visits for chronic obstructive pulmonary disease (COPD) is helping reduce symptom burden, a new retrospective cohort study finds.
Of 286 patients with COPD who participated in the program and reported outcomes, 62.6% said their symptoms improved, 28.7% said they had no change, and 8.7% reported worsening symptoms, according to Edward Portillo, PharmD, and colleagues in Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation. Patients whose medications were changed by VHA pharmacists with prescribing authority were more likely to experience clinically meaningful improvement in symptoms compared to those without this medication change (66.3% vs. 46.6%, respectively, P < .001).
“If you had a debilitating lung disease that was affecting your ability to breathe all day, affected your ability to go to the grocery store, made it hard for you to see your grandkids, and all of a sudden you had this visit and a month to 2 months later reported feeling a heck of a lot better—that’s a really big deal,” Portillo said in an interview with Federal Practitioner.
COPD, a progressive and irreversible lung disease that encompasses emphysema and chronic bronchitis, is the fifth-leading cause of death in the US according to the most recently available data. Research has suggested that many patients do not receive guidance-concordant care.
“The prevalence of COPD among our veteran population is threefold greater than in the civilian population, and 1 in 4 veterans have a COPD diagnosis,” noted Portillo a pharmacist at the William S. Middleton Veterans Affairs (VA) Hospital and an associate professor at the University of Wisconsin, Madison School of Pharmacy.
In 2015, Portillo developed a program called COPD Coordinated Access to Reduce Exacerbations (COPD CARE). The program, now operating at 50 VA medical centers, allows pharmacists to optimize medication, order spirometry, assess symptoms, place referrals for pulmonary rehabilitation, and support inhaler adherence and tobacco cessation. The pharmacists work with other members of the patient care teams such as primary care physicians and nurses.
“It's integrated within the teams themselves that serve our veterans, which is very unique for a service like this,” Portillo said.
The program is especially beneficial for patients within their first 30 to 90 days posthospitalization when they may not normally be seen in the clinic, Portillo said.
“We use a national dashboard to identify patients who left the [emergency department] or hospital, and then we assess if they’d be appropriate candidates for the program,” he said. “Our goal is to see patients as fast as 30 days and as late as 90 days, but ideally within 30 to 60 days of discharge.”
An initial in-person visit of ≤ 30 minutes is followed by a 15-minute follow-up phone call in 30 days to see if interventions have been continued, he said.
The study analyzed data from September 2020 to February 2024 from 28 VA medical centers that administer the COPD CARE program. All patients had an initial wellness visit within 90 days of hospitalization and 2 COPD Assessment Test (CAT) scores. Among 326 patients, the average age was 73.2 years; 95.7% were male; 77.9% were White, 15.6% were Black, and 2.1% had Hispanic ethnicity.
At the time of the wellness visit, patients mean CAT score was 18.4. It improved to 15.2 by follow-up, with especially large improvements in limitations (2.5 to 2.0), tightness (1.7 to 1.2), cough (2.5 to 2.1), energy (2.9 to 2.5), phlegm (2.4 to 2.0), and sleep (1.9 to 1.5).
Pharmacists created 236 COPD action plans, changed 208 medications, provided 151 service referrals, identified 117 nonadherent patients, and identified 62 incorrect techniques.
But only 1 intervention – medication change – was linked to clinically meaningful improvements in symptoms.
“This is not a disease that's easy to change symptomatically,” Portillo said. “My hope is that over time, and with multiple visits, those patients shift into a mode of ‘I am actually feeling much better now.’”
Suzanne Bollmeier, PharmD, professor of Pharmacy Practice at the University of Health Sciences and Pharmacy in St. Louis, who is familiar with the study but did not take part in it, told Federal Practitioner that the results align with previous research.
Bollmeier mentioned several studies that link pharmacist interventions to better health outcomes, including inhalation technique and medication adherence.
“Pharmacists are well-positioned within the health care team to help care for patients with COPD,” she said. “Pharmacists can help with patient adherence, inhaler education, and reduction in disease risk but also identify drug-related problems and modify respiratory regimens to better optimize patient outcomes.”
Moving forward, she said, “it would be interesting to see what specific medication regimen changes were made in this present study that led to improvement in symptoms.”
The study was funded by the VA Office of Rural Health and the University of Wisconsin Institute for Clinical and Translational Research, which is supported by the National Center for Advancing Translational Sciences. The study authors and Bollmeier had no disclosures.
A pharmacist-driven Veterans Health Administration (VHA) care program for veterans recovering from hospital visits for chronic obstructive pulmonary disease (COPD) is helping reduce symptom burden, a new retrospective cohort study finds.
Of 286 patients with COPD who participated in the program and reported outcomes, 62.6% said their symptoms improved, 28.7% said they had no change, and 8.7% reported worsening symptoms, according to Edward Portillo, PharmD, and colleagues in Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation. Patients whose medications were changed by VHA pharmacists with prescribing authority were more likely to experience clinically meaningful improvement in symptoms compared to those without this medication change (66.3% vs. 46.6%, respectively, P < .001).
“If you had a debilitating lung disease that was affecting your ability to breathe all day, affected your ability to go to the grocery store, made it hard for you to see your grandkids, and all of a sudden you had this visit and a month to 2 months later reported feeling a heck of a lot better—that’s a really big deal,” Portillo said in an interview with Federal Practitioner.
COPD, a progressive and irreversible lung disease that encompasses emphysema and chronic bronchitis, is the fifth-leading cause of death in the US according to the most recently available data. Research has suggested that many patients do not receive guidance-concordant care.
“The prevalence of COPD among our veteran population is threefold greater than in the civilian population, and 1 in 4 veterans have a COPD diagnosis,” noted Portillo a pharmacist at the William S. Middleton Veterans Affairs (VA) Hospital and an associate professor at the University of Wisconsin, Madison School of Pharmacy.
In 2015, Portillo developed a program called COPD Coordinated Access to Reduce Exacerbations (COPD CARE). The program, now operating at 50 VA medical centers, allows pharmacists to optimize medication, order spirometry, assess symptoms, place referrals for pulmonary rehabilitation, and support inhaler adherence and tobacco cessation. The pharmacists work with other members of the patient care teams such as primary care physicians and nurses.
“It's integrated within the teams themselves that serve our veterans, which is very unique for a service like this,” Portillo said.
The program is especially beneficial for patients within their first 30 to 90 days posthospitalization when they may not normally be seen in the clinic, Portillo said.
“We use a national dashboard to identify patients who left the [emergency department] or hospital, and then we assess if they’d be appropriate candidates for the program,” he said. “Our goal is to see patients as fast as 30 days and as late as 90 days, but ideally within 30 to 60 days of discharge.”
An initial in-person visit of ≤ 30 minutes is followed by a 15-minute follow-up phone call in 30 days to see if interventions have been continued, he said.
The study analyzed data from September 2020 to February 2024 from 28 VA medical centers that administer the COPD CARE program. All patients had an initial wellness visit within 90 days of hospitalization and 2 COPD Assessment Test (CAT) scores. Among 326 patients, the average age was 73.2 years; 95.7% were male; 77.9% were White, 15.6% were Black, and 2.1% had Hispanic ethnicity.
At the time of the wellness visit, patients mean CAT score was 18.4. It improved to 15.2 by follow-up, with especially large improvements in limitations (2.5 to 2.0), tightness (1.7 to 1.2), cough (2.5 to 2.1), energy (2.9 to 2.5), phlegm (2.4 to 2.0), and sleep (1.9 to 1.5).
Pharmacists created 236 COPD action plans, changed 208 medications, provided 151 service referrals, identified 117 nonadherent patients, and identified 62 incorrect techniques.
But only 1 intervention – medication change – was linked to clinically meaningful improvements in symptoms.
“This is not a disease that's easy to change symptomatically,” Portillo said. “My hope is that over time, and with multiple visits, those patients shift into a mode of ‘I am actually feeling much better now.’”
Suzanne Bollmeier, PharmD, professor of Pharmacy Practice at the University of Health Sciences and Pharmacy in St. Louis, who is familiar with the study but did not take part in it, told Federal Practitioner that the results align with previous research.
Bollmeier mentioned several studies that link pharmacist interventions to better health outcomes, including inhalation technique and medication adherence.
“Pharmacists are well-positioned within the health care team to help care for patients with COPD,” she said. “Pharmacists can help with patient adherence, inhaler education, and reduction in disease risk but also identify drug-related problems and modify respiratory regimens to better optimize patient outcomes.”
Moving forward, she said, “it would be interesting to see what specific medication regimen changes were made in this present study that led to improvement in symptoms.”
The study was funded by the VA Office of Rural Health and the University of Wisconsin Institute for Clinical and Translational Research, which is supported by the National Center for Advancing Translational Sciences. The study authors and Bollmeier had no disclosures.
RAS Drug Nearly Doubles Survival in Metastatic Pancreatic Cancer
RAS Drug Nearly Doubles Survival in Metastatic Pancreatic Cancer
An investigational oral drug that targets RAS, the dominant oncogenic driver in pancreatic cancer, nearly doubled overall survival compared with common second-line chemotherapy regimens in patients with previously treated metastatic disease.
In the 500-patient phase 3 RASolute 302 trial, patients who received daraxonrasib, a RAS(ON) multi-selective inhibitor, lived a median of 13.2 months compared with 6.7 months for those who received chemotherapy. The drug also doubled progression-free survival, tripled the response rate, and delayed deterioration in both pain and quality of life.
“Results from RASolute 302 support daraxonrasib as a new standard of care for patients with previously treated metastatic pancreatic cancer,” said lead investigator Brian Wolpin, MD, MPH, director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute in Boston, who presented the findings at the American Society of Clinical Oncology (ASCO) 2026. The study was also published simultaneously on May 31 in The New England Journal of Medicine.
Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with most patients presenting with advanced disease at diagnosis. For those whose cancer progresses after first-line chemotherapy, no single standard second-line treatment has been established. Available regimens typically produce median progression-free survival of 3-4 months and a median overall survival of 6-7 months.
More than 90% of pancreatic cancers harbor activating RAS mutations — most commonly KRAS G12D and G12V — that drive tumor growth. The first approved KRAS inhibitors — sotorasib and adagrasib for certain lung and colorectal cancers — target KRAS G12C, which is rare in pancreatic cancer. So far, no RAS-targeted therapy has been approved for pancreatic cancer.
Daraxonrasib takes a broader approach. The oral agent can target a range of RAS variants, including mutant and wild-type RAS, by binding the active form of RAS and blocking downstream signaling.
In the phase 3 open-label RASolute 302 trial, researchers randomized 500 patients with previously treated metastatic pancreatic cancer 1:1 to receive daraxonrasib 300 mg orally once daily or investigator’s choice of chemotherapy. The most used regimens in the control arm were gemcitabine plus nab-paclitaxel (56.5%) and liposomal irinotecan plus fluorouracil and leucovorin (32.7%).
Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Documented RAS mutational status was required, and nearly 92% of patients had RAS G12 mutations.
The dual primary endpoints were overall survival and progression-free survival in the RAS G12 population. Key secondary endpoints included the same measures in the overall population as well as objective response rate and patient-reported quality of life. The median follow-up was 8.5 months.
In the RAS G12 population, daraxonrasib reduced the risk for death by 60% (hazard ratio [HR], 0.40; P < .001). The median overall survival was 13.2 months with daraxonrasib vs 6.6 months with chemotherapy. Results were nearly identical in the overall population: 13.2 vs 6.7 months (HR, 0.40; P < .001).
Progression-free survival in the RAS G12 population was 7.3 vs 3.5 months (HR, 0.45; P < .001). The objective response rate was 33.2% vs 11.8%.
Daraxonrasib significantly delayed deterioration in pain (median, 9.0 vs 3.7 months; HR, 0.51; P < .001) and global quality of life (5.6 vs 2.4 months; HR, 0.60; P < .001).
Treatment-related adverse events of grade ≥ 3 occurred in 43.6% of patients on daraxonrasib vs 57.5% of patients on chemotherapy. The most common high-grade events with daraxonrasib were rash (13.7%) and stomatitis (12.0%), whereas neutropenia (27.6%) and anemia (16.4%) were most common with chemotherapy.
One patient in the daraxonrasib arm died from treatment-related pneumonitis. Discontinuation due to adverse events occurred in 1.2% of patients on daraxonrasib vs 11.2% of patients on chemotherapy.
The median duration of treatment was 6.2 months with daraxonrasib vs 1.5-3.2 months across chemotherapy regimens, and 42% of patients on daraxonrasib remained on treatment at data cutoff, Wolpin said.
The open-label design is a limitation. About 15% of patients randomized to chemotherapy never received treatment, largely after learning their treatment assignment, although all were included in the intention-to-treat analysis.
Invited discussant Jennifer Knox, MD, a medical oncologist at Princess Margaret Cancer Center and professor of medicine at the University of Toronto in Toronto, Ontario, Canada, called daraxonrasib a game changer, describing the drug as “probably the most exciting strategy in five decades” for pancreatic cancer.
“It is an absolutely beautiful curve,” Knox said of the overall survival data, noting that the Kaplan-Meier curves separated early and continued to widen over time — a pattern rarely seen in pancreatic cancer trials where initial separation between treatment arms typically narrows as patients in both groups deteriorate.
Knox highlighted the pain and quality-of-life data as “the most important endpoints for our patients,” given the severity of the disease.
She pointed out, however, that the combination of rash and stomatitis will be “challenging” in practice, and called for improved supportive care and closer collaboration with dermatology as oncologists gain experience with this first-in-class drug.
Knox said RAS-targeted therapy “should dominate trials across the full spectrum of pancreatic cancer clinical presentations,” pointing to first-line combination trials already underway and noting that treating a larger, earlier population would have the greatest impact.
“This is the first glimpse at the real power of targeting RAS in pancreas cancer,” Knox said.
The study was funded by Revolution Medicines. Wolpin reported consulting or advisory roles with Revolution Medicines, Mirati Therapeutics, Ipsen, and others, and institutional research funding from Revolution Medicines, Agios, Amgen, AstraZeneca, Lilly, and Novartis. Knox reported receiving honoraria from Astellas Pharma, AstraZeneca, Incyte, and Ipsen, and consulting or advisory roles with AstraZeneca/MedImmune, Incyte, and Ipsen.
A version of this article was previously published on Medscape.com.
An investigational oral drug that targets RAS, the dominant oncogenic driver in pancreatic cancer, nearly doubled overall survival compared with common second-line chemotherapy regimens in patients with previously treated metastatic disease.
In the 500-patient phase 3 RASolute 302 trial, patients who received daraxonrasib, a RAS(ON) multi-selective inhibitor, lived a median of 13.2 months compared with 6.7 months for those who received chemotherapy. The drug also doubled progression-free survival, tripled the response rate, and delayed deterioration in both pain and quality of life.
“Results from RASolute 302 support daraxonrasib as a new standard of care for patients with previously treated metastatic pancreatic cancer,” said lead investigator Brian Wolpin, MD, MPH, director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute in Boston, who presented the findings at the American Society of Clinical Oncology (ASCO) 2026. The study was also published simultaneously on May 31 in The New England Journal of Medicine.
Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with most patients presenting with advanced disease at diagnosis. For those whose cancer progresses after first-line chemotherapy, no single standard second-line treatment has been established. Available regimens typically produce median progression-free survival of 3-4 months and a median overall survival of 6-7 months.
More than 90% of pancreatic cancers harbor activating RAS mutations — most commonly KRAS G12D and G12V — that drive tumor growth. The first approved KRAS inhibitors — sotorasib and adagrasib for certain lung and colorectal cancers — target KRAS G12C, which is rare in pancreatic cancer. So far, no RAS-targeted therapy has been approved for pancreatic cancer.
Daraxonrasib takes a broader approach. The oral agent can target a range of RAS variants, including mutant and wild-type RAS, by binding the active form of RAS and blocking downstream signaling.
In the phase 3 open-label RASolute 302 trial, researchers randomized 500 patients with previously treated metastatic pancreatic cancer 1:1 to receive daraxonrasib 300 mg orally once daily or investigator’s choice of chemotherapy. The most used regimens in the control arm were gemcitabine plus nab-paclitaxel (56.5%) and liposomal irinotecan plus fluorouracil and leucovorin (32.7%).
Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Documented RAS mutational status was required, and nearly 92% of patients had RAS G12 mutations.
The dual primary endpoints were overall survival and progression-free survival in the RAS G12 population. Key secondary endpoints included the same measures in the overall population as well as objective response rate and patient-reported quality of life. The median follow-up was 8.5 months.
In the RAS G12 population, daraxonrasib reduced the risk for death by 60% (hazard ratio [HR], 0.40; P < .001). The median overall survival was 13.2 months with daraxonrasib vs 6.6 months with chemotherapy. Results were nearly identical in the overall population: 13.2 vs 6.7 months (HR, 0.40; P < .001).
Progression-free survival in the RAS G12 population was 7.3 vs 3.5 months (HR, 0.45; P < .001). The objective response rate was 33.2% vs 11.8%.
Daraxonrasib significantly delayed deterioration in pain (median, 9.0 vs 3.7 months; HR, 0.51; P < .001) and global quality of life (5.6 vs 2.4 months; HR, 0.60; P < .001).
Treatment-related adverse events of grade ≥ 3 occurred in 43.6% of patients on daraxonrasib vs 57.5% of patients on chemotherapy. The most common high-grade events with daraxonrasib were rash (13.7%) and stomatitis (12.0%), whereas neutropenia (27.6%) and anemia (16.4%) were most common with chemotherapy.
One patient in the daraxonrasib arm died from treatment-related pneumonitis. Discontinuation due to adverse events occurred in 1.2% of patients on daraxonrasib vs 11.2% of patients on chemotherapy.
The median duration of treatment was 6.2 months with daraxonrasib vs 1.5-3.2 months across chemotherapy regimens, and 42% of patients on daraxonrasib remained on treatment at data cutoff, Wolpin said.
The open-label design is a limitation. About 15% of patients randomized to chemotherapy never received treatment, largely after learning their treatment assignment, although all were included in the intention-to-treat analysis.
Invited discussant Jennifer Knox, MD, a medical oncologist at Princess Margaret Cancer Center and professor of medicine at the University of Toronto in Toronto, Ontario, Canada, called daraxonrasib a game changer, describing the drug as “probably the most exciting strategy in five decades” for pancreatic cancer.
“It is an absolutely beautiful curve,” Knox said of the overall survival data, noting that the Kaplan-Meier curves separated early and continued to widen over time — a pattern rarely seen in pancreatic cancer trials where initial separation between treatment arms typically narrows as patients in both groups deteriorate.
Knox highlighted the pain and quality-of-life data as “the most important endpoints for our patients,” given the severity of the disease.
She pointed out, however, that the combination of rash and stomatitis will be “challenging” in practice, and called for improved supportive care and closer collaboration with dermatology as oncologists gain experience with this first-in-class drug.
Knox said RAS-targeted therapy “should dominate trials across the full spectrum of pancreatic cancer clinical presentations,” pointing to first-line combination trials already underway and noting that treating a larger, earlier population would have the greatest impact.
“This is the first glimpse at the real power of targeting RAS in pancreas cancer,” Knox said.
The study was funded by Revolution Medicines. Wolpin reported consulting or advisory roles with Revolution Medicines, Mirati Therapeutics, Ipsen, and others, and institutional research funding from Revolution Medicines, Agios, Amgen, AstraZeneca, Lilly, and Novartis. Knox reported receiving honoraria from Astellas Pharma, AstraZeneca, Incyte, and Ipsen, and consulting or advisory roles with AstraZeneca/MedImmune, Incyte, and Ipsen.
A version of this article was previously published on Medscape.com.
An investigational oral drug that targets RAS, the dominant oncogenic driver in pancreatic cancer, nearly doubled overall survival compared with common second-line chemotherapy regimens in patients with previously treated metastatic disease.
In the 500-patient phase 3 RASolute 302 trial, patients who received daraxonrasib, a RAS(ON) multi-selective inhibitor, lived a median of 13.2 months compared with 6.7 months for those who received chemotherapy. The drug also doubled progression-free survival, tripled the response rate, and delayed deterioration in both pain and quality of life.
“Results from RASolute 302 support daraxonrasib as a new standard of care for patients with previously treated metastatic pancreatic cancer,” said lead investigator Brian Wolpin, MD, MPH, director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute in Boston, who presented the findings at the American Society of Clinical Oncology (ASCO) 2026. The study was also published simultaneously on May 31 in The New England Journal of Medicine.
Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with most patients presenting with advanced disease at diagnosis. For those whose cancer progresses after first-line chemotherapy, no single standard second-line treatment has been established. Available regimens typically produce median progression-free survival of 3-4 months and a median overall survival of 6-7 months.
More than 90% of pancreatic cancers harbor activating RAS mutations — most commonly KRAS G12D and G12V — that drive tumor growth. The first approved KRAS inhibitors — sotorasib and adagrasib for certain lung and colorectal cancers — target KRAS G12C, which is rare in pancreatic cancer. So far, no RAS-targeted therapy has been approved for pancreatic cancer.
Daraxonrasib takes a broader approach. The oral agent can target a range of RAS variants, including mutant and wild-type RAS, by binding the active form of RAS and blocking downstream signaling.
In the phase 3 open-label RASolute 302 trial, researchers randomized 500 patients with previously treated metastatic pancreatic cancer 1:1 to receive daraxonrasib 300 mg orally once daily or investigator’s choice of chemotherapy. The most used regimens in the control arm were gemcitabine plus nab-paclitaxel (56.5%) and liposomal irinotecan plus fluorouracil and leucovorin (32.7%).
Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Documented RAS mutational status was required, and nearly 92% of patients had RAS G12 mutations.
The dual primary endpoints were overall survival and progression-free survival in the RAS G12 population. Key secondary endpoints included the same measures in the overall population as well as objective response rate and patient-reported quality of life. The median follow-up was 8.5 months.
In the RAS G12 population, daraxonrasib reduced the risk for death by 60% (hazard ratio [HR], 0.40; P < .001). The median overall survival was 13.2 months with daraxonrasib vs 6.6 months with chemotherapy. Results were nearly identical in the overall population: 13.2 vs 6.7 months (HR, 0.40; P < .001).
Progression-free survival in the RAS G12 population was 7.3 vs 3.5 months (HR, 0.45; P < .001). The objective response rate was 33.2% vs 11.8%.
Daraxonrasib significantly delayed deterioration in pain (median, 9.0 vs 3.7 months; HR, 0.51; P < .001) and global quality of life (5.6 vs 2.4 months; HR, 0.60; P < .001).
Treatment-related adverse events of grade ≥ 3 occurred in 43.6% of patients on daraxonrasib vs 57.5% of patients on chemotherapy. The most common high-grade events with daraxonrasib were rash (13.7%) and stomatitis (12.0%), whereas neutropenia (27.6%) and anemia (16.4%) were most common with chemotherapy.
One patient in the daraxonrasib arm died from treatment-related pneumonitis. Discontinuation due to adverse events occurred in 1.2% of patients on daraxonrasib vs 11.2% of patients on chemotherapy.
The median duration of treatment was 6.2 months with daraxonrasib vs 1.5-3.2 months across chemotherapy regimens, and 42% of patients on daraxonrasib remained on treatment at data cutoff, Wolpin said.
The open-label design is a limitation. About 15% of patients randomized to chemotherapy never received treatment, largely after learning their treatment assignment, although all were included in the intention-to-treat analysis.
Invited discussant Jennifer Knox, MD, a medical oncologist at Princess Margaret Cancer Center and professor of medicine at the University of Toronto in Toronto, Ontario, Canada, called daraxonrasib a game changer, describing the drug as “probably the most exciting strategy in five decades” for pancreatic cancer.
“It is an absolutely beautiful curve,” Knox said of the overall survival data, noting that the Kaplan-Meier curves separated early and continued to widen over time — a pattern rarely seen in pancreatic cancer trials where initial separation between treatment arms typically narrows as patients in both groups deteriorate.
Knox highlighted the pain and quality-of-life data as “the most important endpoints for our patients,” given the severity of the disease.
She pointed out, however, that the combination of rash and stomatitis will be “challenging” in practice, and called for improved supportive care and closer collaboration with dermatology as oncologists gain experience with this first-in-class drug.
Knox said RAS-targeted therapy “should dominate trials across the full spectrum of pancreatic cancer clinical presentations,” pointing to first-line combination trials already underway and noting that treating a larger, earlier population would have the greatest impact.
