Iatrogenic pneumothorax, an acute serious complication, is reported to occur in 0.1% to 2% of permanent trans-venous cardiac device implant procedures. ^1,2 A National Cardiovascular Data Registry analysis of data between January 2006 and December 2008 found that pneumothorax incidence after a new defibrillator implant was 0.5%. ¹ Among 4355 Danish patients undergoing a new device implant, 0.9% experienced pneumothorax requiring drainage and 0.7% had pneumothorax treated conservatively. ² Studies have shown a higher risk of complications when procedures were performed at low-volume centers compared with the highest volume quartile (odds ratio, 1.26; 95% confidence interval, 1.05-1.52) or when procedures were performed by low-volume operators. ¹

Methods. At 2 community hospitals, a project to reduce pneumothorax risk related to new device implants was implemented. This project consisted of obtaining a pre-procedure venogram (right anterior oblique [RAO] view, 12–18 degrees, 42 cm magnification), creating a subcutaneous pocket first and then obtaining axillary venous access with a 4Fr micro-puncture needle, and obtaining a post-procedure chest radiograph. During venous access, the needle was never advanced beyond the inner border of the first rib. This new process was fully implemented by January 2015. A chart review of all patients who underwent a new device implant between January 2015 and July 2017 at the 2 community medical centers was performed.

Results. Seventy patients received new implants during the review period (31 female, 39 male). The median age was 78 years (range, 34–94 years), median body mass index was 29.05 (range, 17.3–67.9), median procedural time was 70 minutes (range, 26–146 minutes), and median fluoroscopic time was 6.4 minutes (range, 0.5–35.7 minutes). A total of 131 independent venous accesses were obtained to implant 42 pacemakers and 28 defibrillators (10 single, 54 dual, and 6 biventricular devices). Of these accesses, 127 were axillary and the remainder were cephalic. There was no incidence of pneumothorax reported during these venous accesses.

Discussion. A structured approach to venous access during device implants was associated with zero incidence of pneumothorax in a low-volume center where implants were performed by a low-volume trained operator. The venogram eliminates “blind attempts,” and the RAO view reduces the likelihood of going too posterior. Using caudal fluoroscopy and targeting the axillary vein, other groups have reported a 0% to 0.2% risk for acute pneumothorax in larger patient groups. ^3,4 Creating a subcutaneous pocket first allows the needle to be aligned more longitudinally along the course of the vein. The 4Fr needle increases the ratio of vein-to-needle surface area, reducing risk for pneumothorax.

Standardization of venous access can potentially reduce iatrogenic pneumothorax risk to a never event, similar to the approach used to prevent central line–associated blood stream infections. ⁵

Benjamin Carmel
Lake Erie College of Osteopathic Medicine
Bradenton, FL

Indiresha R. Iyer, MD
Case Western Reserve University
Cleveland, OH

Corresponding author: Indiresha R. Iyer, MD, Indiresha.iyer@ uhhospitals.org.

Financial disclosures: None.

Iatrogenic pneumothorax, an acute serious complication, is reported to occur in 0.1% to 2% of permanent trans-venous cardiac device implant procedures. ^1,2 A National Cardiovascular Data Registry analysis of data between January 2006 and December 2008 found that pneumothorax incidence after a new defibrillator implant was 0.5%. ¹ Among 4355 Danish patients undergoing a new device implant, 0.9% experienced pneumothorax requiring drainage and 0.7% had pneumothorax treated conservatively. ² Studies have shown a higher risk of complications when procedures were performed at low-volume centers compared with the highest volume quartile (odds ratio, 1.26; 95% confidence interval, 1.05-1.52) or when procedures were performed by low-volume operators. ¹

Methods. At 2 community hospitals, a project to reduce pneumothorax risk related to new device implants was implemented. This project consisted of obtaining a pre-procedure venogram (right anterior oblique [RAO] view, 12–18 degrees, 42 cm magnification), creating a subcutaneous pocket first and then obtaining axillary venous access with a 4Fr micro-puncture needle, and obtaining a post-procedure chest radiograph. During venous access, the needle was never advanced beyond the inner border of the first rib. This new process was fully implemented by January 2015. A chart review of all patients who underwent a new device implant between January 2015 and July 2017 at the 2 community medical centers was performed.

Results. Seventy patients received new implants during the review period (31 female, 39 male). The median age was 78 years (range, 34–94 years), median body mass index was 29.05 (range, 17.3–67.9), median procedural time was 70 minutes (range, 26–146 minutes), and median fluoroscopic time was 6.4 minutes (range, 0.5–35.7 minutes). A total of 131 independent venous accesses were obtained to implant 42 pacemakers and 28 defibrillators (10 single, 54 dual, and 6 biventricular devices). Of these accesses, 127 were axillary and the remainder were cephalic. There was no incidence of pneumothorax reported during these venous accesses.

Discussion. A structured approach to venous access during device implants was associated with zero incidence of pneumothorax in a low-volume center where implants were performed by a low-volume trained operator. The venogram eliminates “blind attempts,” and the RAO view reduces the likelihood of going too posterior. Using caudal fluoroscopy and targeting the axillary vein, other groups have reported a 0% to 0.2% risk for acute pneumothorax in larger patient groups. ^3,4 Creating a subcutaneous pocket first allows the needle to be aligned more longitudinally along the course of the vein. The 4Fr needle increases the ratio of vein-to-needle surface area, reducing risk for pneumothorax.

Standardization of venous access can potentially reduce iatrogenic pneumothorax risk to a never event, similar to the approach used to prevent central line–associated blood stream infections. ⁵

Benjamin Carmel
Lake Erie College of Osteopathic Medicine
Bradenton, FL

Indiresha R. Iyer, MD
Case Western Reserve University
Cleveland, OH

Corresponding author: Indiresha R. Iyer, MD, Indiresha.iyer@ uhhospitals.org.

Financial disclosures: None.

Iatrogenic pneumothorax, an acute serious complication, is reported to occur in 0.1% to 2% of permanent trans-venous cardiac device implant procedures. ^1,2 A National Cardiovascular Data Registry analysis of data between January 2006 and December 2008 found that pneumothorax incidence after a new defibrillator implant was 0.5%. ¹ Among 4355 Danish patients undergoing a new device implant, 0.9% experienced pneumothorax requiring drainage and 0.7% had pneumothorax treated conservatively. ² Studies have shown a higher risk of complications when procedures were performed at low-volume centers compared with the highest volume quartile (odds ratio, 1.26; 95% confidence interval, 1.05-1.52) or when procedures were performed by low-volume operators. ¹

Methods. At 2 community hospitals, a project to reduce pneumothorax risk related to new device implants was implemented. This project consisted of obtaining a pre-procedure venogram (right anterior oblique [RAO] view, 12–18 degrees, 42 cm magnification), creating a subcutaneous pocket first and then obtaining axillary venous access with a 4Fr micro-puncture needle, and obtaining a post-procedure chest radiograph. During venous access, the needle was never advanced beyond the inner border of the first rib. This new process was fully implemented by January 2015. A chart review of all patients who underwent a new device implant between January 2015 and July 2017 at the 2 community medical centers was performed.

Results. Seventy patients received new implants during the review period (31 female, 39 male). The median age was 78 years (range, 34–94 years), median body mass index was 29.05 (range, 17.3–67.9), median procedural time was 70 minutes (range, 26–146 minutes), and median fluoroscopic time was 6.4 minutes (range, 0.5–35.7 minutes). A total of 131 independent venous accesses were obtained to implant 42 pacemakers and 28 defibrillators (10 single, 54 dual, and 6 biventricular devices). Of these accesses, 127 were axillary and the remainder were cephalic. There was no incidence of pneumothorax reported during these venous accesses.

Discussion. A structured approach to venous access during device implants was associated with zero incidence of pneumothorax in a low-volume center where implants were performed by a low-volume trained operator. The venogram eliminates “blind attempts,” and the RAO view reduces the likelihood of going too posterior. Using caudal fluoroscopy and targeting the axillary vein, other groups have reported a 0% to 0.2% risk for acute pneumothorax in larger patient groups. ^3,4 Creating a subcutaneous pocket first allows the needle to be aligned more longitudinally along the course of the vein. The 4Fr needle increases the ratio of vein-to-needle surface area, reducing risk for pneumothorax.

Standardization of venous access can potentially reduce iatrogenic pneumothorax risk to a never event, similar to the approach used to prevent central line–associated blood stream infections. ⁵

Benjamin Carmel
Lake Erie College of Osteopathic Medicine
Bradenton, FL

Indiresha R. Iyer, MD
Case Western Reserve University
Cleveland, OH

Corresponding author: Indiresha R. Iyer, MD, Indiresha.iyer@ uhhospitals.org.

Financial disclosures: None.

Study Overview

Objective. To assess whether immediate restoration of sinus rhythm is necessary in hemodynamically stable, recent onset (< 36 hr), symptomatic atrial fibrillation in the emergency department.

Design. Multicenter, randomized, open-label, noninferiority trial, RACE 7 ACWAS (Rate Control versus Electrical Cardioversion Trial 7--Acute Cardioversion versus Wait and See).

Setting and participants. 15 hospitals in the Netherlands, including 3 academic hospitals, 8 nonacademic teaching hospitals, and 4 nonteaching hospitals. Patients 18 years of age or older with recent-onset (< 36 hr), symptomatic atrial fibrillation without signs of myocardial ischemia or a history of persistent atrial fibrillation who presented to the emergency department were randomized in a 1:1 ratio to either a wait-and-see approach or early cardioversion. The wait-and-see approach consisted of the administration of rate-control medication, including intravenous or oral beta-adrenergic-receptor blocking agents, nondihydropyridine calcium-channel blockers, or digoxin to achieve a heart rate of 110 beats per minute or less and symptomatic relief. Patients were then discharged with an outpatient visit scheduled for the next day and a referral for cardioversion as close as possible to 48 hours after the onset of symptoms. The cardioconversion group received pharmacologic cardioversion with flecainide unless contraindicated, then electrical cardioversion was performed.

Main outcome measures. Primary outcome was the presence of sinus rhythm on electrocardiogram (ECG) recorded at the 4-week trial visit. Secondary endpoints included the duration of the index visit at the emergency department, emergency department visits related to atrial fibrillation, cardiovascular complications, and time until recurrence of atrial fibrillation.

Main results. From October 2014 through September 2018, 437 patients underwent randomization, with 218 patients assigned to the delayed cardioversion group and 219 to the early cardioversion group. Mean age was 65 years, and a majority of the patients (60%) were men (n = 261). The primary end point of the presence of sinus rhythm on the ECG recorded at the 4-week visit was present in 193 of 212 patients (91%) in the delayed cardioversion group and in 202 of 215 patients (94%) in the early cardioversion group. The –2.9 percentage points with confidence interval [CI] –8.2 to 2.2 (P = 0.005) met the criteria for the noninferiority of the wait-and-see approach.

For secondary outcomes, the median duration of the index visit was 120 minutes (range, 60 to 253) in the delayed cardioversion group and 158 minutes (range, 110 to 228) in the early cardioversion group. The median difference between the 2 groups was 30 minutes (95% CI, 6 to 51 minutes). There was no significant difference in cardiovascular complications between the 2 groups. Fourteen of 212 patients (7%) in the delayed cardioversion group and 14 of 215 patients (7%) in the early cardioversion group had subsequent visits to the emergency department because of a recurrence of atrial fibrillation. Telemetric ECG recordings were available for 335 of the 437 patients. Recurrence of atrial fibrillation occurred in 49 of the 164 (30%) patients in the delayed cardioversion group and 50 of the 171 (29%) patients in the early cardioversion group.

In terms of treatment, conversion to sinus rhythm within 48 hours occurred spontaneously in 150 of 218 patients (69%) in the delayed cardioversion group after receiving rate-control medications only. Of the 218 patients, 61 (28%) had delayed cardioversion (9 by pharmacologic and 52 by electrical cardioversion) as per protocol and achieved sinus rhythm within 48 hours. In the early cardioversion group, conversion to sinus rhythm occurred spontaneously in 36 of 219 patients (16%) before the initiation of the cardioversion and in 171 of 219 (78%) after cardioversion (83 by pharmacologic and 88 by electrical).

Conclusion. For patients with recent-onset, symptomatic atrial fibrillation, allowing a short time for spontaneous conversion to sinus rhythm is reasonable as demonstrated by this noninferiority study.

Commentary

Atrial fibrillation accounts for nearly 0.5% of all emergency department visits, and this number is increasing.^1,2 Patients commonly undergo immediate restoration of sinus rhythm by means of pharmacologic or electrical cardioversion. However, it is questionable whether immediate restoration of sinus rhythm is necessary, as spontaneous conversion to sinus rhythm occurs frequently. In addition, the safety of cardioversion between 12 and 48 hours after the onset of atrial fibrillation is questionable.^3,4

In this pragmatic trial, the findings suggest that rate-control therapy alone can achieve prompt symptom relief in almost all eligible patients, had a low risk of complications, and reduced the median length of stay in the emergency department to 2 hours. Independent of cardioversion strategy, the authors stressed the importance of management of stroke risk when patients present with atrial fibrillation to the emergency department. In this trial, 2 patients had cerebral embolism even though both were started on anticoagulation in the index visit. One patient from the delayed cardioversion group was on dabigatran after spontaneous conversion to sinus rhythm and had an event 5 days after the index visit. The other patient, from the early cardioversion group, was on rivaroxaban and had an event 10 days after electrical cardiology. In order for the results of this trial to be broadly applicable, exclusion of intraatrial thrombus on transesophageal echocardiography may be necessary when the onset of atrial fibrillation is not as clear.

