User login
Outcomes and Barriers Associated with Telehealth-Based Hepatitis C Treatment During Early Phases of the COVID-19 Pandemic
Although 2.4 million adults in the United States have been diagnosed with hepatitis C virus (HCV) infection, it remains underdiagnosed and undertreated, particularly among difficult to reach populations, such as persons who inject drugs, marginally housed individuals, correctional populations, and pregnant women.1 Though the US Preventive Services Task Force (USPSTF) broadened HCV screening recommendations to include individuals aged 18 to 79 years, rates of new HCV prescriptions sharply declined during the COVID-19 pandemic.2,3
During the pandemic, many health care systems adopted virtual health care modalities. Within the Veteran Health Administration (VHA), there was an 11-fold increase in virtual encounters. However, veterans aged > 45 years, homeless, and had other insurance were less likely to utilize virtual care.4,5 As health care delivery continues to evolve, health systems must adapt and test innovative models for the treatment of HCV.
There is limited understanding of HCV treatments when exclusively conducted virtually. The aim of this study was to evaluate the effects of the HCV treatment program at the Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS) during the early phase of the COVID-19 pandemic, when telehealth modalities and mail-order prescriptions were used for HCV diagnosis and treatment. The secondary aim of this study was to understand patient factors associated with treatment initiation and discontinuation for patients using telehealth.
Methods
The VHA is the largest provider of HCV care in the US.6 At VAGLAHS, veterans with HCV are referred for evaluation to a viral hepatitis clinic staffed by gastroenterologists and infectious disease specialists. Veterans with detectable HCV on an HCV RNA test have an additional workup ordered if necessary and are referred to an HCV-specialist pharmacist or physician’s assistant to start treatment. In March 2020, all HCV evaluations and treatment initiation in the viral hepatitis clinic started being conducted exclusively via telehealth. This was the primary modality of HCV evaluations and treatment initiation until COVID-19 restrictions were lifted to permit in-person evaluations. Prescriptions were delivered by mail to patients following treatment initiation appointments.
We retrospectively reviewed electronic health records of veterans referred to start treatment March 1, 2020, through September 30, 2020. The endpoint of the reviewed records was set because during this specific time frame, VAGLAHS used an exclusively telehealth-based model for HCV evaluation and treatment. Patients were followed until June 15, 2021. Due to evolving COVID-19 restrictions at the time, and despite requests received, treatment initiations by the pharmacy team were suspended in March 2020 but HCV treatments resumed in May. Data collected included baseline demographics (age, sex, race, ethnicity, housing status, distance to VAGLAHS), comorbidities (cirrhosis, hepatitis B virus coinfection, HIV coinfection), psychiatric conditions (mood or psychotic disorder, alcohol use disorder [AUD], opioid use disorder), and treatment characteristics (HCV genotype, HCV treatment regimen, baseline viral load). Distance from the patient’s home to VAGLAHS was calculated using CDXZipStream software. Comorbidities and psychiatric conditions were identified by the presence of the appropriate diagnosis via International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes in the health record and confirmed by review of clinician notes. Active AUD was defined as: (1) the presence of AUD diagnosis code; (2) AUD Identification Test-Consumption (AUDIT-C) score of high or severe risk based on established cutoffs; and (3) active alcohol use noted in the electronic health record. All patients had an AUDIT-C score completed within 1 year of initiating treatment. Opioid use disorder was defined by the presence of diagnostic codes for opioid dependence or opioid abuse.
The reasons for treatment noninitiation and discontinuation were each captured. We calculated descriptive statistics to analyze the frequency distributions of all variables. Independent t tests were used to analyze continuous data and Pearson χ2 test was used to analyze categorical data. Statistical significance was set as P < .05.
Results
From March 1, 2020, through September 30, 2020, 73 veterans were referred to the HCV clinical pharmacist for treatment (Figure). Forty-three veterans (59%) initiated HCV treatment and 34 (79%) completed the full treatment course (Table 1). Twenty-five patients (65%) had their sustained virologic response at 12 weeks (SVR12) testing and 22 patients achieved SVR12 (88%; 30% of total sample). One patient did not achieve SVR, and 2 patients died (variceal hemorrhage and progression of cerebral amyloidosis/function decline) before the completion of laboratory testing. From March 2020 to May 2020, HCV treatments requests were paused as new COVID-19 policies were being introduced; 33 patients were referred during this time and 21 initiated treatment.
Veterans that did not start HCV treatment had a significantly higher rate of active AUD when compared with those that initiated treatment: 30% vs 9% (P = .02). Of the patients who started and discontinued treatment, none had active AUD. Other baseline demographics, clinical characteristics, and treatment characteristics were similar between the groups. No patient demographic characteristics were significantly associated with HCV treatment discontinuation. We did not observe any major health disparities in initiation or discontinuation by sex, race, ethnicity, or geography. Eleven patients (37%) could not be contacted, which was the most common reason veterans did not initiate treatment (Table 2). Of the 9 patients that did not complete SVR12, 5 patients could not be contacted for follow-up, which was the most common reason veterans discontinued treatment.
Discussion
This study highlights the experience of treating patients with HCV with an exclusively telehealth model in the months following implementation of stay-at-home orders from March 19, 2020, to September 30, 2020, during the COVID-19 pandemic at VAGLAHS. We were able to successfully complete treatment for 34 veterans (47%) and achieved SVR rates of 88%. We found that AUD was associated with unsuccessful treatment initiation. There were no statistically significant patient characteristic findings for treatment discontinuation in our study (Table 3). Unhealthy alcohol use and AUD are highly prevalent among veterans with HCV and prior to the pandemic, studies have demonstrated AUD as a barrier to HCV treatment.7
Since worse hepatic outcomes have been observed in veterans with HCV and AUD and increased harmful patterns of drinking occurred during the pandemic, a renewed interest in treating AUD in these veterans during the era of telehealth is critical.8 While we were unable to ascertain whether alcohol misuse in our cohort increased during the pandemic or whether changes in drinking patterns affected HCV treatment outcomes before and after the pandemic, such an association should reinforce the need for clinicians to expeditiously link patients to substance use care. It should also stimulate further considerations of addressing social determinants of health not captured in this study.