“This is the first glimpse at the real power of targeting RAS in pancreas cancer,” Knox said.
The study was funded by Revolution Medicines. Wolpin reported consulting or advisory roles with Revolution Medicines, Mirati Therapeutics, Ipsen, and others, and institutional research funding from Revolution Medicines, Agios, Amgen, AstraZeneca, Lilly, and Novartis. Knox reported receiving honoraria from Astellas Pharma, AstraZeneca, Incyte, and Ipsen, and consulting or advisory roles with AstraZeneca/MedImmune, Incyte, and Ipsen.
A version of this article was previously published on Medscape.com.
RAS Drug Nearly Doubles Survival in Metastatic Pancreatic Cancer
RAS Drug Nearly Doubles Survival in Metastatic Pancreatic Cancer
Streamlining the Acute Care Pharmacy Consultation Process for Patients With Dysphagia or Enteral Feeding Tubes
Streamlining the Acute Care Pharmacy Consultation Process for Patients With Dysphagia or Enteral Feeding Tubes
Medication regimens may require adjustment in acute care settings due to dysphagia and/or enteral feeding tubes. When a patient has dysphagia and/or a feeding tube, the health care team must review the pharmacotherapy regimen to assess the appropriateness of medication formulations. Patient anatomy, the type of feeding tube in place, pharmacokinetic and pharmacodynamic properties of medications, risk of feeding tube obstruction, and potential for interactions between enteral nutrition and medications should be considered when clinicians administer medications through feeding tubes. The risk of feeding tube obstruction and clogging rises with increasing tube length and decreasing tube lumen. Incidence of obstructed percutaneous endoscopic gastrotomy tubes is reported to be 23% to 35%.1
A coordinated effort by all members of the health care team is essential to provide safe and effective care to patients with dysphagia and/or enteral feeding tubes. To decrease the risk of feeding tube obstruction, medications should be dissolved in water or administered in liquid form, saline fluids should be avoided, and the tube should be flushed with water before and after administering medications.
The pharmacokinetics of medications can be altered when tablets are crushed or capsules are opened. The bioavailability of dabigatran, for example, increases by 75% when the capsules are opened and pellets are taken orally.2 Medications may become intolerable after manipulation due to taste.3 Others may also increase the risk of feeding tube obstruction, such as omeprazole granules that increase the risk of small-bore feeding tube obstruction.4
Prior assessments of drug administration for patients with dysphagia and/or enteral feeding tubes has shown medication errors are prevalent.5-7 The Institute for Safe Medication Practices (ISMP) issued a Medication Safety Alert that provides a framework for preventing medication errors when preparing and administering medications via enteral feeding tubes.8 Other resources, such as monographs, are also available to guide pharmacotherapy decisions when oral medications require manipulation for administration to patients with dysphagia and/or enteral feeding tubes.9-11
In 2021, the Kansas City Veterans Affairs Medical Center (KCVAMC) was recognized as a Veterans Health Administration (VHA) Shark Tank finalist for improving the safety of medication administration for patients with enteral feeding tubes.12 This involved the addition of a Computerized Patient Record System (CPRS), clinical reminder order check (CROC), and a comprehensive medication review by a pharmacist. After implementing the CROC alert and pharmacy e-consultation workflow, the KCVAMC team reported that the number of inappropriate medications (ie, drugs on the ISMP do not crush list) was reduced from 41 to 6 in 1 year, resulting in an 85.4% reduction in potential medication errors.13
In 2014, the Richard L. Roudebush VAMC (RLRVAMC) created a pharmacy consultation process for patients with dysphagia and/or enteral feeding tubes. Any clinician could place a pharmacy consultation in CPRS. A pharmacist then reviewed patient charts, medication information resources, the VA formulary, and RLRVAMC pharmacy inventory. The pharmacist conferred with the patient’s care team to adjust pharmacotherapy, completed a consultation note, and updated medication order comments in Veterans Health Information Systems and Technology Architecture (VistA). These comments interfaced with the barcode medication administration software for the health care professional administering medications.
Despite the 2014 quality improvement (QI) process, medication errors involving the inappropriate ordering, preparation, and administration of medications for patients with dysphagia and/or enteral feeding tubes continued to be reported. Additionally, anonymous feedback revealed that only 3 of 10 responding pharmacists were satisfied with the existing medication use process for patients with dysphagia and/or enteral feeding tubes. Pharmacists expressed concerns that (1) clinicians were inappropriately crushing and/or manipulating new medications that were ordered after pharmacy consultations; (2) there was a lack of comprehensive documentation in CPRS; and (3) there were too many manual steps in the process. In response, RLRVAMC initiated a new QI initiative to improve the medication use process for patients with dysphagia and/or enteral feeding tubes in the acute care setting.
Quality Improvement Project
This multidisciplinary RLRVAMC QI project began November 2024 to improve pharmacotherapy care for patients with dysphagia and/or enteral feeding tubes in acute care. It was approved by the RLRVAMC Pharmacy Service. This intervention addressed the pharmacy consultation template, standardization of equipment, standardization of language, creation of clinical alerts, and sustainment (Table 1).
RLRVAMC has about 8600 annual inpatient admissions and 159 acute care beds.14 The project charter was drafted, and local stakeholders were identified including pharmacy technicians, pharmacists, nurses, speech language pathologists, and acute care clinicians. Pharmacy consultation workload was retrospectively reviewed to describe the scope of the existing state.
A workshop with 12 QI project stakeholders in December 2024 used A3 methodology to define the current process and the target state, barriers and solutions, prioritize interventions on an impact-effort matrix, perform a gap analysis, identify rapid plan-do-study-act (PDSA) experiments, and develop a completion plan (Figure). Five postworkshop PDSA experiments engaged additional stakeholders, clinical application coordinators, and medical supply representatives to ascertain the feasibility of the tools implemented.
Abbreviations: BCMA, barcode medication administration; CDSS, clinical decision support system; CPRS, Computerized Patient Record System;
EHR, electronic health record; SOP, standard operating procedure; VistA, Veterans Health Information Systems and Technology Architecture.
About 3% of RLRVAMC admissions involve a pharmacy consultation to review medications for dysphagia and/or enteral feeding tubes. Clinicians reviewed 30 preimplementation inpatient pharmacy consultations involving 200 oral medications. Pharmacists were more frequently consulted for inpatients with dysphagia (19 [63%]) than for patients with enteral feeding tubes (11 [37%]) (Table 2).
Pharmacy Consultation Template
The pharmacy consultation was updated in CPRS. Prior to this QI project, the ordering clinician was prompted to select 1 option for the indication: dysphagia or enteral feeding tube. The type of enteral feeding tube was not prompted by the consultation text nor required to be specified in the consultation. The ordering clinician could provide free-text comments. Of 11 preimplementation consultations, the type of enteral feeding tube was specified in 5 (45%). The consultation template entry was updated to include an option to check a box for the consultation indication from 3 options: dysphagia, enteral feeding, or other patient- specific condition/request. If enteral feeding tube is selected, then the clinician is prompted to select the type of enteral feeding tube. Since the completion of the project, there have been no patient safety reports concerning an erroneous or incomplete consultation entry (Supplemental Material).
The note template was updated to import the list of active inpatient medications and provide sections for the adjudicating pharmacist to document which medications can be crushed (or opened), which require adjustment, and which are hazardous and require special handling. Additionally, the revised template added a statement clarifying that the documented recommendations apply only to the medication regimen at the time of the consultation (Supplemental Material).
Standardizations
There are multiple pill-crushing devices used at RLRVAMC that vary in crushing mechanism, corresponding medication pouches, and degree of protection when manipulating hazardous medications. Prior to this QI project, RLRVAMC used 3 pill-crushing devices (about 30 total devices in inpatient care areas). Only 1 device with corresponding closed pouches for preparation of hazardous medications was available, which was stored in the RLRVAMC inpatient pharmacy. This workflow resulted in waste and posed potential risks for delays in care. This project incorporated a standard pill-crushing system with the corresponding medication pouches in all inpatient care areas, which provided safeguards for clinicians to prepare and administer hazardous medications (Supplemental Material).
Patients requiring medications to be crushed or opened on discharge should receive education, written instruction, and have care plans documented in CPRS. RLRVAMC patients receive education and a printed medication list. Prior to this QI project, the instructions for crushing or opening medications could only be entered by free text in the electronic medication reconciliation tool, allowing for the potential for inconsistent language or omissions.
This QI project included an update to the electronic medication reconciliation tool. An optional checkbox selection was added for patients requiring medications to be manipulated. When checked, a radial selection for individual medications is displayed, prompting the clinician and pharmacist to indicate either do not crush tablet or OK to crush tablet. These selections appear in clinical care notes and on the printed medication list provided to the patient (Supplemental Material).
Clinical Alerts
As part of the RLRVAMC QI initiative, a CROC alert was implemented, based on the KCVAMC intervention for patients with enteral feeding tubes.13 The RLRVAMC CROC alert also included patients with dysphagia. A nursing text order was made available in CPRS for patients requiring medications and remains active throughout the duration of the patient’s admission or until discontinued. It generates CROC alerts in CPRS and VistA when new medication orders are entered and reviewed by pharmacists.
Clinicians used clinical decision support systems to create daily lists of patients receiving medications by feeding tube and patients receiving crushed/opened medications due to dysphagia. This allows pharmacists to perform a census review of all inpatients to confirm appropriateness of medication orders. Clinical alerts for patients with enteral feeding tubes are advised by the ISMP and have data demonstrating a reduction in medication errors (Supplemental Material).14,15
Sustainment
During the sustainment phase, process owners were identified and a Pharmacy Service standard operating procedure (SOP) was written. The development of an institutional do not crush medication list was discussed; however, it was determined to be difficult to develop and maintain. An institutional tertiary resource list was selected in favor of a locally developed resource. These resources include the Handbook of Drug Administration via Enteral Feeding Tubes, Third Edition, the Pharmacist’s Letter list, “Meds that Should Not be Crushed,” and the Up- ToDate Lexidrug list, “Oral Medications That Should Not Be Crushed or Altered.”9-11 Links to the resources were added to the RLRVAMC pharmacy service SharePoint. In addition to defining the preferred tertiary resources, the SOP defined the process for reviewing inventory and the process for reviewing medication orders for hazard risk.
Discussion
Continued patient safety reports and low satisfaction rates among pharmacists prompted this QI project to improve safety for patients with dysphagia and/or enteral feeding tubes at RLRVAMC. The project engaged stakeholders and also identified and addressed gaps with potential for patient harm.
The tools implemented by this initiative drew from previous work by the KCVAMC and from framework provided by the ISMP.8,13 We expanded the QI intervention to include acute care patients with dysphagia.
RLRVAMC did not take steps to track the impact of the interventions on medication errors. However, no patient safety reports concerning an erroneous or incomplete pharmacy consultation entry have been reported. We also think that it is reasonable to assume that the adoption of the safety tools described here will have a positive impact on patient safety. RLRVAMC pharmacists have noted an increased appreciation for medication safety when processing medication orders for patients with dysphagia and/or enteral feeding tubes. While the workflow took time to adopt and integrate, clinical pharmacists perceived it as an improvement in patient safety. Our future focus is aimed at translating the process improvement into the Oracle/Cerner electronic health record, which is scheduled to be deployed at the RLRVAMC in August 2026.
Limitations
This QI project did not aim to quantify or compare medication errors before and after the intervention. An accurate number of unreported errors in the medication use process for patients with dysphagia and/or enteral feeding tubes would be challenging to quantify without direct observation. Multiple clinicians are engaged in the medication use process and individual steps may not be documented at all, or documented properly. In addition, medication errors are often underreported and may not reflect the total number of errors and/or potential for errors. That said, reported medication errors in the medication use process for patients with dysphagia and/or enteral feeding tubes are reviewed on a monthly basis by the RLRVAMC Multidisciplinary Medication Safety committee to continuously improve patient safety.
Another potential limitation is the extent to which the project can be adapted at other VHA sites. For example, RLRVAMC uses CPRS; the framework and tools to improve medication safety may not translate to sites using the Oracle/Cerner electronic health record. Furthermore, this QI project included a pharmacy consultation workflow that relied on pharmacists who are available at any hour. Other facilities may not have continuous consultation coverage to review medications for patients with dysphagia and/or enteral feeding tubes.
Conclusions
This QI project drew from ISMP recommendations, previous work within the VHA, local practice, and insight from multiple disciplines on the health care team to revise and create tools to improve medication safety for patients with dysphagia and/or enteral feeding tubes in the acute care setting. These tools included a revised pharmacy consultation workflow with improvements to the pharmacy consultation template, standardization of the pill-crushing devices and language used for patient medication lists, implementation of CROC alerts within the EHR, and development of an SOP.
The RLRVAMC Pharmacy Service intends to continue reviewing patient safety reports, assessing staff perspectives, and refining (and potentially adding) tools for medication safety. Future QI initiatives may focus on improving medication safety for outpatients with dysphagia and/or enteral feeding tubes. We also hope that these tools can be adapted at other VAMCs to promote medication safety for patients with dysphagia and/or enteral feeding tubes.
- Blumenstein I, Shastri YM, Stein J. Gastroenteric tube feeding: techniques, problems and solutions. World J Gastroenterol. 2014;20:8505-8524. doi:10.3748/wjg.v20.i26.8505
- Pradaxa (dabigatran etexilate). Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc; 2025. https:// pro.boehringer-ingelheim.com/us/products/pradaxa/bipdf /pradaxa-capsules-us-pi
- Lovell AG, Protus BM, Dickman JR, et al. Palatability of crushed over-the-counter medications. J Pain Symptom Manage. 2021;61:755-762. doi:10.1016/j.jpainsymman.2020.09.020
- Messaouik D, Sautou-Miranda V, Bagel-Boithias S, et al. Comparative study and optimisation of the administration mode of three proton pump inhibitors by nasogastric tube. Int J Pharm. 2005;299:65-72. doi:10.1016/j.ijpharm.2005.04.034
- Demirkan K, Bayraktar-Ekincioglu A, Gulhan-Halil M, et al. Assessment of drug administration via feeding tube and the knowledge of health-care professionals in a university hospital. Eur J Clin Nutr. 2017;71:164-168. doi:10.1038/ejcn.2016.147
- Fodil M, Nghiem D, Colas M, et al. Assessment of clinical practices for crushing medication in geriatric units. J Nutr Health Aging. 2017;21:904-908. doi:10.1007/s12603-017-0886-3
- Zhu LL, Xu LC, Wang HQ, et al. Appropriateness of administration of nasogastric medication and preliminary intervention. Ther Clin Risk Manag. 2012;8:393-401. doi:10.2147/TCRM.S37785
- Institute for Safe Medication Practices (ISMP). Preventing errors when preparing and administering medications via enteral feeding tubes. Acute Care ISMP Medication Safety Alert. November 17, 2022. Accessed March 17, 2026. https://nutritioncare.org/wp-content/uploads/2025/02 /ISMP-Safety-Alert_Medications-and-Enteral-Feeding -Tubes.pdf
- White R, Bradnam V. Handbook of Drug Administration via Enteral Feeding Tubes. 3rd ed. Pharmaceutical Press; 2015.
- Clinical resource, meds that should not be crushed. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. Updated April 2025. Accessed March 17, 2026. https://pharmacist.therapeuticresearch.com/en/Content /Segments/PRL/2014/Aug/Meds-That-Should-Not-Be -Crushed-7309
- Oral medications that should not be crushed or altered. In: Lexidrug. UpToDate, Inc. https://online.lexi.com/lco /action/doc/retrieve/docid/patch_f/4227
- Uttaro E, Zhao F, Schweighardt A. Filling the gaps on the Institute for Safe Medication Practices (ISMP) do not crush list for immediate-release products. Int J Pharm Compd. 2021;25:364-371.
- US Dept of Veterans Affairs. VA Diffusion Marketplace. Improved safety of enteral tube medication administration. Updated 2024. Accessed March 17, 2026. https:// marketplace.va.gov/innovations/improved-safety-of -enteral-tube-medication-administration
- US Dept of Veterans Affairs. About us. VA Indiana Healthcare System. Updated October 17, 2024. Accessed March 2, 2026. https://www.va.gov/indiana-health-care/about-us/
- Wasylewicz ATM, van Grinsven RJB, Bikker JMW, et al. Clinical decision support system-assisted pharmacy intervention reduces feeding tube-related medication errors in hospitalized patients: a focus on medication suitable for feeding-tube administration. JPEN J Parenter Enteral Nutr. 2021;45:625-632. doi:10.1002/jpen.1869
Medication regimens may require adjustment in acute care settings due to dysphagia and/or enteral feeding tubes. When a patient has dysphagia and/or a feeding tube, the health care team must review the pharmacotherapy regimen to assess the appropriateness of medication formulations. Patient anatomy, the type of feeding tube in place, pharmacokinetic and pharmacodynamic properties of medications, risk of feeding tube obstruction, and potential for interactions between enteral nutrition and medications should be considered when clinicians administer medications through feeding tubes. The risk of feeding tube obstruction and clogging rises with increasing tube length and decreasing tube lumen. Incidence of obstructed percutaneous endoscopic gastrotomy tubes is reported to be 23% to 35%.1
A coordinated effort by all members of the health care team is essential to provide safe and effective care to patients with dysphagia and/or enteral feeding tubes. To decrease the risk of feeding tube obstruction, medications should be dissolved in water or administered in liquid form, saline fluids should be avoided, and the tube should be flushed with water before and after administering medications.
The pharmacokinetics of medications can be altered when tablets are crushed or capsules are opened. The bioavailability of dabigatran, for example, increases by 75% when the capsules are opened and pellets are taken orally.2 Medications may become intolerable after manipulation due to taste.3 Others may also increase the risk of feeding tube obstruction, such as omeprazole granules that increase the risk of small-bore feeding tube obstruction.4
Prior assessments of drug administration for patients with dysphagia and/or enteral feeding tubes has shown medication errors are prevalent.5-7 The Institute for Safe Medication Practices (ISMP) issued a Medication Safety Alert that provides a framework for preventing medication errors when preparing and administering medications via enteral feeding tubes.8 Other resources, such as monographs, are also available to guide pharmacotherapy decisions when oral medications require manipulation for administration to patients with dysphagia and/or enteral feeding tubes.9-11
In 2021, the Kansas City Veterans Affairs Medical Center (KCVAMC) was recognized as a Veterans Health Administration (VHA) Shark Tank finalist for improving the safety of medication administration for patients with enteral feeding tubes.12 This involved the addition of a Computerized Patient Record System (CPRS), clinical reminder order check (CROC), and a comprehensive medication review by a pharmacist. After implementing the CROC alert and pharmacy e-consultation workflow, the KCVAMC team reported that the number of inappropriate medications (ie, drugs on the ISMP do not crush list) was reduced from 41 to 6 in 1 year, resulting in an 85.4% reduction in potential medication errors.13
In 2014, the Richard L. Roudebush VAMC (RLRVAMC) created a pharmacy consultation process for patients with dysphagia and/or enteral feeding tubes. Any clinician could place a pharmacy consultation in CPRS. A pharmacist then reviewed patient charts, medication information resources, the VA formulary, and RLRVAMC pharmacy inventory. The pharmacist conferred with the patient’s care team to adjust pharmacotherapy, completed a consultation note, and updated medication order comments in Veterans Health Information Systems and Technology Architecture (VistA). These comments interfaced with the barcode medication administration software for the health care professional administering medications.
Despite the 2014 quality improvement (QI) process, medication errors involving the inappropriate ordering, preparation, and administration of medications for patients with dysphagia and/or enteral feeding tubes continued to be reported. Additionally, anonymous feedback revealed that only 3 of 10 responding pharmacists were satisfied with the existing medication use process for patients with dysphagia and/or enteral feeding tubes. Pharmacists expressed concerns that (1) clinicians were inappropriately crushing and/or manipulating new medications that were ordered after pharmacy consultations; (2) there was a lack of comprehensive documentation in CPRS; and (3) there were too many manual steps in the process. In response, RLRVAMC initiated a new QI initiative to improve the medication use process for patients with dysphagia and/or enteral feeding tubes in the acute care setting.
Quality Improvement Project
This multidisciplinary RLRVAMC QI project began November 2024 to improve pharmacotherapy care for patients with dysphagia and/or enteral feeding tubes in acute care. It was approved by the RLRVAMC Pharmacy Service. This intervention addressed the pharmacy consultation template, standardization of equipment, standardization of language, creation of clinical alerts, and sustainment (Table 1).
RLRVAMC has about 8600 annual inpatient admissions and 159 acute care beds.14 The project charter was drafted, and local stakeholders were identified including pharmacy technicians, pharmacists, nurses, speech language pathologists, and acute care clinicians. Pharmacy consultation workload was retrospectively reviewed to describe the scope of the existing state.
A workshop with 12 QI project stakeholders in December 2024 used A3 methodology to define the current process and the target state, barriers and solutions, prioritize interventions on an impact-effort matrix, perform a gap analysis, identify rapid plan-do-study-act (PDSA) experiments, and develop a completion plan (Figure). Five postworkshop PDSA experiments engaged additional stakeholders, clinical application coordinators, and medical supply representatives to ascertain the feasibility of the tools implemented.
Abbreviations: BCMA, barcode medication administration; CDSS, clinical decision support system; CPRS, Computerized Patient Record System;
EHR, electronic health record; SOP, standard operating procedure; VistA, Veterans Health Information Systems and Technology Architecture.
About 3% of RLRVAMC admissions involve a pharmacy consultation to review medications for dysphagia and/or enteral feeding tubes. Clinicians reviewed 30 preimplementation inpatient pharmacy consultations involving 200 oral medications. Pharmacists were more frequently consulted for inpatients with dysphagia (19 [63%]) than for patients with enteral feeding tubes (11 [37%]) (Table 2).
Pharmacy Consultation Template
The pharmacy consultation was updated in CPRS. Prior to this QI project, the ordering clinician was prompted to select 1 option for the indication: dysphagia or enteral feeding tube. The type of enteral feeding tube was not prompted by the consultation text nor required to be specified in the consultation. The ordering clinician could provide free-text comments. Of 11 preimplementation consultations, the type of enteral feeding tube was specified in 5 (45%). The consultation template entry was updated to include an option to check a box for the consultation indication from 3 options: dysphagia, enteral feeding, or other patient- specific condition/request. If enteral feeding tube is selected, then the clinician is prompted to select the type of enteral feeding tube. Since the completion of the project, there have been no patient safety reports concerning an erroneous or incomplete consultation entry (Supplemental Material).
The note template was updated to import the list of active inpatient medications and provide sections for the adjudicating pharmacist to document which medications can be crushed (or opened), which require adjustment, and which are hazardous and require special handling. Additionally, the revised template added a statement clarifying that the documented recommendations apply only to the medication regimen at the time of the consultation (Supplemental Material).
Standardizations
There are multiple pill-crushing devices used at RLRVAMC that vary in crushing mechanism, corresponding medication pouches, and degree of protection when manipulating hazardous medications. Prior to this QI project, RLRVAMC used 3 pill-crushing devices (about 30 total devices in inpatient care areas). Only 1 device with corresponding closed pouches for preparation of hazardous medications was available, which was stored in the RLRVAMC inpatient pharmacy. This workflow resulted in waste and posed potential risks for delays in care. This project incorporated a standard pill-crushing system with the corresponding medication pouches in all inpatient care areas, which provided safeguards for clinicians to prepare and administer hazardous medications (Supplemental Material).
Patients requiring medications to be crushed or opened on discharge should receive education, written instruction, and have care plans documented in CPRS. RLRVAMC patients receive education and a printed medication list. Prior to this QI project, the instructions for crushing or opening medications could only be entered by free text in the electronic medication reconciliation tool, allowing for the potential for inconsistent language or omissions.
This QI project included an update to the electronic medication reconciliation tool. An optional checkbox selection was added for patients requiring medications to be manipulated. When checked, a radial selection for individual medications is displayed, prompting the clinician and pharmacist to indicate either do not crush tablet or OK to crush tablet. These selections appear in clinical care notes and on the printed medication list provided to the patient (Supplemental Material).
Clinical Alerts
As part of the RLRVAMC QI initiative, a CROC alert was implemented, based on the KCVAMC intervention for patients with enteral feeding tubes.13 The RLRVAMC CROC alert also included patients with dysphagia. A nursing text order was made available in CPRS for patients requiring medications and remains active throughout the duration of the patient’s admission or until discontinued. It generates CROC alerts in CPRS and VistA when new medication orders are entered and reviewed by pharmacists.