There are several limitations of this study. First, this study included only 171 of the 3706 patients (4.6%) screened systematically at the 2 academic centers, but included 266 from 13 centers without systematic screening. The large amount of patients excluded from the controlled environment made the results less generalizable in the broader scope. Second, the reported incidence of recurrent atrial fibrillation within 4 weeks after randomization was an underestimation of the true recurrence rate since the trial used intermittent monitoring. Although the incidence of about 30% was similar between the 2 groups, the authors suggested that the probability of recurrence of atrial fibrillation was not affected by management approach during the acute event. Finally, for these results to be applicable in the general population, defined treatment algorithms and access to prompt follow-up are needed, and these may not be practical in other clinical settings.^2,5

Applications for Clinical Practice

The current study demonstrated immediate cardioversion is not necessary for patients with recent-onset, symptomatic atrial fibrillation in the emergency department. Allowing a short time for spontaneous conversion to sinus rhythm is reasonable as long as the total time in atrial fibrillation is less than 48 hours. Special consideration for anticoagulation is critical because stroke has been associated with atrial fibrillation duration between 24 and 48 hours.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess whether immediate restoration of sinus rhythm is necessary in hemodynamically stable, recent onset (< 36 hr), symptomatic atrial fibrillation in the emergency department.

Design. Multicenter, randomized, open-label, noninferiority trial, RACE 7 ACWAS (Rate Control versus Electrical Cardioversion Trial 7--Acute Cardioversion versus Wait and See).

Setting and participants. 15 hospitals in the Netherlands, including 3 academic hospitals, 8 nonacademic teaching hospitals, and 4 nonteaching hospitals. Patients 18 years of age or older with recent-onset (< 36 hr), symptomatic atrial fibrillation without signs of myocardial ischemia or a history of persistent atrial fibrillation who presented to the emergency department were randomized in a 1:1 ratio to either a wait-and-see approach or early cardioversion. The wait-and-see approach consisted of the administration of rate-control medication, including intravenous or oral beta-adrenergic-receptor blocking agents, nondihydropyridine calcium-channel blockers, or digoxin to achieve a heart rate of 110 beats per minute or less and symptomatic relief. Patients were then discharged with an outpatient visit scheduled for the next day and a referral for cardioversion as close as possible to 48 hours after the onset of symptoms. The cardioconversion group received pharmacologic cardioversion with flecainide unless contraindicated, then electrical cardioversion was performed.

Main outcome measures. Primary outcome was the presence of sinus rhythm on electrocardiogram (ECG) recorded at the 4-week trial visit. Secondary endpoints included the duration of the index visit at the emergency department, emergency department visits related to atrial fibrillation, cardiovascular complications, and time until recurrence of atrial fibrillation.

Main results. From October 2014 through September 2018, 437 patients underwent randomization, with 218 patients assigned to the delayed cardioversion group and 219 to the early cardioversion group. Mean age was 65 years, and a majority of the patients (60%) were men (n = 261). The primary end point of the presence of sinus rhythm on the ECG recorded at the 4-week visit was present in 193 of 212 patients (91%) in the delayed cardioversion group and in 202 of 215 patients (94%) in the early cardioversion group. The –2.9 percentage points with confidence interval [CI] –8.2 to 2.2 (P = 0.005) met the criteria for the noninferiority of the wait-and-see approach.

For secondary outcomes, the median duration of the index visit was 120 minutes (range, 60 to 253) in the delayed cardioversion group and 158 minutes (range, 110 to 228) in the early cardioversion group. The median difference between the 2 groups was 30 minutes (95% CI, 6 to 51 minutes). There was no significant difference in cardiovascular complications between the 2 groups. Fourteen of 212 patients (7%) in the delayed cardioversion group and 14 of 215 patients (7%) in the early cardioversion group had subsequent visits to the emergency department because of a recurrence of atrial fibrillation. Telemetric ECG recordings were available for 335 of the 437 patients. Recurrence of atrial fibrillation occurred in 49 of the 164 (30%) patients in the delayed cardioversion group and 50 of the 171 (29%) patients in the early cardioversion group.

In terms of treatment, conversion to sinus rhythm within 48 hours occurred spontaneously in 150 of 218 patients (69%) in the delayed cardioversion group after receiving rate-control medications only. Of the 218 patients, 61 (28%) had delayed cardioversion (9 by pharmacologic and 52 by electrical cardioversion) as per protocol and achieved sinus rhythm within 48 hours. In the early cardioversion group, conversion to sinus rhythm occurred spontaneously in 36 of 219 patients (16%) before the initiation of the cardioversion and in 171 of 219 (78%) after cardioversion (83 by pharmacologic and 88 by electrical).

Conclusion. For patients with recent-onset, symptomatic atrial fibrillation, allowing a short time for spontaneous conversion to sinus rhythm is reasonable as demonstrated by this noninferiority study.

Commentary

Atrial fibrillation accounts for nearly 0.5% of all emergency department visits, and this number is increasing.^1,2 Patients commonly undergo immediate restoration of sinus rhythm by means of pharmacologic or electrical cardioversion. However, it is questionable whether immediate restoration of sinus rhythm is necessary, as spontaneous conversion to sinus rhythm occurs frequently. In addition, the safety of cardioversion between 12 and 48 hours after the onset of atrial fibrillation is questionable.^3,4

In this pragmatic trial, the findings suggest that rate-control therapy alone can achieve prompt symptom relief in almost all eligible patients, had a low risk of complications, and reduced the median length of stay in the emergency department to 2 hours. Independent of cardioversion strategy, the authors stressed the importance of management of stroke risk when patients present with atrial fibrillation to the emergency department. In this trial, 2 patients had cerebral embolism even though both were started on anticoagulation in the index visit. One patient from the delayed cardioversion group was on dabigatran after spontaneous conversion to sinus rhythm and had an event 5 days after the index visit. The other patient, from the early cardioversion group, was on rivaroxaban and had an event 10 days after electrical cardiology. In order for the results of this trial to be broadly applicable, exclusion of intraatrial thrombus on transesophageal echocardiography may be necessary when the onset of atrial fibrillation is not as clear.

There are several limitations of this study. First, this study included only 171 of the 3706 patients (4.6%) screened systematically at the 2 academic centers, but included 266 from 13 centers without systematic screening. The large amount of patients excluded from the controlled environment made the results less generalizable in the broader scope. Second, the reported incidence of recurrent atrial fibrillation within 4 weeks after randomization was an underestimation of the true recurrence rate since the trial used intermittent monitoring. Although the incidence of about 30% was similar between the 2 groups, the authors suggested that the probability of recurrence of atrial fibrillation was not affected by management approach during the acute event. Finally, for these results to be applicable in the general population, defined treatment algorithms and access to prompt follow-up are needed, and these may not be practical in other clinical settings.^2,5

Applications for Clinical Practice

The current study demonstrated immediate cardioversion is not necessary for patients with recent-onset, symptomatic atrial fibrillation in the emergency department. Allowing a short time for spontaneous conversion to sinus rhythm is reasonable as long as the total time in atrial fibrillation is less than 48 hours. Special consideration for anticoagulation is critical because stroke has been associated with atrial fibrillation duration between 24 and 48 hours.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess whether immediate restoration of sinus rhythm is necessary in hemodynamically stable, recent onset (< 36 hr), symptomatic atrial fibrillation in the emergency department.

Design. Multicenter, randomized, open-label, noninferiority trial, RACE 7 ACWAS (Rate Control versus Electrical Cardioversion Trial 7--Acute Cardioversion versus Wait and See).

Setting and participants. 15 hospitals in the Netherlands, including 3 academic hospitals, 8 nonacademic teaching hospitals, and 4 nonteaching hospitals. Patients 18 years of age or older with recent-onset (< 36 hr), symptomatic atrial fibrillation without signs of myocardial ischemia or a history of persistent atrial fibrillation who presented to the emergency department were randomized in a 1:1 ratio to either a wait-and-see approach or early cardioversion. The wait-and-see approach consisted of the administration of rate-control medication, including intravenous or oral beta-adrenergic-receptor blocking agents, nondihydropyridine calcium-channel blockers, or digoxin to achieve a heart rate of 110 beats per minute or less and symptomatic relief. Patients were then discharged with an outpatient visit scheduled for the next day and a referral for cardioversion as close as possible to 48 hours after the onset of symptoms. The cardioconversion group received pharmacologic cardioversion with flecainide unless contraindicated, then electrical cardioversion was performed.

Main outcome measures. Primary outcome was the presence of sinus rhythm on electrocardiogram (ECG) recorded at the 4-week trial visit. Secondary endpoints included the duration of the index visit at the emergency department, emergency department visits related to atrial fibrillation, cardiovascular complications, and time until recurrence of atrial fibrillation.

Main results. From October 2014 through September 2018, 437 patients underwent randomization, with 218 patients assigned to the delayed cardioversion group and 219 to the early cardioversion group. Mean age was 65 years, and a majority of the patients (60%) were men (n = 261). The primary end point of the presence of sinus rhythm on the ECG recorded at the 4-week visit was present in 193 of 212 patients (91%) in the delayed cardioversion group and in 202 of 215 patients (94%) in the early cardioversion group. The –2.9 percentage points with confidence interval [CI] –8.2 to 2.2 (P = 0.005) met the criteria for the noninferiority of the wait-and-see approach.

For secondary outcomes, the median duration of the index visit was 120 minutes (range, 60 to 253) in the delayed cardioversion group and 158 minutes (range, 110 to 228) in the early cardioversion group. The median difference between the 2 groups was 30 minutes (95% CI, 6 to 51 minutes). There was no significant difference in cardiovascular complications between the 2 groups. Fourteen of 212 patients (7%) in the delayed cardioversion group and 14 of 215 patients (7%) in the early cardioversion group had subsequent visits to the emergency department because of a recurrence of atrial fibrillation. Telemetric ECG recordings were available for 335 of the 437 patients. Recurrence of atrial fibrillation occurred in 49 of the 164 (30%) patients in the delayed cardioversion group and 50 of the 171 (29%) patients in the early cardioversion group.

In terms of treatment, conversion to sinus rhythm within 48 hours occurred spontaneously in 150 of 218 patients (69%) in the delayed cardioversion group after receiving rate-control medications only. Of the 218 patients, 61 (28%) had delayed cardioversion (9 by pharmacologic and 52 by electrical cardioversion) as per protocol and achieved sinus rhythm within 48 hours. In the early cardioversion group, conversion to sinus rhythm occurred spontaneously in 36 of 219 patients (16%) before the initiation of the cardioversion and in 171 of 219 (78%) after cardioversion (83 by pharmacologic and 88 by electrical).

Conclusion. For patients with recent-onset, symptomatic atrial fibrillation, allowing a short time for spontaneous conversion to sinus rhythm is reasonable as demonstrated by this noninferiority study.

Commentary

Atrial fibrillation accounts for nearly 0.5% of all emergency department visits, and this number is increasing.^1,2 Patients commonly undergo immediate restoration of sinus rhythm by means of pharmacologic or electrical cardioversion. However, it is questionable whether immediate restoration of sinus rhythm is necessary, as spontaneous conversion to sinus rhythm occurs frequently. In addition, the safety of cardioversion between 12 and 48 hours after the onset of atrial fibrillation is questionable.^3,4

In this pragmatic trial, the findings suggest that rate-control therapy alone can achieve prompt symptom relief in almost all eligible patients, had a low risk of complications, and reduced the median length of stay in the emergency department to 2 hours. Independent of cardioversion strategy, the authors stressed the importance of management of stroke risk when patients present with atrial fibrillation to the emergency department. In this trial, 2 patients had cerebral embolism even though both were started on anticoagulation in the index visit. One patient from the delayed cardioversion group was on dabigatran after spontaneous conversion to sinus rhythm and had an event 5 days after the index visit. The other patient, from the early cardioversion group, was on rivaroxaban and had an event 10 days after electrical cardiology. In order for the results of this trial to be broadly applicable, exclusion of intraatrial thrombus on transesophageal echocardiography may be necessary when the onset of atrial fibrillation is not as clear.

There are several limitations of this study. First, this study included only 171 of the 3706 patients (4.6%) screened systematically at the 2 academic centers, but included 266 from 13 centers without systematic screening. The large amount of patients excluded from the controlled environment made the results less generalizable in the broader scope. Second, the reported incidence of recurrent atrial fibrillation within 4 weeks after randomization was an underestimation of the true recurrence rate since the trial used intermittent monitoring. Although the incidence of about 30% was similar between the 2 groups, the authors suggested that the probability of recurrence of atrial fibrillation was not affected by management approach during the acute event. Finally, for these results to be applicable in the general population, defined treatment algorithms and access to prompt follow-up are needed, and these may not be practical in other clinical settings.^2,5

Applications for Clinical Practice

The current study demonstrated immediate cardioversion is not necessary for patients with recent-onset, symptomatic atrial fibrillation in the emergency department. Allowing a short time for spontaneous conversion to sinus rhythm is reasonable as long as the total time in atrial fibrillation is less than 48 hours. Special consideration for anticoagulation is critical because stroke has been associated with atrial fibrillation duration between 24 and 48 hours.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To test the effect of 12 months of vitamin D supplementation on lower-extremity power and function in older community-dwelling adults screened for low serum 25-hydroxyvitamin D (25(OH)D).

Design. A single-center, double-blind, randomized placebo-controlled study in which participants were assigned to 800 IU of vitamin D₃ supplementation or placebo daily and were followed over a total period of 12 months.

Setting and participants. A total of 100 community-dwelling men and women aged ≥ 60 years with serum 25(OH)D ≤ 20 ng/mL at screening participated. Participants were prescreened by phone, and were excluded if they met any of the following exclusion criteria: vitamin D supplement use > 600 IU/day (for age 60-70 years) or > 800 IU/day (for age ≥ 71 years); vitamin D injection within the previous 3 months; > 2 falls or 1 fall with injury in past year; use of cane, walker, or other indoor walking aid; history of kidney stones within past 3 years; hypercalcemia (serum calcium > 10.8 mg/dL); renal dysfunction (glomerular filtration rate, < 30 mL/min); history of liver disease, sarcoidosis, lymphoma, dysphagia, or other gastrointestinal disorder; neuromuscular disorder affecting lower-extremity function; hip replacement within the past year; cancer treatment in the past 3 years; treatment with thiazide diuretics > 37.5 mg, teriparatide, denosumab, or bisphosphonates within the past 2 years; oral steroids (for > 3 weeks in the past 6 months); and use of fat malabsorption products or anticonvulsive therapy.