During the pandemic, veterans with posttraumatic stress disorder, a history of serving in combat roles, and experiencing related financial stressors had higher risk of AUD.9,10 For veterans with AUD who initiated HCV treatment, none discontinued their therapy, aligning with other studies showed that patients with AUD were able to achieve high rates of SVR and emphasizing that veterans should be treated irrespective of an AUD diagnosis.11 However, more innovative engagement initiatives for veterans with AUD should be explored as we continue to adapt more telehealth-based care for HCV direct-acting antiviral treatments. A more in-depth understanding of how alcohol use relates to treatment noninitiation is warranted, as this may stem from behavioral patterns that could not be captured in the present study.
The inability to reach veterans by telephone was a major reason for noninitiation and discontinuation of treatment. While the expansion of telehealth services has been noted across the VHA, there is still room for improving methods of engaging veterans in health care postpandemic.12 Prior studies in veteran populations that were successful in increasing uptake of HCV treatment have employed telehealth strategies that further emphasizes its integral role in HCV elimination.13 Although our study did not show mental health comorbidities and housing status as statistically significant, it is important to note that 20% of patients referred for HCV treatment had an incomplete evaluation which can lead to potentially unobserved indicators not captured by our study such as quality of linkage to care. It is imperative to stress the best practices for HCV initiation by integrating a multidisciplinary team to address patients’ psychosocial comorbidities.14 Finally, we did not observe any major disparities in treating veterans with HCV during the pandemic. This observation is reassuring and consistent with other VHA data given the heightened recognition of health disparities seen in health care sectors across the country, especially evident during the COVID-19 pandemic and the current era of increased adaptation of telehealth.
Limitations
Limitations to this study include its retrospective nature, small sample size, and short study time frame as a proportion of veterans have yet to complete HCV treatment which can potentially explain how larger studies were able to find other statistically significant patient-related factors impacting treatment initiation compared to ours. Given the lack of universal standardized diagnostic criterion of AUD, this can limit how our study can be compared to others in similar populations. Additionally, this study was conducted at a single facility with a predominantly older male veteran population, which may not be generalizable to other populations.
Conclusions
Treating HCV during the COVID-19 pandemic with telehealth and mail-out medications was feasible and led to high SVR rates, but unhealthy alcohol use and an inability to contact veterans were predominant barriers to success. Future quality improvement efforts should focus on addressing these barriers and exploring the relationship between alcohol use and HCV treatment initiation.
1. Patel AA, Bui A, Prohl E, et al. Innovations in Hepatitis C Screening and Treatment. Hepatol Commun. 2020;5(3):371-386. Published 2020 Dec 7. doi:10.1002/hep4.1646
2. US Preventive Services Task Force, Owens DK, Davidson KW, et al. Screening for Hepatitis C Virus Infection in Adolescents and Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2020;323(10):970-975. doi:10.1001/jama.2020.1123
3. Kaufman HW, Bull-Otterson L, Meyer WA 3rd, et al. Decreases in Hepatitis C Testing and Treatment During the COVID-19 Pandemic. Am J Prev Med. 2021;61(3):369-376. doi:10.1016/j.amepre.2021.03.011
4. Rosen CS, Morland LA, Glassman LH, et al. Virtual mental health care in the Veterans Health Administration’s immediate response to coronavirus disease-19. Am Psychol. 2021;76(1):26-38. doi:10.1037/amp0000751
5. Balut MD, Wyte-Lake T, Steers WN, et al. Expansion of telemedicine during COVID-19 at a VA specialty clinic. Healthc (Amst). 2022;10(1):100599. doi:10.1016/j.hjdsi.2021.100599
6. Belperio PS, Chartier M, Ross DB, Alaigh P, Shulkin D. Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs. Ann Intern Med. 2017;167(7):499-504. doi:10.7326/M17-1073
7. Lin M, Kramer J, White D, et al. Barriers to hepatitis C treatment in the era of direct-acting anti-viral agents. Aliment Pharmacol Ther. 2017;46(10):992-1000. doi:10.1111/apt.14328
8. Alavi M, Janjua NZ, Chong M, et al. The contribution of alcohol use disorder to decompensated cirrhosis among people with hepatitis C: An international study. J Hepatol. 2018;68(3):393-401. doi:10.1016/j.jhep.2017.10.019
9. Pedersen ER, Davis JP, Fitzke RE, Lee DS, Saba S. American Veterans in the Era of COVID-19: Reactions to the Pandemic, Posttraumatic Stress Disorder, and Substance Use Behaviors. Int J Ment Health Addict. 2023;21(2):767-782. doi:10.1007/s11469-021-00620-0
10. Na PJ, Norman SB, Nichter B, et al. Prevalence, risk and protective factors of alcohol use disorder during the COVID-19 pandemic in U.S. military veterans. Drug Alcohol Depend. 2021;225:108818. doi:10.1016/j.drugalcdep.2021.108818
11. Tsui JI, Williams EC, Green PK, Berry K, Su F, Ioannou GN. Alcohol use and hepatitis C virus treatment outcomes among patients receiving direct antiviral agents. Drug Alcohol Depend. 2016;169:101-109. doi:10.1016/j.drugalcdep.2016.10.021
12. Baum A, Kaboli PJ, Schwartz MD. Reduced In-Person and Increased Telehealth Outpatient Visits During the COVID-19 Pandemic. Ann Intern Med. 2021;174(1):129-131. doi:10.7326/M20-3026
13. Fleming BS, Ifeachor AP, Andres AM, et al. Improving Veteran Access to Treatment for Hepatitis C Virus Infection: Addressing social issues and treatment barriers significantly increases access to HCV care, and many veterans successfully start therapy with the help of additional support staff. Fed Pract. 2017;34(Suppl 4):S24-S28.