Clinicians used clinical decision support systems to create daily lists of patients receiving medications by feeding tube and patients receiving crushed/opened medications due to dysphagia. This allows pharmacists to perform a census review of all inpatients to confirm appropriateness of medication orders. Clinical alerts for patients with enteral feeding tubes are advised by the ISMP and have data demonstrating a reduction in medication errors (Supplemental Material).14,15
Sustainment
During the sustainment phase, process owners were identified and a Pharmacy Service standard operating procedure (SOP) was written. The development of an institutional do not crush medication list was discussed; however, it was determined to be difficult to develop and maintain. An institutional tertiary resource list was selected in favor of a locally developed resource. These resources include the Handbook of Drug Administration via Enteral Feeding Tubes, Third Edition, the Pharmacist’s Letter list, “Meds that Should Not be Crushed,” and the Up- ToDate Lexidrug list, “Oral Medications That Should Not Be Crushed or Altered.”9-11 Links to the resources were added to the RLRVAMC pharmacy service SharePoint. In addition to defining the preferred tertiary resources, the SOP defined the process for reviewing inventory and the process for reviewing medication orders for hazard risk.
Discussion
Continued patient safety reports and low satisfaction rates among pharmacists prompted this QI project to improve safety for patients with dysphagia and/or enteral feeding tubes at RLRVAMC. The project engaged stakeholders and also identified and addressed gaps with potential for patient harm.
The tools implemented by this initiative drew from previous work by the KCVAMC and from framework provided by the ISMP.8,13 We expanded the QI intervention to include acute care patients with dysphagia.
RLRVAMC did not take steps to track the impact of the interventions on medication errors. However, no patient safety reports concerning an erroneous or incomplete pharmacy consultation entry have been reported. We also think that it is reasonable to assume that the adoption of the safety tools described here will have a positive impact on patient safety. RLRVAMC pharmacists have noted an increased appreciation for medication safety when processing medication orders for patients with dysphagia and/or enteral feeding tubes. While the workflow took time to adopt and integrate, clinical pharmacists perceived it as an improvement in patient safety. Our future focus is aimed at translating the process improvement into the Oracle/Cerner electronic health record, which is scheduled to be deployed at the RLRVAMC in August 2026.
Limitations
This QI project did not aim to quantify or compare medication errors before and after the intervention. An accurate number of unreported errors in the medication use process for patients with dysphagia and/or enteral feeding tubes would be challenging to quantify without direct observation. Multiple clinicians are engaged in the medication use process and individual steps may not be documented at all, or documented properly. In addition, medication errors are often underreported and may not reflect the total number of errors and/or potential for errors. That said, reported medication errors in the medication use process for patients with dysphagia and/or enteral feeding tubes are reviewed on a monthly basis by the RLRVAMC Multidisciplinary Medication Safety committee to continuously improve patient safety.
Another potential limitation is the extent to which the project can be adapted at other VHA sites. For example, RLRVAMC uses CPRS; the framework and tools to improve medication safety may not translate to sites using the Oracle/Cerner electronic health record. Furthermore, this QI project included a pharmacy consultation workflow that relied on pharmacists who are available at any hour. Other facilities may not have continuous consultation coverage to review medications for patients with dysphagia and/or enteral feeding tubes.
Conclusions
This QI project drew from ISMP recommendations, previous work within the VHA, local practice, and insight from multiple disciplines on the health care team to revise and create tools to improve medication safety for patients with dysphagia and/or enteral feeding tubes in the acute care setting. These tools included a revised pharmacy consultation workflow with improvements to the pharmacy consultation template, standardization of the pill-crushing devices and language used for patient medication lists, implementation of CROC alerts within the EHR, and development of an SOP.
The RLRVAMC Pharmacy Service intends to continue reviewing patient safety reports, assessing staff perspectives, and refining (and potentially adding) tools for medication safety. Future QI initiatives may focus on improving medication safety for outpatients with dysphagia and/or enteral feeding tubes. We also hope that these tools can be adapted at other VAMCs to promote medication safety for patients with dysphagia and/or enteral feeding tubes.
Medication regimens may require adjustment in acute care settings due to dysphagia and/or enteral feeding tubes. When a patient has dysphagia and/or a feeding tube, the health care team must review the pharmacotherapy regimen to assess the appropriateness of medication formulations. Patient anatomy, the type of feeding tube in place, pharmacokinetic and pharmacodynamic properties of medications, risk of feeding tube obstruction, and potential for interactions between enteral nutrition and medications should be considered when clinicians administer medications through feeding tubes. The risk of feeding tube obstruction and clogging rises with increasing tube length and decreasing tube lumen. Incidence of obstructed percutaneous endoscopic gastrotomy tubes is reported to be 23% to 35%.1
A coordinated effort by all members of the health care team is essential to provide safe and effective care to patients with dysphagia and/or enteral feeding tubes. To decrease the risk of feeding tube obstruction, medications should be dissolved in water or administered in liquid form, saline fluids should be avoided, and the tube should be flushed with water before and after administering medications.
The pharmacokinetics of medications can be altered when tablets are crushed or capsules are opened. The bioavailability of dabigatran, for example, increases by 75% when the capsules are opened and pellets are taken orally.2 Medications may become intolerable after manipulation due to taste.3 Others may also increase the risk of feeding tube obstruction, such as omeprazole granules that increase the risk of small-bore feeding tube obstruction.4
Prior assessments of drug administration for patients with dysphagia and/or enteral feeding tubes has shown medication errors are prevalent.5-7 The Institute for Safe Medication Practices (ISMP) issued a Medication Safety Alert that provides a framework for preventing medication errors when preparing and administering medications via enteral feeding tubes.8 Other resources, such as monographs, are also available to guide pharmacotherapy decisions when oral medications require manipulation for administration to patients with dysphagia and/or enteral feeding tubes.9-11
In 2021, the Kansas City Veterans Affairs Medical Center (KCVAMC) was recognized as a Veterans Health Administration (VHA) Shark Tank finalist for improving the safety of medication administration for patients with enteral feeding tubes.12 This involved the addition of a Computerized Patient Record System (CPRS), clinical reminder order check (CROC), and a comprehensive medication review by a pharmacist. After implementing the CROC alert and pharmacy e-consultation workflow, the KCVAMC team reported that the number of inappropriate medications (ie, drugs on the ISMP do not crush list) was reduced from 41 to 6 in 1 year, resulting in an 85.4% reduction in potential medication errors.13
In 2014, the Richard L. Roudebush VAMC (RLRVAMC) created a pharmacy consultation process for patients with dysphagia and/or enteral feeding tubes. Any clinician could place a pharmacy consultation in CPRS. A pharmacist then reviewed patient charts, medication information resources, the VA formulary, and RLRVAMC pharmacy inventory. The pharmacist conferred with the patient’s care team to adjust pharmacotherapy, completed a consultation note, and updated medication order comments in Veterans Health Information Systems and Technology Architecture (VistA). These comments interfaced with the barcode medication administration software for the health care professional administering medications.
Despite the 2014 quality improvement (QI) process, medication errors involving the inappropriate ordering, preparation, and administration of medications for patients with dysphagia and/or enteral feeding tubes continued to be reported. Additionally, anonymous feedback revealed that only 3 of 10 responding pharmacists were satisfied with the existing medication use process for patients with dysphagia and/or enteral feeding tubes. Pharmacists expressed concerns that (1) clinicians were inappropriately crushing and/or manipulating new medications that were ordered after pharmacy consultations; (2) there was a lack of comprehensive documentation in CPRS; and (3) there were too many manual steps in the process. In response, RLRVAMC initiated a new QI initiative to improve the medication use process for patients with dysphagia and/or enteral feeding tubes in the acute care setting.
Quality Improvement Project
This multidisciplinary RLRVAMC QI project began November 2024 to improve pharmacotherapy care for patients with dysphagia and/or enteral feeding tubes in acute care. It was approved by the RLRVAMC Pharmacy Service. This intervention addressed the pharmacy consultation template, standardization of equipment, standardization of language, creation of clinical alerts, and sustainment (Table 1).
RLRVAMC has about 8600 annual inpatient admissions and 159 acute care beds.14 The project charter was drafted, and local stakeholders were identified including pharmacy technicians, pharmacists, nurses, speech language pathologists, and acute care clinicians. Pharmacy consultation workload was retrospectively reviewed to describe the scope of the existing state.
A workshop with 12 QI project stakeholders in December 2024 used A3 methodology to define the current process and the target state, barriers and solutions, prioritize interventions on an impact-effort matrix, perform a gap analysis, identify rapid plan-do-study-act (PDSA) experiments, and develop a completion plan (Figure). Five postworkshop PDSA experiments engaged additional stakeholders, clinical application coordinators, and medical supply representatives to ascertain the feasibility of the tools implemented.
Abbreviations: BCMA, barcode medication administration; CDSS, clinical decision support system; CPRS, Computerized Patient Record System;
EHR, electronic health record; SOP, standard operating procedure; VistA, Veterans Health Information Systems and Technology Architecture.
About 3% of RLRVAMC admissions involve a pharmacy consultation to review medications for dysphagia and/or enteral feeding tubes. Clinicians reviewed 30 preimplementation inpatient pharmacy consultations involving 200 oral medications. Pharmacists were more frequently consulted for inpatients with dysphagia (19 [63%]) than for patients with enteral feeding tubes (11 [37%]) (Table 2).
Pharmacy Consultation Template
The pharmacy consultation was updated in CPRS. Prior to this QI project, the ordering clinician was prompted to select 1 option for the indication: dysphagia or enteral feeding tube. The type of enteral feeding tube was not prompted by the consultation text nor required to be specified in the consultation. The ordering clinician could provide free-text comments. Of 11 preimplementation consultations, the type of enteral feeding tube was specified in 5 (45%). The consultation template entry was updated to include an option to check a box for the consultation indication from 3 options: dysphagia, enteral feeding, or other patient- specific condition/request. If enteral feeding tube is selected, then the clinician is prompted to select the type of enteral feeding tube. Since the completion of the project, there have been no patient safety reports concerning an erroneous or incomplete consultation entry (Supplemental Material).
The note template was updated to import the list of active inpatient medications and provide sections for the adjudicating pharmacist to document which medications can be crushed (or opened), which require adjustment, and which are hazardous and require special handling. Additionally, the revised template added a statement clarifying that the documented recommendations apply only to the medication regimen at the time of the consultation (Supplemental Material).
Standardizations
There are multiple pill-crushing devices used at RLRVAMC that vary in crushing mechanism, corresponding medication pouches, and degree of protection when manipulating hazardous medications. Prior to this QI project, RLRVAMC used 3 pill-crushing devices (about 30 total devices in inpatient care areas). Only 1 device with corresponding closed pouches for preparation of hazardous medications was available, which was stored in the RLRVAMC inpatient pharmacy. This workflow resulted in waste and posed potential risks for delays in care. This project incorporated a standard pill-crushing system with the corresponding medication pouches in all inpatient care areas, which provided safeguards for clinicians to prepare and administer hazardous medications (Supplemental Material).
Patients requiring medications to be crushed or opened on discharge should receive education, written instruction, and have care plans documented in CPRS. RLRVAMC patients receive education and a printed medication list. Prior to this QI project, the instructions for crushing or opening medications could only be entered by free text in the electronic medication reconciliation tool, allowing for the potential for inconsistent language or omissions.
This QI project included an update to the electronic medication reconciliation tool. An optional checkbox selection was added for patients requiring medications to be manipulated. When checked, a radial selection for individual medications is displayed, prompting the clinician and pharmacist to indicate either do not crush tablet or OK to crush tablet. These selections appear in clinical care notes and on the printed medication list provided to the patient (Supplemental Material).
Clinical Alerts
As part of the RLRVAMC QI initiative, a CROC alert was implemented, based on the KCVAMC intervention for patients with enteral feeding tubes.13 The RLRVAMC CROC alert also included patients with dysphagia. A nursing text order was made available in CPRS for patients requiring medications and remains active throughout the duration of the patient’s admission or until discontinued. It generates CROC alerts in CPRS and VistA when new medication orders are entered and reviewed by pharmacists.
Clinicians used clinical decision support systems to create daily lists of patients receiving medications by feeding tube and patients receiving crushed/opened medications due to dysphagia. This allows pharmacists to perform a census review of all inpatients to confirm appropriateness of medication orders. Clinical alerts for patients with enteral feeding tubes are advised by the ISMP and have data demonstrating a reduction in medication errors (Supplemental Material).14,15
Sustainment
During the sustainment phase, process owners were identified and a Pharmacy Service standard operating procedure (SOP) was written. The development of an institutional do not crush medication list was discussed; however, it was determined to be difficult to develop and maintain. An institutional tertiary resource list was selected in favor of a locally developed resource. These resources include the Handbook of Drug Administration via Enteral Feeding Tubes, Third Edition, the Pharmacist’s Letter list, “Meds that Should Not be Crushed,” and the Up- ToDate Lexidrug list, “Oral Medications That Should Not Be Crushed or Altered.”9-11 Links to the resources were added to the RLRVAMC pharmacy service SharePoint. In addition to defining the preferred tertiary resources, the SOP defined the process for reviewing inventory and the process for reviewing medication orders for hazard risk.
Discussion
Continued patient safety reports and low satisfaction rates among pharmacists prompted this QI project to improve safety for patients with dysphagia and/or enteral feeding tubes at RLRVAMC. The project engaged stakeholders and also identified and addressed gaps with potential for patient harm.
The tools implemented by this initiative drew from previous work by the KCVAMC and from framework provided by the ISMP.8,13 We expanded the QI intervention to include acute care patients with dysphagia.
RLRVAMC did not take steps to track the impact of the interventions on medication errors. However, no patient safety reports concerning an erroneous or incomplete pharmacy consultation entry have been reported. We also think that it is reasonable to assume that the adoption of the safety tools described here will have a positive impact on patient safety. RLRVAMC pharmacists have noted an increased appreciation for medication safety when processing medication orders for patients with dysphagia and/or enteral feeding tubes. While the workflow took time to adopt and integrate, clinical pharmacists perceived it as an improvement in patient safety. Our future focus is aimed at translating the process improvement into the Oracle/Cerner electronic health record, which is scheduled to be deployed at the RLRVAMC in August 2026.
Limitations
This QI project did not aim to quantify or compare medication errors before and after the intervention. An accurate number of unreported errors in the medication use process for patients with dysphagia and/or enteral feeding tubes would be challenging to quantify without direct observation. Multiple clinicians are engaged in the medication use process and individual steps may not be documented at all, or documented properly. In addition, medication errors are often underreported and may not reflect the total number of errors and/or potential for errors. That said, reported medication errors in the medication use process for patients with dysphagia and/or enteral feeding tubes are reviewed on a monthly basis by the RLRVAMC Multidisciplinary Medication Safety committee to continuously improve patient safety.
Another potential limitation is the extent to which the project can be adapted at other VHA sites. For example, RLRVAMC uses CPRS; the framework and tools to improve medication safety may not translate to sites using the Oracle/Cerner electronic health record. Furthermore, this QI project included a pharmacy consultation workflow that relied on pharmacists who are available at any hour. Other facilities may not have continuous consultation coverage to review medications for patients with dysphagia and/or enteral feeding tubes.
Conclusions
This QI project drew from ISMP recommendations, previous work within the VHA, local practice, and insight from multiple disciplines on the health care team to revise and create tools to improve medication safety for patients with dysphagia and/or enteral feeding tubes in the acute care setting. These tools included a revised pharmacy consultation workflow with improvements to the pharmacy consultation template, standardization of the pill-crushing devices and language used for patient medication lists, implementation of CROC alerts within the EHR, and development of an SOP.
The RLRVAMC Pharmacy Service intends to continue reviewing patient safety reports, assessing staff perspectives, and refining (and potentially adding) tools for medication safety. Future QI initiatives may focus on improving medication safety for outpatients with dysphagia and/or enteral feeding tubes. We also hope that these tools can be adapted at other VAMCs to promote medication safety for patients with dysphagia and/or enteral feeding tubes.
- Blumenstein I, Shastri YM, Stein J. Gastroenteric tube feeding: techniques, problems and solutions. World J Gastroenterol. 2014;20:8505-8524. doi:10.3748/wjg.v20.i26.8505
- Pradaxa (dabigatran etexilate). Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc; 2025. https:// pro.boehringer-ingelheim.com/us/products/pradaxa/bipdf /pradaxa-capsules-us-pi
- Lovell AG, Protus BM, Dickman JR, et al. Palatability of crushed over-the-counter medications. J Pain Symptom Manage. 2021;61:755-762. doi:10.1016/j.jpainsymman.2020.09.020
- Messaouik D, Sautou-Miranda V, Bagel-Boithias S, et al. Comparative study and optimisation of the administration mode of three proton pump inhibitors by nasogastric tube. Int J Pharm. 2005;299:65-72. doi:10.1016/j.ijpharm.2005.04.034
- Demirkan K, Bayraktar-Ekincioglu A, Gulhan-Halil M, et al. Assessment of drug administration via feeding tube and the knowledge of health-care professionals in a university hospital. Eur J Clin Nutr. 2017;71:164-168. doi:10.1038/ejcn.2016.147
- Fodil M, Nghiem D, Colas M, et al. Assessment of clinical practices for crushing medication in geriatric units. J Nutr Health Aging. 2017;21:904-908. doi:10.1007/s12603-017-0886-3
- Zhu LL, Xu LC, Wang HQ, et al. Appropriateness of administration of nasogastric medication and preliminary intervention. Ther Clin Risk Manag. 2012;8:393-401. doi:10.2147/TCRM.S37785
- Institute for Safe Medication Practices (ISMP). Preventing errors when preparing and administering medications via enteral feeding tubes. Acute Care ISMP Medication Safety Alert. November 17, 2022. Accessed March 17, 2026. https://nutritioncare.org/wp-content/uploads/2025/02 /ISMP-Safety-Alert_Medications-and-Enteral-Feeding -Tubes.pdf
- White R, Bradnam V. Handbook of Drug Administration via Enteral Feeding Tubes. 3rd ed. Pharmaceutical Press; 2015.
- Clinical resource, meds that should not be crushed. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. Updated April 2025. Accessed March 17, 2026. https://pharmacist.therapeuticresearch.com/en/Content /Segments/PRL/2014/Aug/Meds-That-Should-Not-Be -Crushed-7309
- Oral medications that should not be crushed or altered. In: Lexidrug. UpToDate, Inc. https://online.lexi.com/lco /action/doc/retrieve/docid/patch_f/4227
- Uttaro E, Zhao F, Schweighardt A. Filling the gaps on the Institute for Safe Medication Practices (ISMP) do not crush list for immediate-release products. Int J Pharm Compd. 2021;25:364-371.
- US Dept of Veterans Affairs. VA Diffusion Marketplace. Improved safety of enteral tube medication administration. Updated 2024. Accessed March 17, 2026. https:// marketplace.va.gov/innovations/improved-safety-of -enteral-tube-medication-administration
- US Dept of Veterans Affairs. About us. VA Indiana Healthcare System. Updated October 17, 2024. Accessed March 2, 2026. https://www.va.gov/indiana-health-care/about-us/
- Wasylewicz ATM, van Grinsven RJB, Bikker JMW, et al. Clinical decision support system-assisted pharmacy intervention reduces feeding tube-related medication errors in hospitalized patients: a focus on medication suitable for feeding-tube administration. JPEN J Parenter Enteral Nutr. 2021;45:625-632. doi:10.1002/jpen.1869
- Blumenstein I, Shastri YM, Stein J. Gastroenteric tube feeding: techniques, problems and solutions. World J Gastroenterol. 2014;20:8505-8524. doi:10.3748/wjg.v20.i26.8505
- Pradaxa (dabigatran etexilate). Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc; 2025. https:// pro.boehringer-ingelheim.com/us/products/pradaxa/bipdf /pradaxa-capsules-us-pi
- Lovell AG, Protus BM, Dickman JR, et al. Palatability of crushed over-the-counter medications. J Pain Symptom Manage. 2021;61:755-762. doi:10.1016/j.jpainsymman.2020.09.020
- Messaouik D, Sautou-Miranda V, Bagel-Boithias S, et al. Comparative study and optimisation of the administration mode of three proton pump inhibitors by nasogastric tube. Int J Pharm. 2005;299:65-72. doi:10.1016/j.ijpharm.2005.04.034
- Demirkan K, Bayraktar-Ekincioglu A, Gulhan-Halil M, et al. Assessment of drug administration via feeding tube and the knowledge of health-care professionals in a university hospital. Eur J Clin Nutr. 2017;71:164-168. doi:10.1038/ejcn.2016.147
- Fodil M, Nghiem D, Colas M, et al. Assessment of clinical practices for crushing medication in geriatric units. J Nutr Health Aging. 2017;21:904-908. doi:10.1007/s12603-017-0886-3
- Zhu LL, Xu LC, Wang HQ, et al. Appropriateness of administration of nasogastric medication and preliminary intervention. Ther Clin Risk Manag. 2012;8:393-401. doi:10.2147/TCRM.S37785
- Institute for Safe Medication Practices (ISMP). Preventing errors when preparing and administering medications via enteral feeding tubes. Acute Care ISMP Medication Safety Alert. November 17, 2022. Accessed March 17, 2026. https://nutritioncare.org/wp-content/uploads/2025/02 /ISMP-Safety-Alert_Medications-and-Enteral-Feeding -Tubes.pdf
- White R, Bradnam V. Handbook of Drug Administration via Enteral Feeding Tubes. 3rd ed. Pharmaceutical Press; 2015.
- Clinical resource, meds that should not be crushed. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. Updated April 2025. Accessed March 17, 2026. https://pharmacist.therapeuticresearch.com/en/Content /Segments/PRL/2014/Aug/Meds-That-Should-Not-Be -Crushed-7309
- Oral medications that should not be crushed or altered. In: Lexidrug. UpToDate, Inc. https://online.lexi.com/lco /action/doc/retrieve/docid/patch_f/4227
- Uttaro E, Zhao F, Schweighardt A. Filling the gaps on the Institute for Safe Medication Practices (ISMP) do not crush list for immediate-release products. Int J Pharm Compd. 2021;25:364-371.
- US Dept of Veterans Affairs. VA Diffusion Marketplace. Improved safety of enteral tube medication administration. Updated 2024. Accessed March 17, 2026. https:// marketplace.va.gov/innovations/improved-safety-of -enteral-tube-medication-administration
- US Dept of Veterans Affairs. About us. VA Indiana Healthcare System. Updated October 17, 2024. Accessed March 2, 2026. https://www.va.gov/indiana-health-care/about-us/
- Wasylewicz ATM, van Grinsven RJB, Bikker JMW, et al. Clinical decision support system-assisted pharmacy intervention reduces feeding tube-related medication errors in hospitalized patients: a focus on medication suitable for feeding-tube administration. JPEN J Parenter Enteral Nutr. 2021;45:625-632. doi:10.1002/jpen.1869
Streamlining the Acute Care Pharmacy Consultation Process for Patients With Dysphagia or Enteral Feeding Tubes
Streamlining the Acute Care Pharmacy Consultation Process for Patients With Dysphagia or Enteral Feeding Tubes
Effectiveness and Safety of Droperidol Use in the VA Greater Los Angeles Healthcare System Emergency Department
Effectiveness and Safety of Droperidol Use in the VA Greater Los Angeles Healthcare System Emergency Department
Droperidol is a butyrophenone antipsychotic approved by the US Food and Drug Administration (FDA) for use in postoperative nausea and vomiting (PONV). Off-label, it has also been utilized for its sedative, anxiolytic, and analgesic properties.1 While its exact mechanism of action remains elusive, it is believed that binding to postsynaptic γ-aminobutyric acid receptors induces anxiolysis and sedation, while dopaminergic activity in the chemoreceptor trigger zone contributes to its antiemetic effects.2 Since the introduction of droperidol in 1967, it has been widely used by emergency physicians, psychiatrists, and anesthesiologists globally.1
Despite its therapeutic efficacy, use of droperidol has been tempered by concerns regarding its cardiovascular safety profile, specifically its potential to prolong the QT interval and precipitate cardiac arrhythmias. In 2001, the FDA placed a boxed warning on droperidol that mandated electrocardiogram (EKG) monitoring before and after treatment. This requirement has led to a widespread decrease in use, and the FDA decision sparked significant controversy among clinicians, with many organizations arguing that the evidence did not support this mandate.1
Further review of the cases cited by the FDA revealed that there were 277 reported cases of droperidol-related adverse events (AEs), but many of these cases were duplicates and occurred outside the US.3 Additionally, the doses of droperidol used in these cases were significantly higher than the typical doses used in the emergency department (ED), ranging from 25 to 250 mg.4 Typical doses for PONV range from 0.625 to 2.5 mg intravenous (IV) or intramuscular (IM). Recommended doses for agitation typically range from 2.5 to 10 mg IV and 5 to 10 mg IM.5
There has been growing interest in reevaluating the risk-benefit profile of droperidol in the ED. Since the original decision by the FDA, multiple publications have challenged the idea that droperidol has significantly higher risks associated with its use. The 2014 review by the Clinical Guidelines Committee of the American Academy of Emergency Medicine did not find evidence that low-dose droperidol (< 2.5 is unsafe for use in the ED.6 A retrospective cohort study from 2020 found no fatalities in 5784 patients. Furthermore, a prospective observational study of 1009 patients at 6 EDs who received high-dose droperidol (≤ 20.0 mg) found no evidence of increased risk for QT prolongation.7 The evidence supports the safety of droperidol for use in prehospital and hospital settings as well as in pediatric, adult, and geriatric populations.8-14 Droperidol was eventually reintroduced in 2019, which led to increased use.