Main outcome measures. The primary outcome was leg extensor power assessed using a computer-interfaced bilateral Keiser pneumatic leg press. Secondary outcomes to measure physical function included: (1) backward tandem walk test (which is an indicator of balance and postural control during movement¹); (2) Short Physical Performance Battery (SPPB) testing, which includes a balance assessment (ability to stand with feet positioned normally, semi-tandem, and tandem for 10s), a timed 4-m walk, and a chair stand test (time to complete 5 repeated chair stands); (3) stair climbing (ie, time to climb 10 steps, as a measure of knee extensor strength and functional capacity); and (4) handgrip strength (using a dynamometer). Lean tissue mass was assessed by dual X-ray absorptiometry (DEXA scan). Finally, other measures included serum total 25(OH)D levels measured at baseline, 4, 8, and 12 months, as well as 24-hour urine collection for urea-nitrogen and creatinine measurements.

Main results. Of the 2289 individuals screened for the study, 100 met eligibility criteria and underwent randomization to receive either 800 IU vitamin D supplementation daily (n = 49) or placebo (n = 51). Three patients (2 in vitamin D group and 1 in placebo group) were lost to follow up. The mean age of all participants was 69.6 ± 6.9 years. In the vitamin D group versus the control group, respectively, the percent male: female ratio was 66:34 versus 63:37, and percent Caucasian was 75% versus 82%. Mean body mass index was 28.2 ± 7.0 and mean serum 25(OH)D was 20.2 ± 6.7 ng/mL. At the end of the study (12 months), 70% of participants given vitamin D supplementation had 25(OH)D levels ≥ 30 ng/mL and all participants had levels ≥ 20 ng/mL. In the placebo group, the serum 25(OH)D level was ≥ 20 ng/mL in 54% and ≥ 30 ng/mL in 6%. The mean serum 25(OH)D level increased to 32.5 ± 5.1 ng/mL in the vitamin D–supplemented group, but no significant change was found in the placebo group (treatment × time, P < 0.001). Overall, the serum 1,25 (OH)2D3 levels did not differ between the 2 groups over the intervention period (time, P = 0.49; treatment × time, P = 0.27). Dietary intake of vitamin D, calcium, nitrogen, and protein did not differ or change over time between the 2 groups. The change in leg press power, function, and strength did not differ between the groups over 12 months (all treatment × time, P values ≥ 0.60). A total of 27 falls were reported (14 in vitamin D versus 9 in control group), of which 9 were associated with injuries. There was no significant change in lean body mass at the end of the study period in either group (treatment × time, P = 0.98).

Conclusion. In community-dwelling older adults with vitamin D deficiency (≤ 20 ng/mL), 12-month daily supplementation with 800 IU of vitamin D₃ resulted in sufficient increases in serum 25(OH)D levels, but did not improve lower-extremity power, strength, or lean mass.

Commentary

Vitamin D deficiency is common in older adults (prevalence of about 41% in US adults ≥ 65 years old, according to Forrest et al²) and is likely due to dietary deficiency, reduced sun exposure (lifestyle), and decreased intestinal calcium absorption. As such, vitamin D deficiency has historically been a topic of debate and of interest in geriatric medicine, as it relates to muscle weakness, which in turn leads to increased susceptibility to falls.³ Interestingly, vitamin D receptors are expressed in human skeletal muscle,⁴ and in one study, 3-month supplementation of vitamin D led to an increase in type II skeletal muscle fibers in older women.⁵ Similarly, results from a meta-analysis of 5 randomized controlled trials (RCTs)⁶ showed that vitamin D supplementation may reduce fall risk in older adults by 22% (corrected odds ratio, 0.78; 95% confidence interval, 0.64-0.92). Thus, in keeping with this general theme of vitamin D supplementation yielding beneficial effects in clinical outcomes, clinicians have long accepted and practiced routine vitamin D supplementation in caring for older adults.

In more recent years, the role of vitamin D supplementation in primary care has become controversial,⁷ as observed in a recent paradigm shift of moving away from routine supplementation for fall and fracture prevention in clinical practice.⁸ In a recent meta-analysis of 33 RCTs in older community-dwelling adults, supplementation with vitamin D with or without calcium did not result in a reduction of hip fracture or total number of fractures.⁹ Moreover, the United States Preventive Services Task Force (USPSTF) recently published updated recommendations on the use of vitamin D supplementation for primary prevention of fractures¹⁰ and prevention of falls¹¹ in community-dwelling adults. In these updated recommendations, the USPSTF indicated that insufficient evidence exists to recommend vitamin D supplementation to prevent fractures in men and premenopausal women, and recommends against vitamin D supplementation for prevention of falls. Finally, USPSTF recommends against low-dose vitamin D (400 IU or less) supplementation for primary prevention of fractures in community-dwelling, postmenopausal women.¹⁰ Nevertheless, these statements are not applicable for individuals with a prior history of osteoporotic fractures, increased risk of falls, or a diagnosis of vitamin D deficiency or osteoporosis. Therefore, vitamin D supplementation for prevention of fall and fractures should be practiced with caution.

Vitamin D supplementation is no longer routinely recommended for fall and fracture prevention. However, if we believe that poor lower extremity muscle strength is a risk factor for falls,¹² then the question of whether vitamin D has a beneficial role in improving lower extremity strength in older adults needs to be addressed. Results regarding the effect of vitamin D supplementation on muscle function have so far been mixed. For example, in a randomized, double-blinded, placebo-controlled trial of 160 postmenopausal women with low vitamin D level (< 20 ng/mL), vitamin D₃ supplementation at 1000 IU/day for 9 months showed a significant increase in lower extremity muscle strength.¹³ However, in another randomized double-blinded, placebo-controlled trial of 130 men aged 65 to 90 years with low vitamin D level (< 30 ng/mL) and an SPPB score of ≤ 9 (mild-moderate limitation in mobility), daily supplementation with 4000 IU of vitamin D₃ for 9 months did not result in improved SPPB score or gait speed.¹⁴ In the study reported by Shea et al, the authors showed that 800 IU of daily vitamin D supplementation (consistent with the Institute of Medicine [IOM] recommendations for older adults¹⁵) in community-dwelling older adults with vitamin D deficiency (< 20 ng/mL) did not improve lower extremity muscle strength. This finding is significant in that it adds further evidence to support the rationale against using vitamin D supplementation for the sole purpose of improving lower extremity muscle function in older adults with vitamin D deficiency.

Valuable strengths of this study include its randomized, double-blinded, placebo-controlled trial design testing the IOM recommended dose of daily vitamin D supplementation for older adults. In addition, compared to some of the prior studies mentioned above, the study population included both males and females, although the final study population resulted in some gender bias (with male predominance). Moreover, participants were followed for a sufficient amount of time (1 year), with an excellent adherence rate (only 3 were lost to follow-up) and with corresponding improvement in vitamin D levels. Finally, the use of SPPB as a readout for primary outcome should also be commended, as this assessment is a well-validated method for measuring lower extremity function with scaled scores that predict poor outcomes.¹⁶ However, some limitations include the aforementioned predominance of male participants and Caucasian race in both intervention and control groups, as well as discrepancies between the measurement methods for serum vitamin D levels (ie, finger-stick cards versus clinical lab measurement) that may have underestimated the actual serum 25(OH)D levels.

Applications for Clinical Practice

While the null findings from the Shea and colleagues study are applicable to healthier community-dwelling older adults, they may not be generalizable to the care of more frail older patients due to their increased risks for falls and high vulnerability to adverse outcomes. Thus, further studies that account for baseline sarcopenia, frailty, and other fall-risk factors (eg, polypharmacy) are needed to better evaluate the value of vitamin D supplementation in this most vulnerable population.

— Caroline Park, MD, PhD, and Fred Ko, MD
Icahn School of Medicine at Mount Sinai, New York, NY

Study Overview

Objective. To test the effect of 12 months of vitamin D supplementation on lower-extremity power and function in older community-dwelling adults screened for low serum 25-hydroxyvitamin D (25(OH)D).

Design. A single-center, double-blind, randomized placebo-controlled study in which participants were assigned to 800 IU of vitamin D₃ supplementation or placebo daily and were followed over a total period of 12 months.

Setting and participants. A total of 100 community-dwelling men and women aged ≥ 60 years with serum 25(OH)D ≤ 20 ng/mL at screening participated. Participants were prescreened by phone, and were excluded if they met any of the following exclusion criteria: vitamin D supplement use > 600 IU/day (for age 60-70 years) or > 800 IU/day (for age ≥ 71 years); vitamin D injection within the previous 3 months; > 2 falls or 1 fall with injury in past year; use of cane, walker, or other indoor walking aid; history of kidney stones within past 3 years; hypercalcemia (serum calcium > 10.8 mg/dL); renal dysfunction (glomerular filtration rate, < 30 mL/min); history of liver disease, sarcoidosis, lymphoma, dysphagia, or other gastrointestinal disorder; neuromuscular disorder affecting lower-extremity function; hip replacement within the past year; cancer treatment in the past 3 years; treatment with thiazide diuretics > 37.5 mg, teriparatide, denosumab, or bisphosphonates within the past 2 years; oral steroids (for > 3 weeks in the past 6 months); and use of fat malabsorption products or anticonvulsive therapy.

Main outcome measures. The primary outcome was leg extensor power assessed using a computer-interfaced bilateral Keiser pneumatic leg press. Secondary outcomes to measure physical function included: (1) backward tandem walk test (which is an indicator of balance and postural control during movement¹); (2) Short Physical Performance Battery (SPPB) testing, which includes a balance assessment (ability to stand with feet positioned normally, semi-tandem, and tandem for 10s), a timed 4-m walk, and a chair stand test (time to complete 5 repeated chair stands); (3) stair climbing (ie, time to climb 10 steps, as a measure of knee extensor strength and functional capacity); and (4) handgrip strength (using a dynamometer). Lean tissue mass was assessed by dual X-ray absorptiometry (DEXA scan). Finally, other measures included serum total 25(OH)D levels measured at baseline, 4, 8, and 12 months, as well as 24-hour urine collection for urea-nitrogen and creatinine measurements.

Main results. Of the 2289 individuals screened for the study, 100 met eligibility criteria and underwent randomization to receive either 800 IU vitamin D supplementation daily (n = 49) or placebo (n = 51). Three patients (2 in vitamin D group and 1 in placebo group) were lost to follow up. The mean age of all participants was 69.6 ± 6.9 years. In the vitamin D group versus the control group, respectively, the percent male: female ratio was 66:34 versus 63:37, and percent Caucasian was 75% versus 82%. Mean body mass index was 28.2 ± 7.0 and mean serum 25(OH)D was 20.2 ± 6.7 ng/mL. At the end of the study (12 months), 70% of participants given vitamin D supplementation had 25(OH)D levels ≥ 30 ng/mL and all participants had levels ≥ 20 ng/mL. In the placebo group, the serum 25(OH)D level was ≥ 20 ng/mL in 54% and ≥ 30 ng/mL in 6%. The mean serum 25(OH)D level increased to 32.5 ± 5.1 ng/mL in the vitamin D–supplemented group, but no significant change was found in the placebo group (treatment × time, P < 0.001). Overall, the serum 1,25 (OH)2D3 levels did not differ between the 2 groups over the intervention period (time, P = 0.49; treatment × time, P = 0.27). Dietary intake of vitamin D, calcium, nitrogen, and protein did not differ or change over time between the 2 groups. The change in leg press power, function, and strength did not differ between the groups over 12 months (all treatment × time, P values ≥ 0.60). A total of 27 falls were reported (14 in vitamin D versus 9 in control group), of which 9 were associated with injuries. There was no significant change in lean body mass at the end of the study period in either group (treatment × time, P = 0.98).

Conclusion. In community-dwelling older adults with vitamin D deficiency (≤ 20 ng/mL), 12-month daily supplementation with 800 IU of vitamin D₃ resulted in sufficient increases in serum 25(OH)D levels, but did not improve lower-extremity power, strength, or lean mass.

Commentary

Vitamin D deficiency is common in older adults (prevalence of about 41% in US adults ≥ 65 years old, according to Forrest et al²) and is likely due to dietary deficiency, reduced sun exposure (lifestyle), and decreased intestinal calcium absorption. As such, vitamin D deficiency has historically been a topic of debate and of interest in geriatric medicine, as it relates to muscle weakness, which in turn leads to increased susceptibility to falls.³ Interestingly, vitamin D receptors are expressed in human skeletal muscle,⁴ and in one study, 3-month supplementation of vitamin D led to an increase in type II skeletal muscle fibers in older women.⁵ Similarly, results from a meta-analysis of 5 randomized controlled trials (RCTs)⁶ showed that vitamin D supplementation may reduce fall risk in older adults by 22% (corrected odds ratio, 0.78; 95% confidence interval, 0.64-0.92). Thus, in keeping with this general theme of vitamin D supplementation yielding beneficial effects in clinical outcomes, clinicians have long accepted and practiced routine vitamin D supplementation in caring for older adults.

In more recent years, the role of vitamin D supplementation in primary care has become controversial,⁷ as observed in a recent paradigm shift of moving away from routine supplementation for fall and fracture prevention in clinical practice.⁸ In a recent meta-analysis of 33 RCTs in older community-dwelling adults, supplementation with vitamin D with or without calcium did not result in a reduction of hip fracture or total number of fractures.⁹ Moreover, the United States Preventive Services Task Force (USPSTF) recently published updated recommendations on the use of vitamin D supplementation for primary prevention of fractures¹⁰ and prevention of falls¹¹ in community-dwelling adults. In these updated recommendations, the USPSTF indicated that insufficient evidence exists to recommend vitamin D supplementation to prevent fractures in men and premenopausal women, and recommends against vitamin D supplementation for prevention of falls. Finally, USPSTF recommends against low-dose vitamin D (400 IU or less) supplementation for primary prevention of fractures in community-dwelling, postmenopausal women.¹⁰ Nevertheless, these statements are not applicable for individuals with a prior history of osteoporotic fractures, increased risk of falls, or a diagnosis of vitamin D deficiency or osteoporosis. Therefore, vitamin D supplementation for prevention of fall and fractures should be practiced with caution.