14. Belperio PS, Chartier M, Ross DB, Alaigh P, Shulkin D. Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs. Ann Intern Med. 2017;167(7):499-504. doi:10.7326/M17-1073
Although 2.4 million adults in the United States have been diagnosed with hepatitis C virus (HCV) infection, it remains underdiagnosed and undertreated, particularly among difficult to reach populations, such as persons who inject drugs, marginally housed individuals, correctional populations, and pregnant women.1 Though the US Preventive Services Task Force (USPSTF) broadened HCV screening recommendations to include individuals aged 18 to 79 years, rates of new HCV prescriptions sharply declined during the COVID-19 pandemic.2,3
During the pandemic, many health care systems adopted virtual health care modalities. Within the Veteran Health Administration (VHA), there was an 11-fold increase in virtual encounters. However, veterans aged > 45 years, homeless, and had other insurance were less likely to utilize virtual care.4,5 As health care delivery continues to evolve, health systems must adapt and test innovative models for the treatment of HCV.
There is limited understanding of HCV treatments when exclusively conducted virtually. The aim of this study was to evaluate the effects of the HCV treatment program at the Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS) during the early phase of the COVID-19 pandemic, when telehealth modalities and mail-order prescriptions were used for HCV diagnosis and treatment. The secondary aim of this study was to understand patient factors associated with treatment initiation and discontinuation for patients using telehealth.
Methods
The VHA is the largest provider of HCV care in the US.6 At VAGLAHS, veterans with HCV are referred for evaluation to a viral hepatitis clinic staffed by gastroenterologists and infectious disease specialists. Veterans with detectable HCV on an HCV RNA test have an additional workup ordered if necessary and are referred to an HCV-specialist pharmacist or physician’s assistant to start treatment. In March 2020, all HCV evaluations and treatment initiation in the viral hepatitis clinic started being conducted exclusively via telehealth. This was the primary modality of HCV evaluations and treatment initiation until COVID-19 restrictions were lifted to permit in-person evaluations. Prescriptions were delivered by mail to patients following treatment initiation appointments.
We retrospectively reviewed electronic health records of veterans referred to start treatment March 1, 2020, through September 30, 2020. The endpoint of the reviewed records was set because during this specific time frame, VAGLAHS used an exclusively telehealth-based model for HCV evaluation and treatment. Patients were followed until June 15, 2021. Due to evolving COVID-19 restrictions at the time, and despite requests received, treatment initiations by the pharmacy team were suspended in March 2020 but HCV treatments resumed in May. Data collected included baseline demographics (age, sex, race, ethnicity, housing status, distance to VAGLAHS), comorbidities (cirrhosis, hepatitis B virus coinfection, HIV coinfection), psychiatric conditions (mood or psychotic disorder, alcohol use disorder [AUD], opioid use disorder), and treatment characteristics (HCV genotype, HCV treatment regimen, baseline viral load). Distance from the patient’s home to VAGLAHS was calculated using CDXZipStream software. Comorbidities and psychiatric conditions were identified by the presence of the appropriate diagnosis via International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes in the health record and confirmed by review of clinician notes. Active AUD was defined as: (1) the presence of AUD diagnosis code; (2) AUD Identification Test-Consumption (AUDIT-C) score of high or severe risk based on established cutoffs; and (3) active alcohol use noted in the electronic health record. All patients had an AUDIT-C score completed within 1 year of initiating treatment. Opioid use disorder was defined by the presence of diagnostic codes for opioid dependence or opioid abuse.
The reasons for treatment noninitiation and discontinuation were each captured. We calculated descriptive statistics to analyze the frequency distributions of all variables. Independent t tests were used to analyze continuous data and Pearson χ2 test was used to analyze categorical data. Statistical significance was set as P < .05.
Results
From March 1, 2020, through September 30, 2020, 73 veterans were referred to the HCV clinical pharmacist for treatment (Figure). Forty-three veterans (59%) initiated HCV treatment and 34 (79%) completed the full treatment course (Table 1). Twenty-five patients (65%) had their sustained virologic response at 12 weeks (SVR12) testing and 22 patients achieved SVR12 (88%; 30% of total sample). One patient did not achieve SVR, and 2 patients died (variceal hemorrhage and progression of cerebral amyloidosis/function decline) before the completion of laboratory testing. From March 2020 to May 2020, HCV treatments requests were paused as new COVID-19 policies were being introduced; 33 patients were referred during this time and 21 initiated treatment.
Veterans that did not start HCV treatment had a significantly higher rate of active AUD when compared with those that initiated treatment: 30% vs 9% (P = .02). Of the patients who started and discontinued treatment, none had active AUD. Other baseline demographics, clinical characteristics, and treatment characteristics were similar between the groups. No patient demographic characteristics were significantly associated with HCV treatment discontinuation. We did not observe any major health disparities in initiation or discontinuation by sex, race, ethnicity, or geography. Eleven patients (37%) could not be contacted, which was the most common reason veterans did not initiate treatment (Table 2). Of the 9 patients that did not complete SVR12, 5 patients could not be contacted for follow-up, which was the most common reason veterans discontinued treatment.