The US Department of Veterans Affairs (VA) formulary has limited options (eg, haloperidol and olanzapine) that have robust evidence supporting their use to treat aggression or psychosis-related agitation. Ziprasidone injections are not on the formulary and require authorization for use, which may delay patient care and pose a safety risk. In 2021, VA Greater Los Angeles Healthcare System (VAGLAHS) received Pharmacy and Therapeutics Committee approval to use droperidol in the ED for agitation or nausea and vomiting. The purpose of this study was to evaluate safety outcomes for patients prescribed droperidol and the need for rescue medications (ie, effectiveness) in the VAGLAHS ED.
Methods
This retrospective chart review analyzed patients administered droperidol in the VAGLAHS ED from February 1, 2021, through April 30, 2023. A list of patients who had droperidol ordered in the VAGLAHS ED was obtained from the Veterans Health Information Systems and Technology Architecture. Charts were reviewed using the Computerized Patient Record System to confirm droperidol administration. Nurse documentation was reviewed to confirm the time, dose, and route of administration. In addition, droperidol dosages were categorized as < 5 mg, 5 to 10 mg, and > 10 mg to review outcomes based on the total amount administered to each patient.
Patients included in the study received droperidol in the ED within the study period, were aged ≥ 18 years, and received droperidol for acute agitation or antiemesis. Patients were excluded if they received droperidol for an indication other than agitation or antiemesis.
The study team reviewed the list of patients and audited the collected data. Reviewers were trained on the study protocols and variables identified. The following data were collected: patient demographics (age, sex, race, height, weight, allergies), Charlson Comorbidity Index (CCI) conditions, cardiac comorbidities, laboratory values at admission, basic metabolic panels, liver function tests, droperidol use (doses, indications, and documentation of safety), concomitant medications ordered with the initial droperidol order, AEs (arrhythmias, extrapyramidal symptoms [EPS], respiratory depression, mortality), medications used within 60 minutes of droperidol administration (rescue medications), other medications used within 24 hours after droperidol administration, and EKG/QTc (corrected QT interval) intervals. The data reviewed and recorded were from the date of the initial patient ED visit.
Outcomes
The primary outcome was all-cause mortality within 24 hours after droperidol administration. This outcome was measured in all patients included in this study. Secondary outcomes included rescue medications needed after droperidol administration, incidence of QT prolongation, incidence of EPS (defined as akathisia, dystonia, parkinsonism, or tardive dyskinesia), and incidence of respiratory depression. Clinically significant QTc was defined as an interval of ≥ 500 ms with incidence of arrhythmias, code blues, or intubations. Baseline risk factors for QTc prolongation were taken into consideration including electrolyte abnormalities, concomitant QT-prolonging medications, CCI score, and cardiac comorbidities. Incidence of EPS was counted if patients received medications such as diphenhydramine or benztropine after droperidol administration in addition to documentation of EPS signs and symptoms. Incidences of EPS findings were reviewed by emergency department physicians to confirm the diagnosis.
Safety was assessed by quantifying mortality rates 24 hours after droperidol administration along with incidence of AEs associated with droperidol use including QT prolongation, EPS, and respiratory depression.
The necessity of rescue medication use was assessed by nursing documentation, additional medications ordered, and/or no additional medications required for agitation within 60 minutes of droperidol administration. Sixty minutes was the chosen timeframe given that the onset of droperidol action is between 3 and 10 minutes and peaks in about 30 minutes. Medications that were considered rescue medications included diphenhydramine < 25 mg, diphenhydramine 25 to 50 mg, lorazepam < 1 mg, lorazepam 1 to 2 mg, diphenhydramine < 25 mg and lorazepam < 1 mg, diphenhydramine < 25 mg and lorazepam 1 to 2 mg, diphenhydramine 25 to 50 mg and lorazepam 1 to 2 mg, and other medications, the names and doses of which were manually documented by investigators.
Statistical Analysis
For all variables in the study, descriptive analysis was used to categorize findings. Microsoft Excel was used to calculate means, frequency counts, percentages, and categorize data.
Results
Between February 1, 2021, and April 16, 2023, 214 patients received droperidol in the VAGLAHS ED, and 207 patients were included in the study. Seven patients did not receive droperidol for the indications included (acute agitation or antiemesis). Most of the study population (89.4%) was male, and the mean age was 51.0 years. The mean CCI was 1.6. In the study, 183 (88.4%) patients received droperidol for agitation and 24 (11.6%) for nausea and vomiting (Table 1).
Primary Outcome
No deaths were observed in a 24-hour period after droperidol administration among the 207 patients included in the study. There were also no arrhythmias, code blues, or intubations observed with the administration of droperidol (Table 2).
Secondary Outcomes
A total of 144 patients (69.6%) received droperidol alone to resolve agitation or nausea and vomiting. In the remaining population, 63 (30.4%) patients were given medications concomitantly with droperidol.
Fifteen patients (7.2%) required rescue medications that were administered within 60 minutes of droperidol administration. Rescue medications were required for 7 patients (4.9%) who initially received droperidol alone compared with 8 patients (12.7%) who were administered concomitant medications with droperidol (Figure).
Extrapyramidal Symptoms
EPS occurred in 2 patients (1.0%). There was 1 incidence of tardive dyskinesia (TD) in which the patient received droperidol 2.5 mg IM for emesis. TD was resolved with diphenhydramine 50 mg. A second patient who experienced dystonia received droperidol 10 mg IM for agitation. Dystonia was resolved with benztropine 2 mg. Both patients had a CCI of 0, no cardiac comorbidities, and laboratory test results were within reference ranges. The second patient received olanzapine within 24 hours of droperidol administration; however, it was after the EPS event.
QTc Prolongation
Baseline EKGs (within 6 months prior to ED visit) were available for 102 patients (49.3%). Nine patients (8.8%) had a reported baseline QTc of ≥ 500 ms (Table 3). Of these patients, 6 had a repeat EKG and 5 had a repeat QTc < 500 ms. One patient had a baseline and repeated QTc of 512 ms with essentially no change after droperidol administration. Only 1 patient was on a potentially QTc-prolonging medication at home. None of the patients with baseline QTc > 500 ms experienced arrhythmias after droperidol administration.
We found that 59 patients (28.5%) had EKGs performed within 24 hours after droperidol administration. Five patients had documented QTc ≥ 500 ms, but no arrhythmias were observed in a 24-hour period. Table 4 describes the additional medications administered after the 60-minute window but within 24 hours after droperidol administration. Quetiapine 300 mg and metoclopramide 5 mg were the only medications documented that can potentially increase QTc. Patient adherence to home medications and the timing of the last dose prior to ED visit were unknown. However, no arrhythmias were noted in these patients with QTc changes. No patients experienced respiratory depression within 24 hours of droperidol administration.
Older Adult Patients
Thirty-eight patients were aged ≥ 65 years with a mean age of 74.2 years. Thirty-four patients (89.5%) received droperidol for agitation and 4 (10.6%) for nausea and vomiting. Only 21 patients had a baseline EKG, and 4 had QTc ≤ 500 ms. At 24 hours, EKGs were performed for 18 patients and 3 had a QTc ≤ 500 ms. No mortality or arrhythmias were reported and there were no incidences of rescue medications, EPS, or respiratory depression.
Discussion
The study included 207 patients who received droperidol for either agitation or nausea/vomiting in the VAGLAHS ED. No mortality occurred within 24 hours of droperidol administration, which is consistent with recent studies.8-14
Furthermore, 59 patients (28.5%) had an EKG performed within 24 hours of droperidol administration; 5 patients had documented QTc ≥ 500 ms. Only 3 of the patients with prolonged QTc had baseline readings for comparison. Only 2 patients had an increase in QTc interval. No arrhythmias were observed; however, the effects of observing QTc prolongation were limited due to the lack of post-EKG readings following droperidol administration. Because of the retrospective nature of the study, neither standardization of EKG at baseline nor 24-hour postadministration were possible. The study found that droperidol was effective with only 15 patients (7.3%) requiring rescue medications. In the patients who were given medications concomitantly with droperidol, it was not possible to conclude whether the patients would have required rescue medications to resolve their agitation or nausea/vomiting. Administration of concomitant medications with droperidol may be attributed to practice patterns associated with haloperidol use, which is frequently administered with concomitant medications such as diphenhydramine and/or a benzodiazepine.
AEs were rare with no documentation of respiratory depression and 2 cases (1.0%) of EPS. Both incidences of EPS resolved with diphenhydramine or benztropine. However, given the reliance on nursing documentation to capture AEs, the number of events may have been underreported.
Limitations
Standardization of dosing was a limiting factor that could affect the need for rescue medications. Another limitation was reliance on nursing reports of resolution of symptoms and comfort with agitated patients. Given the retrospective design and small sample size, this study may not have captured all potential AEs. However, the doses administered within this study population were consistent with what was expected based on other studies.8-14
Conclusions
Droperidol, an antipsychotic, is currently approved for PONV, but is also used off-label for agitation. This study found no fatalities among patients who received droperidol in the ED. The findings suggest that droperidol used for agitation and as an antiemetic, despite its FDA boxed warning, appears to be safe and showed no evidence of mortality, arrhythmias, code blues, or intubations despite the lack of postdose EKG monitoring. Among the 38 patients aged ≥ 65 years, the use of droperidol revealed no increased risks. It should be noted that droperidol appeared safe and few patients required rescue medications within this study population.
- Perkins J, Ho JD, Vilke GM, DeMers G. American Academy of Emergency Medicine Position Statement: Safety of droperidol use in the emergency department. J Emerg Med. 2015;49:91-97. doi:10.1016/j.jemermed.2014.12.024
- Siegel RB, Motov SM, Marcolini EG. Droperidol use in the emergency department: a clinical review. J Emerg Med. 2023;64:289-294. doi:10.1016/j.jemermed.2022.12.012
- Jackson CW, Sheehan AH, Reddan JG. Evidencebased review of the black-box warning for droperidol. Am J Health Syst Pharm. 2007;64:1174-1186. doi:10.2146/ajhp060505
- Habib AS, Gan TJ. Food and Drug Administration black box warning on the perioperative use of droperidol: a review of the cases. Anesth Analg. 2003;96(5):1377-1379. doi:10.1213/01.ane.0000063923.87560.37
- Droperidol. In: Micromedex (electronic version). IBM Watson Health; 2019. Accessed March 2, 2026. https://www .micromedexsolutions.com
- Gaw CM, Cabrera D, Bellolio F, Mattson AE, Lohse CM, Jeffery MM. Effectiveness and safety of droperidol in a United States emergency department. Am J Emerg Med. 2020;38:1310-1314. doi:10.1016/j.ajem.2019.09.007
- Calver L, Page CB, Downes MA, et al. The safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department. Ann Emerg Med. 2015;66(3):230-238.e1. doi:10.1016/j.annemergmed.2015.03.016
- Ernst R, Wagstaff H, Smith M, et al. Droperidol administration among emergency department patients with abdominal pain, nausea, and vomiting. Am J Emerg Med. 2024;85:44-47. doi:10.1016/j.ajem.2024.07.060
- Szwak K, Sacchetti A. Droperidol use in pediatric emergency department patients. Pediatr Emerg Care. 2010;26:248-250. doi:10.1097/pec.0b013e3181d6d9f2
- Chase PB, Biros MH. A retrospective review of the use and safety of droperidol in a large, high-risk, inner-city emergency department patient population. Acad Emerg Med. 2002;9:1402-1410. doi:10.1111/j.1553-2712.2002.tb01609.x
- Mattson A, Friend K, Brown CS, Cabrera D. Reintegrating droperidol into emergency medicine practice. Am J Health Syst Pharm. 2020;77(22):1838-1845. doi:10.1093/ajhp/zxaa271
- Cole JB, Stang JL, DeVries PA, Martel ML, Miner JR, Driver BE. A prospective study of intramuscular droperidol or olanzapine for acute agitation in the emergency department: a natural experiment owing to drug shortages. Ann Emerg Med. 2021;78(2):274-286. doi:10.1016/j.annemergmed.2021.01.005
- Page CB, Parker LE, Rashford SJ, et al. Prospective study of the safety and effectiveness of droperidol in elderly patients for pre-hospital acute behavioural disturbance. Emerg Med Australas. 2020;32(5):731-736. doi:10.1111/1742-6723.13496
- Page CB, Parker LE, Rashford SJ, et al. A prospective study of the safety and effectiveness of droperidol inchildren for prehospital acute behavioral disturbance. Prehosp Emerg Care. 2018;23:519-526. doi:10.1080/10903127.2018.1542473
Droperidol is a butyrophenone antipsychotic approved by the US Food and Drug Administration (FDA) for use in postoperative nausea and vomiting (PONV). Off-label, it has also been utilized for its sedative, anxiolytic, and analgesic properties.1 While its exact mechanism of action remains elusive, it is believed that binding to postsynaptic γ-aminobutyric acid receptors induces anxiolysis and sedation, while dopaminergic activity in the chemoreceptor trigger zone contributes to its antiemetic effects.2 Since the introduction of droperidol in 1967, it has been widely used by emergency physicians, psychiatrists, and anesthesiologists globally.1
Despite its therapeutic efficacy, use of droperidol has been tempered by concerns regarding its cardiovascular safety profile, specifically its potential to prolong the QT interval and precipitate cardiac arrhythmias. In 2001, the FDA placed a boxed warning on droperidol that mandated electrocardiogram (EKG) monitoring before and after treatment. This requirement has led to a widespread decrease in use, and the FDA decision sparked significant controversy among clinicians, with many organizations arguing that the evidence did not support this mandate.1
Further review of the cases cited by the FDA revealed that there were 277 reported cases of droperidol-related adverse events (AEs), but many of these cases were duplicates and occurred outside the US.3 Additionally, the doses of droperidol used in these cases were significantly higher than the typical doses used in the emergency department (ED), ranging from 25 to 250 mg.4 Typical doses for PONV range from 0.625 to 2.5 mg intravenous (IV) or intramuscular (IM). Recommended doses for agitation typically range from 2.5 to 10 mg IV and 5 to 10 mg IM.5
There has been growing interest in reevaluating the risk-benefit profile of droperidol in the ED. Since the original decision by the FDA, multiple publications have challenged the idea that droperidol has significantly higher risks associated with its use. The 2014 review by the Clinical Guidelines Committee of the American Academy of Emergency Medicine did not find evidence that low-dose droperidol (< 2.5 is unsafe for use in the ED.6 A retrospective cohort study from 2020 found no fatalities in 5784 patients. Furthermore, a prospective observational study of 1009 patients at 6 EDs who received high-dose droperidol (≤ 20.0 mg) found no evidence of increased risk for QT prolongation.7 The evidence supports the safety of droperidol for use in prehospital and hospital settings as well as in pediatric, adult, and geriatric populations.8-14 Droperidol was eventually reintroduced in 2019, which led to increased use.
The US Department of Veterans Affairs (VA) formulary has limited options (eg, haloperidol and olanzapine) that have robust evidence supporting their use to treat aggression or psychosis-related agitation. Ziprasidone injections are not on the formulary and require authorization for use, which may delay patient care and pose a safety risk. In 2021, VA Greater Los Angeles Healthcare System (VAGLAHS) received Pharmacy and Therapeutics Committee approval to use droperidol in the ED for agitation or nausea and vomiting. The purpose of this study was to evaluate safety outcomes for patients prescribed droperidol and the need for rescue medications (ie, effectiveness) in the VAGLAHS ED.
Methods
This retrospective chart review analyzed patients administered droperidol in the VAGLAHS ED from February 1, 2021, through April 30, 2023. A list of patients who had droperidol ordered in the VAGLAHS ED was obtained from the Veterans Health Information Systems and Technology Architecture. Charts were reviewed using the Computerized Patient Record System to confirm droperidol administration. Nurse documentation was reviewed to confirm the time, dose, and route of administration. In addition, droperidol dosages were categorized as < 5 mg, 5 to 10 mg, and > 10 mg to review outcomes based on the total amount administered to each patient.
Patients included in the study received droperidol in the ED within the study period, were aged ≥ 18 years, and received droperidol for acute agitation or antiemesis. Patients were excluded if they received droperidol for an indication other than agitation or antiemesis.
The study team reviewed the list of patients and audited the collected data. Reviewers were trained on the study protocols and variables identified. The following data were collected: patient demographics (age, sex, race, height, weight, allergies), Charlson Comorbidity Index (CCI) conditions, cardiac comorbidities, laboratory values at admission, basic metabolic panels, liver function tests, droperidol use (doses, indications, and documentation of safety), concomitant medications ordered with the initial droperidol order, AEs (arrhythmias, extrapyramidal symptoms [EPS], respiratory depression, mortality), medications used within 60 minutes of droperidol administration (rescue medications), other medications used within 24 hours after droperidol administration, and EKG/QTc (corrected QT interval) intervals. The data reviewed and recorded were from the date of the initial patient ED visit.
Outcomes
The primary outcome was all-cause mortality within 24 hours after droperidol administration. This outcome was measured in all patients included in this study. Secondary outcomes included rescue medications needed after droperidol administration, incidence of QT prolongation, incidence of EPS (defined as akathisia, dystonia, parkinsonism, or tardive dyskinesia), and incidence of respiratory depression. Clinically significant QTc was defined as an interval of ≥ 500 ms with incidence of arrhythmias, code blues, or intubations. Baseline risk factors for QTc prolongation were taken into consideration including electrolyte abnormalities, concomitant QT-prolonging medications, CCI score, and cardiac comorbidities. Incidence of EPS was counted if patients received medications such as diphenhydramine or benztropine after droperidol administration in addition to documentation of EPS signs and symptoms. Incidences of EPS findings were reviewed by emergency department physicians to confirm the diagnosis.
Safety was assessed by quantifying mortality rates 24 hours after droperidol administration along with incidence of AEs associated with droperidol use including QT prolongation, EPS, and respiratory depression.
The necessity of rescue medication use was assessed by nursing documentation, additional medications ordered, and/or no additional medications required for agitation within 60 minutes of droperidol administration. Sixty minutes was the chosen timeframe given that the onset of droperidol action is between 3 and 10 minutes and peaks in about 30 minutes. Medications that were considered rescue medications included diphenhydramine < 25 mg, diphenhydramine 25 to 50 mg, lorazepam < 1 mg, lorazepam 1 to 2 mg, diphenhydramine < 25 mg and lorazepam < 1 mg, diphenhydramine < 25 mg and lorazepam 1 to 2 mg, diphenhydramine 25 to 50 mg and lorazepam 1 to 2 mg, and other medications, the names and doses of which were manually documented by investigators.
Statistical Analysis
For all variables in the study, descriptive analysis was used to categorize findings. Microsoft Excel was used to calculate means, frequency counts, percentages, and categorize data.
Results
Between February 1, 2021, and April 16, 2023, 214 patients received droperidol in the VAGLAHS ED, and 207 patients were included in the study. Seven patients did not receive droperidol for the indications included (acute agitation or antiemesis). Most of the study population (89.4%) was male, and the mean age was 51.0 years. The mean CCI was 1.6. In the study, 183 (88.4%) patients received droperidol for agitation and 24 (11.6%) for nausea and vomiting (Table 1).
Primary Outcome
No deaths were observed in a 24-hour period after droperidol administration among the 207 patients included in the study. There were also no arrhythmias, code blues, or intubations observed with the administration of droperidol (Table 2).
Secondary Outcomes
A total of 144 patients (69.6%) received droperidol alone to resolve agitation or nausea and vomiting. In the remaining population, 63 (30.4%) patients were given medications concomitantly with droperidol.
Fifteen patients (7.2%) required rescue medications that were administered within 60 minutes of droperidol administration. Rescue medications were required for 7 patients (4.9%) who initially received droperidol alone compared with 8 patients (12.7%) who were administered concomitant medications with droperidol (Figure).
Extrapyramidal Symptoms
EPS occurred in 2 patients (1.0%). There was 1 incidence of tardive dyskinesia (TD) in which the patient received droperidol 2.5 mg IM for emesis. TD was resolved with diphenhydramine 50 mg. A second patient who experienced dystonia received droperidol 10 mg IM for agitation. Dystonia was resolved with benztropine 2 mg. Both patients had a CCI of 0, no cardiac comorbidities, and laboratory test results were within reference ranges. The second patient received olanzapine within 24 hours of droperidol administration; however, it was after the EPS event.
QTc Prolongation
Baseline EKGs (within 6 months prior to ED visit) were available for 102 patients (49.3%). Nine patients (8.8%) had a reported baseline QTc of ≥ 500 ms (Table 3). Of these patients, 6 had a repeat EKG and 5 had a repeat QTc < 500 ms. One patient had a baseline and repeated QTc of 512 ms with essentially no change after droperidol administration. Only 1 patient was on a potentially QTc-prolonging medication at home. None of the patients with baseline QTc > 500 ms experienced arrhythmias after droperidol administration.
We found that 59 patients (28.5%) had EKGs performed within 24 hours after droperidol administration. Five patients had documented QTc ≥ 500 ms, but no arrhythmias were observed in a 24-hour period. Table 4 describes the additional medications administered after the 60-minute window but within 24 hours after droperidol administration. Quetiapine 300 mg and metoclopramide 5 mg were the only medications documented that can potentially increase QTc. Patient adherence to home medications and the timing of the last dose prior to ED visit were unknown. However, no arrhythmias were noted in these patients with QTc changes. No patients experienced respiratory depression within 24 hours of droperidol administration.
Older Adult Patients
Thirty-eight patients were aged ≥ 65 years with a mean age of 74.2 years. Thirty-four patients (89.5%) received droperidol for agitation and 4 (10.6%) for nausea and vomiting. Only 21 patients had a baseline EKG, and 4 had QTc ≤ 500 ms. At 24 hours, EKGs were performed for 18 patients and 3 had a QTc ≤ 500 ms. No mortality or arrhythmias were reported and there were no incidences of rescue medications, EPS, or respiratory depression.
Discussion
The study included 207 patients who received droperidol for either agitation or nausea/vomiting in the VAGLAHS ED. No mortality occurred within 24 hours of droperidol administration, which is consistent with recent studies.8-14
Furthermore, 59 patients (28.5%) had an EKG performed within 24 hours of droperidol administration; 5 patients had documented QTc ≥ 500 ms. Only 3 of the patients with prolonged QTc had baseline readings for comparison. Only 2 patients had an increase in QTc interval. No arrhythmias were observed; however, the effects of observing QTc prolongation were limited due to the lack of post-EKG readings following droperidol administration. Because of the retrospective nature of the study, neither standardization of EKG at baseline nor 24-hour postadministration were possible. The study found that droperidol was effective with only 15 patients (7.3%) requiring rescue medications. In the patients who were given medications concomitantly with droperidol, it was not possible to conclude whether the patients would have required rescue medications to resolve their agitation or nausea/vomiting. Administration of concomitant medications with droperidol may be attributed to practice patterns associated with haloperidol use, which is frequently administered with concomitant medications such as diphenhydramine and/or a benzodiazepine.
AEs were rare with no documentation of respiratory depression and 2 cases (1.0%) of EPS. Both incidences of EPS resolved with diphenhydramine or benztropine. However, given the reliance on nursing documentation to capture AEs, the number of events may have been underreported.