Vitamin D supplementation is no longer routinely recommended for fall and fracture prevention. However, if we believe that poor lower extremity muscle strength is a risk factor for falls,¹² then the question of whether vitamin D has a beneficial role in improving lower extremity strength in older adults needs to be addressed. Results regarding the effect of vitamin D supplementation on muscle function have so far been mixed. For example, in a randomized, double-blinded, placebo-controlled trial of 160 postmenopausal women with low vitamin D level (< 20 ng/mL), vitamin D₃ supplementation at 1000 IU/day for 9 months showed a significant increase in lower extremity muscle strength.¹³ However, in another randomized double-blinded, placebo-controlled trial of 130 men aged 65 to 90 years with low vitamin D level (< 30 ng/mL) and an SPPB score of ≤ 9 (mild-moderate limitation in mobility), daily supplementation with 4000 IU of vitamin D₃ for 9 months did not result in improved SPPB score or gait speed.¹⁴ In the study reported by Shea et al, the authors showed that 800 IU of daily vitamin D supplementation (consistent with the Institute of Medicine [IOM] recommendations for older adults¹⁵) in community-dwelling older adults with vitamin D deficiency (< 20 ng/mL) did not improve lower extremity muscle strength. This finding is significant in that it adds further evidence to support the rationale against using vitamin D supplementation for the sole purpose of improving lower extremity muscle function in older adults with vitamin D deficiency.

Valuable strengths of this study include its randomized, double-blinded, placebo-controlled trial design testing the IOM recommended dose of daily vitamin D supplementation for older adults. In addition, compared to some of the prior studies mentioned above, the study population included both males and females, although the final study population resulted in some gender bias (with male predominance). Moreover, participants were followed for a sufficient amount of time (1 year), with an excellent adherence rate (only 3 were lost to follow-up) and with corresponding improvement in vitamin D levels. Finally, the use of SPPB as a readout for primary outcome should also be commended, as this assessment is a well-validated method for measuring lower extremity function with scaled scores that predict poor outcomes.¹⁶ However, some limitations include the aforementioned predominance of male participants and Caucasian race in both intervention and control groups, as well as discrepancies between the measurement methods for serum vitamin D levels (ie, finger-stick cards versus clinical lab measurement) that may have underestimated the actual serum 25(OH)D levels.

Applications for Clinical Practice

While the null findings from the Shea and colleagues study are applicable to healthier community-dwelling older adults, they may not be generalizable to the care of more frail older patients due to their increased risks for falls and high vulnerability to adverse outcomes. Thus, further studies that account for baseline sarcopenia, frailty, and other fall-risk factors (eg, polypharmacy) are needed to better evaluate the value of vitamin D supplementation in this most vulnerable population.

— Caroline Park, MD, PhD, and Fred Ko, MD
Icahn School of Medicine at Mount Sinai, New York, NY

Study Overview

Objective. To test the effect of 12 months of vitamin D supplementation on lower-extremity power and function in older community-dwelling adults screened for low serum 25-hydroxyvitamin D (25(OH)D).

Design. A single-center, double-blind, randomized placebo-controlled study in which participants were assigned to 800 IU of vitamin D₃ supplementation or placebo daily and were followed over a total period of 12 months.

Setting and participants. A total of 100 community-dwelling men and women aged ≥ 60 years with serum 25(OH)D ≤ 20 ng/mL at screening participated. Participants were prescreened by phone, and were excluded if they met any of the following exclusion criteria: vitamin D supplement use > 600 IU/day (for age 60-70 years) or > 800 IU/day (for age ≥ 71 years); vitamin D injection within the previous 3 months; > 2 falls or 1 fall with injury in past year; use of cane, walker, or other indoor walking aid; history of kidney stones within past 3 years; hypercalcemia (serum calcium > 10.8 mg/dL); renal dysfunction (glomerular filtration rate, < 30 mL/min); history of liver disease, sarcoidosis, lymphoma, dysphagia, or other gastrointestinal disorder; neuromuscular disorder affecting lower-extremity function; hip replacement within the past year; cancer treatment in the past 3 years; treatment with thiazide diuretics > 37.5 mg, teriparatide, denosumab, or bisphosphonates within the past 2 years; oral steroids (for > 3 weeks in the past 6 months); and use of fat malabsorption products or anticonvulsive therapy.

Main outcome measures. The primary outcome was leg extensor power assessed using a computer-interfaced bilateral Keiser pneumatic leg press. Secondary outcomes to measure physical function included: (1) backward tandem walk test (which is an indicator of balance and postural control during movement¹); (2) Short Physical Performance Battery (SPPB) testing, which includes a balance assessment (ability to stand with feet positioned normally, semi-tandem, and tandem for 10s), a timed 4-m walk, and a chair stand test (time to complete 5 repeated chair stands); (3) stair climbing (ie, time to climb 10 steps, as a measure of knee extensor strength and functional capacity); and (4) handgrip strength (using a dynamometer). Lean tissue mass was assessed by dual X-ray absorptiometry (DEXA scan). Finally, other measures included serum total 25(OH)D levels measured at baseline, 4, 8, and 12 months, as well as 24-hour urine collection for urea-nitrogen and creatinine measurements.

Main results. Of the 2289 individuals screened for the study, 100 met eligibility criteria and underwent randomization to receive either 800 IU vitamin D supplementation daily (n = 49) or placebo (n = 51). Three patients (2 in vitamin D group and 1 in placebo group) were lost to follow up. The mean age of all participants was 69.6 ± 6.9 years. In the vitamin D group versus the control group, respectively, the percent male: female ratio was 66:34 versus 63:37, and percent Caucasian was 75% versus 82%. Mean body mass index was 28.2 ± 7.0 and mean serum 25(OH)D was 20.2 ± 6.7 ng/mL. At the end of the study (12 months), 70% of participants given vitamin D supplementation had 25(OH)D levels ≥ 30 ng/mL and all participants had levels ≥ 20 ng/mL. In the placebo group, the serum 25(OH)D level was ≥ 20 ng/mL in 54% and ≥ 30 ng/mL in 6%. The mean serum 25(OH)D level increased to 32.5 ± 5.1 ng/mL in the vitamin D–supplemented group, but no significant change was found in the placebo group (treatment × time, P < 0.001). Overall, the serum 1,25 (OH)2D3 levels did not differ between the 2 groups over the intervention period (time, P = 0.49; treatment × time, P = 0.27). Dietary intake of vitamin D, calcium, nitrogen, and protein did not differ or change over time between the 2 groups. The change in leg press power, function, and strength did not differ between the groups over 12 months (all treatment × time, P values ≥ 0.60). A total of 27 falls were reported (14 in vitamin D versus 9 in control group), of which 9 were associated with injuries. There was no significant change in lean body mass at the end of the study period in either group (treatment × time, P = 0.98).

Conclusion. In community-dwelling older adults with vitamin D deficiency (≤ 20 ng/mL), 12-month daily supplementation with 800 IU of vitamin D₃ resulted in sufficient increases in serum 25(OH)D levels, but did not improve lower-extremity power, strength, or lean mass.

Commentary

Vitamin D deficiency is common in older adults (prevalence of about 41% in US adults ≥ 65 years old, according to Forrest et al²) and is likely due to dietary deficiency, reduced sun exposure (lifestyle), and decreased intestinal calcium absorption. As such, vitamin D deficiency has historically been a topic of debate and of interest in geriatric medicine, as it relates to muscle weakness, which in turn leads to increased susceptibility to falls.³ Interestingly, vitamin D receptors are expressed in human skeletal muscle,⁴ and in one study, 3-month supplementation of vitamin D led to an increase in type II skeletal muscle fibers in older women.⁵ Similarly, results from a meta-analysis of 5 randomized controlled trials (RCTs)⁶ showed that vitamin D supplementation may reduce fall risk in older adults by 22% (corrected odds ratio, 0.78; 95% confidence interval, 0.64-0.92). Thus, in keeping with this general theme of vitamin D supplementation yielding beneficial effects in clinical outcomes, clinicians have long accepted and practiced routine vitamin D supplementation in caring for older adults.

In more recent years, the role of vitamin D supplementation in primary care has become controversial,⁷ as observed in a recent paradigm shift of moving away from routine supplementation for fall and fracture prevention in clinical practice.⁸ In a recent meta-analysis of 33 RCTs in older community-dwelling adults, supplementation with vitamin D with or without calcium did not result in a reduction of hip fracture or total number of fractures.⁹ Moreover, the United States Preventive Services Task Force (USPSTF) recently published updated recommendations on the use of vitamin D supplementation for primary prevention of fractures¹⁰ and prevention of falls¹¹ in community-dwelling adults. In these updated recommendations, the USPSTF indicated that insufficient evidence exists to recommend vitamin D supplementation to prevent fractures in men and premenopausal women, and recommends against vitamin D supplementation for prevention of falls. Finally, USPSTF recommends against low-dose vitamin D (400 IU or less) supplementation for primary prevention of fractures in community-dwelling, postmenopausal women.¹⁰ Nevertheless, these statements are not applicable for individuals with a prior history of osteoporotic fractures, increased risk of falls, or a diagnosis of vitamin D deficiency or osteoporosis. Therefore, vitamin D supplementation for prevention of fall and fractures should be practiced with caution.

Vitamin D supplementation is no longer routinely recommended for fall and fracture prevention. However, if we believe that poor lower extremity muscle strength is a risk factor for falls,¹² then the question of whether vitamin D has a beneficial role in improving lower extremity strength in older adults needs to be addressed. Results regarding the effect of vitamin D supplementation on muscle function have so far been mixed. For example, in a randomized, double-blinded, placebo-controlled trial of 160 postmenopausal women with low vitamin D level (< 20 ng/mL), vitamin D₃ supplementation at 1000 IU/day for 9 months showed a significant increase in lower extremity muscle strength.¹³ However, in another randomized double-blinded, placebo-controlled trial of 130 men aged 65 to 90 years with low vitamin D level (< 30 ng/mL) and an SPPB score of ≤ 9 (mild-moderate limitation in mobility), daily supplementation with 4000 IU of vitamin D₃ for 9 months did not result in improved SPPB score or gait speed.¹⁴ In the study reported by Shea et al, the authors showed that 800 IU of daily vitamin D supplementation (consistent with the Institute of Medicine [IOM] recommendations for older adults¹⁵) in community-dwelling older adults with vitamin D deficiency (< 20 ng/mL) did not improve lower extremity muscle strength. This finding is significant in that it adds further evidence to support the rationale against using vitamin D supplementation for the sole purpose of improving lower extremity muscle function in older adults with vitamin D deficiency.

Valuable strengths of this study include its randomized, double-blinded, placebo-controlled trial design testing the IOM recommended dose of daily vitamin D supplementation for older adults. In addition, compared to some of the prior studies mentioned above, the study population included both males and females, although the final study population resulted in some gender bias (with male predominance). Moreover, participants were followed for a sufficient amount of time (1 year), with an excellent adherence rate (only 3 were lost to follow-up) and with corresponding improvement in vitamin D levels. Finally, the use of SPPB as a readout for primary outcome should also be commended, as this assessment is a well-validated method for measuring lower extremity function with scaled scores that predict poor outcomes.¹⁶ However, some limitations include the aforementioned predominance of male participants and Caucasian race in both intervention and control groups, as well as discrepancies between the measurement methods for serum vitamin D levels (ie, finger-stick cards versus clinical lab measurement) that may have underestimated the actual serum 25(OH)D levels.

Applications for Clinical Practice

While the null findings from the Shea and colleagues study are applicable to healthier community-dwelling older adults, they may not be generalizable to the care of more frail older patients due to their increased risks for falls and high vulnerability to adverse outcomes. Thus, further studies that account for baseline sarcopenia, frailty, and other fall-risk factors (eg, polypharmacy) are needed to better evaluate the value of vitamin D supplementation in this most vulnerable population.

— Caroline Park, MD, PhD, and Fred Ko, MD
Icahn School of Medicine at Mount Sinai, New York, NY

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

 

 

Commentary

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

 

 

Commentary

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ

Study Overview

Objective. To evaluate the efficacy and safety of a once-daily 2-drug antiretroviral (ARV) regimen, dolutegravir plus lamivudine, for the treatment of HIV-1 infection in adults naive to antiretroviral therapy (ART).

Design. GEMINI-1 and GEMINI-2 were 2 identically designed multicenter, double-blind, randomized, noninferiority, phase 3 clinical trials conducted between July 18, 2016 and March 31, 2017. Participants were stratified to receive 1 of 2 once-daily HIV regimens: the study regimen, consisting of once-daily dolutegravir 50 mg plus lamivudine 300 mg, or the standard-of-care regimen, consisting of once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate (TDF) 300 mg plus emtricitabine 200 mg. While this article presents results at week 48, both trials are scheduled to evaluate participants up to week 148 in an attempt to evaluate long-term efficacy and safety.

Setting and participants. Eligible participants had to be aged 18 years or older with treatment-naive HIV-1 infection. Women were eligible if they were not (1) pregnant, (2) lactating, or (3) of reproductive potential, defined by various means, including tubal ligation, hysterectomy, postmenopausal, and the use of highly effective contraception. Initially, eligibility screening restricted participation to those with viral loads between 1000 and 100,000 copies/mL. However, the upper limit was later increased to 500,000 copies/mL based on an independent review of results from other clinical trials^1,2 evaluating dual therapy with dolutegravir and lamivudine, which indicated efficacy in patients with viral loads up to 500,000.^3-5

Notable exclusion criteria included: (1) major mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors; (2) evidence of hepatitis B infection; (3) hepatitis C infection with anticipation of initiating treatment within 48 weeks of study enrollment; and (4) stage 3 HIV disease, per Centers for Disease Control and Prevention criteria, with the exception of cutaneous Kaposi sarcoma and CD4 cell counts < 200 cells/mL.

Main outcome measures. The primary endpoint was demonstration of noninferiority of the 2-drug ARV regimen through assessment of the proportion of participants who achieved virologic suppression at week 48 in the intent-to-treat-exposed population. For the purposes of this study, virologic suppression was defined as having fewer than 50 copies of HIV-1 RNA per mL at week 48. For evaluation of safety and toxicity concerns, renal and bone biomarkers were assessed at study entry and at weeks 24 and 48. In addition, participants who met virological withdrawal criteria were evaluated for integrase strand transfer inhibitor mutations. Virological withdrawal was defined as the presence of 1 of the following: (1) HIV RNA > 200 copies/mL at week 24, (2) HIV RNA > 200 copies/mL after previous HIV RNA < 200 copies/mL (confirmed rebound), and (3) a < 1 log₁₀ copies/mL decrease from baseline (unless already < 200 copies/mL).