Discussion
This study highlights the experience of treating patients with HCV with an exclusively telehealth model in the months following implementation of stay-at-home orders from March 19, 2020, to September 30, 2020, during the COVID-19 pandemic at VAGLAHS. We were able to successfully complete treatment for 34 veterans (47%) and achieved SVR rates of 88%. We found that AUD was associated with unsuccessful treatment initiation. There were no statistically significant patient characteristic findings for treatment discontinuation in our study (Table 3). Unhealthy alcohol use and AUD are highly prevalent among veterans with HCV and prior to the pandemic, studies have demonstrated AUD as a barrier to HCV treatment.7
Since worse hepatic outcomes have been observed in veterans with HCV and AUD and increased harmful patterns of drinking occurred during the pandemic, a renewed interest in treating AUD in these veterans during the era of telehealth is critical.8 While we were unable to ascertain whether alcohol misuse in our cohort increased during the pandemic or whether changes in drinking patterns affected HCV treatment outcomes before and after the pandemic, such an association should reinforce the need for clinicians to expeditiously link patients to substance use care. It should also stimulate further considerations of addressing social determinants of health not captured in this study.
During the pandemic, veterans with posttraumatic stress disorder, a history of serving in combat roles, and experiencing related financial stressors had higher risk of AUD.9,10 For veterans with AUD who initiated HCV treatment, none discontinued their therapy, aligning with other studies showed that patients with AUD were able to achieve high rates of SVR and emphasizing that veterans should be treated irrespective of an AUD diagnosis.11 However, more innovative engagement initiatives for veterans with AUD should be explored as we continue to adapt more telehealth-based care for HCV direct-acting antiviral treatments. A more in-depth understanding of how alcohol use relates to treatment noninitiation is warranted, as this may stem from behavioral patterns that could not be captured in the present study.
The inability to reach veterans by telephone was a major reason for noninitiation and discontinuation of treatment. While the expansion of telehealth services has been noted across the VHA, there is still room for improving methods of engaging veterans in health care postpandemic.12 Prior studies in veteran populations that were successful in increasing uptake of HCV treatment have employed telehealth strategies that further emphasizes its integral role in HCV elimination.13 Although our study did not show mental health comorbidities and housing status as statistically significant, it is important to note that 20% of patients referred for HCV treatment had an incomplete evaluation which can lead to potentially unobserved indicators not captured by our study such as quality of linkage to care. It is imperative to stress the best practices for HCV initiation by integrating a multidisciplinary team to address patients’ psychosocial comorbidities.14 Finally, we did not observe any major disparities in treating veterans with HCV during the pandemic. This observation is reassuring and consistent with other VHA data given the heightened recognition of health disparities seen in health care sectors across the country, especially evident during the COVID-19 pandemic and the current era of increased adaptation of telehealth.
Limitations
Limitations to this study include its retrospective nature, small sample size, and short study time frame as a proportion of veterans have yet to complete HCV treatment which can potentially explain how larger studies were able to find other statistically significant patient-related factors impacting treatment initiation compared to ours. Given the lack of universal standardized diagnostic criterion of AUD, this can limit how our study can be compared to others in similar populations. Additionally, this study was conducted at a single facility with a predominantly older male veteran population, which may not be generalizable to other populations.
Conclusions
Treating HCV during the COVID-19 pandemic with telehealth and mail-out medications was feasible and led to high SVR rates, but unhealthy alcohol use and an inability to contact veterans were predominant barriers to success. Future quality improvement efforts should focus on addressing these barriers and exploring the relationship between alcohol use and HCV treatment initiation.
Although 2.4 million adults in the United States have been diagnosed with hepatitis C virus (HCV) infection, it remains underdiagnosed and undertreated, particularly among difficult to reach populations, such as persons who inject drugs, marginally housed individuals, correctional populations, and pregnant women.1 Though the US Preventive Services Task Force (USPSTF) broadened HCV screening recommendations to include individuals aged 18 to 79 years, rates of new HCV prescriptions sharply declined during the COVID-19 pandemic.2,3
During the pandemic, many health care systems adopted virtual health care modalities. Within the Veteran Health Administration (VHA), there was an 11-fold increase in virtual encounters. However, veterans aged > 45 years, homeless, and had other insurance were less likely to utilize virtual care.4,5 As health care delivery continues to evolve, health systems must adapt and test innovative models for the treatment of HCV.
There is limited understanding of HCV treatments when exclusively conducted virtually. The aim of this study was to evaluate the effects of the HCV treatment program at the Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS) during the early phase of the COVID-19 pandemic, when telehealth modalities and mail-order prescriptions were used for HCV diagnosis and treatment. The secondary aim of this study was to understand patient factors associated with treatment initiation and discontinuation for patients using telehealth.
Methods
The VHA is the largest provider of HCV care in the US.6 At VAGLAHS, veterans with HCV are referred for evaluation to a viral hepatitis clinic staffed by gastroenterologists and infectious disease specialists. Veterans with detectable HCV on an HCV RNA test have an additional workup ordered if necessary and are referred to an HCV-specialist pharmacist or physician’s assistant to start treatment. In March 2020, all HCV evaluations and treatment initiation in the viral hepatitis clinic started being conducted exclusively via telehealth. This was the primary modality of HCV evaluations and treatment initiation until COVID-19 restrictions were lifted to permit in-person evaluations. Prescriptions were delivered by mail to patients following treatment initiation appointments.
We retrospectively reviewed electronic health records of veterans referred to start treatment March 1, 2020, through September 30, 2020. The endpoint of the reviewed records was set because during this specific time frame, VAGLAHS used an exclusively telehealth-based model for HCV evaluation and treatment. Patients were followed until June 15, 2021. Due to evolving COVID-19 restrictions at the time, and despite requests received, treatment initiations by the pharmacy team were suspended in March 2020 but HCV treatments resumed in May. Data collected included baseline demographics (age, sex, race, ethnicity, housing status, distance to VAGLAHS), comorbidities (cirrhosis, hepatitis B virus coinfection, HIV coinfection), psychiatric conditions (mood or psychotic disorder, alcohol use disorder [AUD], opioid use disorder), and treatment characteristics (HCV genotype, HCV treatment regimen, baseline viral load). Distance from the patient’s home to VAGLAHS was calculated using CDXZipStream software. Comorbidities and psychiatric conditions were identified by the presence of the appropriate diagnosis via International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes in the health record and confirmed by review of clinician notes. Active AUD was defined as: (1) the presence of AUD diagnosis code; (2) AUD Identification Test-Consumption (AUDIT-C) score of high or severe risk based on established cutoffs; and (3) active alcohol use noted in the electronic health record. All patients had an AUDIT-C score completed within 1 year of initiating treatment. Opioid use disorder was defined by the presence of diagnostic codes for opioid dependence or opioid abuse.