Limitations
Standardization of dosing was a limiting factor that could affect the need for rescue medications. Another limitation was reliance on nursing reports of resolution of symptoms and comfort with agitated patients. Given the retrospective design and small sample size, this study may not have captured all potential AEs. However, the doses administered within this study population were consistent with what was expected based on other studies.8-14
Conclusions
Droperidol, an antipsychotic, is currently approved for PONV, but is also used off-label for agitation. This study found no fatalities among patients who received droperidol in the ED. The findings suggest that droperidol used for agitation and as an antiemetic, despite its FDA boxed warning, appears to be safe and showed no evidence of mortality, arrhythmias, code blues, or intubations despite the lack of postdose EKG monitoring. Among the 38 patients aged ≥ 65 years, the use of droperidol revealed no increased risks. It should be noted that droperidol appeared safe and few patients required rescue medications within this study population.
Droperidol is a butyrophenone antipsychotic approved by the US Food and Drug Administration (FDA) for use in postoperative nausea and vomiting (PONV). Off-label, it has also been utilized for its sedative, anxiolytic, and analgesic properties.1 While its exact mechanism of action remains elusive, it is believed that binding to postsynaptic γ-aminobutyric acid receptors induces anxiolysis and sedation, while dopaminergic activity in the chemoreceptor trigger zone contributes to its antiemetic effects.2 Since the introduction of droperidol in 1967, it has been widely used by emergency physicians, psychiatrists, and anesthesiologists globally.1
Despite its therapeutic efficacy, use of droperidol has been tempered by concerns regarding its cardiovascular safety profile, specifically its potential to prolong the QT interval and precipitate cardiac arrhythmias. In 2001, the FDA placed a boxed warning on droperidol that mandated electrocardiogram (EKG) monitoring before and after treatment. This requirement has led to a widespread decrease in use, and the FDA decision sparked significant controversy among clinicians, with many organizations arguing that the evidence did not support this mandate.1
Further review of the cases cited by the FDA revealed that there were 277 reported cases of droperidol-related adverse events (AEs), but many of these cases were duplicates and occurred outside the US.3 Additionally, the doses of droperidol used in these cases were significantly higher than the typical doses used in the emergency department (ED), ranging from 25 to 250 mg.4 Typical doses for PONV range from 0.625 to 2.5 mg intravenous (IV) or intramuscular (IM). Recommended doses for agitation typically range from 2.5 to 10 mg IV and 5 to 10 mg IM.5
There has been growing interest in reevaluating the risk-benefit profile of droperidol in the ED. Since the original decision by the FDA, multiple publications have challenged the idea that droperidol has significantly higher risks associated with its use. The 2014 review by the Clinical Guidelines Committee of the American Academy of Emergency Medicine did not find evidence that low-dose droperidol (< 2.5 is unsafe for use in the ED.6 A retrospective cohort study from 2020 found no fatalities in 5784 patients. Furthermore, a prospective observational study of 1009 patients at 6 EDs who received high-dose droperidol (≤ 20.0 mg) found no evidence of increased risk for QT prolongation.7 The evidence supports the safety of droperidol for use in prehospital and hospital settings as well as in pediatric, adult, and geriatric populations.8-14 Droperidol was eventually reintroduced in 2019, which led to increased use.
The US Department of Veterans Affairs (VA) formulary has limited options (eg, haloperidol and olanzapine) that have robust evidence supporting their use to treat aggression or psychosis-related agitation. Ziprasidone injections are not on the formulary and require authorization for use, which may delay patient care and pose a safety risk. In 2021, VA Greater Los Angeles Healthcare System (VAGLAHS) received Pharmacy and Therapeutics Committee approval to use droperidol in the ED for agitation or nausea and vomiting. The purpose of this study was to evaluate safety outcomes for patients prescribed droperidol and the need for rescue medications (ie, effectiveness) in the VAGLAHS ED.
Methods
This retrospective chart review analyzed patients administered droperidol in the VAGLAHS ED from February 1, 2021, through April 30, 2023. A list of patients who had droperidol ordered in the VAGLAHS ED was obtained from the Veterans Health Information Systems and Technology Architecture. Charts were reviewed using the Computerized Patient Record System to confirm droperidol administration. Nurse documentation was reviewed to confirm the time, dose, and route of administration. In addition, droperidol dosages were categorized as < 5 mg, 5 to 10 mg, and > 10 mg to review outcomes based on the total amount administered to each patient.
Patients included in the study received droperidol in the ED within the study period, were aged ≥ 18 years, and received droperidol for acute agitation or antiemesis. Patients were excluded if they received droperidol for an indication other than agitation or antiemesis.
The study team reviewed the list of patients and audited the collected data. Reviewers were trained on the study protocols and variables identified. The following data were collected: patient demographics (age, sex, race, height, weight, allergies), Charlson Comorbidity Index (CCI) conditions, cardiac comorbidities, laboratory values at admission, basic metabolic panels, liver function tests, droperidol use (doses, indications, and documentation of safety), concomitant medications ordered with the initial droperidol order, AEs (arrhythmias, extrapyramidal symptoms [EPS], respiratory depression, mortality), medications used within 60 minutes of droperidol administration (rescue medications), other medications used within 24 hours after droperidol administration, and EKG/QTc (corrected QT interval) intervals. The data reviewed and recorded were from the date of the initial patient ED visit.
Outcomes
The primary outcome was all-cause mortality within 24 hours after droperidol administration. This outcome was measured in all patients included in this study. Secondary outcomes included rescue medications needed after droperidol administration, incidence of QT prolongation, incidence of EPS (defined as akathisia, dystonia, parkinsonism, or tardive dyskinesia), and incidence of respiratory depression. Clinically significant QTc was defined as an interval of ≥ 500 ms with incidence of arrhythmias, code blues, or intubations. Baseline risk factors for QTc prolongation were taken into consideration including electrolyte abnormalities, concomitant QT-prolonging medications, CCI score, and cardiac comorbidities. Incidence of EPS was counted if patients received medications such as diphenhydramine or benztropine after droperidol administration in addition to documentation of EPS signs and symptoms. Incidences of EPS findings were reviewed by emergency department physicians to confirm the diagnosis.
Safety was assessed by quantifying mortality rates 24 hours after droperidol administration along with incidence of AEs associated with droperidol use including QT prolongation, EPS, and respiratory depression.
The necessity of rescue medication use was assessed by nursing documentation, additional medications ordered, and/or no additional medications required for agitation within 60 minutes of droperidol administration. Sixty minutes was the chosen timeframe given that the onset of droperidol action is between 3 and 10 minutes and peaks in about 30 minutes. Medications that were considered rescue medications included diphenhydramine < 25 mg, diphenhydramine 25 to 50 mg, lorazepam < 1 mg, lorazepam 1 to 2 mg, diphenhydramine < 25 mg and lorazepam < 1 mg, diphenhydramine < 25 mg and lorazepam 1 to 2 mg, diphenhydramine 25 to 50 mg and lorazepam 1 to 2 mg, and other medications, the names and doses of which were manually documented by investigators.
Statistical Analysis
For all variables in the study, descriptive analysis was used to categorize findings. Microsoft Excel was used to calculate means, frequency counts, percentages, and categorize data.
Results
Between February 1, 2021, and April 16, 2023, 214 patients received droperidol in the VAGLAHS ED, and 207 patients were included in the study. Seven patients did not receive droperidol for the indications included (acute agitation or antiemesis). Most of the study population (89.4%) was male, and the mean age was 51.0 years. The mean CCI was 1.6. In the study, 183 (88.4%) patients received droperidol for agitation and 24 (11.6%) for nausea and vomiting (Table 1).
Primary Outcome
No deaths were observed in a 24-hour period after droperidol administration among the 207 patients included in the study. There were also no arrhythmias, code blues, or intubations observed with the administration of droperidol (Table 2).
Secondary Outcomes
A total of 144 patients (69.6%) received droperidol alone to resolve agitation or nausea and vomiting. In the remaining population, 63 (30.4%) patients were given medications concomitantly with droperidol.
Fifteen patients (7.2%) required rescue medications that were administered within 60 minutes of droperidol administration. Rescue medications were required for 7 patients (4.9%) who initially received droperidol alone compared with 8 patients (12.7%) who were administered concomitant medications with droperidol (Figure).
Extrapyramidal Symptoms
EPS occurred in 2 patients (1.0%). There was 1 incidence of tardive dyskinesia (TD) in which the patient received droperidol 2.5 mg IM for emesis. TD was resolved with diphenhydramine 50 mg. A second patient who experienced dystonia received droperidol 10 mg IM for agitation. Dystonia was resolved with benztropine 2 mg. Both patients had a CCI of 0, no cardiac comorbidities, and laboratory test results were within reference ranges. The second patient received olanzapine within 24 hours of droperidol administration; however, it was after the EPS event.
QTc Prolongation
Baseline EKGs (within 6 months prior to ED visit) were available for 102 patients (49.3%). Nine patients (8.8%) had a reported baseline QTc of ≥ 500 ms (Table 3). Of these patients, 6 had a repeat EKG and 5 had a repeat QTc < 500 ms. One patient had a baseline and repeated QTc of 512 ms with essentially no change after droperidol administration. Only 1 patient was on a potentially QTc-prolonging medication at home. None of the patients with baseline QTc > 500 ms experienced arrhythmias after droperidol administration.
We found that 59 patients (28.5%) had EKGs performed within 24 hours after droperidol administration. Five patients had documented QTc ≥ 500 ms, but no arrhythmias were observed in a 24-hour period. Table 4 describes the additional medications administered after the 60-minute window but within 24 hours after droperidol administration. Quetiapine 300 mg and metoclopramide 5 mg were the only medications documented that can potentially increase QTc. Patient adherence to home medications and the timing of the last dose prior to ED visit were unknown. However, no arrhythmias were noted in these patients with QTc changes. No patients experienced respiratory depression within 24 hours of droperidol administration.
Older Adult Patients
Thirty-eight patients were aged ≥ 65 years with a mean age of 74.2 years. Thirty-four patients (89.5%) received droperidol for agitation and 4 (10.6%) for nausea and vomiting. Only 21 patients had a baseline EKG, and 4 had QTc ≤ 500 ms. At 24 hours, EKGs were performed for 18 patients and 3 had a QTc ≤ 500 ms. No mortality or arrhythmias were reported and there were no incidences of rescue medications, EPS, or respiratory depression.
Discussion
The study included 207 patients who received droperidol for either agitation or nausea/vomiting in the VAGLAHS ED. No mortality occurred within 24 hours of droperidol administration, which is consistent with recent studies.8-14
Furthermore, 59 patients (28.5%) had an EKG performed within 24 hours of droperidol administration; 5 patients had documented QTc ≥ 500 ms. Only 3 of the patients with prolonged QTc had baseline readings for comparison. Only 2 patients had an increase in QTc interval. No arrhythmias were observed; however, the effects of observing QTc prolongation were limited due to the lack of post-EKG readings following droperidol administration. Because of the retrospective nature of the study, neither standardization of EKG at baseline nor 24-hour postadministration were possible. The study found that droperidol was effective with only 15 patients (7.3%) requiring rescue medications. In the patients who were given medications concomitantly with droperidol, it was not possible to conclude whether the patients would have required rescue medications to resolve their agitation or nausea/vomiting. Administration of concomitant medications with droperidol may be attributed to practice patterns associated with haloperidol use, which is frequently administered with concomitant medications such as diphenhydramine and/or a benzodiazepine.
AEs were rare with no documentation of respiratory depression and 2 cases (1.0%) of EPS. Both incidences of EPS resolved with diphenhydramine or benztropine. However, given the reliance on nursing documentation to capture AEs, the number of events may have been underreported.
Limitations
Standardization of dosing was a limiting factor that could affect the need for rescue medications. Another limitation was reliance on nursing reports of resolution of symptoms and comfort with agitated patients. Given the retrospective design and small sample size, this study may not have captured all potential AEs. However, the doses administered within this study population were consistent with what was expected based on other studies.8-14
Conclusions
Droperidol, an antipsychotic, is currently approved for PONV, but is also used off-label for agitation. This study found no fatalities among patients who received droperidol in the ED. The findings suggest that droperidol used for agitation and as an antiemetic, despite its FDA boxed warning, appears to be safe and showed no evidence of mortality, arrhythmias, code blues, or intubations despite the lack of postdose EKG monitoring. Among the 38 patients aged ≥ 65 years, the use of droperidol revealed no increased risks. It should be noted that droperidol appeared safe and few patients required rescue medications within this study population.
- Perkins J, Ho JD, Vilke GM, DeMers G. American Academy of Emergency Medicine Position Statement: Safety of droperidol use in the emergency department. J Emerg Med. 2015;49:91-97. doi:10.1016/j.jemermed.2014.12.024
- Siegel RB, Motov SM, Marcolini EG. Droperidol use in the emergency department: a clinical review. J Emerg Med. 2023;64:289-294. doi:10.1016/j.jemermed.2022.12.012
- Jackson CW, Sheehan AH, Reddan JG. Evidencebased review of the black-box warning for droperidol. Am J Health Syst Pharm. 2007;64:1174-1186. doi:10.2146/ajhp060505
- Habib AS, Gan TJ. Food and Drug Administration black box warning on the perioperative use of droperidol: a review of the cases. Anesth Analg. 2003;96(5):1377-1379. doi:10.1213/01.ane.0000063923.87560.37
- Droperidol. In: Micromedex (electronic version). IBM Watson Health; 2019. Accessed March 2, 2026. https://www .micromedexsolutions.com
- Gaw CM, Cabrera D, Bellolio F, Mattson AE, Lohse CM, Jeffery MM. Effectiveness and safety of droperidol in a United States emergency department. Am J Emerg Med. 2020;38:1310-1314. doi:10.1016/j.ajem.2019.09.007
- Calver L, Page CB, Downes MA, et al. The safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department. Ann Emerg Med. 2015;66(3):230-238.e1. doi:10.1016/j.annemergmed.2015.03.016
- Ernst R, Wagstaff H, Smith M, et al. Droperidol administration among emergency department patients with abdominal pain, nausea, and vomiting. Am J Emerg Med. 2024;85:44-47. doi:10.1016/j.ajem.2024.07.060
- Szwak K, Sacchetti A. Droperidol use in pediatric emergency department patients. Pediatr Emerg Care. 2010;26:248-250. doi:10.1097/pec.0b013e3181d6d9f2
- Chase PB, Biros MH. A retrospective review of the use and safety of droperidol in a large, high-risk, inner-city emergency department patient population. Acad Emerg Med. 2002;9:1402-1410. doi:10.1111/j.1553-2712.2002.tb01609.x
- Mattson A, Friend K, Brown CS, Cabrera D. Reintegrating droperidol into emergency medicine practice. Am J Health Syst Pharm. 2020;77(22):1838-1845. doi:10.1093/ajhp/zxaa271
- Cole JB, Stang JL, DeVries PA, Martel ML, Miner JR, Driver BE. A prospective study of intramuscular droperidol or olanzapine for acute agitation in the emergency department: a natural experiment owing to drug shortages. Ann Emerg Med. 2021;78(2):274-286. doi:10.1016/j.annemergmed.2021.01.005
- Page CB, Parker LE, Rashford SJ, et al. Prospective study of the safety and effectiveness of droperidol in elderly patients for pre-hospital acute behavioural disturbance. Emerg Med Australas. 2020;32(5):731-736. doi:10.1111/1742-6723.13496
- Page CB, Parker LE, Rashford SJ, et al. A prospective study of the safety and effectiveness of droperidol inchildren for prehospital acute behavioral disturbance. Prehosp Emerg Care. 2018;23:519-526. doi:10.1080/10903127.2018.1542473
- Perkins J, Ho JD, Vilke GM, DeMers G. American Academy of Emergency Medicine Position Statement: Safety of droperidol use in the emergency department. J Emerg Med. 2015;49:91-97. doi:10.1016/j.jemermed.2014.12.024
- Siegel RB, Motov SM, Marcolini EG. Droperidol use in the emergency department: a clinical review. J Emerg Med. 2023;64:289-294. doi:10.1016/j.jemermed.2022.12.012
- Jackson CW, Sheehan AH, Reddan JG. Evidencebased review of the black-box warning for droperidol. Am J Health Syst Pharm. 2007;64:1174-1186. doi:10.2146/ajhp060505
- Habib AS, Gan TJ. Food and Drug Administration black box warning on the perioperative use of droperidol: a review of the cases. Anesth Analg. 2003;96(5):1377-1379. doi:10.1213/01.ane.0000063923.87560.37
- Droperidol. In: Micromedex (electronic version). IBM Watson Health; 2019. Accessed March 2, 2026. https://www .micromedexsolutions.com
- Gaw CM, Cabrera D, Bellolio F, Mattson AE, Lohse CM, Jeffery MM. Effectiveness and safety of droperidol in a United States emergency department. Am J Emerg Med. 2020;38:1310-1314. doi:10.1016/j.ajem.2019.09.007
- Calver L, Page CB, Downes MA, et al. The safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department. Ann Emerg Med. 2015;66(3):230-238.e1. doi:10.1016/j.annemergmed.2015.03.016
- Ernst R, Wagstaff H, Smith M, et al. Droperidol administration among emergency department patients with abdominal pain, nausea, and vomiting. Am J Emerg Med. 2024;85:44-47. doi:10.1016/j.ajem.2024.07.060
- Szwak K, Sacchetti A. Droperidol use in pediatric emergency department patients. Pediatr Emerg Care. 2010;26:248-250. doi:10.1097/pec.0b013e3181d6d9f2
- Chase PB, Biros MH. A retrospective review of the use and safety of droperidol in a large, high-risk, inner-city emergency department patient population. Acad Emerg Med. 2002;9:1402-1410. doi:10.1111/j.1553-2712.2002.tb01609.x
- Mattson A, Friend K, Brown CS, Cabrera D. Reintegrating droperidol into emergency medicine practice. Am J Health Syst Pharm. 2020;77(22):1838-1845. doi:10.1093/ajhp/zxaa271
- Cole JB, Stang JL, DeVries PA, Martel ML, Miner JR, Driver BE. A prospective study of intramuscular droperidol or olanzapine for acute agitation in the emergency department: a natural experiment owing to drug shortages. Ann Emerg Med. 2021;78(2):274-286. doi:10.1016/j.annemergmed.2021.01.005
- Page CB, Parker LE, Rashford SJ, et al. Prospective study of the safety and effectiveness of droperidol in elderly patients for pre-hospital acute behavioural disturbance. Emerg Med Australas. 2020;32(5):731-736. doi:10.1111/1742-6723.13496
- Page CB, Parker LE, Rashford SJ, et al. A prospective study of the safety and effectiveness of droperidol inchildren for prehospital acute behavioral disturbance. Prehosp Emerg Care. 2018;23:519-526. doi:10.1080/10903127.2018.1542473
Effectiveness and Safety of Droperidol Use in the VA Greater Los Angeles Healthcare System Emergency Department
Effectiveness and Safety of Droperidol Use in the VA Greater Los Angeles Healthcare System Emergency Department
Investigating Real-World Tolerance and Dose Reductions of Oncology Multikinase Inhibitors in a VA Population
Investigating Real-World Tolerance and Dose Reductions of Oncology Multikinase Inhibitors in a VA Population
The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.
The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.7,8
MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.9 Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.10 Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.9
At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.
To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.
METHODS
This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.
The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.11 This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.11 Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.
The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.
Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.
RESULTS
Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.
The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).
Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).
DISCUSSION
The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.14 However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.15,16
Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.17 Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.18 Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.19 The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.17-19
This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.
Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.21
Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.22 This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.23
It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.7,8,24
Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.
Limitations
The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.
CONCLUSIONS
Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.
This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.
- Frequently asked questions. VA National Oncology Program. 2025. Accessed December 15, 2025. https://www.cancer.va.gov/CANCER/faqs.html
- Torez L. Reigniting the cancer moonshot to beat cancer. VA News. April 20, 2023. Accessed April 6, 2026. https://news.va.gov/118378/reigniting-the-cancer-moonshot-to-beat-cancer
- Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12:e71-e76. doi:10.1200/JOP.2015.007260
- Hussaarts KGAM, Veerman GDM, Jansman FGA, et al. Clinically relevant drug interactions with multikinase inhibitors: a review. Ther Adv Med Oncol. 2019;11:1758835918818347. doi:10.1177/1758835918818347
- Shyam Sunder S, Sharma UC, Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduct Target Ther. 2023;8:262. doi:10.1038/s41392-023-01469-6
- Thomson RJ, Moshirfar M, Ronquillo Y. Tyrosine kinase inhibitors. In: StatPearls [Internet]. StatPearls Publishing; updated July 18, 2023. Accessed December 15, 2025. https://www.ncbi.nlm.nih.gov/books/NBK563322/
- Project Optimus. US Food and Drug Administration. Updated December 6, 2024. Accessed December 15, 2025. https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
- Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases: Guidance for Industry. Docket number FDA-2022-D-2827. US Food and Drug Administration. August 2024. Accessed December 15, 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases
- Schnadig ID, Hutson TE, Chung H, et al. Dosing patterns, toxicity, and outcomes in patients treated with first-line sunitinib for advanced renal cell carcinoma in community-based practices. Clin Genitourin Cancer. 2014;12:413-421. doi:10.1016/j.clgc.2014.06.015
- Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124. doi:10.1056/nejmoa065044
- Hawn C, Bansal D. Relative dose intensity in oncology trials: a discussion of two approaches. PharmaSUG. 2024. Accessed April 6, 2026. https://pharmasug.org/proceedings/2024/ST/PharmaSUG-2024-ST-297.pdf
- George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009;27:3154-3160. doi:10.1200/jco.2008.20.9890
- George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009;45:1959-1968. doi:10.1016/j.ejca.2009.02.011
- Denduluri N, Patt DA, Wang Y, et al. Dose delays, dose reductions, and relative dose intensity in patients with cancer who received adjuvant or neoadjuvant chemotherapy in community oncology practices. J Natl Compr Canc Netw. 2015;13:1383-1393. doi:10.6004/jnccn.2015.0166
- Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103-1115. doi:10.1056/nejmoa1816047
- Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289-1300. doi:10.1056/nejmoa2035716
- Kirino S, Tsuchiya K, Kurosaki M, et al. Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma. PloS One. 2020;15:e0231828. doi:10.1371/journal.pone.0231828
- Ishihara H, Takagi T, Kondo T, et al. Decreased relative dose intensity during the early phase of treatment impacts the therapeutic efficacy of sunitinib in metastatic renal cell carcinoma. Jpn J Clin Oncol. 2018;48:667-672. doi:10.1093/jjco/hyy078
- Alghamdi MA, Amaro CP, Lee-Ying R, et al. Effect of sorafenib starting dose and dose intensity on survival in patients with hepatocellular carcinoma: results from a Canadian Multicenter Database. Cancer Med. 2020;9:4918-4928. doi:10.1002/cam4.3228
- Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295:2516-2524. doi:10.1001/jama.295.21.2516
- Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27:1800-1805. doi:10.1200/jco.2008.20.0931
- Boucai L, Zafereo M, Cabanillas ME. Thyroid cancer: a review. JAMA. 2024;331:425-435. doi:10.1001/jama.2023.26348
- Amin N, Anwar J, Sulaiman A, et al. Hepatocellular carcinoma: a comprehensive review. Diseases. 2025;13:207. doi:10.3390/diseases13070207
- Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20:1070-1082. doi:10.1016/s1470-2045(19)30272-4
The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.
The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.7,8
MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.9 Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.10 Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.9
At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.
To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.
METHODS
This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.
The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.11 This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.11 Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.
The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.
Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.
RESULTS
Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.
The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).
Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).
DISCUSSION
The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.14 However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.15,16
Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.17 Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.18 Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.19 The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.17-19
This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.
Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.21
Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.22 This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.23
It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.7,8,24
Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.
Limitations
The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.
CONCLUSIONS
Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.
This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.
The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.
The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.7,8
MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.9 Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.10 Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.9
At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.
To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.
METHODS
This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.
The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.11 This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.11 Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.
The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.
Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.
RESULTS
Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.
The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).
Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).
DISCUSSION
The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.14 However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.15,16
Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.17 Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.18 Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.19 The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.17-19
This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.
Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.21
Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.22 This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.23
It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.7,8,24
Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.
Limitations
The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.
CONCLUSIONS
Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.
This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.