Main results. GEMINI-1 and GEMINI-2 randomized a combined total of 1441 participants to receive either the once-daily 2-drug ARV regimen (dolutegravir and lamivudine, n = 719) or the once-daily 3-drug ARV regimen (dolutegravir, TDF, and emtricitabine, n = 722). Of the 533 participants who did not meet inclusion criteria, the predominant reasons for exclusion were either having preexisting major viral resistance mutations (n = 246) or viral loads outside the range of 1000 to 500,000 copies/mL (n = 133).

Baseline demographic and clinical characteristics were similar between both groups. The median age was 33 years (10% were over 50 years of age), and participants were mostly male (85%) and white (68%). Baseline HIV RNA counts of > 100,000 copies/mL were found in 293 participants (20%), and 188 (8%) participants had CD4 counts of ≤ 200 cells/mL.

Noninferiority of the once-daily 2-drug versus the once-daily 3-drug ARV regimen was demonstrated in both the GEMINI-1 and GEMINI-2 trials for the intent-to-treat-exposed population. In GEMINI-1, 90% (n = 320) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 93% (n = 332) in the 3-drug ARV group (no statistically significant difference). In GEMINI-2, 93% (n =335 ) in the 2-drug ARV group achieved virologic suppression at week 48 compared to 94% (n = 337) in the 3-drug ARV group (no statistically significant difference).

A subgroup analysis found no significant impact of baseline HIV RNA (> 100,000 compared to ≤ 100,000 copies/mL) on achieving virologic suppression at week 48. However, a subgroup analysis did find that participants with CD4 counts < 200 copies/mL had a reduced response in the once-daily 2-drug versus 3-drug ARV regimen for achieving virologic response at week 48 (79% versus 93%, respectively).

Overall, 10 participants met virological withdrawal criteria during the study period, and 4 of these were on the 2-drug ARV regimen. For these 10 participants, genotypic testing did not find emergence of resistance to either nucleoside reverse transcriptase or integrase strand transfer inhibitors.

Regarding renal biomarkers, increases of both serum creatinine and urinary excretion of protein creatinine were significantly greater in the 3-drug ARV group. Also, biomarkers indicating increased bone turnover were elevated in both groups, but the degree of elevation was significantly lower in the 2-drug ARV regimen cohort. It is unclear whether these findings reflect an increased or decreased risk of developing osteopenia or osteoporosis in the 2 study groups.

Conclusion. The once-daily 2-drug ARV regimen dolutegravir and lamivudine is noninferior to the guideline-recommended once-daily 3-drug ARV regimen dolutegravir, TDF, and emtricitabine at achieving viral suppression in ART-naive HIV-1 infected individuals with HIV RNA counts < 500,000 copies/mL. However, the efficacy of this ARV regimen may be compromised in individuals with CD4 counts < 200 cells/mL.

 

 

Commentary

Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.⁶ Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.^7-10

The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).¹⁰ Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.

The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.¹⁰ Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.^11,12

A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.^13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.

Applications for Clinical Practice

Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.¹⁵ Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.¹⁶ Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.

—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ

CHICAGO – The Food and Drug Administration launched a new call center project to assist physicians seeking to help cancer patients access unapproved therapies.

MDedge/Neil Osterweil

Entitled “Project Facilitate,” the program aims to create a single point of contact with FDA oncology staff who can guide physicians through the process of submitting Expanded Access (EA) requests on behalf of individual patients.

“This is a pilot program to provide continuous support to health care professionals throughout the entire Expanded Access process,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products said during the unveiling of the project during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Physicians utilizing Project Facilitate can expect a “concierge service” experience including advice on the information needed to complete requests, assistance completing forms, pharma/biotech contact information, independent review board resource options, and follow-up on patient outcomes.

The project will work in synergy with the Reagan-Udall EA Navigator website, an “online road map” for physicians and patients that was launched 2 years ago “to facilitate and coordinate and collaborate with the FDA to advance the science mission of FDA,” and which has been expanded in conjunction with Project Facilitate, Ellen V. Sigal, PhD, chair of the board of the Reagan-Udall Foundation for the FDA, said at the press briefing.

“EA Navigator delivers transparent, concise, and searchable information provided by companies about their Expanded Access policies,” Dr. Sigal said. “Today I’m pleased to announce that the Navigator now features Expanded Access opportunities listed in ClinicalTrials.gov for companies in the directory.

“For the first time, those who need quick access to drug availability and Expanded Access options will find it in one place without having to visit site by site by site, or sift through thousands of studies that don’t merit their needs,” she added, noting that EA Navigator will often be the first step for physicians before they engage with Project Facilitate.

Project Facilitate can be reached Monday-Friday, 9 a.m.-5 p.m. ET at 240-402-0004, or by email at OncProjectFacilitate@fda.hhs.gov.

CHICAGO – The Food and Drug Administration launched a new call center project to assist physicians seeking to help cancer patients access unapproved therapies.

MDedge/Neil Osterweil

Entitled “Project Facilitate,” the program aims to create a single point of contact with FDA oncology staff who can guide physicians through the process of submitting Expanded Access (EA) requests on behalf of individual patients.

“This is a pilot program to provide continuous support to health care professionals throughout the entire Expanded Access process,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products said during the unveiling of the project during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Physicians utilizing Project Facilitate can expect a “concierge service” experience including advice on the information needed to complete requests, assistance completing forms, pharma/biotech contact information, independent review board resource options, and follow-up on patient outcomes.

The project will work in synergy with the Reagan-Udall EA Navigator website, an “online road map” for physicians and patients that was launched 2 years ago “to facilitate and coordinate and collaborate with the FDA to advance the science mission of FDA,” and which has been expanded in conjunction with Project Facilitate, Ellen V. Sigal, PhD, chair of the board of the Reagan-Udall Foundation for the FDA, said at the press briefing.

“EA Navigator delivers transparent, concise, and searchable information provided by companies about their Expanded Access policies,” Dr. Sigal said. “Today I’m pleased to announce that the Navigator now features Expanded Access opportunities listed in ClinicalTrials.gov for companies in the directory.

“For the first time, those who need quick access to drug availability and Expanded Access options will find it in one place without having to visit site by site by site, or sift through thousands of studies that don’t merit their needs,” she added, noting that EA Navigator will often be the first step for physicians before they engage with Project Facilitate.

Project Facilitate can be reached Monday-Friday, 9 a.m.-5 p.m. ET at 240-402-0004, or by email at OncProjectFacilitate@fda.hhs.gov.

CHICAGO – The Food and Drug Administration launched a new call center project to assist physicians seeking to help cancer patients access unapproved therapies.

MDedge/Neil Osterweil

Entitled “Project Facilitate,” the program aims to create a single point of contact with FDA oncology staff who can guide physicians through the process of submitting Expanded Access (EA) requests on behalf of individual patients.

“This is a pilot program to provide continuous support to health care professionals throughout the entire Expanded Access process,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products said during the unveiling of the project during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Physicians utilizing Project Facilitate can expect a “concierge service” experience including advice on the information needed to complete requests, assistance completing forms, pharma/biotech contact information, independent review board resource options, and follow-up on patient outcomes.

The project will work in synergy with the Reagan-Udall EA Navigator website, an “online road map” for physicians and patients that was launched 2 years ago “to facilitate and coordinate and collaborate with the FDA to advance the science mission of FDA,” and which has been expanded in conjunction with Project Facilitate, Ellen V. Sigal, PhD, chair of the board of the Reagan-Udall Foundation for the FDA, said at the press briefing.

“EA Navigator delivers transparent, concise, and searchable information provided by companies about their Expanded Access policies,” Dr. Sigal said. “Today I’m pleased to announce that the Navigator now features Expanded Access opportunities listed in ClinicalTrials.gov for companies in the directory.

“For the first time, those who need quick access to drug availability and Expanded Access options will find it in one place without having to visit site by site by site, or sift through thousands of studies that don’t merit their needs,” she added, noting that EA Navigator will often be the first step for physicians before they engage with Project Facilitate.

Project Facilitate can be reached Monday-Friday, 9 a.m.-5 p.m. ET at 240-402-0004, or by email at OncProjectFacilitate@fda.hhs.gov.

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

bjancin@mdedge.com

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

Studies have shown that a majority of patients remain confused about their health care plans after being discharged from the hospital.^1,2 Furthermore, most patients do not recognize their lack of comprehension.² A substantial proportion of medical information is forgotten immediately after discharge. Kessels found that when larger amounts of information were presented, less was recalled, and almost half of the recalled information was incorrect.³ Researchers also have found that health information that was focused on individual needs not only increased patients’ understanding of their health needs and improved their health literacy, but supported self-management and promoted health outcomes for adults with chronic illness.^4,5

Health literacy is the “capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁶ To read instructions on a prescription bottle, patients need an intermediate level of health literacy. Even for patients with such a level of health literacy, comprehending and managing a health care plan for a chronic disease can be challenging. About 35% of Americans had lower than an intermediate level of health literacy.⁷ Insufficient health literacy is associated with increased health system use and costs, health disparities, and poor health outcomes.⁸ As a result, it is crucial to gear oral instructions to patients’ health literacy levels to ensure that patients understand health information and instructions and perform self-care at home. The teach-back method, a technique for verifying patients’ understanding of their health information, has been recommended by the Agency for Healthcare Research and Quality (AHRQ) and the Institute for Healthcare Improvement (IHI) as a strategy for taking universal precautions for health literacy. Patients are asked to repeat the instructions they receive from their health care professionals (HCPs). HCPs should use caring and plain language in a shame-free environment during patient education. By using the teach-back method, HCPs can assess patients’ understanding, and reteach or modify teaching if comprehension is not demonstrated. Patients have an important role in their health and their ability to understand health information has a significant impact on their health behavior and outcomes.

In our systematic research, we examined the effectiveness of using the teach-back method to understand health education as well as the impact of this method on patients’ disease self-management and health outcomes.

Methods

In the teach-back method, patients explain health information in their own words.⁹ To gauge the use and effectiveness of this method, investigators have studied patient perceptions and acknowledgments of the method as well as the effects of the method on health interventions. According to Dorothea Orem’s self-care deficit nursing theory, disease self-management is an “executive ability” to “control, handle, direct or govern” self-care activities.¹⁰ We define disease self-management as disease knowledge and disease management changes that promote self-care activities. In addition, we define health outcomes as health changes that result from the teach-back method, such as changes in postdischarge readmission rates, patient satisfaction, and health behavior.

Inclusion Criteria

We systematically reviewed evidence regarding the teach-back method as an educational intervention for patients aged ≥ 18 years. We included articles if they reported the process and outcomes of using the method alone or in combination with other educational strategies. The literature search focused on English-language articles published in peer-reviewed journals. Included in the review were qualitative, randomized controlled trials (RCTs); quasi-experimental studies; cohort studies; and pretest–posttest studies on the effects of the teach-back method. As the method can be applied in any health care setting, we used studies conducted in a variety of settings, including primary care, inpatient, outpatient, emergency department (ED), and community, in any time frame. Study participants had heart failure, diabetes mellitus (DM), hypertension, asthma, or other chronic diseases.

Exclusion Criteria

Studies that used the teach-back method as an outcome measurement but not an intervention were excluded. For example, those that used the method to measure patients’ postintervention understanding were excluded. Also excluded were those that used the method to examine HCP training or to measure HCP outcomes (ie, studies that did not use the method for patient education or outcomes).

Literature Search

In September 2017, we searched 4 databases: Ovid Medline, PubMed, EBSCO (Elton B. Stephens Co), CINAHL (Cumulative Index to Nursing and Allied Health Literature), and ProQuest. Also included were relevant studies from cited reference searching (Figure).

This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline for searches and formatting results. The literature search was performed with the term teach-back and terms from the structured PICO (population, intervention, comparison, outcomes) statement. The study population consisted of patients who received the teach-back intervention as part of the patient education process in a medical care setting, and the comparator population consisted of patients who did not receive the intervention in their patient education. Target outcomes were disease self-management, self-care, patient satisfaction, patient perception and acknowledgment of the teach-back method, and other health outcomes.

Data Collection

Data collected included authors, publication date, and journal; purpose; study design; setting, sample, and population; intervention; and outcomes.

The methodologic quality of papers retrieved for review was determined with Critical Appraisals Skills Programme (CASP) guidelines (casp-uk.net/casp-tools-checklists). CASP randomised controlled trial, cohort study, case control study, and qualitative checklists were used. The authors assessed the full texts for eligibility. Disagreements were resolved through discussion.

The initial literature search found 112, 135, and 161 articles from EBSCO CINAHL, Ovid Medline, and PubMed, respectively. Five articles from ProQuest were identified through the EBSCO CINAHL search. After inclusion and exclusion criteria were applied, duplicate articles removed, a cited reference added, and CASP criteria assessed, 26 articles remained in the review. The 26 studies consisted of 15 cohort studies, 5 case–control studies, 5 RCTs, and 1 qualitative interview. Twenty-two of the articles were published in the US, the other 4 in Australia and Iran (2 each).^11-14 All 26 studies used the teach-back method with other educational interventions to reinforce learning (eg, the method was used after heart failure or DM education). Of the 26 studies, 10 used a pretest–posttest intervention design,^15-24 and 10 used a quasi-experimental or experimental design.^{11,13,14,25-31}

Results

The common outcome measures used in the 26 studies fall into 5 categories: patient satisfaction; postdischarge readmission; patient perception of teach-back method effectiveness; disease knowledge and disease management improvements; and intervention effects on health-related quality of life (HR-QOL). A summary of included articles, study setting, design, outcomes, and details is available from the author.