The reasons for treatment noninitiation and discontinuation were each captured. We calculated descriptive statistics to analyze the frequency distributions of all variables. Independent t tests were used to analyze continuous data and Pearson χ2 test was used to analyze categorical data. Statistical significance was set as P < .05.
Results
From March 1, 2020, through September 30, 2020, 73 veterans were referred to the HCV clinical pharmacist for treatment (Figure). Forty-three veterans (59%) initiated HCV treatment and 34 (79%) completed the full treatment course (Table 1). Twenty-five patients (65%) had their sustained virologic response at 12 weeks (SVR12) testing and 22 patients achieved SVR12 (88%; 30% of total sample). One patient did not achieve SVR, and 2 patients died (variceal hemorrhage and progression of cerebral amyloidosis/function decline) before the completion of laboratory testing. From March 2020 to May 2020, HCV treatments requests were paused as new COVID-19 policies were being introduced; 33 patients were referred during this time and 21 initiated treatment.
Veterans that did not start HCV treatment had a significantly higher rate of active AUD when compared with those that initiated treatment: 30% vs 9% (P = .02). Of the patients who started and discontinued treatment, none had active AUD. Other baseline demographics, clinical characteristics, and treatment characteristics were similar between the groups. No patient demographic characteristics were significantly associated with HCV treatment discontinuation. We did not observe any major health disparities in initiation or discontinuation by sex, race, ethnicity, or geography. Eleven patients (37%) could not be contacted, which was the most common reason veterans did not initiate treatment (Table 2). Of the 9 patients that did not complete SVR12, 5 patients could not be contacted for follow-up, which was the most common reason veterans discontinued treatment.
Discussion
This study highlights the experience of treating patients with HCV with an exclusively telehealth model in the months following implementation of stay-at-home orders from March 19, 2020, to September 30, 2020, during the COVID-19 pandemic at VAGLAHS. We were able to successfully complete treatment for 34 veterans (47%) and achieved SVR rates of 88%. We found that AUD was associated with unsuccessful treatment initiation. There were no statistically significant patient characteristic findings for treatment discontinuation in our study (Table 3). Unhealthy alcohol use and AUD are highly prevalent among veterans with HCV and prior to the pandemic, studies have demonstrated AUD as a barrier to HCV treatment.7
Since worse hepatic outcomes have been observed in veterans with HCV and AUD and increased harmful patterns of drinking occurred during the pandemic, a renewed interest in treating AUD in these veterans during the era of telehealth is critical.8 While we were unable to ascertain whether alcohol misuse in our cohort increased during the pandemic or whether changes in drinking patterns affected HCV treatment outcomes before and after the pandemic, such an association should reinforce the need for clinicians to expeditiously link patients to substance use care. It should also stimulate further considerations of addressing social determinants of health not captured in this study.
During the pandemic, veterans with posttraumatic stress disorder, a history of serving in combat roles, and experiencing related financial stressors had higher risk of AUD.9,10 For veterans with AUD who initiated HCV treatment, none discontinued their therapy, aligning with other studies showed that patients with AUD were able to achieve high rates of SVR and emphasizing that veterans should be treated irrespective of an AUD diagnosis.11 However, more innovative engagement initiatives for veterans with AUD should be explored as we continue to adapt more telehealth-based care for HCV direct-acting antiviral treatments. A more in-depth understanding of how alcohol use relates to treatment noninitiation is warranted, as this may stem from behavioral patterns that could not be captured in the present study.
The inability to reach veterans by telephone was a major reason for noninitiation and discontinuation of treatment. While the expansion of telehealth services has been noted across the VHA, there is still room for improving methods of engaging veterans in health care postpandemic.12 Prior studies in veteran populations that were successful in increasing uptake of HCV treatment have employed telehealth strategies that further emphasizes its integral role in HCV elimination.13 Although our study did not show mental health comorbidities and housing status as statistically significant, it is important to note that 20% of patients referred for HCV treatment had an incomplete evaluation which can lead to potentially unobserved indicators not captured by our study such as quality of linkage to care. It is imperative to stress the best practices for HCV initiation by integrating a multidisciplinary team to address patients’ psychosocial comorbidities.14 Finally, we did not observe any major disparities in treating veterans with HCV during the pandemic. This observation is reassuring and consistent with other VHA data given the heightened recognition of health disparities seen in health care sectors across the country, especially evident during the COVID-19 pandemic and the current era of increased adaptation of telehealth.
Limitations
Limitations to this study include its retrospective nature, small sample size, and short study time frame as a proportion of veterans have yet to complete HCV treatment which can potentially explain how larger studies were able to find other statistically significant patient-related factors impacting treatment initiation compared to ours. Given the lack of universal standardized diagnostic criterion of AUD, this can limit how our study can be compared to others in similar populations. Additionally, this study was conducted at a single facility with a predominantly older male veteran population, which may not be generalizable to other populations.
Conclusions
Treating HCV during the COVID-19 pandemic with telehealth and mail-out medications was feasible and led to high SVR rates, but unhealthy alcohol use and an inability to contact veterans were predominant barriers to success. Future quality improvement efforts should focus on addressing these barriers and exploring the relationship between alcohol use and HCV treatment initiation.