- Frequently asked questions. VA National Oncology Program. 2025. Accessed December 15, 2025. https://www.cancer.va.gov/CANCER/faqs.html
- Torez L. Reigniting the cancer moonshot to beat cancer. VA News. April 20, 2023. Accessed April 6, 2026. https://news.va.gov/118378/reigniting-the-cancer-moonshot-to-beat-cancer
- Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12:e71-e76. doi:10.1200/JOP.2015.007260
- Hussaarts KGAM, Veerman GDM, Jansman FGA, et al. Clinically relevant drug interactions with multikinase inhibitors: a review. Ther Adv Med Oncol. 2019;11:1758835918818347. doi:10.1177/1758835918818347
- Shyam Sunder S, Sharma UC, Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduct Target Ther. 2023;8:262. doi:10.1038/s41392-023-01469-6
- Thomson RJ, Moshirfar M, Ronquillo Y. Tyrosine kinase inhibitors. In: StatPearls [Internet]. StatPearls Publishing; updated July 18, 2023. Accessed December 15, 2025. https://www.ncbi.nlm.nih.gov/books/NBK563322/
- Project Optimus. US Food and Drug Administration. Updated December 6, 2024. Accessed December 15, 2025. https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
- Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases: Guidance for Industry. Docket number FDA-2022-D-2827. US Food and Drug Administration. August 2024. Accessed December 15, 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases
- Schnadig ID, Hutson TE, Chung H, et al. Dosing patterns, toxicity, and outcomes in patients treated with first-line sunitinib for advanced renal cell carcinoma in community-based practices. Clin Genitourin Cancer. 2014;12:413-421. doi:10.1016/j.clgc.2014.06.015
- Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124. doi:10.1056/nejmoa065044
- Hawn C, Bansal D. Relative dose intensity in oncology trials: a discussion of two approaches. PharmaSUG. 2024. Accessed April 6, 2026. https://pharmasug.org/proceedings/2024/ST/PharmaSUG-2024-ST-297.pdf
- George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009;27:3154-3160. doi:10.1200/jco.2008.20.9890
- George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009;45:1959-1968. doi:10.1016/j.ejca.2009.02.011
- Denduluri N, Patt DA, Wang Y, et al. Dose delays, dose reductions, and relative dose intensity in patients with cancer who received adjuvant or neoadjuvant chemotherapy in community oncology practices. J Natl Compr Canc Netw. 2015;13:1383-1393. doi:10.6004/jnccn.2015.0166
- Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103-1115. doi:10.1056/nejmoa1816047
- Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289-1300. doi:10.1056/nejmoa2035716
- Kirino S, Tsuchiya K, Kurosaki M, et al. Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma. PloS One. 2020;15:e0231828. doi:10.1371/journal.pone.0231828
- Ishihara H, Takagi T, Kondo T, et al. Decreased relative dose intensity during the early phase of treatment impacts the therapeutic efficacy of sunitinib in metastatic renal cell carcinoma. Jpn J Clin Oncol. 2018;48:667-672. doi:10.1093/jjco/hyy078
- Alghamdi MA, Amaro CP, Lee-Ying R, et al. Effect of sorafenib starting dose and dose intensity on survival in patients with hepatocellular carcinoma: results from a Canadian Multicenter Database. Cancer Med. 2020;9:4918-4928. doi:10.1002/cam4.3228
- Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295:2516-2524. doi:10.1001/jama.295.21.2516
- Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27:1800-1805. doi:10.1200/jco.2008.20.0931
- Boucai L, Zafereo M, Cabanillas ME. Thyroid cancer: a review. JAMA. 2024;331:425-435. doi:10.1001/jama.2023.26348
- Amin N, Anwar J, Sulaiman A, et al. Hepatocellular carcinoma: a comprehensive review. Diseases. 2025;13:207. doi:10.3390/diseases13070207
- Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20:1070-1082. doi:10.1016/s1470-2045(19)30272-4
- Frequently asked questions. VA National Oncology Program. 2025. Accessed December 15, 2025. https://www.cancer.va.gov/CANCER/faqs.html
- Torez L. Reigniting the cancer moonshot to beat cancer. VA News. April 20, 2023. Accessed April 6, 2026. https://news.va.gov/118378/reigniting-the-cancer-moonshot-to-beat-cancer
- Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12:e71-e76. doi:10.1200/JOP.2015.007260
- Hussaarts KGAM, Veerman GDM, Jansman FGA, et al. Clinically relevant drug interactions with multikinase inhibitors: a review. Ther Adv Med Oncol. 2019;11:1758835918818347. doi:10.1177/1758835918818347
- Shyam Sunder S, Sharma UC, Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduct Target Ther. 2023;8:262. doi:10.1038/s41392-023-01469-6
- Thomson RJ, Moshirfar M, Ronquillo Y. Tyrosine kinase inhibitors. In: StatPearls [Internet]. StatPearls Publishing; updated July 18, 2023. Accessed December 15, 2025. https://www.ncbi.nlm.nih.gov/books/NBK563322/
- Project Optimus. US Food and Drug Administration. Updated December 6, 2024. Accessed December 15, 2025. https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
- Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases: Guidance for Industry. Docket number FDA-2022-D-2827. US Food and Drug Administration. August 2024. Accessed December 15, 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases
- Schnadig ID, Hutson TE, Chung H, et al. Dosing patterns, toxicity, and outcomes in patients treated with first-line sunitinib for advanced renal cell carcinoma in community-based practices. Clin Genitourin Cancer. 2014;12:413-421. doi:10.1016/j.clgc.2014.06.015
- Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124. doi:10.1056/nejmoa065044
- Hawn C, Bansal D. Relative dose intensity in oncology trials: a discussion of two approaches. PharmaSUG. 2024. Accessed April 6, 2026. https://pharmasug.org/proceedings/2024/ST/PharmaSUG-2024-ST-297.pdf
- George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009;27:3154-3160. doi:10.1200/jco.2008.20.9890
- George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009;45:1959-1968. doi:10.1016/j.ejca.2009.02.011
- Denduluri N, Patt DA, Wang Y, et al. Dose delays, dose reductions, and relative dose intensity in patients with cancer who received adjuvant or neoadjuvant chemotherapy in community oncology practices. J Natl Compr Canc Netw. 2015;13:1383-1393. doi:10.6004/jnccn.2015.0166
- Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103-1115. doi:10.1056/nejmoa1816047
- Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289-1300. doi:10.1056/nejmoa2035716
- Kirino S, Tsuchiya K, Kurosaki M, et al. Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma. PloS One. 2020;15:e0231828. doi:10.1371/journal.pone.0231828
- Ishihara H, Takagi T, Kondo T, et al. Decreased relative dose intensity during the early phase of treatment impacts the therapeutic efficacy of sunitinib in metastatic renal cell carcinoma. Jpn J Clin Oncol. 2018;48:667-672. doi:10.1093/jjco/hyy078
- Alghamdi MA, Amaro CP, Lee-Ying R, et al. Effect of sorafenib starting dose and dose intensity on survival in patients with hepatocellular carcinoma: results from a Canadian Multicenter Database. Cancer Med. 2020;9:4918-4928. doi:10.1002/cam4.3228
- Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295:2516-2524. doi:10.1001/jama.295.21.2516
- Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27:1800-1805. doi:10.1200/jco.2008.20.0931
- Boucai L, Zafereo M, Cabanillas ME. Thyroid cancer: a review. JAMA. 2024;331:425-435. doi:10.1001/jama.2023.26348
- Amin N, Anwar J, Sulaiman A, et al. Hepatocellular carcinoma: a comprehensive review. Diseases. 2025;13:207. doi:10.3390/diseases13070207
- Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20:1070-1082. doi:10.1016/s1470-2045(19)30272-4
Investigating Real-World Tolerance and Dose Reductions of Oncology Multikinase Inhibitors in a VA Population
Investigating Real-World Tolerance and Dose Reductions of Oncology Multikinase Inhibitors in a VA Population
Implementation of a Pharmacist-Led Penicillin Allergy Interview at a Veterans Care Facility
Implementation of a Pharmacist-Led Penicillin Allergy Interview at a Veterans Care Facility
Self-reported penicillin allergies are common, with a prevalence of about 10% of patients, according to the Centers for Disease Control and Prevention (CDC).1 However, only about 1% of patients have a true immunoglobulin E (IgE)-mediated allergy. This issue is often further complicated by inaccurate classification of nonallergic adverse effects as an allergy, resulting in incomplete allergy documentation in the electronic health record (EHR). The cross-reactivity rate with cephalosporins (Β-lactam antibiotics) in patients reporting a penicillin allergy is < 1%, which suggests that many patients with reported penicillin allergies can safely receive them.2 Despite this, patients with self-reported penicillin allergies often receive non–Β-lactam antibiotic agents, which may be associated with an increased risk of adverse drug reactions (ADRs), increased health care costs, and inferior clinical outcomes.3
Several strategies are recommended to assess patients with self-reported penicillin allergies. According to the CDC, evaluating a patient who reports a penicillin or other Β-lactam antibiotic allergy involves 3 steps: (1) obtaining a thorough medical history, including previous exposures to penicillin or other Β-lactam antibiotic; (2) performing a skin test using the penicillin major and minor determinants; and (3) among those who have a negative penicillin skin test, performing an observed oral challenge with 250 mg amoxicillin before proceeding directly to treatment with the indicated Β-lactam therapy.4
Most existing clinical guidance for assessing patients with self-reported penicillin allergies stems from site-specific policies and primarily focuses on oral amoxicillin challenges or penicillin skin testing (PST). However, performing these tests may not be feasible at all facilities due to time constraints and lack of allergists. Therefore, alternative strategies are necessary, such as conducting detailed patient interviews. Few studies have evaluated switching to Β-lactam agents following a penicillin allergy interview alone. However, with thorough patient histories and detailed interviews, patients with reported penicillin allergies can safely use Β-lactam antibiotics.5 Implementing this procedure provides a cost-savings opportunity by not having to administer additional antibiotics for testing in addition to improving antibiotic stewardship.
The Memphis Veterans Affairs Medical Center (MVAMC) created the Allergy to Β-Lactam Evaluation (ABLE) process to clarify and remove penicillin allergies. The process involves conducting a thorough chart review and patient interview followed by completion of a note template that provides recommendations about patient allergies and Β-lactam prescribing. Mitchell et al found that the pharmacist-led process to be beneficial for addressing Β-lactam allergy clearance.6 As a result, the ABLE process was implemented at several other US Department of Veterans Affairs (VA) medical centers (VAMCs). Using the ABLE template, the purpose of this study was to evaluate the impact of a pharmacist-led penicillin allergy initiative on penicillin allergy delabeling with an interview process alone.
Methods
Prior to ABLE process implementation, there were no standardized procedures for documenting allergy histories. ABLE was implemented at the Robley Rex VAMC (RRVAMC) in November 2022. During the interview phase, patients were initially identified during admission via TheraDoc as having either a penicillin allergy or ADR. The infectious disease pharmacist or pharmacy resident interviewed patients with documented penicillin allergies or ADRs using a standardized questionnaire (eAppendix 1). Not all identified patients could be interviewed. Patients currently receiving an antibiotic were prioritized for interviews. Patients were excluded if they declined or were unable to be interviewed, although a patient’s caregiver(s) could be interviewed in person or via telephone, if the patient was not available.
Following the interview, pharmacists used guidance from the ABLE process in addition to a detailed EHR review to determine whether the patient was eligible for an allergy update or removal and/or switch to a Β-lactam antibiotic (Figure). If eligible for modification, the interviewing pharmacist made the necessary changes. A templated process note with patient-specific recommendations was entered into the Computerized Patient Record System (CPRS) and the primary care team attending physician was added as an additional signer to be alerted in the system note (eAppendix 2).
This single-center, retrospective cohort study involved review of CPRS notes and clinical interviews in the interviewed group. Hospitalized patients at the RRVAMC aged ≥ 18 years with a documented penicillin allergy or ADR were included. The historical control group consisted of patients admitted between October 31, 2019, and October 31, 2022, and the intervention group consisted of patients admitted between November 1, 2022, and March 1, 2023. Patients in the historical control group were matched 1:1 to the intervention group for penicillin allergy severity (allergy [IgE-mediated], unknown, adverse effect, severe cutaneous or other non–IgE-mediated reaction) and whether they received a noncarbapenem non–Β-lactam antibiotic.
The primary outcome was the number of patient allergies/ADRs removed or changed on patient profiles regardless of whether their antibiotic regimen was changed. This outcome was further assessed by evaluating the number of patient allergies or ADRs removed or changed on patient profiles with or without a change in antibiotic regimen. Primary outcomes were analyzed using χ2 and/ or Fisher exact tests, as appropriate to determine statistically significant differences between the interviewed group and the historical control.
Results
Seventy patients were included: 35 patients in the interviewed group and 35 patients in the historical control group, respectively. Both groups had a mean age of 72 years and predominantly included White male patients (Table 1). Following the interview, the allergy profile was modified for 6 patients (17%) in the interview group vs 0 patients in the control group (P = .03) (Table 2). The primary outcome was analyzed separately regardless of an antibiotic regimen change. There was not a statistically significant difference between groups when assessing patients for change in therapy (P > .99). All 6 patients with an allergy profile modification had no change in antibiotic regimen.
Discussion
This study suggests the ABLE process may be a valuable tool for adjusting penicillin allergies or ADRs within patient EHRs. In the interview group, allergies were modified in 6 (17%) patients while no patients in the control group had allergy modifications. Of the 6 allergy profile modifications, 4 allergy labels were changed from an allergy to an ADR. These patients were cleared to receive future Β-lactam antibiotics after clinicians recognized the lack of a true IgE-mediated allergic reaction. In addition, 2 of the modified allergy profiles removed the allergy designation. Although this represents a small subset of interviewed patients, it illustrates the clinical effectiveness of an interview process alone to remove penicillin allergy designations.
Previous research has assessed the impact of pharmacist intervention on penicillin allergy clarification. Mitchell et al implemented a pharmacist-driven Β-lactam allergy assessment and penicillin allergy clinic (PAC) at the MVAMC with the goal of evaluating its impact on allergy clearance. In their study, clinical pharmacy specialists evaluated patients with Β-lactam allergies, and those deemed eligible were later seen in the PAC. Among the 246 patients evaluated using the Β-lactam allergy assessment alone and who were not seen in the PAC, 25% had their penicillin allergy removed following a detailed assessment.6
Song et al evaluated the effectiveness and feasibility of a pharmacist-driven penicillin allergy delabeling pilot program without skin testing or oral challenges. Patients with penicillin allergies were interviewed by a pharmacy resident using a standardized checklist. Among the 66 patients interviewed, 12 (18%) met the criteria for delabeling and consented to removal of their allergy.7 The delabeling rates in these 2 studies are similar to the 17% rate of allergy modification in our study, although this study is the only one to compare results to a historical control group.
Harper et al evaluated the impact of a penicillin allergy assessment, including penicillin skin testing and oral amoxicillin challenges, on delabeling penicillin allergies. Pharmacists completed a penicillin allergy assessment and performed penicillin skin testing and/or oral amoxicillin challenges for eligible patients. Of 35 patients, 31 (89%) had their penicillin allergies delabeled in the EHR.8 The rate of penicillin allergy delabeling in Harper et al was likely higher than that seen in our study due to the use of oral challenge and skin testing. Regardless, a detailed penicillin allergy interview alone was effective at RRVAMC, resulting in a significant rate of allergy removal or change. This supports the use of detailed penicillin allergy assessments in settings where penicillin skin testing or oral challenges may not be feasible.
Mann et al demonstrated the effectiveness of penicillin allergy assessments in switching eligible patients to Β-lactam antibiotics. Their single-center, prospective study assessed the impact of a pharmacist-driven detailed penicillin allergy interview initiative. Interviews that evaluated potential changes to allergy profiles were conducted with 175 patients. Of these patients, 135 (77.1%) were on antimicrobial therapy and 42 (31.1%) patients receiving therapy met criteria to switch to a noncarbapenem Β-lactam antibiotic. Thirty-one patients (73.8%) switched with no signs or symptoms of intolerance demonstrating that an interview can be a valuable tool for antibiotic optimization, specifically in patients with penicillin allergy.9 No patients in our study switched antibiotic therapy, likely because only a small number of patients were eligible for transition to a noncarbapenem Β-lactam antibiotic. In the Mann et al study, non–Β-lactam antibiotics, such as fluoroquinolones and carbapenems, accounted for > 75% of the antibiotics used.
Limitations
The sample size of this study was small and its duration was short. There is a risk for selection bias as not all identified patients were able to be interviewed while admitted, but patients on antibiotics were prioritized as they were most likely to directly benefit during their current admission from a modification of their allergy. Most patients in the study were White and male, which may limit the generalizability of the results. Additionally, recommendations regarding antibiotic changes were primarily communicated to the treatment team based on a templated note in CPRS alone. Therefore, implementation of these recommendations largely relied upon nonverbal communication. Direct pharmacist-physician communication could have led to a larger impact on antimicrobial therapy changes. The interviewer’s participation in daily rounds with time allotted to discuss this topic can be considered in the future to improve these processes.
Conclusions
This study found that the ABLE process identified patients for penicillin allergy delabeling. With the high prevalence of inaccurate penicillin allergy documentation, this tool offers VA health care systems a way to empower pharmacists in allergy clarification, leading to improvements in antibiotic stewardship. Although the sample size was small, the ABLE process may provide a framework for VA clinicians. Future research has the potential to demonstrate the practicality and effectiveness this pharmacist-led penicillin allergy interview process can offer clinicians.
- Health care providers. Clinical features of penicillin allergy. Centers for Disease Control and Prevention. August 25, 2025. Accessed February 4, 2026. https://www.cdc.gov /antibiotic-use/hcp/clinical-signs/index.html
- Wrynn AF. Penicillin allergies: A guide for NPs. Nurse Pract. 2022;47:30-36. doi:10.1097/01.NPR.0000855312.11145.78
- Mohsen S, Dickinson JA, Somayaji R. Update on the adverse effects of antimicrobial therapies in community practice. Can Fam Physician. 2020;66:651-659.
- Sexually Transmitted Infections Treatment Guidelines, 2021. Managing persons who have a history of penicillin allergy. Centers for Disease Control and Prevention. September 21, 2022. Accessed February 4, 2026. https:// www.cdc.gov/std/treatment-guidelines/penicillin-allergy .htm
- Holmes AK, Bennett NT, Berry TP. Pharmacy driven assessment of appropriate antibiotic selection in patients with reported beta-lactam allergy. J Am Coll Clin Pharm. 2019;2:509-514. doi:10.1002/jac5.1135
- Mitchell AB, Ness RA, Bennett JG, et al. Implementation and impact of a Β-lactam allergy assessment protocol in a veteran population. Fed Pract. 2021;38:420-425. doi:10.12788/fp.0172
- Song YC, Nelson ZJ, Wankum MA, et al. Effectiveness and feasibility of pharmacist-driven penicillin allergy de-labeling pilot program without skin testing or oral challenges. Pharmacy (Basel). 2021;9:127. doi:10.3390/pharmacy9030127
- Harper HM, Sanchez M. Review of pharmacist driven penicillin allergy assessments and skin testing: a multicenter case-series. Hosp Pharm. 2022;57:469-473. doi:10.1177/00185787211046862
- Mann KL, Wu JY, Shah SS. Implementation of a pharmacist- driven detailed penicillin allergy interview. Ann Pharmacother. 2020;54:364-370. doi:10.1177/1060028019884874
Self-reported penicillin allergies are common, with a prevalence of about 10% of patients, according to the Centers for Disease Control and Prevention (CDC).1 However, only about 1% of patients have a true immunoglobulin E (IgE)-mediated allergy. This issue is often further complicated by inaccurate classification of nonallergic adverse effects as an allergy, resulting in incomplete allergy documentation in the electronic health record (EHR). The cross-reactivity rate with cephalosporins (Β-lactam antibiotics) in patients reporting a penicillin allergy is < 1%, which suggests that many patients with reported penicillin allergies can safely receive them.2 Despite this, patients with self-reported penicillin allergies often receive non–Β-lactam antibiotic agents, which may be associated with an increased risk of adverse drug reactions (ADRs), increased health care costs, and inferior clinical outcomes.3
Several strategies are recommended to assess patients with self-reported penicillin allergies. According to the CDC, evaluating a patient who reports a penicillin or other Β-lactam antibiotic allergy involves 3 steps: (1) obtaining a thorough medical history, including previous exposures to penicillin or other Β-lactam antibiotic; (2) performing a skin test using the penicillin major and minor determinants; and (3) among those who have a negative penicillin skin test, performing an observed oral challenge with 250 mg amoxicillin before proceeding directly to treatment with the indicated Β-lactam therapy.4
Most existing clinical guidance for assessing patients with self-reported penicillin allergies stems from site-specific policies and primarily focuses on oral amoxicillin challenges or penicillin skin testing (PST). However, performing these tests may not be feasible at all facilities due to time constraints and lack of allergists. Therefore, alternative strategies are necessary, such as conducting detailed patient interviews. Few studies have evaluated switching to Β-lactam agents following a penicillin allergy interview alone. However, with thorough patient histories and detailed interviews, patients with reported penicillin allergies can safely use Β-lactam antibiotics.5 Implementing this procedure provides a cost-savings opportunity by not having to administer additional antibiotics for testing in addition to improving antibiotic stewardship.
The Memphis Veterans Affairs Medical Center (MVAMC) created the Allergy to Β-Lactam Evaluation (ABLE) process to clarify and remove penicillin allergies. The process involves conducting a thorough chart review and patient interview followed by completion of a note template that provides recommendations about patient allergies and Β-lactam prescribing. Mitchell et al found that the pharmacist-led process to be beneficial for addressing Β-lactam allergy clearance.6 As a result, the ABLE process was implemented at several other US Department of Veterans Affairs (VA) medical centers (VAMCs). Using the ABLE template, the purpose of this study was to evaluate the impact of a pharmacist-led penicillin allergy initiative on penicillin allergy delabeling with an interview process alone.
Methods
Prior to ABLE process implementation, there were no standardized procedures for documenting allergy histories. ABLE was implemented at the Robley Rex VAMC (RRVAMC) in November 2022. During the interview phase, patients were initially identified during admission via TheraDoc as having either a penicillin allergy or ADR. The infectious disease pharmacist or pharmacy resident interviewed patients with documented penicillin allergies or ADRs using a standardized questionnaire (eAppendix 1). Not all identified patients could be interviewed. Patients currently receiving an antibiotic were prioritized for interviews. Patients were excluded if they declined or were unable to be interviewed, although a patient’s caregiver(s) could be interviewed in person or via telephone, if the patient was not available.
Following the interview, pharmacists used guidance from the ABLE process in addition to a detailed EHR review to determine whether the patient was eligible for an allergy update or removal and/or switch to a Β-lactam antibiotic (Figure). If eligible for modification, the interviewing pharmacist made the necessary changes. A templated process note with patient-specific recommendations was entered into the Computerized Patient Record System (CPRS) and the primary care team attending physician was added as an additional signer to be alerted in the system note (eAppendix 2).
This single-center, retrospective cohort study involved review of CPRS notes and clinical interviews in the interviewed group. Hospitalized patients at the RRVAMC aged ≥ 18 years with a documented penicillin allergy or ADR were included. The historical control group consisted of patients admitted between October 31, 2019, and October 31, 2022, and the intervention group consisted of patients admitted between November 1, 2022, and March 1, 2023. Patients in the historical control group were matched 1:1 to the intervention group for penicillin allergy severity (allergy [IgE-mediated], unknown, adverse effect, severe cutaneous or other non–IgE-mediated reaction) and whether they received a noncarbapenem non–Β-lactam antibiotic.
The primary outcome was the number of patient allergies/ADRs removed or changed on patient profiles regardless of whether their antibiotic regimen was changed. This outcome was further assessed by evaluating the number of patient allergies or ADRs removed or changed on patient profiles with or without a change in antibiotic regimen. Primary outcomes were analyzed using χ2 and/ or Fisher exact tests, as appropriate to determine statistically significant differences between the interviewed group and the historical control.
Results
Seventy patients were included: 35 patients in the interviewed group and 35 patients in the historical control group, respectively. Both groups had a mean age of 72 years and predominantly included White male patients (Table 1). Following the interview, the allergy profile was modified for 6 patients (17%) in the interview group vs 0 patients in the control group (P = .03) (Table 2). The primary outcome was analyzed separately regardless of an antibiotic regimen change. There was not a statistically significant difference between groups when assessing patients for change in therapy (P > .99). All 6 patients with an allergy profile modification had no change in antibiotic regimen.