Patient Satisfaction

Ten studies examined the impact of the teach-back method on patient satisfaction.^{15,17,19,21,23,26,27,29,31,32} Of these 10 studies, 6 explored the influence of the method on Hospital Consumer Assessment of Healthcare Providers and Systems survey scores.^{15,17,19,21,22,26} All included studies indicated improved satisfaction with medication education, discharge information, and health management—except for the Silva study, who found an upward trend but not a statistically significant improvement in patient understanding of the purpose of a medication.²³

Grice and colleagues also found that community-dwelling seniors expressed satisfaction with using the teach-back method while being evaluated and assessed for health services at home.³² Improvement or a positive trend in teach-back groups was reported in a majority of the studies except for those by Hyrkas and Wiggins, and Griffey and colleagues.^27,29 Hyrkas and Wiggins found the method slightly improved patients’ medication confidence after hospital discharge, though patient satisfaction scores were associated with patient–nurse relationships, not with use of the teach-back method and a motivational interview.²⁷ Similarly, Griffey and colleagues found that patients who had limited health literacy and received a standard discharge with teach-back scored higher on medication comprehension, compared with patients who received only a standard discharge, but there was no difference in patient satisfaction after an ED visit.²⁹

Postdischarge Readmission

Results emphasized the importance of teach-back in reinforcing discharge instructions and improving postdischarge readmission rates. Of the 6 studies on the effect that teach-back with discharge summary had on readmission rates, 2 found statistically significant improvement for patients with heart failure at 12 months (teach-back, 59%; non-teach-back, 44%; P = .005) and patients with coronary artery bypass grafting (CABG) at 30 days (preintervention, 25%; postintervention, 12%; P = .02).^11,16 In addition, 3 of the 6 studies reported improvement but did not provide P values.^18,20,22 One study indicated improvement in other measured outcomes but found no significant difference for patients who received teach-back with their discharge summaries.²⁷ In all studies, teach-back was added to an intervention and used to confirm and promote knowledge and self-care management.

Patient Perception of Teach-Back Effectiveness

In 2 qualitative studies, patients indicated teach-back was an effective educational method.^16,33 For patients with CABG, Bates and colleagues added a scheduled cardiology follow-up appointment and teach-back patient education to their State Action on Avoidable Rehospitalizations interventions; 96% of participants rated teach-back effective or highly effective.¹⁶ In the other study, Samuels-Kalow and colleagues interviewed 51 patients and parents who received teach-back as part of the discharge process in 2 EDs; participants indicated teach-back helped them remember what they learned from their HCPs, and gave them the opportunity to connect with their HCPs, though some with lower health literacy expressed concerns about perceived judgment by HCPs.³³

Disease Knowledge and Management

Thirteen studies examined knowledge improvement after interventions that included teach-back. Study participants answered most questions correctly after receiving teach-back.^20,32,34,35 Slater and colleagues found ED patients who received discharge instructions with teach-back had significantly higher scores measuring knowledge of diagnosis (P < .001), signs and symptoms indicating a need to return to the ED (P < .001), and follow-up instructions (P = .03); scores measuring knowledge of medication were higher as well, but were not statistically different (P = .14).²⁴ In multiple studies, improvement was not always statistically significant in terms of knowledge retention.^{12,25,29-31,36} Studies that compared medication adherence found teach-back was more effective than motivational interviews (P = .56).²⁷

Teach-back has been widely used in primary care, inpatient, and ED settings. Two studies on the effect of teach-back in primary care sampled patients with DM.^28,36 Kandula and colleagues found that participants who answered questions incorrectly after watching a multimedia DM education program could significantly improve their DM knowledge by engaging in teach-back immediately after the intervention; however, knowledge retention was not improved at 2-week follow-up (phone call).²⁸ In contrast, Swavely and colleagues compared patients who completed a 13-hour DM education program with or without teach-back and found that teach-back patients demonstrated significantly improved DM knowledge and self-care activities at 3 months.³⁶

Effects of Interventions on HR-QOL

The teach-back method had been used with QOL improvement programs and other interventions. Ahmadidarrehsima and colleagues incorporated teach-back into their medical self-management program (8 to 11 sessions, each lasting 1.5 to 2 hours) for women with breast cancer and found that the mean happiness score increased to 62.9 from 37.2 (P < .001) in the intervention group, whereas the score for the usual-care group decreased from 41.4 to 29.8.¹³ Ghiasvand and colleagues compared QOL of postpartum mothers who received routine care with QOL of those who received routine care plus 2 sessions of postpartum self-care with teach-back; mean QOL scores were significantly (P < .001) higher for the teach-back group (124.73) than for the no teach-back group (115.03).¹⁴

Discussion

This review examined the use and effectiveness of the teach-back method in health education and its influence in patients’ disease self-management and health outcomes. Results showed positive effects of teach-back on patient satisfaction, patient perceptions and acknowledgments, postdischarge readmissions, disease self-management and knowledge, and HR-QOL.

The teach-back method has been widely used in inpatient, outpatient, ED, and community settings as part of health education programs and interventions. It has been paired with educational interventions ranging from short instructions to 20-hour programs. These differences reflect the broad application of the method in patient education. Many studies have found that teach-back improves disease knowledge and self-management, though their results are not always statistically significant. In an RCT of patients with low health literacy, Griffey and colleagues studied the effect of ED discharge education with and without teach-back and found teach-back did not increase post-ED comprehension of diagnoses, medical examinations, and treatments or perceived comprehension of treatment and care; however, compared with the no teach-back group, the teach-back group had significantly higher scores on comprehension of post-ED self-care (P < .02), follow-up (P < .0001), and medication (P = .054).²⁹ This finding indicates teach-back is an effective method for helping patients understand self-care and disease self-management at home.

Comprehending medical diagnoses, examinations, and treatments involves acquiring, analyzing, and comparing multiple pieces of health information. Because comprehension requires a level of abstract thinking usually present in patients with intermediate and proficient health literacy,improvements might be more difficult to see in patients with low health literacy.⁸ Press and colleagues found that asthma patients who repeated respiratory inhaler instructions with teach-back during discharge education had less misuse of (P = .01) metered-dose and Diskus (P = .05) inhalers and lower 30-day readmission rates (P = .02) compared with the misuse of patients who received only 1 set of oral and written instructions.³¹ Even though the Diskus result was not statistically significant, it demonstrated teach-back can be used to improve patient self-care and education.³¹

Most participants in the reviewed studies improved their disease knowledge with teach-back, though the evidence regarding improved health care knowledge retention was limited. For example, the 2 studies on use of teach-back in primary care clinics had contradictory knowledge retention results.^28,36 As both studies incorporated teach-back into existing interventions, these results could be associated with those interventions and not with the teach-back method.

Health literacy is achieved through a complicated process of obtaining, analyzing, choosing, and communicating health information. Even though its knowledge retention results are inconsistent, the teach-back method is recommended by the American Academy of Family Physicians at strength of recommendation taxonomy level C.⁸ Such a designation indicates that the recommendation is based on expert opinion, bench research, consensus guideline, usual practice, clinical experience, or a case series and is appropriate for assessment of patient comprehension.³⁷ Teach-back is also suggested by AHRQ and IHI for university precautions regarding health literacy and as such should remain a standard of practice. More study is needed to understand the inconsistent results of knowledge retention and the long-term effects of the teach-back method.

Limitations

Although this review did not limit the publication years of its articles, no pre-2011 articles were found. The teach-back method has been used to measure patients’ postintervention understanding and to educate HCPs on ways to improve patient communication. As this review did not include studies of teach-back as an outcome measurement or studies of training and adaptation of teach-back in HCP or nurse education, other study results may have a bearing on the current findings. Teach-back has been used to close communication gaps between patients and HCPs.

All articles included in this review used the teach-back method with other educational or organizational interventions. The outcomes found in this review may be associated with those interventions and not with teach-back itself. Data reported here have not demonstrated a definite association between teach-back and the measured outcomes; therefore, caution should be exercised when drawing conclusions based on these data. In addition, most of the studies considered in this review were cohort or case–control studies; only 5 RCTs were included. Other confounding factors, including patient health literacy levels, HCP types, HCP competencies in use of teach-back, and type and duration of interventions used before teach-back, may have contributed to this review’s findings.

Conclusion

Findings of this systematic review support use of the teach-back method as effective in reinforcing or confirming patient education. As none of the included studies reported harmful outcomes, the teach-back method poses little risk with respect to increasing patients’ understanding of their education. The findings emphasize the importance of conducting more studies to try to understand the inconsistent results of knowledge retention and determine ways to preserve the long-term effects of teach-back.

Studies have shown that a majority of patients remain confused about their health care plans after being discharged from the hospital.^1,2 Furthermore, most patients do not recognize their lack of comprehension.² A substantial proportion of medical information is forgotten immediately after discharge. Kessels found that when larger amounts of information were presented, less was recalled, and almost half of the recalled information was incorrect.³ Researchers also have found that health information that was focused on individual needs not only increased patients’ understanding of their health needs and improved their health literacy, but supported self-management and promoted health outcomes for adults with chronic illness.^4,5

Health literacy is the “capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁶ To read instructions on a prescription bottle, patients need an intermediate level of health literacy. Even for patients with such a level of health literacy, comprehending and managing a health care plan for a chronic disease can be challenging. About 35% of Americans had lower than an intermediate level of health literacy.⁷ Insufficient health literacy is associated with increased health system use and costs, health disparities, and poor health outcomes.⁸ As a result, it is crucial to gear oral instructions to patients’ health literacy levels to ensure that patients understand health information and instructions and perform self-care at home. The teach-back method, a technique for verifying patients’ understanding of their health information, has been recommended by the Agency for Healthcare Research and Quality (AHRQ) and the Institute for Healthcare Improvement (IHI) as a strategy for taking universal precautions for health literacy. Patients are asked to repeat the instructions they receive from their health care professionals (HCPs). HCPs should use caring and plain language in a shame-free environment during patient education. By using the teach-back method, HCPs can assess patients’ understanding, and reteach or modify teaching if comprehension is not demonstrated. Patients have an important role in their health and their ability to understand health information has a significant impact on their health behavior and outcomes.

In our systematic research, we examined the effectiveness of using the teach-back method to understand health education as well as the impact of this method on patients’ disease self-management and health outcomes.

Methods

In the teach-back method, patients explain health information in their own words.⁹ To gauge the use and effectiveness of this method, investigators have studied patient perceptions and acknowledgments of the method as well as the effects of the method on health interventions. According to Dorothea Orem’s self-care deficit nursing theory, disease self-management is an “executive ability” to “control, handle, direct or govern” self-care activities.¹⁰ We define disease self-management as disease knowledge and disease management changes that promote self-care activities. In addition, we define health outcomes as health changes that result from the teach-back method, such as changes in postdischarge readmission rates, patient satisfaction, and health behavior.

Inclusion Criteria

We systematically reviewed evidence regarding the teach-back method as an educational intervention for patients aged ≥ 18 years. We included articles if they reported the process and outcomes of using the method alone or in combination with other educational strategies. The literature search focused on English-language articles published in peer-reviewed journals. Included in the review were qualitative, randomized controlled trials (RCTs); quasi-experimental studies; cohort studies; and pretest–posttest studies on the effects of the teach-back method. As the method can be applied in any health care setting, we used studies conducted in a variety of settings, including primary care, inpatient, outpatient, emergency department (ED), and community, in any time frame. Study participants had heart failure, diabetes mellitus (DM), hypertension, asthma, or other chronic diseases.

Exclusion Criteria

Studies that used the teach-back method as an outcome measurement but not an intervention were excluded. For example, those that used the method to measure patients’ postintervention understanding were excluded. Also excluded were those that used the method to examine HCP training or to measure HCP outcomes (ie, studies that did not use the method for patient education or outcomes).

Literature Search

In September 2017, we searched 4 databases: Ovid Medline, PubMed, EBSCO (Elton B. Stephens Co), CINAHL (Cumulative Index to Nursing and Allied Health Literature), and ProQuest. Also included were relevant studies from cited reference searching (Figure).

This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline for searches and formatting results. The literature search was performed with the term teach-back and terms from the structured PICO (population, intervention, comparison, outcomes) statement. The study population consisted of patients who received the teach-back intervention as part of the patient education process in a medical care setting, and the comparator population consisted of patients who did not receive the intervention in their patient education. Target outcomes were disease self-management, self-care, patient satisfaction, patient perception and acknowledgment of the teach-back method, and other health outcomes.

Data Collection

Data collected included authors, publication date, and journal; purpose; study design; setting, sample, and population; intervention; and outcomes.

The methodologic quality of papers retrieved for review was determined with Critical Appraisals Skills Programme (CASP) guidelines (casp-uk.net/casp-tools-checklists). CASP randomised controlled trial, cohort study, case control study, and qualitative checklists were used. The authors assessed the full texts for eligibility. Disagreements were resolved through discussion.

The initial literature search found 112, 135, and 161 articles from EBSCO CINAHL, Ovid Medline, and PubMed, respectively. Five articles from ProQuest were identified through the EBSCO CINAHL search. After inclusion and exclusion criteria were applied, duplicate articles removed, a cited reference added, and CASP criteria assessed, 26 articles remained in the review. The 26 studies consisted of 15 cohort studies, 5 case–control studies, 5 RCTs, and 1 qualitative interview. Twenty-two of the articles were published in the US, the other 4 in Australia and Iran (2 each).^11-14 All 26 studies used the teach-back method with other educational interventions to reinforce learning (eg, the method was used after heart failure or DM education). Of the 26 studies, 10 used a pretest–posttest intervention design,^15-24 and 10 used a quasi-experimental or experimental design.^{11,13,14,25-31}

Results

The common outcome measures used in the 26 studies fall into 5 categories: patient satisfaction; postdischarge readmission; patient perception of teach-back method effectiveness; disease knowledge and disease management improvements; and intervention effects on health-related quality of life (HR-QOL). A summary of included articles, study setting, design, outcomes, and details is available from the author.