1. Patel AA, Bui A, Prohl E, et al. Innovations in Hepatitis C Screening and Treatment. Hepatol Commun. 2020;5(3):371-386. Published 2020 Dec 7. doi:10.1002/hep4.1646
2. US Preventive Services Task Force, Owens DK, Davidson KW, et al. Screening for Hepatitis C Virus Infection in Adolescents and Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2020;323(10):970-975. doi:10.1001/jama.2020.1123
3. Kaufman HW, Bull-Otterson L, Meyer WA 3rd, et al. Decreases in Hepatitis C Testing and Treatment During the COVID-19 Pandemic. Am J Prev Med. 2021;61(3):369-376. doi:10.1016/j.amepre.2021.03.011
4. Rosen CS, Morland LA, Glassman LH, et al. Virtual mental health care in the Veterans Health Administration’s immediate response to coronavirus disease-19. Am Psychol. 2021;76(1):26-38. doi:10.1037/amp0000751
5. Balut MD, Wyte-Lake T, Steers WN, et al. Expansion of telemedicine during COVID-19 at a VA specialty clinic. Healthc (Amst). 2022;10(1):100599. doi:10.1016/j.hjdsi.2021.100599
6. Belperio PS, Chartier M, Ross DB, Alaigh P, Shulkin D. Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs. Ann Intern Med. 2017;167(7):499-504. doi:10.7326/M17-1073
7. Lin M, Kramer J, White D, et al. Barriers to hepatitis C treatment in the era of direct-acting anti-viral agents. Aliment Pharmacol Ther. 2017;46(10):992-1000. doi:10.1111/apt.14328
8. Alavi M, Janjua NZ, Chong M, et al. The contribution of alcohol use disorder to decompensated cirrhosis among people with hepatitis C: An international study. J Hepatol. 2018;68(3):393-401. doi:10.1016/j.jhep.2017.10.019
9. Pedersen ER, Davis JP, Fitzke RE, Lee DS, Saba S. American Veterans in the Era of COVID-19: Reactions to the Pandemic, Posttraumatic Stress Disorder, and Substance Use Behaviors. Int J Ment Health Addict. 2023;21(2):767-782. doi:10.1007/s11469-021-00620-0
10. Na PJ, Norman SB, Nichter B, et al. Prevalence, risk and protective factors of alcohol use disorder during the COVID-19 pandemic in U.S. military veterans. Drug Alcohol Depend. 2021;225:108818. doi:10.1016/j.drugalcdep.2021.108818
11. Tsui JI, Williams EC, Green PK, Berry K, Su F, Ioannou GN. Alcohol use and hepatitis C virus treatment outcomes among patients receiving direct antiviral agents. Drug Alcohol Depend. 2016;169:101-109. doi:10.1016/j.drugalcdep.2016.10.021
12. Baum A, Kaboli PJ, Schwartz MD. Reduced In-Person and Increased Telehealth Outpatient Visits During the COVID-19 Pandemic. Ann Intern Med. 2021;174(1):129-131. doi:10.7326/M20-3026
13. Fleming BS, Ifeachor AP, Andres AM, et al. Improving Veteran Access to Treatment for Hepatitis C Virus Infection: Addressing social issues and treatment barriers significantly increases access to HCV care, and many veterans successfully start therapy with the help of additional support staff. Fed Pract. 2017;34(Suppl 4):S24-S28.
14. Belperio PS, Chartier M, Ross DB, Alaigh P, Shulkin D. Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs. Ann Intern Med. 2017;167(7):499-504. doi:10.7326/M17-1073
1. Patel AA, Bui A, Prohl E, et al. Innovations in Hepatitis C Screening and Treatment. Hepatol Commun. 2020;5(3):371-386. Published 2020 Dec 7. doi:10.1002/hep4.1646
2. US Preventive Services Task Force, Owens DK, Davidson KW, et al. Screening for Hepatitis C Virus Infection in Adolescents and Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2020;323(10):970-975. doi:10.1001/jama.2020.1123
3. Kaufman HW, Bull-Otterson L, Meyer WA 3rd, et al. Decreases in Hepatitis C Testing and Treatment During the COVID-19 Pandemic. Am J Prev Med. 2021;61(3):369-376. doi:10.1016/j.amepre.2021.03.011
4. Rosen CS, Morland LA, Glassman LH, et al. Virtual mental health care in the Veterans Health Administration’s immediate response to coronavirus disease-19. Am Psychol. 2021;76(1):26-38. doi:10.1037/amp0000751
5. Balut MD, Wyte-Lake T, Steers WN, et al. Expansion of telemedicine during COVID-19 at a VA specialty clinic. Healthc (Amst). 2022;10(1):100599. doi:10.1016/j.hjdsi.2021.100599
6. Belperio PS, Chartier M, Ross DB, Alaigh P, Shulkin D. Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs. Ann Intern Med. 2017;167(7):499-504. doi:10.7326/M17-1073
7. Lin M, Kramer J, White D, et al. Barriers to hepatitis C treatment in the era of direct-acting anti-viral agents. Aliment Pharmacol Ther. 2017;46(10):992-1000. doi:10.1111/apt.14328
8. Alavi M, Janjua NZ, Chong M, et al. The contribution of alcohol use disorder to decompensated cirrhosis among people with hepatitis C: An international study. J Hepatol. 2018;68(3):393-401. doi:10.1016/j.jhep.2017.10.019
9. Pedersen ER, Davis JP, Fitzke RE, Lee DS, Saba S. American Veterans in the Era of COVID-19: Reactions to the Pandemic, Posttraumatic Stress Disorder, and Substance Use Behaviors. Int J Ment Health Addict. 2023;21(2):767-782. doi:10.1007/s11469-021-00620-0
10. Na PJ, Norman SB, Nichter B, et al. Prevalence, risk and protective factors of alcohol use disorder during the COVID-19 pandemic in U.S. military veterans. Drug Alcohol Depend. 2021;225:108818. doi:10.1016/j.drugalcdep.2021.108818
11. Tsui JI, Williams EC, Green PK, Berry K, Su F, Ioannou GN. Alcohol use and hepatitis C virus treatment outcomes among patients receiving direct antiviral agents. Drug Alcohol Depend. 2016;169:101-109. doi:10.1016/j.drugalcdep.2016.10.021
12. Baum A, Kaboli PJ, Schwartz MD. Reduced In-Person and Increased Telehealth Outpatient Visits During the COVID-19 Pandemic. Ann Intern Med. 2021;174(1):129-131. doi:10.7326/M20-3026
13. Fleming BS, Ifeachor AP, Andres AM, et al. Improving Veteran Access to Treatment for Hepatitis C Virus Infection: Addressing social issues and treatment barriers significantly increases access to HCV care, and many veterans successfully start therapy with the help of additional support staff. Fed Pract. 2017;34(Suppl 4):S24-S28.