Discussion
This study suggests the ABLE process may be a valuable tool for adjusting penicillin allergies or ADRs within patient EHRs. In the interview group, allergies were modified in 6 (17%) patients while no patients in the control group had allergy modifications. Of the 6 allergy profile modifications, 4 allergy labels were changed from an allergy to an ADR. These patients were cleared to receive future Β-lactam antibiotics after clinicians recognized the lack of a true IgE-mediated allergic reaction. In addition, 2 of the modified allergy profiles removed the allergy designation. Although this represents a small subset of interviewed patients, it illustrates the clinical effectiveness of an interview process alone to remove penicillin allergy designations.
Previous research has assessed the impact of pharmacist intervention on penicillin allergy clarification. Mitchell et al implemented a pharmacist-driven Β-lactam allergy assessment and penicillin allergy clinic (PAC) at the MVAMC with the goal of evaluating its impact on allergy clearance. In their study, clinical pharmacy specialists evaluated patients with Β-lactam allergies, and those deemed eligible were later seen in the PAC. Among the 246 patients evaluated using the Β-lactam allergy assessment alone and who were not seen in the PAC, 25% had their penicillin allergy removed following a detailed assessment.6
Song et al evaluated the effectiveness and feasibility of a pharmacist-driven penicillin allergy delabeling pilot program without skin testing or oral challenges. Patients with penicillin allergies were interviewed by a pharmacy resident using a standardized checklist. Among the 66 patients interviewed, 12 (18%) met the criteria for delabeling and consented to removal of their allergy.7 The delabeling rates in these 2 studies are similar to the 17% rate of allergy modification in our study, although this study is the only one to compare results to a historical control group.
Harper et al evaluated the impact of a penicillin allergy assessment, including penicillin skin testing and oral amoxicillin challenges, on delabeling penicillin allergies. Pharmacists completed a penicillin allergy assessment and performed penicillin skin testing and/or oral amoxicillin challenges for eligible patients. Of 35 patients, 31 (89%) had their penicillin allergies delabeled in the EHR.8 The rate of penicillin allergy delabeling in Harper et al was likely higher than that seen in our study due to the use of oral challenge and skin testing. Regardless, a detailed penicillin allergy interview alone was effective at RRVAMC, resulting in a significant rate of allergy removal or change. This supports the use of detailed penicillin allergy assessments in settings where penicillin skin testing or oral challenges may not be feasible.
Mann et al demonstrated the effectiveness of penicillin allergy assessments in switching eligible patients to Β-lactam antibiotics. Their single-center, prospective study assessed the impact of a pharmacist-driven detailed penicillin allergy interview initiative. Interviews that evaluated potential changes to allergy profiles were conducted with 175 patients. Of these patients, 135 (77.1%) were on antimicrobial therapy and 42 (31.1%) patients receiving therapy met criteria to switch to a noncarbapenem Β-lactam antibiotic. Thirty-one patients (73.8%) switched with no signs or symptoms of intolerance demonstrating that an interview can be a valuable tool for antibiotic optimization, specifically in patients with penicillin allergy.9 No patients in our study switched antibiotic therapy, likely because only a small number of patients were eligible for transition to a noncarbapenem Β-lactam antibiotic. In the Mann et al study, non–Β-lactam antibiotics, such as fluoroquinolones and carbapenems, accounted for > 75% of the antibiotics used.
Limitations
The sample size of this study was small and its duration was short. There is a risk for selection bias as not all identified patients were able to be interviewed while admitted, but patients on antibiotics were prioritized as they were most likely to directly benefit during their current admission from a modification of their allergy. Most patients in the study were White and male, which may limit the generalizability of the results. Additionally, recommendations regarding antibiotic changes were primarily communicated to the treatment team based on a templated note in CPRS alone. Therefore, implementation of these recommendations largely relied upon nonverbal communication. Direct pharmacist-physician communication could have led to a larger impact on antimicrobial therapy changes. The interviewer’s participation in daily rounds with time allotted to discuss this topic can be considered in the future to improve these processes.
Conclusions
This study found that the ABLE process identified patients for penicillin allergy delabeling. With the high prevalence of inaccurate penicillin allergy documentation, this tool offers VA health care systems a way to empower pharmacists in allergy clarification, leading to improvements in antibiotic stewardship. Although the sample size was small, the ABLE process may provide a framework for VA clinicians. Future research has the potential to demonstrate the practicality and effectiveness this pharmacist-led penicillin allergy interview process can offer clinicians.
Self-reported penicillin allergies are common, with a prevalence of about 10% of patients, according to the Centers for Disease Control and Prevention (CDC).1 However, only about 1% of patients have a true immunoglobulin E (IgE)-mediated allergy. This issue is often further complicated by inaccurate classification of nonallergic adverse effects as an allergy, resulting in incomplete allergy documentation in the electronic health record (EHR). The cross-reactivity rate with cephalosporins (Β-lactam antibiotics) in patients reporting a penicillin allergy is < 1%, which suggests that many patients with reported penicillin allergies can safely receive them.2 Despite this, patients with self-reported penicillin allergies often receive non–Β-lactam antibiotic agents, which may be associated with an increased risk of adverse drug reactions (ADRs), increased health care costs, and inferior clinical outcomes.3
Several strategies are recommended to assess patients with self-reported penicillin allergies. According to the CDC, evaluating a patient who reports a penicillin or other Β-lactam antibiotic allergy involves 3 steps: (1) obtaining a thorough medical history, including previous exposures to penicillin or other Β-lactam antibiotic; (2) performing a skin test using the penicillin major and minor determinants; and (3) among those who have a negative penicillin skin test, performing an observed oral challenge with 250 mg amoxicillin before proceeding directly to treatment with the indicated Β-lactam therapy.4
Most existing clinical guidance for assessing patients with self-reported penicillin allergies stems from site-specific policies and primarily focuses on oral amoxicillin challenges or penicillin skin testing (PST). However, performing these tests may not be feasible at all facilities due to time constraints and lack of allergists. Therefore, alternative strategies are necessary, such as conducting detailed patient interviews. Few studies have evaluated switching to Β-lactam agents following a penicillin allergy interview alone. However, with thorough patient histories and detailed interviews, patients with reported penicillin allergies can safely use Β-lactam antibiotics.5 Implementing this procedure provides a cost-savings opportunity by not having to administer additional antibiotics for testing in addition to improving antibiotic stewardship.
The Memphis Veterans Affairs Medical Center (MVAMC) created the Allergy to Β-Lactam Evaluation (ABLE) process to clarify and remove penicillin allergies. The process involves conducting a thorough chart review and patient interview followed by completion of a note template that provides recommendations about patient allergies and Β-lactam prescribing. Mitchell et al found that the pharmacist-led process to be beneficial for addressing Β-lactam allergy clearance.6 As a result, the ABLE process was implemented at several other US Department of Veterans Affairs (VA) medical centers (VAMCs). Using the ABLE template, the purpose of this study was to evaluate the impact of a pharmacist-led penicillin allergy initiative on penicillin allergy delabeling with an interview process alone.
Methods
Prior to ABLE process implementation, there were no standardized procedures for documenting allergy histories. ABLE was implemented at the Robley Rex VAMC (RRVAMC) in November 2022. During the interview phase, patients were initially identified during admission via TheraDoc as having either a penicillin allergy or ADR. The infectious disease pharmacist or pharmacy resident interviewed patients with documented penicillin allergies or ADRs using a standardized questionnaire (eAppendix 1). Not all identified patients could be interviewed. Patients currently receiving an antibiotic were prioritized for interviews. Patients were excluded if they declined or were unable to be interviewed, although a patient’s caregiver(s) could be interviewed in person or via telephone, if the patient was not available.
Following the interview, pharmacists used guidance from the ABLE process in addition to a detailed EHR review to determine whether the patient was eligible for an allergy update or removal and/or switch to a Β-lactam antibiotic (Figure). If eligible for modification, the interviewing pharmacist made the necessary changes. A templated process note with patient-specific recommendations was entered into the Computerized Patient Record System (CPRS) and the primary care team attending physician was added as an additional signer to be alerted in the system note (eAppendix 2).
This single-center, retrospective cohort study involved review of CPRS notes and clinical interviews in the interviewed group. Hospitalized patients at the RRVAMC aged ≥ 18 years with a documented penicillin allergy or ADR were included. The historical control group consisted of patients admitted between October 31, 2019, and October 31, 2022, and the intervention group consisted of patients admitted between November 1, 2022, and March 1, 2023. Patients in the historical control group were matched 1:1 to the intervention group for penicillin allergy severity (allergy [IgE-mediated], unknown, adverse effect, severe cutaneous or other non–IgE-mediated reaction) and whether they received a noncarbapenem non–Β-lactam antibiotic.
The primary outcome was the number of patient allergies/ADRs removed or changed on patient profiles regardless of whether their antibiotic regimen was changed. This outcome was further assessed by evaluating the number of patient allergies or ADRs removed or changed on patient profiles with or without a change in antibiotic regimen. Primary outcomes were analyzed using χ2 and/ or Fisher exact tests, as appropriate to determine statistically significant differences between the interviewed group and the historical control.
Results
Seventy patients were included: 35 patients in the interviewed group and 35 patients in the historical control group, respectively. Both groups had a mean age of 72 years and predominantly included White male patients (Table 1). Following the interview, the allergy profile was modified for 6 patients (17%) in the interview group vs 0 patients in the control group (P = .03) (Table 2). The primary outcome was analyzed separately regardless of an antibiotic regimen change. There was not a statistically significant difference between groups when assessing patients for change in therapy (P > .99). All 6 patients with an allergy profile modification had no change in antibiotic regimen.
Discussion
This study suggests the ABLE process may be a valuable tool for adjusting penicillin allergies or ADRs within patient EHRs. In the interview group, allergies were modified in 6 (17%) patients while no patients in the control group had allergy modifications. Of the 6 allergy profile modifications, 4 allergy labels were changed from an allergy to an ADR. These patients were cleared to receive future Β-lactam antibiotics after clinicians recognized the lack of a true IgE-mediated allergic reaction. In addition, 2 of the modified allergy profiles removed the allergy designation. Although this represents a small subset of interviewed patients, it illustrates the clinical effectiveness of an interview process alone to remove penicillin allergy designations.
Previous research has assessed the impact of pharmacist intervention on penicillin allergy clarification. Mitchell et al implemented a pharmacist-driven Β-lactam allergy assessment and penicillin allergy clinic (PAC) at the MVAMC with the goal of evaluating its impact on allergy clearance. In their study, clinical pharmacy specialists evaluated patients with Β-lactam allergies, and those deemed eligible were later seen in the PAC. Among the 246 patients evaluated using the Β-lactam allergy assessment alone and who were not seen in the PAC, 25% had their penicillin allergy removed following a detailed assessment.6
Song et al evaluated the effectiveness and feasibility of a pharmacist-driven penicillin allergy delabeling pilot program without skin testing or oral challenges. Patients with penicillin allergies were interviewed by a pharmacy resident using a standardized checklist. Among the 66 patients interviewed, 12 (18%) met the criteria for delabeling and consented to removal of their allergy.7 The delabeling rates in these 2 studies are similar to the 17% rate of allergy modification in our study, although this study is the only one to compare results to a historical control group.
Harper et al evaluated the impact of a penicillin allergy assessment, including penicillin skin testing and oral amoxicillin challenges, on delabeling penicillin allergies. Pharmacists completed a penicillin allergy assessment and performed penicillin skin testing and/or oral amoxicillin challenges for eligible patients. Of 35 patients, 31 (89%) had their penicillin allergies delabeled in the EHR.8 The rate of penicillin allergy delabeling in Harper et al was likely higher than that seen in our study due to the use of oral challenge and skin testing. Regardless, a detailed penicillin allergy interview alone was effective at RRVAMC, resulting in a significant rate of allergy removal or change. This supports the use of detailed penicillin allergy assessments in settings where penicillin skin testing or oral challenges may not be feasible.
Mann et al demonstrated the effectiveness of penicillin allergy assessments in switching eligible patients to Β-lactam antibiotics. Their single-center, prospective study assessed the impact of a pharmacist-driven detailed penicillin allergy interview initiative. Interviews that evaluated potential changes to allergy profiles were conducted with 175 patients. Of these patients, 135 (77.1%) were on antimicrobial therapy and 42 (31.1%) patients receiving therapy met criteria to switch to a noncarbapenem Β-lactam antibiotic. Thirty-one patients (73.8%) switched with no signs or symptoms of intolerance demonstrating that an interview can be a valuable tool for antibiotic optimization, specifically in patients with penicillin allergy.9 No patients in our study switched antibiotic therapy, likely because only a small number of patients were eligible for transition to a noncarbapenem Β-lactam antibiotic. In the Mann et al study, non–Β-lactam antibiotics, such as fluoroquinolones and carbapenems, accounted for > 75% of the antibiotics used.
Limitations
The sample size of this study was small and its duration was short. There is a risk for selection bias as not all identified patients were able to be interviewed while admitted, but patients on antibiotics were prioritized as they were most likely to directly benefit during their current admission from a modification of their allergy. Most patients in the study were White and male, which may limit the generalizability of the results. Additionally, recommendations regarding antibiotic changes were primarily communicated to the treatment team based on a templated note in CPRS alone. Therefore, implementation of these recommendations largely relied upon nonverbal communication. Direct pharmacist-physician communication could have led to a larger impact on antimicrobial therapy changes. The interviewer’s participation in daily rounds with time allotted to discuss this topic can be considered in the future to improve these processes.
Conclusions
This study found that the ABLE process identified patients for penicillin allergy delabeling. With the high prevalence of inaccurate penicillin allergy documentation, this tool offers VA health care systems a way to empower pharmacists in allergy clarification, leading to improvements in antibiotic stewardship. Although the sample size was small, the ABLE process may provide a framework for VA clinicians. Future research has the potential to demonstrate the practicality and effectiveness this pharmacist-led penicillin allergy interview process can offer clinicians.
- Health care providers. Clinical features of penicillin allergy. Centers for Disease Control and Prevention. August 25, 2025. Accessed February 4, 2026. https://www.cdc.gov /antibiotic-use/hcp/clinical-signs/index.html
- Wrynn AF. Penicillin allergies: A guide for NPs. Nurse Pract. 2022;47:30-36. doi:10.1097/01.NPR.0000855312.11145.78
- Mohsen S, Dickinson JA, Somayaji R. Update on the adverse effects of antimicrobial therapies in community practice. Can Fam Physician. 2020;66:651-659.
- Sexually Transmitted Infections Treatment Guidelines, 2021. Managing persons who have a history of penicillin allergy. Centers for Disease Control and Prevention. September 21, 2022. Accessed February 4, 2026. https:// www.cdc.gov/std/treatment-guidelines/penicillin-allergy .htm
- Holmes AK, Bennett NT, Berry TP. Pharmacy driven assessment of appropriate antibiotic selection in patients with reported beta-lactam allergy. J Am Coll Clin Pharm. 2019;2:509-514. doi:10.1002/jac5.1135
- Mitchell AB, Ness RA, Bennett JG, et al. Implementation and impact of a Β-lactam allergy assessment protocol in a veteran population. Fed Pract. 2021;38:420-425. doi:10.12788/fp.0172
- Song YC, Nelson ZJ, Wankum MA, et al. Effectiveness and feasibility of pharmacist-driven penicillin allergy de-labeling pilot program without skin testing or oral challenges. Pharmacy (Basel). 2021;9:127. doi:10.3390/pharmacy9030127
- Harper HM, Sanchez M. Review of pharmacist driven penicillin allergy assessments and skin testing: a multicenter case-series. Hosp Pharm. 2022;57:469-473. doi:10.1177/00185787211046862
- Mann KL, Wu JY, Shah SS. Implementation of a pharmacist- driven detailed penicillin allergy interview. Ann Pharmacother. 2020;54:364-370. doi:10.1177/1060028019884874
- Health care providers. Clinical features of penicillin allergy. Centers for Disease Control and Prevention. August 25, 2025. Accessed February 4, 2026. https://www.cdc.gov /antibiotic-use/hcp/clinical-signs/index.html
- Wrynn AF. Penicillin allergies: A guide for NPs. Nurse Pract. 2022;47:30-36. doi:10.1097/01.NPR.0000855312.11145.78
- Mohsen S, Dickinson JA, Somayaji R. Update on the adverse effects of antimicrobial therapies in community practice. Can Fam Physician. 2020;66:651-659.
- Sexually Transmitted Infections Treatment Guidelines, 2021. Managing persons who have a history of penicillin allergy. Centers for Disease Control and Prevention. September 21, 2022. Accessed February 4, 2026. https:// www.cdc.gov/std/treatment-guidelines/penicillin-allergy .htm
- Holmes AK, Bennett NT, Berry TP. Pharmacy driven assessment of appropriate antibiotic selection in patients with reported beta-lactam allergy. J Am Coll Clin Pharm. 2019;2:509-514. doi:10.1002/jac5.1135
- Mitchell AB, Ness RA, Bennett JG, et al. Implementation and impact of a Β-lactam allergy assessment protocol in a veteran population. Fed Pract. 2021;38:420-425. doi:10.12788/fp.0172
- Song YC, Nelson ZJ, Wankum MA, et al. Effectiveness and feasibility of pharmacist-driven penicillin allergy de-labeling pilot program without skin testing or oral challenges. Pharmacy (Basel). 2021;9:127. doi:10.3390/pharmacy9030127
- Harper HM, Sanchez M. Review of pharmacist driven penicillin allergy assessments and skin testing: a multicenter case-series. Hosp Pharm. 2022;57:469-473. doi:10.1177/00185787211046862
- Mann KL, Wu JY, Shah SS. Implementation of a pharmacist- driven detailed penicillin allergy interview. Ann Pharmacother. 2020;54:364-370. doi:10.1177/1060028019884874
Implementation of a Pharmacist-Led Penicillin Allergy Interview at a Veterans Care Facility
Implementation of a Pharmacist-Led Penicillin Allergy Interview at a Veterans Care Facility
Outcomes From the Use of Cefazolin for Surgical Prophylaxis in Patients Allergic to Penicillin
Outcomes From the Use of Cefazolin for Surgical Prophylaxis in Patients Allergic to Penicillin
Given its safety profile and bactericidal activity against the predominant organisms causing surgical site infections (SSIs), cefazolin remains the most popular choice for surgical prophylaxis.1 Cefazolin offers protection against the pathogens most likely to contaminate the surgical site while minimizing inappropriate methicillin- resistant Staphylococcus aureus coverage that occurs with alternatives such as vancomycin and clindamycin. Documented allergies to Β-lactam antibiotics have historically forced clinicians to avoid the use of cephalosporins due to the potential risk of cross-reactivity. True type 1 (immunoglobin E [IgE]-mediated) cross-allergic reactions between penicillin and cephalosporins are rare, and previously reported data indicate cross-reactivity as a result of antibody recognition is more closely related to the side-chain identity rather than the Β-lactam ring.2,3
About 10% of US patients report having a penicillin allergy; however, < 1% of the population has a true IgE-mediated allergic reaction.4 Previous research that has challenged penicillin allergies with cefazolin for surgical prophylaxis has reported minimal rates of allergic reactions.2-5
In previous trials, patients with a history of delayed skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), were excluded. Additionally, patients with an allergy to cefazolin including those with urticaria, angioedema, bronchospasm, or anaphylaxis, were excluded from perioperative retrial of cefazolin. Grant et al found that cefazolin can be safely given to patients with IgE-mediated reactions to penicillin and other cephalosporins due to a structurally different side chain.3
In January 2023, the Veteran Health Indiana (VHI) pharmacy team in conjunction with surgery, infectious disease, and anesthesiology, implemented a screening tool as an amendment to perioperative antibiotic guidance to help determine which patients with a documented penicillin allergy could be candidates for perioperative cefazolin. The implemented screening tool (Allergy Clarification for Cefazolin Evidence-Based Prescribing Tool) has been described by Lam et al, who reported that an increased proportion of patients with documented penicillin allergy received cefazolin without more adverse drug reactions (ADRs).5 Patients with a Β-lactam allergy were eligible to receive cefazolin unless the ADR was SJS, TEN, or DRESS, or the offending agent was cefazolin and the patient experienced urticaria, angioedema, bronchospasm, or anaphylaxis. If the reaction was not from cefazolin or was unknown, patients were eligible to receive cefazolin (Figure).
To date, minimal data exist to evaluate the incidence of ADRs when cefazolin is given perioperatively to patients with a previously documented penicillin allergy. The purpose of this study was to evaluate the incidence of allergic ADRs in patients who had a documented penicillin allergy and received periprocedural antibiotics.
Methods
This single-center, retrospective chart review used the US Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) to identify patients with a documented penicillin allergy who underwent an operation and received periprocedural antibiotics between February 1, 2023, and January 31, 2024. This study was reviewed and approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.
Patients were enrolled if they were aged ≥ 18 years, had a documented penicillin allergy, underwent a surgical intervention, and received perioperative antibiotics during the study period. Patients were excluded if they had a documented penicillin allergy resulting in severe delayed skin reactions (ie, SJS, TEN, or DRESS). These criteria produced 197 surgical procedures. Data were collected for each surgical procedure, so patients could be included more than once. Patient history of allergic reaction to penicillin was obtained through CPRS.
The primary endpoint was the percentage of allergic ADRs in patients with penicillin allergies receiving cefazolin perioperatively. Secondary outcomes included the appropriateness of the antibiotic regimen in congruence with American System of Health Pharmacists (ASHP) recommendations, incidence of SSIs within 30 days of the procedure, incidence of ADRs in those with a history of anaphylaxis vs nonanaphylaxis allergy, incidence of allergic reaction requiring pharmacologic and nonpharmacologic interventions, and incidence of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours or an increase in serum creatinine to ≥ 1.5 times baseline.
Demographic data included sex, age, race, preoperative serum creatinine, and postoperative serum creatinine. Anaphylaxis was defined as an acute onset of illness (within minutes to several hours) with involvement of skin, mucosal tissue, or both involving either respiratory compromise or reduced blood pressures. Allergic reactions were defined as facial, tongue, throat, airway, lip, mouth, periorbital, or eye swelling, urticaria, angioedema, dyspnea, anaphylaxis, or a positive penicillin skin test. Additionally, data collected included the description and severity of postprophylactic antibiotic reaction, antibiotic choice, interventions required for the allergic reaction, SSI occurrence, date of SSI, operating specialty, and postoperative change in renal function.
Descriptive statistics, including mean, SD, and percentages were reported for baseline characteristics of the study population. Percentages were used to demonstrate the differences in primary and secondary outcomes for each study group. Fisher exact tests were used for incidence of ADRs in patients with penicillin allergy who received cefazolin and reported incidence of SSIs.
Results
A total of 197 surgical procedures in patients with a documented penicillin allergy were included; 127 procedures used cefazolin perioperatively, 3 procedures used cefazolin plus gentamicin, and 67 procedures used other antibiotics. Most patients were White (n = 160; 81.2%), male (n = 158; 80.2%), and had a mean age of 64.9 years. Urology was the most common surgical specialty (n = 59; 29.9%) (Table 1). Of the 16 patients with documented penicillin anaphylaxis reaction, 8 received cefazolin and 8 received a different antibiotic. A total of 181 patients reported a nonanaphylaxis allergy. One hundred fifty-one patients (68.6%) reported a reaction history of hives, rash, or swelling (Table 2). Patients could report ≥ 1 reaction. The most prevalent antibiotics used were cefazolin, which was used by 130 patients (61.3%), and clindamycin which was used by 33 patients (15.6%) (Table 3). Patients could receive ≥ 1 antibiotic.
For the primary outcome, the incidence of allergic reactions in patients allergic to penicillin, there was no incidence of allergic reactions in either the cefazolin or other group. Given the absence of reactions, no interventions were required.
There were no ADRs in those with history of anaphylaxis or nonanaphylaxis allergy. In the cefazolin group, 126 of 127 surgical procedure regimens (99.2%) were congruent with ASHP recommendations, all 3 surgical procedures regimens in the cefazolin plus gentamicin group were congruent with ASHP recommendations, and 58 of 67 surgical procedure regimens (86.6%) in the other antibiotic group were congruent with ASHP recommendations. None of the 127 patients in the cefazolin group or of the 3 patients in the cefazolin plus gentamicin group reported an SSI, and 3 of 67 patients (4.5%) had an SSI in the other antibiotic group. One procedure that resulted in SSI was not congruent with ASHP recommendations. Twenty-four patients had 2 serum creatinine levels drawn within 48 hours of surgery. One of 12 patients (8.3%) and 0 of 12 patients had an AKI in the cefazolin and other antibiotic group, respectively (Table 4).