Patient Satisfaction

Ten studies examined the impact of the teach-back method on patient satisfaction.^{15,17,19,21,23,26,27,29,31,32} Of these 10 studies, 6 explored the influence of the method on Hospital Consumer Assessment of Healthcare Providers and Systems survey scores.^{15,17,19,21,22,26} All included studies indicated improved satisfaction with medication education, discharge information, and health management—except for the Silva study, who found an upward trend but not a statistically significant improvement in patient understanding of the purpose of a medication.²³

Grice and colleagues also found that community-dwelling seniors expressed satisfaction with using the teach-back method while being evaluated and assessed for health services at home.³² Improvement or a positive trend in teach-back groups was reported in a majority of the studies except for those by Hyrkas and Wiggins, and Griffey and colleagues.^27,29 Hyrkas and Wiggins found the method slightly improved patients’ medication confidence after hospital discharge, though patient satisfaction scores were associated with patient–nurse relationships, not with use of the teach-back method and a motivational interview.²⁷ Similarly, Griffey and colleagues found that patients who had limited health literacy and received a standard discharge with teach-back scored higher on medication comprehension, compared with patients who received only a standard discharge, but there was no difference in patient satisfaction after an ED visit.²⁹

Postdischarge Readmission

Results emphasized the importance of teach-back in reinforcing discharge instructions and improving postdischarge readmission rates. Of the 6 studies on the effect that teach-back with discharge summary had on readmission rates, 2 found statistically significant improvement for patients with heart failure at 12 months (teach-back, 59%; non-teach-back, 44%; P = .005) and patients with coronary artery bypass grafting (CABG) at 30 days (preintervention, 25%; postintervention, 12%; P = .02).^11,16 In addition, 3 of the 6 studies reported improvement but did not provide P values.^18,20,22 One study indicated improvement in other measured outcomes but found no significant difference for patients who received teach-back with their discharge summaries.²⁷ In all studies, teach-back was added to an intervention and used to confirm and promote knowledge and self-care management.

Patient Perception of Teach-Back Effectiveness

In 2 qualitative studies, patients indicated teach-back was an effective educational method.^16,33 For patients with CABG, Bates and colleagues added a scheduled cardiology follow-up appointment and teach-back patient education to their State Action on Avoidable Rehospitalizations interventions; 96% of participants rated teach-back effective or highly effective.¹⁶ In the other study, Samuels-Kalow and colleagues interviewed 51 patients and parents who received teach-back as part of the discharge process in 2 EDs; participants indicated teach-back helped them remember what they learned from their HCPs, and gave them the opportunity to connect with their HCPs, though some with lower health literacy expressed concerns about perceived judgment by HCPs.³³

Disease Knowledge and Management

Thirteen studies examined knowledge improvement after interventions that included teach-back. Study participants answered most questions correctly after receiving teach-back.^20,32,34,35 Slater and colleagues found ED patients who received discharge instructions with teach-back had significantly higher scores measuring knowledge of diagnosis (P < .001), signs and symptoms indicating a need to return to the ED (P < .001), and follow-up instructions (P = .03); scores measuring knowledge of medication were higher as well, but were not statistically different (P = .14).²⁴ In multiple studies, improvement was not always statistically significant in terms of knowledge retention.^{12,25,29-31,36} Studies that compared medication adherence found teach-back was more effective than motivational interviews (P = .56).²⁷

Teach-back has been widely used in primary care, inpatient, and ED settings. Two studies on the effect of teach-back in primary care sampled patients with DM.^28,36 Kandula and colleagues found that participants who answered questions incorrectly after watching a multimedia DM education program could significantly improve their DM knowledge by engaging in teach-back immediately after the intervention; however, knowledge retention was not improved at 2-week follow-up (phone call).²⁸ In contrast, Swavely and colleagues compared patients who completed a 13-hour DM education program with or without teach-back and found that teach-back patients demonstrated significantly improved DM knowledge and self-care activities at 3 months.³⁶

Effects of Interventions on HR-QOL

The teach-back method had been used with QOL improvement programs and other interventions. Ahmadidarrehsima and colleagues incorporated teach-back into their medical self-management program (8 to 11 sessions, each lasting 1.5 to 2 hours) for women with breast cancer and found that the mean happiness score increased to 62.9 from 37.2 (P < .001) in the intervention group, whereas the score for the usual-care group decreased from 41.4 to 29.8.¹³ Ghiasvand and colleagues compared QOL of postpartum mothers who received routine care with QOL of those who received routine care plus 2 sessions of postpartum self-care with teach-back; mean QOL scores were significantly (P < .001) higher for the teach-back group (124.73) than for the no teach-back group (115.03).¹⁴

Discussion

This review examined the use and effectiveness of the teach-back method in health education and its influence in patients’ disease self-management and health outcomes. Results showed positive effects of teach-back on patient satisfaction, patient perceptions and acknowledgments, postdischarge readmissions, disease self-management and knowledge, and HR-QOL.

The teach-back method has been widely used in inpatient, outpatient, ED, and community settings as part of health education programs and interventions. It has been paired with educational interventions ranging from short instructions to 20-hour programs. These differences reflect the broad application of the method in patient education. Many studies have found that teach-back improves disease knowledge and self-management, though their results are not always statistically significant. In an RCT of patients with low health literacy, Griffey and colleagues studied the effect of ED discharge education with and without teach-back and found teach-back did not increase post-ED comprehension of diagnoses, medical examinations, and treatments or perceived comprehension of treatment and care; however, compared with the no teach-back group, the teach-back group had significantly higher scores on comprehension of post-ED self-care (P < .02), follow-up (P < .0001), and medication (P = .054).²⁹ This finding indicates teach-back is an effective method for helping patients understand self-care and disease self-management at home.

Comprehending medical diagnoses, examinations, and treatments involves acquiring, analyzing, and comparing multiple pieces of health information. Because comprehension requires a level of abstract thinking usually present in patients with intermediate and proficient health literacy,improvements might be more difficult to see in patients with low health literacy.⁸ Press and colleagues found that asthma patients who repeated respiratory inhaler instructions with teach-back during discharge education had less misuse of (P = .01) metered-dose and Diskus (P = .05) inhalers and lower 30-day readmission rates (P = .02) compared with the misuse of patients who received only 1 set of oral and written instructions.³¹ Even though the Diskus result was not statistically significant, it demonstrated teach-back can be used to improve patient self-care and education.³¹

Most participants in the reviewed studies improved their disease knowledge with teach-back, though the evidence regarding improved health care knowledge retention was limited. For example, the 2 studies on use of teach-back in primary care clinics had contradictory knowledge retention results.^28,36 As both studies incorporated teach-back into existing interventions, these results could be associated with those interventions and not with the teach-back method.

Health literacy is achieved through a complicated process of obtaining, analyzing, choosing, and communicating health information. Even though its knowledge retention results are inconsistent, the teach-back method is recommended by the American Academy of Family Physicians at strength of recommendation taxonomy level C.⁸ Such a designation indicates that the recommendation is based on expert opinion, bench research, consensus guideline, usual practice, clinical experience, or a case series and is appropriate for assessment of patient comprehension.³⁷ Teach-back is also suggested by AHRQ and IHI for university precautions regarding health literacy and as such should remain a standard of practice. More study is needed to understand the inconsistent results of knowledge retention and the long-term effects of the teach-back method.

Limitations

Although this review did not limit the publication years of its articles, no pre-2011 articles were found. The teach-back method has been used to measure patients’ postintervention understanding and to educate HCPs on ways to improve patient communication. As this review did not include studies of teach-back as an outcome measurement or studies of training and adaptation of teach-back in HCP or nurse education, other study results may have a bearing on the current findings. Teach-back has been used to close communication gaps between patients and HCPs.

All articles included in this review used the teach-back method with other educational or organizational interventions. The outcomes found in this review may be associated with those interventions and not with teach-back itself. Data reported here have not demonstrated a definite association between teach-back and the measured outcomes; therefore, caution should be exercised when drawing conclusions based on these data. In addition, most of the studies considered in this review were cohort or case–control studies; only 5 RCTs were included. Other confounding factors, including patient health literacy levels, HCP types, HCP competencies in use of teach-back, and type and duration of interventions used before teach-back, may have contributed to this review’s findings.

Conclusion

Findings of this systematic review support use of the teach-back method as effective in reinforcing or confirming patient education. As none of the included studies reported harmful outcomes, the teach-back method poses little risk with respect to increasing patients’ understanding of their education. The findings emphasize the importance of conducting more studies to try to understand the inconsistent results of knowledge retention and determine ways to preserve the long-term effects of teach-back.

Studies have shown that a majority of patients remain confused about their health care plans after being discharged from the hospital.^1,2 Furthermore, most patients do not recognize their lack of comprehension.² A substantial proportion of medical information is forgotten immediately after discharge. Kessels found that when larger amounts of information were presented, less was recalled, and almost half of the recalled information was incorrect.³ Researchers also have found that health information that was focused on individual needs not only increased patients’ understanding of their health needs and improved their health literacy, but supported self-management and promoted health outcomes for adults with chronic illness.^4,5

Health literacy is the “capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁶ To read instructions on a prescription bottle, patients need an intermediate level of health literacy. Even for patients with such a level of health literacy, comprehending and managing a health care plan for a chronic disease can be challenging. About 35% of Americans had lower than an intermediate level of health literacy.⁷ Insufficient health literacy is associated with increased health system use and costs, health disparities, and poor health outcomes.⁸ As a result, it is crucial to gear oral instructions to patients’ health literacy levels to ensure that patients understand health information and instructions and perform self-care at home. The teach-back method, a technique for verifying patients’ understanding of their health information, has been recommended by the Agency for Healthcare Research and Quality (AHRQ) and the Institute for Healthcare Improvement (IHI) as a strategy for taking universal precautions for health literacy. Patients are asked to repeat the instructions they receive from their health care professionals (HCPs). HCPs should use caring and plain language in a shame-free environment during patient education. By using the teach-back method, HCPs can assess patients’ understanding, and reteach or modify teaching if comprehension is not demonstrated. Patients have an important role in their health and their ability to understand health information has a significant impact on their health behavior and outcomes.

In our systematic research, we examined the effectiveness of using the teach-back method to understand health education as well as the impact of this method on patients’ disease self-management and health outcomes.

Methods

In the teach-back method, patients explain health information in their own words.⁹ To gauge the use and effectiveness of this method, investigators have studied patient perceptions and acknowledgments of the method as well as the effects of the method on health interventions. According to Dorothea Orem’s self-care deficit nursing theory, disease self-management is an “executive ability” to “control, handle, direct or govern” self-care activities.¹⁰ We define disease self-management as disease knowledge and disease management changes that promote self-care activities. In addition, we define health outcomes as health changes that result from the teach-back method, such as changes in postdischarge readmission rates, patient satisfaction, and health behavior.

Inclusion Criteria

We systematically reviewed evidence regarding the teach-back method as an educational intervention for patients aged ≥ 18 years. We included articles if they reported the process and outcomes of using the method alone or in combination with other educational strategies. The literature search focused on English-language articles published in peer-reviewed journals. Included in the review were qualitative, randomized controlled trials (RCTs); quasi-experimental studies; cohort studies; and pretest–posttest studies on the effects of the teach-back method. As the method can be applied in any health care setting, we used studies conducted in a variety of settings, including primary care, inpatient, outpatient, emergency department (ED), and community, in any time frame. Study participants had heart failure, diabetes mellitus (DM), hypertension, asthma, or other chronic diseases.

Exclusion Criteria

Studies that used the teach-back method as an outcome measurement but not an intervention were excluded. For example, those that used the method to measure patients’ postintervention understanding were excluded. Also excluded were those that used the method to examine HCP training or to measure HCP outcomes (ie, studies that did not use the method for patient education or outcomes).

Literature Search

In September 2017, we searched 4 databases: Ovid Medline, PubMed, EBSCO (Elton B. Stephens Co), CINAHL (Cumulative Index to Nursing and Allied Health Literature), and ProQuest. Also included were relevant studies from cited reference searching (Figure).

This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline for searches and formatting results. The literature search was performed with the term teach-back and terms from the structured PICO (population, intervention, comparison, outcomes) statement. The study population consisted of patients who received the teach-back intervention as part of the patient education process in a medical care setting, and the comparator population consisted of patients who did not receive the intervention in their patient education. Target outcomes were disease self-management, self-care, patient satisfaction, patient perception and acknowledgment of the teach-back method, and other health outcomes.

Data Collection

Data collected included authors, publication date, and journal; purpose; study design; setting, sample, and population; intervention; and outcomes.

The methodologic quality of papers retrieved for review was determined with Critical Appraisals Skills Programme (CASP) guidelines (casp-uk.net/casp-tools-checklists). CASP randomised controlled trial, cohort study, case control study, and qualitative checklists were used. The authors assessed the full texts for eligibility. Disagreements were resolved through discussion.

The initial literature search found 112, 135, and 161 articles from EBSCO CINAHL, Ovid Medline, and PubMed, respectively. Five articles from ProQuest were identified through the EBSCO CINAHL search. After inclusion and exclusion criteria were applied, duplicate articles removed, a cited reference added, and CASP criteria assessed, 26 articles remained in the review. The 26 studies consisted of 15 cohort studies, 5 case–control studies, 5 RCTs, and 1 qualitative interview. Twenty-two of the articles were published in the US, the other 4 in Australia and Iran (2 each).^11-14 All 26 studies used the teach-back method with other educational interventions to reinforce learning (eg, the method was used after heart failure or DM education). Of the 26 studies, 10 used a pretest–posttest intervention design,^15-24 and 10 used a quasi-experimental or experimental design.^{11,13,14,25-31}

Results

The common outcome measures used in the 26 studies fall into 5 categories: patient satisfaction; postdischarge readmission; patient perception of teach-back method effectiveness; disease knowledge and disease management improvements; and intervention effects on health-related quality of life (HR-QOL). A summary of included articles, study setting, design, outcomes, and details is available from the author.