14. Belperio PS, Chartier M, Ross DB, Alaigh P, Shulkin D. Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs. Ann Intern Med. 2017;167(7):499-504. doi:10.7326/M17-1073
Clinical Implications of a Formulary Conversion From Budesonide/formoterol to Fluticasone/salmeterol at a VA Medical Center
Chronic obstructive pulmonary disease (COPD) is a respiratory disorder associated with slowly progressive systemic inflammation. It includes emphysema, chronic bronchitis, and small airway disease. Patients with COPD have an incomplete reversibility of airway obstruction, the key differentiating factor between it and asthma.1
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend a combination inhaler consisting of a long-acting β-2 agonist (LABA) and inhaled corticosteroid (ICS) for patients with a history of COPD exacerbations.2 Blood eosinophil count is another marker for the initiation of an ICS in patients with COPD. According to the 2023 GOLD Report, ICS therapy is appropriate for patients who experience frequent exacerbations and have a blood eosinophil count > 100 cells/μL, while on maximum tolerated inhaler therapy.3 A 2019 meta-analysis found an overall reduction in the risk of exacerbations in patients with blood eosinophil counts ≥ 100 cells/µL after initiating an ICS.4
Common ICS-LABA inhalers include the combination of budesonide/formoterol as well as fluticasone/salmeterol. Though these combinations are within the same therapeutic class, they have different delivery systems: budesonide/formoterol is a metered dose inhaler, while fluticasone/salmeterol is a dry powder inhaler. The PATHOS study compared the exacerbation rates for the 2 inhalers in primary care patients with COPD. Patients treated long-term with the budesonide/formoterol inhaler were significantly less likely to experience a COPD exacerbation than those treated with the fluticasone/salmeterol inhaler.5
In 2021, The Veteran Health Administration transitioned patients from budesonide/formoterol inhalers to fluticasone/salmeterol inhalers through a formulary conversion. The purpose of this study was to examine the outcomes for patients undergoing the transition.
Methods
A retrospective chart review was conducted on patients at the Hershel “Woody” Williams Veterans Affairs Medical Center in Huntington, West Virginia, with COPD and prescriptions for both budesonide/formoterol and fluticasone/salmeterol inhalers between February 1, 2021, and May 30, 2022. In 2018, the prevalence of COPD in West Virginia was 13.9%, highest in the US.6 Data was obtained through the US Department of Veteran Affairs (VA) Corporate Data Warehouse and stored on a VA Informatics and Computing Infrastructure server. Patients were randomly selected from this cohort and included if they were aged 18 to 89 years, prescribed both inhalers, and had a confirmed COPD diagnosis. Patients were excluded if they also had an asthma diagnosis, if they had an interstitial lung disease, or any tracheostomy tubes. The date of transition from a budesonide/formoterol inhaler to a fluticasone/salmeterol inhaler was collected to establish a timeline of 6 months before and 6 months after the transition.
The primary endpoint was to assess clinical outcomes such as the number of COPD exacerbations and hospitalizations within 6 months of the transition for patients affected by the formulary conversion. Secondary outcomes included the incidence of adverse effects (AEs), treatment failure, tobacco use, and systemic corticosteroid/antimicrobial utilization.
Statistical analyses were performed using STATA v.15. Numerical data was analyzed using a Wilcoxon signed rank test. Categorical data was analyzed by a logistic regression analysis.
Results
Of 1497 included patients who transitioned from budesonide/formoterol to fluticasone/salmeterol inhalers, 165 were randomly selected and 100 patients were included in this analysis. Of the 100 patients, 99 were male with a mean (SEM) age of 71 (0.69) years (range, 54-87) (Table).
The transition from budesonide/formoterol to fluticasone/salmeterol inhalers did not have a statistically significant impact on exacerbations (P = .56). Thirty patients had ≥ 1 exacerbation: 12 had an exacerbation before the transition, 10 had an exacerbation after the transition, and 8 had exacerbations before and after the transition. In the 6 months prior to the transition while on a budesonide/formoterol inhaler, there were 24 exacerbations among 20 patients. Five patients had > 1 exacerbation, accounting for 11 of the 24 exacerbations. There were 29 exacerbations among 19 patients while on a fluticasone/salmeterol inhaler in the 6 months after the transition. Four of these patients had > 1 exacerbation, accounting for 14 of 29 exacerbations (Figure).
Secondary endpoints showed 3 patients experienced an AE related to fluticasone/salmeterol, including thrush, coughing and throat irritation, and dyspnea. Eighteen fluticasone/salmeterol therapeutic failures were indicated by related prior authorization medication requests in the electronic health record. Twelve of 18 patients experienced no difference in exacerbations before vs after the transition to budesonide/formoterol. Twenty-three patients transitioned from fluticasone/salmeterol to a different ICS-LABA therapy; 20 of those 23 patients transitioned back to a budesonide/formoterol inhaler.