Discussion
Implementation of a screening tool at VHI allowed patients with documented penicillin allergy, including anaphylaxis, to receive cefazolin perioperatively. Broad spectrum antibiotics such as vancomycin, clindamycin, and fluoroquinolones are frequently used in patients allergic to penicillin, which can increase health care costs, risk of toxicity, and antimicrobial resistance.4 There was no incidence of allergic reactions noted in patients allergic to penicillin who received cefazolin. When comparing the incidence of observed allergic reactions to received perioperative antibiotics in the cefazolin group to previously published literature, no difference in allergy rates (P = .09) was found.3 Most antibiotics administered were congruent with ASHP guideline recommendations, and most patients eligible for cefazolin received it perioperatively.
Similar to this study, Goodman et al concluded that cefazolin appears to be a safe regimen in patients with documented penicillin anaphylactic reaction for surgical prophylaxis with only 1 (0.2%) potential allergic reaction.6 Patients who received cefazolin perioperatively had a statistically significant decrease in SSI rates. There were no clinically or statistically significant differences found between the proportion of allergic reactions or ADRs when compared to alternative antibiotics. Lessard et al concluded that a pharmacist-led interdisciplinary collaborative practice agreement increased cefazolin use in patients allergic to penicillin, including those with urticaria and anaphylaxis, with no reported ADRs.7 This study further demonstrated the safety of cefazolin use in patients with anaphylaxis to penicillin.
Limitations
This study’s single-center, retrospective design, patient population, and small sample size limit the generalizability of its results. The data collected are dependent on documentation in the chart. No ADRs were reported from the antibiotics patients received perioperatively. When considering safety data, information such as serum creatinine were available only in CPRS and some patients did not receive a postprocedure serum creatinine level. Additionally, this study did not investigate whether there was an increase in preferred preoperative antimicrobial prophylaxis after implementation of this protocol.
Conclusions
The results of this study support the use of cefazolin perioperatively in patients allergic to penicillin, including those with a history of anaphylaxis. Additional research should be conducted to validate data given the low incidence of ADRs. The primary outcome did not reach statistical significance, but the results may be clinically significant from a stewardship and safety perspective. VHI continues to use the screening tool described in this article.
- Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195-283. doi:10.2146/ajhp120568
- Romano A, Valluzzi RL, Caruso C, et al. Tolerability of cefazolin and ceftibuten in patients with IgE-mediated aminopenicillin allergy. J Allergy Clin Immunol Pract. 2020;8:1989-1993.e2. doi:10.1016/j.jaip.2020.02.025
- Grant JM, Song WHC, Shajari S, et al. Safety of administering cefazolin versus other antibiotics in penicillin- allergic patients for surgical prophylaxis at a major Canadian teaching hospital. Surgery. 2021;170:783-789. doi:10.1016/j.surg.2021.03.022
- Centers for Disease Control and Prevention. Clinical Features of Penicillin Allergy. August 25, 2025. Accessed January 6, 2026. https://www.cdc.gov/antibiotic-use/hcp/clinical-signs/index.html
- Lam PW, Tarighi P, Elligsen M, et al. Impact of the allergy clarification for cefazolin evidence-based prescribing tool on receipt of preferred perioperative prophylaxis: an interrupted time series study. Clin Infect Dis. 2020;71:2955- 2957. doi:10.1093/cid/ciaa516
- Goodman EJ, Morgan MJ, Johnson Pa, et al. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response. J Clin Anesth. 2001;13:561-564. doi:10.1016/s0952-8180(01)00329-4
- Lessard S, Huiras C, Dababneh A, et al. Pharmacist adjustment of preoperative antibiotic orders to the preferred preoperative antibiotic cefazolin for patients with penicillin allergy labeling. Am J Health Syst Pharm. 2023;80:532- 536. doi:10.1093/ajhp/zxac385
Given its safety profile and bactericidal activity against the predominant organisms causing surgical site infections (SSIs), cefazolin remains the most popular choice for surgical prophylaxis.1 Cefazolin offers protection against the pathogens most likely to contaminate the surgical site while minimizing inappropriate methicillin- resistant Staphylococcus aureus coverage that occurs with alternatives such as vancomycin and clindamycin. Documented allergies to Β-lactam antibiotics have historically forced clinicians to avoid the use of cephalosporins due to the potential risk of cross-reactivity. True type 1 (immunoglobin E [IgE]-mediated) cross-allergic reactions between penicillin and cephalosporins are rare, and previously reported data indicate cross-reactivity as a result of antibody recognition is more closely related to the side-chain identity rather than the Β-lactam ring.2,3
About 10% of US patients report having a penicillin allergy; however, < 1% of the population has a true IgE-mediated allergic reaction.4 Previous research that has challenged penicillin allergies with cefazolin for surgical prophylaxis has reported minimal rates of allergic reactions.2-5
In previous trials, patients with a history of delayed skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), were excluded. Additionally, patients with an allergy to cefazolin including those with urticaria, angioedema, bronchospasm, or anaphylaxis, were excluded from perioperative retrial of cefazolin. Grant et al found that cefazolin can be safely given to patients with IgE-mediated reactions to penicillin and other cephalosporins due to a structurally different side chain.3
In January 2023, the Veteran Health Indiana (VHI) pharmacy team in conjunction with surgery, infectious disease, and anesthesiology, implemented a screening tool as an amendment to perioperative antibiotic guidance to help determine which patients with a documented penicillin allergy could be candidates for perioperative cefazolin. The implemented screening tool (Allergy Clarification for Cefazolin Evidence-Based Prescribing Tool) has been described by Lam et al, who reported that an increased proportion of patients with documented penicillin allergy received cefazolin without more adverse drug reactions (ADRs).5 Patients with a Β-lactam allergy were eligible to receive cefazolin unless the ADR was SJS, TEN, or DRESS, or the offending agent was cefazolin and the patient experienced urticaria, angioedema, bronchospasm, or anaphylaxis. If the reaction was not from cefazolin or was unknown, patients were eligible to receive cefazolin (Figure).
To date, minimal data exist to evaluate the incidence of ADRs when cefazolin is given perioperatively to patients with a previously documented penicillin allergy. The purpose of this study was to evaluate the incidence of allergic ADRs in patients who had a documented penicillin allergy and received periprocedural antibiotics.
Methods
This single-center, retrospective chart review used the US Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) to identify patients with a documented penicillin allergy who underwent an operation and received periprocedural antibiotics between February 1, 2023, and January 31, 2024. This study was reviewed and approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.
Patients were enrolled if they were aged ≥ 18 years, had a documented penicillin allergy, underwent a surgical intervention, and received perioperative antibiotics during the study period. Patients were excluded if they had a documented penicillin allergy resulting in severe delayed skin reactions (ie, SJS, TEN, or DRESS). These criteria produced 197 surgical procedures. Data were collected for each surgical procedure, so patients could be included more than once. Patient history of allergic reaction to penicillin was obtained through CPRS.
The primary endpoint was the percentage of allergic ADRs in patients with penicillin allergies receiving cefazolin perioperatively. Secondary outcomes included the appropriateness of the antibiotic regimen in congruence with American System of Health Pharmacists (ASHP) recommendations, incidence of SSIs within 30 days of the procedure, incidence of ADRs in those with a history of anaphylaxis vs nonanaphylaxis allergy, incidence of allergic reaction requiring pharmacologic and nonpharmacologic interventions, and incidence of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours or an increase in serum creatinine to ≥ 1.5 times baseline.
Demographic data included sex, age, race, preoperative serum creatinine, and postoperative serum creatinine. Anaphylaxis was defined as an acute onset of illness (within minutes to several hours) with involvement of skin, mucosal tissue, or both involving either respiratory compromise or reduced blood pressures. Allergic reactions were defined as facial, tongue, throat, airway, lip, mouth, periorbital, or eye swelling, urticaria, angioedema, dyspnea, anaphylaxis, or a positive penicillin skin test. Additionally, data collected included the description and severity of postprophylactic antibiotic reaction, antibiotic choice, interventions required for the allergic reaction, SSI occurrence, date of SSI, operating specialty, and postoperative change in renal function.
Descriptive statistics, including mean, SD, and percentages were reported for baseline characteristics of the study population. Percentages were used to demonstrate the differences in primary and secondary outcomes for each study group. Fisher exact tests were used for incidence of ADRs in patients with penicillin allergy who received cefazolin and reported incidence of SSIs.
Results
A total of 197 surgical procedures in patients with a documented penicillin allergy were included; 127 procedures used cefazolin perioperatively, 3 procedures used cefazolin plus gentamicin, and 67 procedures used other antibiotics. Most patients were White (n = 160; 81.2%), male (n = 158; 80.2%), and had a mean age of 64.9 years. Urology was the most common surgical specialty (n = 59; 29.9%) (Table 1). Of the 16 patients with documented penicillin anaphylaxis reaction, 8 received cefazolin and 8 received a different antibiotic. A total of 181 patients reported a nonanaphylaxis allergy. One hundred fifty-one patients (68.6%) reported a reaction history of hives, rash, or swelling (Table 2). Patients could report ≥ 1 reaction. The most prevalent antibiotics used were cefazolin, which was used by 130 patients (61.3%), and clindamycin which was used by 33 patients (15.6%) (Table 3). Patients could receive ≥ 1 antibiotic.
For the primary outcome, the incidence of allergic reactions in patients allergic to penicillin, there was no incidence of allergic reactions in either the cefazolin or other group. Given the absence of reactions, no interventions were required.
There were no ADRs in those with history of anaphylaxis or nonanaphylaxis allergy. In the cefazolin group, 126 of 127 surgical procedure regimens (99.2%) were congruent with ASHP recommendations, all 3 surgical procedures regimens in the cefazolin plus gentamicin group were congruent with ASHP recommendations, and 58 of 67 surgical procedure regimens (86.6%) in the other antibiotic group were congruent with ASHP recommendations. None of the 127 patients in the cefazolin group or of the 3 patients in the cefazolin plus gentamicin group reported an SSI, and 3 of 67 patients (4.5%) had an SSI in the other antibiotic group. One procedure that resulted in SSI was not congruent with ASHP recommendations. Twenty-four patients had 2 serum creatinine levels drawn within 48 hours of surgery. One of 12 patients (8.3%) and 0 of 12 patients had an AKI in the cefazolin and other antibiotic group, respectively (Table 4).
Discussion
Implementation of a screening tool at VHI allowed patients with documented penicillin allergy, including anaphylaxis, to receive cefazolin perioperatively. Broad spectrum antibiotics such as vancomycin, clindamycin, and fluoroquinolones are frequently used in patients allergic to penicillin, which can increase health care costs, risk of toxicity, and antimicrobial resistance.4 There was no incidence of allergic reactions noted in patients allergic to penicillin who received cefazolin. When comparing the incidence of observed allergic reactions to received perioperative antibiotics in the cefazolin group to previously published literature, no difference in allergy rates (P = .09) was found.3 Most antibiotics administered were congruent with ASHP guideline recommendations, and most patients eligible for cefazolin received it perioperatively.
Similar to this study, Goodman et al concluded that cefazolin appears to be a safe regimen in patients with documented penicillin anaphylactic reaction for surgical prophylaxis with only 1 (0.2%) potential allergic reaction.6 Patients who received cefazolin perioperatively had a statistically significant decrease in SSI rates. There were no clinically or statistically significant differences found between the proportion of allergic reactions or ADRs when compared to alternative antibiotics. Lessard et al concluded that a pharmacist-led interdisciplinary collaborative practice agreement increased cefazolin use in patients allergic to penicillin, including those with urticaria and anaphylaxis, with no reported ADRs.7 This study further demonstrated the safety of cefazolin use in patients with anaphylaxis to penicillin.
Limitations
This study’s single-center, retrospective design, patient population, and small sample size limit the generalizability of its results. The data collected are dependent on documentation in the chart. No ADRs were reported from the antibiotics patients received perioperatively. When considering safety data, information such as serum creatinine were available only in CPRS and some patients did not receive a postprocedure serum creatinine level. Additionally, this study did not investigate whether there was an increase in preferred preoperative antimicrobial prophylaxis after implementation of this protocol.
Conclusions
The results of this study support the use of cefazolin perioperatively in patients allergic to penicillin, including those with a history of anaphylaxis. Additional research should be conducted to validate data given the low incidence of ADRs. The primary outcome did not reach statistical significance, but the results may be clinically significant from a stewardship and safety perspective. VHI continues to use the screening tool described in this article.
Given its safety profile and bactericidal activity against the predominant organisms causing surgical site infections (SSIs), cefazolin remains the most popular choice for surgical prophylaxis.1 Cefazolin offers protection against the pathogens most likely to contaminate the surgical site while minimizing inappropriate methicillin- resistant Staphylococcus aureus coverage that occurs with alternatives such as vancomycin and clindamycin. Documented allergies to Β-lactam antibiotics have historically forced clinicians to avoid the use of cephalosporins due to the potential risk of cross-reactivity. True type 1 (immunoglobin E [IgE]-mediated) cross-allergic reactions between penicillin and cephalosporins are rare, and previously reported data indicate cross-reactivity as a result of antibody recognition is more closely related to the side-chain identity rather than the Β-lactam ring.2,3
About 10% of US patients report having a penicillin allergy; however, < 1% of the population has a true IgE-mediated allergic reaction.4 Previous research that has challenged penicillin allergies with cefazolin for surgical prophylaxis has reported minimal rates of allergic reactions.2-5
In previous trials, patients with a history of delayed skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), were excluded. Additionally, patients with an allergy to cefazolin including those with urticaria, angioedema, bronchospasm, or anaphylaxis, were excluded from perioperative retrial of cefazolin. Grant et al found that cefazolin can be safely given to patients with IgE-mediated reactions to penicillin and other cephalosporins due to a structurally different side chain.3
In January 2023, the Veteran Health Indiana (VHI) pharmacy team in conjunction with surgery, infectious disease, and anesthesiology, implemented a screening tool as an amendment to perioperative antibiotic guidance to help determine which patients with a documented penicillin allergy could be candidates for perioperative cefazolin. The implemented screening tool (Allergy Clarification for Cefazolin Evidence-Based Prescribing Tool) has been described by Lam et al, who reported that an increased proportion of patients with documented penicillin allergy received cefazolin without more adverse drug reactions (ADRs).5 Patients with a Β-lactam allergy were eligible to receive cefazolin unless the ADR was SJS, TEN, or DRESS, or the offending agent was cefazolin and the patient experienced urticaria, angioedema, bronchospasm, or anaphylaxis. If the reaction was not from cefazolin or was unknown, patients were eligible to receive cefazolin (Figure).
To date, minimal data exist to evaluate the incidence of ADRs when cefazolin is given perioperatively to patients with a previously documented penicillin allergy. The purpose of this study was to evaluate the incidence of allergic ADRs in patients who had a documented penicillin allergy and received periprocedural antibiotics.
Methods
This single-center, retrospective chart review used the US Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) to identify patients with a documented penicillin allergy who underwent an operation and received periprocedural antibiotics between February 1, 2023, and January 31, 2024. This study was reviewed and approved by the Indiana University Health Institutional Review Board and the VHI Research and Development Committee.
Patients were enrolled if they were aged ≥ 18 years, had a documented penicillin allergy, underwent a surgical intervention, and received perioperative antibiotics during the study period. Patients were excluded if they had a documented penicillin allergy resulting in severe delayed skin reactions (ie, SJS, TEN, or DRESS). These criteria produced 197 surgical procedures. Data were collected for each surgical procedure, so patients could be included more than once. Patient history of allergic reaction to penicillin was obtained through CPRS.
The primary endpoint was the percentage of allergic ADRs in patients with penicillin allergies receiving cefazolin perioperatively. Secondary outcomes included the appropriateness of the antibiotic regimen in congruence with American System of Health Pharmacists (ASHP) recommendations, incidence of SSIs within 30 days of the procedure, incidence of ADRs in those with a history of anaphylaxis vs nonanaphylaxis allergy, incidence of allergic reaction requiring pharmacologic and nonpharmacologic interventions, and incidence of acute kidney injury (AKI). AKI was defined as an increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours or an increase in serum creatinine to ≥ 1.5 times baseline.
Demographic data included sex, age, race, preoperative serum creatinine, and postoperative serum creatinine. Anaphylaxis was defined as an acute onset of illness (within minutes to several hours) with involvement of skin, mucosal tissue, or both involving either respiratory compromise or reduced blood pressures. Allergic reactions were defined as facial, tongue, throat, airway, lip, mouth, periorbital, or eye swelling, urticaria, angioedema, dyspnea, anaphylaxis, or a positive penicillin skin test. Additionally, data collected included the description and severity of postprophylactic antibiotic reaction, antibiotic choice, interventions required for the allergic reaction, SSI occurrence, date of SSI, operating specialty, and postoperative change in renal function.
Descriptive statistics, including mean, SD, and percentages were reported for baseline characteristics of the study population. Percentages were used to demonstrate the differences in primary and secondary outcomes for each study group. Fisher exact tests were used for incidence of ADRs in patients with penicillin allergy who received cefazolin and reported incidence of SSIs.
Results
A total of 197 surgical procedures in patients with a documented penicillin allergy were included; 127 procedures used cefazolin perioperatively, 3 procedures used cefazolin plus gentamicin, and 67 procedures used other antibiotics. Most patients were White (n = 160; 81.2%), male (n = 158; 80.2%), and had a mean age of 64.9 years. Urology was the most common surgical specialty (n = 59; 29.9%) (Table 1). Of the 16 patients with documented penicillin anaphylaxis reaction, 8 received cefazolin and 8 received a different antibiotic. A total of 181 patients reported a nonanaphylaxis allergy. One hundred fifty-one patients (68.6%) reported a reaction history of hives, rash, or swelling (Table 2). Patients could report ≥ 1 reaction. The most prevalent antibiotics used were cefazolin, which was used by 130 patients (61.3%), and clindamycin which was used by 33 patients (15.6%) (Table 3). Patients could receive ≥ 1 antibiotic.
For the primary outcome, the incidence of allergic reactions in patients allergic to penicillin, there was no incidence of allergic reactions in either the cefazolin or other group. Given the absence of reactions, no interventions were required.
There were no ADRs in those with history of anaphylaxis or nonanaphylaxis allergy. In the cefazolin group, 126 of 127 surgical procedure regimens (99.2%) were congruent with ASHP recommendations, all 3 surgical procedures regimens in the cefazolin plus gentamicin group were congruent with ASHP recommendations, and 58 of 67 surgical procedure regimens (86.6%) in the other antibiotic group were congruent with ASHP recommendations. None of the 127 patients in the cefazolin group or of the 3 patients in the cefazolin plus gentamicin group reported an SSI, and 3 of 67 patients (4.5%) had an SSI in the other antibiotic group. One procedure that resulted in SSI was not congruent with ASHP recommendations. Twenty-four patients had 2 serum creatinine levels drawn within 48 hours of surgery. One of 12 patients (8.3%) and 0 of 12 patients had an AKI in the cefazolin and other antibiotic group, respectively (Table 4).
Discussion
Implementation of a screening tool at VHI allowed patients with documented penicillin allergy, including anaphylaxis, to receive cefazolin perioperatively. Broad spectrum antibiotics such as vancomycin, clindamycin, and fluoroquinolones are frequently used in patients allergic to penicillin, which can increase health care costs, risk of toxicity, and antimicrobial resistance.4 There was no incidence of allergic reactions noted in patients allergic to penicillin who received cefazolin. When comparing the incidence of observed allergic reactions to received perioperative antibiotics in the cefazolin group to previously published literature, no difference in allergy rates (P = .09) was found.3 Most antibiotics administered were congruent with ASHP guideline recommendations, and most patients eligible for cefazolin received it perioperatively.
Similar to this study, Goodman et al concluded that cefazolin appears to be a safe regimen in patients with documented penicillin anaphylactic reaction for surgical prophylaxis with only 1 (0.2%) potential allergic reaction.6 Patients who received cefazolin perioperatively had a statistically significant decrease in SSI rates. There were no clinically or statistically significant differences found between the proportion of allergic reactions or ADRs when compared to alternative antibiotics. Lessard et al concluded that a pharmacist-led interdisciplinary collaborative practice agreement increased cefazolin use in patients allergic to penicillin, including those with urticaria and anaphylaxis, with no reported ADRs.7 This study further demonstrated the safety of cefazolin use in patients with anaphylaxis to penicillin.
Limitations
This study’s single-center, retrospective design, patient population, and small sample size limit the generalizability of its results. The data collected are dependent on documentation in the chart. No ADRs were reported from the antibiotics patients received perioperatively. When considering safety data, information such as serum creatinine were available only in CPRS and some patients did not receive a postprocedure serum creatinine level. Additionally, this study did not investigate whether there was an increase in preferred preoperative antimicrobial prophylaxis after implementation of this protocol.
Conclusions
The results of this study support the use of cefazolin perioperatively in patients allergic to penicillin, including those with a history of anaphylaxis. Additional research should be conducted to validate data given the low incidence of ADRs. The primary outcome did not reach statistical significance, but the results may be clinically significant from a stewardship and safety perspective. VHI continues to use the screening tool described in this article.
- Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195-283. doi:10.2146/ajhp120568
- Romano A, Valluzzi RL, Caruso C, et al. Tolerability of cefazolin and ceftibuten in patients with IgE-mediated aminopenicillin allergy. J Allergy Clin Immunol Pract. 2020;8:1989-1993.e2. doi:10.1016/j.jaip.2020.02.025
- Grant JM, Song WHC, Shajari S, et al. Safety of administering cefazolin versus other antibiotics in penicillin- allergic patients for surgical prophylaxis at a major Canadian teaching hospital. Surgery. 2021;170:783-789. doi:10.1016/j.surg.2021.03.022
- Centers for Disease Control and Prevention. Clinical Features of Penicillin Allergy. August 25, 2025. Accessed January 6, 2026. https://www.cdc.gov/antibiotic-use/hcp/clinical-signs/index.html
- Lam PW, Tarighi P, Elligsen M, et al. Impact of the allergy clarification for cefazolin evidence-based prescribing tool on receipt of preferred perioperative prophylaxis: an interrupted time series study. Clin Infect Dis. 2020;71:2955- 2957. doi:10.1093/cid/ciaa516
- Goodman EJ, Morgan MJ, Johnson Pa, et al. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response. J Clin Anesth. 2001;13:561-564. doi:10.1016/s0952-8180(01)00329-4
- Lessard S, Huiras C, Dababneh A, et al. Pharmacist adjustment of preoperative antibiotic orders to the preferred preoperative antibiotic cefazolin for patients with penicillin allergy labeling. Am J Health Syst Pharm. 2023;80:532- 536. doi:10.1093/ajhp/zxac385
- Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195-283. doi:10.2146/ajhp120568
- Romano A, Valluzzi RL, Caruso C, et al. Tolerability of cefazolin and ceftibuten in patients with IgE-mediated aminopenicillin allergy. J Allergy Clin Immunol Pract. 2020;8:1989-1993.e2. doi:10.1016/j.jaip.2020.02.025
- Grant JM, Song WHC, Shajari S, et al. Safety of administering cefazolin versus other antibiotics in penicillin- allergic patients for surgical prophylaxis at a major Canadian teaching hospital. Surgery. 2021;170:783-789. doi:10.1016/j.surg.2021.03.022
- Centers for Disease Control and Prevention. Clinical Features of Penicillin Allergy. August 25, 2025. Accessed January 6, 2026. https://www.cdc.gov/antibiotic-use/hcp/clinical-signs/index.html
- Lam PW, Tarighi P, Elligsen M, et al. Impact of the allergy clarification for cefazolin evidence-based prescribing tool on receipt of preferred perioperative prophylaxis: an interrupted time series study. Clin Infect Dis. 2020;71:2955- 2957. doi:10.1093/cid/ciaa516
- Goodman EJ, Morgan MJ, Johnson Pa, et al. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response. J Clin Anesth. 2001;13:561-564. doi:10.1016/s0952-8180(01)00329-4
- Lessard S, Huiras C, Dababneh A, et al. Pharmacist adjustment of preoperative antibiotic orders to the preferred preoperative antibiotic cefazolin for patients with penicillin allergy labeling. Am J Health Syst Pharm. 2023;80:532- 536. doi:10.1093/ajhp/zxac385
Outcomes From the Use of Cefazolin for Surgical Prophylaxis in Patients Allergic to Penicillin
Outcomes From the Use of Cefazolin for Surgical Prophylaxis in Patients Allergic to Penicillin