Patient Satisfaction

Ten studies examined the impact of the teach-back method on patient satisfaction.^{15,17,19,21,23,26,27,29,31,32} Of these 10 studies, 6 explored the influence of the method on Hospital Consumer Assessment of Healthcare Providers and Systems survey scores.^{15,17,19,21,22,26} All included studies indicated improved satisfaction with medication education, discharge information, and health management—except for the Silva study, who found an upward trend but not a statistically significant improvement in patient understanding of the purpose of a medication.²³

Grice and colleagues also found that community-dwelling seniors expressed satisfaction with using the teach-back method while being evaluated and assessed for health services at home.³² Improvement or a positive trend in teach-back groups was reported in a majority of the studies except for those by Hyrkas and Wiggins, and Griffey and colleagues.^27,29 Hyrkas and Wiggins found the method slightly improved patients’ medication confidence after hospital discharge, though patient satisfaction scores were associated with patient–nurse relationships, not with use of the teach-back method and a motivational interview.²⁷ Similarly, Griffey and colleagues found that patients who had limited health literacy and received a standard discharge with teach-back scored higher on medication comprehension, compared with patients who received only a standard discharge, but there was no difference in patient satisfaction after an ED visit.²⁹

Postdischarge Readmission

Results emphasized the importance of teach-back in reinforcing discharge instructions and improving postdischarge readmission rates. Of the 6 studies on the effect that teach-back with discharge summary had on readmission rates, 2 found statistically significant improvement for patients with heart failure at 12 months (teach-back, 59%; non-teach-back, 44%; P = .005) and patients with coronary artery bypass grafting (CABG) at 30 days (preintervention, 25%; postintervention, 12%; P = .02).^11,16 In addition, 3 of the 6 studies reported improvement but did not provide P values.^18,20,22 One study indicated improvement in other measured outcomes but found no significant difference for patients who received teach-back with their discharge summaries.²⁷ In all studies, teach-back was added to an intervention and used to confirm and promote knowledge and self-care management.

Patient Perception of Teach-Back Effectiveness

In 2 qualitative studies, patients indicated teach-back was an effective educational method.^16,33 For patients with CABG, Bates and colleagues added a scheduled cardiology follow-up appointment and teach-back patient education to their State Action on Avoidable Rehospitalizations interventions; 96% of participants rated teach-back effective or highly effective.¹⁶ In the other study, Samuels-Kalow and colleagues interviewed 51 patients and parents who received teach-back as part of the discharge process in 2 EDs; participants indicated teach-back helped them remember what they learned from their HCPs, and gave them the opportunity to connect with their HCPs, though some with lower health literacy expressed concerns about perceived judgment by HCPs.³³

Disease Knowledge and Management

Thirteen studies examined knowledge improvement after interventions that included teach-back. Study participants answered most questions correctly after receiving teach-back.^20,32,34,35 Slater and colleagues found ED patients who received discharge instructions with teach-back had significantly higher scores measuring knowledge of diagnosis (P < .001), signs and symptoms indicating a need to return to the ED (P < .001), and follow-up instructions (P = .03); scores measuring knowledge of medication were higher as well, but were not statistically different (P = .14).²⁴ In multiple studies, improvement was not always statistically significant in terms of knowledge retention.^{12,25,29-31,36} Studies that compared medication adherence found teach-back was more effective than motivational interviews (P = .56).²⁷

Teach-back has been widely used in primary care, inpatient, and ED settings. Two studies on the effect of teach-back in primary care sampled patients with DM.^28,36 Kandula and colleagues found that participants who answered questions incorrectly after watching a multimedia DM education program could significantly improve their DM knowledge by engaging in teach-back immediately after the intervention; however, knowledge retention was not improved at 2-week follow-up (phone call).²⁸ In contrast, Swavely and colleagues compared patients who completed a 13-hour DM education program with or without teach-back and found that teach-back patients demonstrated significantly improved DM knowledge and self-care activities at 3 months.³⁶

Effects of Interventions on HR-QOL

The teach-back method had been used with QOL improvement programs and other interventions. Ahmadidarrehsima and colleagues incorporated teach-back into their medical self-management program (8 to 11 sessions, each lasting 1.5 to 2 hours) for women with breast cancer and found that the mean happiness score increased to 62.9 from 37.2 (P < .001) in the intervention group, whereas the score for the usual-care group decreased from 41.4 to 29.8.¹³ Ghiasvand and colleagues compared QOL of postpartum mothers who received routine care with QOL of those who received routine care plus 2 sessions of postpartum self-care with teach-back; mean QOL scores were significantly (P < .001) higher for the teach-back group (124.73) than for the no teach-back group (115.03).¹⁴

Discussion

This review examined the use and effectiveness of the teach-back method in health education and its influence in patients’ disease self-management and health outcomes. Results showed positive effects of teach-back on patient satisfaction, patient perceptions and acknowledgments, postdischarge readmissions, disease self-management and knowledge, and HR-QOL.

The teach-back method has been widely used in inpatient, outpatient, ED, and community settings as part of health education programs and interventions. It has been paired with educational interventions ranging from short instructions to 20-hour programs. These differences reflect the broad application of the method in patient education. Many studies have found that teach-back improves disease knowledge and self-management, though their results are not always statistically significant. In an RCT of patients with low health literacy, Griffey and colleagues studied the effect of ED discharge education with and without teach-back and found teach-back did not increase post-ED comprehension of diagnoses, medical examinations, and treatments or perceived comprehension of treatment and care; however, compared with the no teach-back group, the teach-back group had significantly higher scores on comprehension of post-ED self-care (P < .02), follow-up (P < .0001), and medication (P = .054).²⁹ This finding indicates teach-back is an effective method for helping patients understand self-care and disease self-management at home.

Comprehending medical diagnoses, examinations, and treatments involves acquiring, analyzing, and comparing multiple pieces of health information. Because comprehension requires a level of abstract thinking usually present in patients with intermediate and proficient health literacy,improvements might be more difficult to see in patients with low health literacy.⁸ Press and colleagues found that asthma patients who repeated respiratory inhaler instructions with teach-back during discharge education had less misuse of (P = .01) metered-dose and Diskus (P = .05) inhalers and lower 30-day readmission rates (P = .02) compared with the misuse of patients who received only 1 set of oral and written instructions.³¹ Even though the Diskus result was not statistically significant, it demonstrated teach-back can be used to improve patient self-care and education.³¹

Most participants in the reviewed studies improved their disease knowledge with teach-back, though the evidence regarding improved health care knowledge retention was limited. For example, the 2 studies on use of teach-back in primary care clinics had contradictory knowledge retention results.^28,36 As both studies incorporated teach-back into existing interventions, these results could be associated with those interventions and not with the teach-back method.

Health literacy is achieved through a complicated process of obtaining, analyzing, choosing, and communicating health information. Even though its knowledge retention results are inconsistent, the teach-back method is recommended by the American Academy of Family Physicians at strength of recommendation taxonomy level C.⁸ Such a designation indicates that the recommendation is based on expert opinion, bench research, consensus guideline, usual practice, clinical experience, or a case series and is appropriate for assessment of patient comprehension.³⁷ Teach-back is also suggested by AHRQ and IHI for university precautions regarding health literacy and as such should remain a standard of practice. More study is needed to understand the inconsistent results of knowledge retention and the long-term effects of the teach-back method.

Limitations

Although this review did not limit the publication years of its articles, no pre-2011 articles were found. The teach-back method has been used to measure patients’ postintervention understanding and to educate HCPs on ways to improve patient communication. As this review did not include studies of teach-back as an outcome measurement or studies of training and adaptation of teach-back in HCP or nurse education, other study results may have a bearing on the current findings. Teach-back has been used to close communication gaps between patients and HCPs.

All articles included in this review used the teach-back method with other educational or organizational interventions. The outcomes found in this review may be associated with those interventions and not with teach-back itself. Data reported here have not demonstrated a definite association between teach-back and the measured outcomes; therefore, caution should be exercised when drawing conclusions based on these data. In addition, most of the studies considered in this review were cohort or case–control studies; only 5 RCTs were included. Other confounding factors, including patient health literacy levels, HCP types, HCP competencies in use of teach-back, and type and duration of interventions used before teach-back, may have contributed to this review’s findings.

Conclusion

Findings of this systematic review support use of the teach-back method as effective in reinforcing or confirming patient education. As none of the included studies reported harmful outcomes, the teach-back method poses little risk with respect to increasing patients’ understanding of their education. The findings emphasize the importance of conducting more studies to try to understand the inconsistent results of knowledge retention and determine ways to preserve the long-term effects of teach-back.

ANSWER

The correct interpretation includes normal sinus rhythm, possible left atrial enlargement (LAE), and left ventricular hypertrophy (LVH).

Normal sinus rhythm is defined as a P for every QRS and a QRS for every P, with a normal PR interval and a rate > 60 and < 100 beats/min.

Criteria for LAE include a P wave > 120 ms in lead II and/or a biphasic P wave in lead V₁ with a downward deflection > 40 ms in length with a > 1-mm negative deflection. This ECG does not meet criteria for LAE; however, it is suspicious, particularly in the context of mitral regurgitation and LVH.

LVH is diagnosed using either the Sokolow-Lyon criteria (the sum of the S wave in V₁ and the R wave in V₅ or V₆ ≥ 35 mm) or the Cornell voltage criteria (the S in V₃ plus the R in aVL > 20 mm for women [> 28 mm for men]).

LVH is usually not a target of therapy. Management is typically directed at treating the underlying pathology. For this patient, it is important to manage her hypertension and provide follow-up—including periodic echocardiography of her left atrium, mitral valve, and left ventricle—to determine response to hypertensive therapy.

ANSWER

The correct interpretation includes normal sinus rhythm, possible left atrial enlargement (LAE), and left ventricular hypertrophy (LVH).

Normal sinus rhythm is defined as a P for every QRS and a QRS for every P, with a normal PR interval and a rate > 60 and < 100 beats/min.

Criteria for LAE include a P wave > 120 ms in lead II and/or a biphasic P wave in lead V₁ with a downward deflection > 40 ms in length with a > 1-mm negative deflection. This ECG does not meet criteria for LAE; however, it is suspicious, particularly in the context of mitral regurgitation and LVH.

LVH is diagnosed using either the Sokolow-Lyon criteria (the sum of the S wave in V₁ and the R wave in V₅ or V₆ ≥ 35 mm) or the Cornell voltage criteria (the S in V₃ plus the R in aVL > 20 mm for women [> 28 mm for men]).

LVH is usually not a target of therapy. Management is typically directed at treating the underlying pathology. For this patient, it is important to manage her hypertension and provide follow-up—including periodic echocardiography of her left atrium, mitral valve, and left ventricle—to determine response to hypertensive therapy.

ANSWER

The correct interpretation includes normal sinus rhythm, possible left atrial enlargement (LAE), and left ventricular hypertrophy (LVH).

Normal sinus rhythm is defined as a P for every QRS and a QRS for every P, with a normal PR interval and a rate > 60 and < 100 beats/min.

Criteria for LAE include a P wave > 120 ms in lead II and/or a biphasic P wave in lead V₁ with a downward deflection > 40 ms in length with a > 1-mm negative deflection. This ECG does not meet criteria for LAE; however, it is suspicious, particularly in the context of mitral regurgitation and LVH.

LVH is diagnosed using either the Sokolow-Lyon criteria (the sum of the S wave in V₁ and the R wave in V₅ or V₆ ≥ 35 mm) or the Cornell voltage criteria (the S in V₃ plus the R in aVL > 20 mm for women [> 28 mm for men]).

LVH is usually not a target of therapy. Management is typically directed at treating the underlying pathology. For this patient, it is important to manage her hypertension and provide follow-up—including periodic echocardiography of her left atrium, mitral valve, and left ventricle—to determine response to hypertensive therapy.

CHICAGO – For colorectal cancer patients with liver metastases, laparoscopic surgery has short-term advantages over open surgery, including fewer complications and better quality of life as compared to open surgery. Now, there are data to show that long-term outcomes with the laparoscopic approach aren’t any worse with the laparoscopic approach.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Åsmund Avdem Fretland, MD, discusses results of the 280-patient randomized OSLO-COMET study, including 5-year survival of 56% for the laparoscopic approach, and similarly, 57% for the open procedure.

Based on lower morbidity, and now similar life expectancy, more centers should be doing laparoscopic procedures for liver metastases, said Dr. Fretland, a surgeon in the department of HPB surgery at Oslo University Hospital.

For now, however, open surgery appears to be the dominant approach. According to a recent survey, just 22% of U.S. patients with colorectal liver metastases have laparoscopic surgery.

More data could help. Dr. Fretland said in the interview that more randomized trials are underway aimed at evaluating the long-term outcomes of laparoscopic versus open procedures.

Dr. Fretland reported honoraria from Olympus Medical Systems.

CHICAGO – For colorectal cancer patients with liver metastases, laparoscopic surgery has short-term advantages over open surgery, including fewer complications and better quality of life as compared to open surgery. Now, there are data to show that long-term outcomes with the laparoscopic approach aren’t any worse with the laparoscopic approach.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Åsmund Avdem Fretland, MD, discusses results of the 280-patient randomized OSLO-COMET study, including 5-year survival of 56% for the laparoscopic approach, and similarly, 57% for the open procedure.

Based on lower morbidity, and now similar life expectancy, more centers should be doing laparoscopic procedures for liver metastases, said Dr. Fretland, a surgeon in the department of HPB surgery at Oslo University Hospital.

For now, however, open surgery appears to be the dominant approach. According to a recent survey, just 22% of U.S. patients with colorectal liver metastases have laparoscopic surgery.

More data could help. Dr. Fretland said in the interview that more randomized trials are underway aimed at evaluating the long-term outcomes of laparoscopic versus open procedures.

Dr. Fretland reported honoraria from Olympus Medical Systems.

CHICAGO – For colorectal cancer patients with liver metastases, laparoscopic surgery has short-term advantages over open surgery, including fewer complications and better quality of life as compared to open surgery. Now, there are data to show that long-term outcomes with the laparoscopic approach aren’t any worse with the laparoscopic approach.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Åsmund Avdem Fretland, MD, discusses results of the 280-patient randomized OSLO-COMET study, including 5-year survival of 56% for the laparoscopic approach, and similarly, 57% for the open procedure.

Based on lower morbidity, and now similar life expectancy, more centers should be doing laparoscopic procedures for liver metastases, said Dr. Fretland, a surgeon in the department of HPB surgery at Oslo University Hospital.

For now, however, open surgery appears to be the dominant approach. According to a recent survey, just 22% of U.S. patients with colorectal liver metastases have laparoscopic surgery.

More data could help. Dr. Fretland said in the interview that more randomized trials are underway aimed at evaluating the long-term outcomes of laparoscopic versus open procedures.

Dr. Fretland reported honoraria from Olympus Medical Systems.