There were 48 documented active tobacco users in the study. There was no statistically significant correlation (P = .52) when comparing tobacco use at time of conversion and exacerbation frequency, although the coefficient showed a negative correlation of -0.387. In the 6 months prior to the transition, there were 17 prescriptions for systemic corticosteroids and 24 for antibiotics to treat COPD exacerbations. Following the transition, there were only 12 prescriptions for systemic corticosteroids and 23 for antibiotics. Fifty-two patients had an active prescription for a fluticasone/salmeterol inhaler at the time of the data review (November to December 2022); of the 48 patients who did not, 10 were no longer active due to patient death between the study period and data retrieval.
Discussion
Patients who transitioned from budesonide/formoterol to fluticasone/salmeterol inhalers did not show a significant difference in clinical COPD outcomes. While the total number of exacerbations increased after switching to the fluticasone/salmeterol inhaler, fewer patients had exacerbations during fluticasone/salmeterol therapy when compared with budesonide/fluticasone therapy. The number of patients receiving systemic corticosteroids and antibiotics to treat exacerbations before and after the transition were similar.
The frequency of treatment failures and AEs to the fluticasone/salmeterol inhaler could be due to the change of the inhaler delivery systems. Budesonide/formoterol is a metered dose inhaler (MDI). It is equipped with a pressurized canister that allows a spacer to be used to maximize benefit. Spacers can assist in preventing oral candidiasis by reducing the amount of medication that touches the back of the throat. Spacers are an option for patients, but not all use them for their MDIs, which can result in a less effective administered dose. Fluticasone/salmeterol is a dry powder inhaler, which requires a deep, fast breath to maximize the benefit, and spacers cannot be used with them. MDIs have been shown to be responsible for a negative impact on climate change, which can be reduced by switching to a dry powder inhaler.7
Tobacco cessation is very important in limiting the progression of COPD. As shown with the negative coefficient correlation, not being an active tobacco user at the time of transition correlated (although not significantly) with less frequent exacerbations. When comparing this study to similar research, such as the PATHOS study, several differences are observed.5 The PATHOS study compared long term treatment (> 1 year) of budesonide/formoterol or fluticasone/salmeterol, a longer period than this study. It regarded similar outcomes for the definition of an exacerbation, such as antibiotic/steroid use or hospital admission. While the current study showed no significant difference between the 2 inhalers and their effect on exacerbations, the PATHOS study found that those treated with a budesonide/formoterol inhaler were less likely to experience COPD-related exacerbations than those treated with the fluticasone/salmeterol inhaler. The PATHOS study had a larger mainly Scandinavian sample (N = 5500). This population could exhibit baseline differences from a study of US veterans.5 A similar Canadian matched cohort study of 2262 patients compared the 2 inhalers to assess their relative effectiveness. It found that COPD exacerbations did not differ between the 2 groups, but the budesonide/formoterol group was significantly less likely to have an emergency department visit compared to the fluticasone salmeterol group.8 Like the PATHOS study, the Canadian study had a larger sample size and longer timeframe than did our study.
Limitations
There are various limitations to this study. It was a retrospective, single-center study and the patient population was relatively homogenous, with only 1 female and a mean age of 71 years. As a study conducted in a veteran population in West Virginia, the findings may not be representative of the general population with COPD, which includes more women and more racial diversity.9 The American Lung Association discusses how environmental exposures to hazardous conditions increase the risks of pulmonary diseases for veterans.10 It has been reported that the prevalence of COPD is higher among veterans compared to the general population, but it is not different in terms of disease manifestation.10
Another limitation is the short time frame. Clinical guidelines, including the GOLD Report, typically track the number of exacerbations for 1 year to escalate therapy.3 Six months was a relatively short time frame, and it is possible that more exacerbations may have occurred beyond the study time frame. Ten patients in the sample died between the end of the study period and data retrieval, which might have been caught by a longer study period. An additional limitation was the inability to measure adherence. As this was a formulary conversion, many patients had been mailed a 30- or 90-day prescription of the budesonide/formoterol inhaler when transitioned to the fluticasone/salmeterol inhaler. There was no way to accurately determine when the patient made the switch to the fluticasone/salmeterol inhaler. This study also had a small sample group (a pre-post analysis of the same group), a limitation when evaluating the impact of this formulary change on a small percentage of the population transitioned.
This formulary conversion occurred during the COVID-19 pandemic, and some exacerbations could have been the result of a misdiagnosed COVID-19 infection. Respiratory infections, including COVID-19, are common causes of exacerbations. It is also possible that some patients elected not to receive medical care for symptoms of an exacerbation during the pandemic.11
Conclusions
Switching from the budesonide/formoterol inhaler to the fluticasone/salmeterol inhaler through formulary conversion did not have a significant impact on the clinical outcomes in patients with COPD. This study found that although the inhalers contain different active ingredients, products within the same therapeutic class yielded nonsignificant changes. When conducting formulary conversions, intolerances and treatment failures should be expected when switching from different inhaler delivery systems. This study further justifies the ability to be cost effective by making formulary conversions within the same therapeutic class within a veterans population.
Acknowledgments
The authors would like to acknowledge James Brown, PharmD, PhD.
1. US Department of Veterans Affairs. VA/DOD Clinical Practice Guideline. Management of Outpatient Chronic Obstructive Pulmonary Disease. 2021. Accessed January 22, 2024. https://www.healthquality.va.gov/guidelines/cd/copd/
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD Report. 2022. Accessed January 22, 2024. https://goldcopd.org/2022-gold-reports/
3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis management, and prevention of chronic obstructive pulmonary disease 2023 report. Accessed January 26, 2024. https://goldcopd.org/wp-content/uploads/2023/03/GOLD-2023-ver-1.3-17Feb2023_WMV.pdf
4. Oshagbemi OA, Odiba JO, Daniel A, Yunusa I. Absolute blood eosinophil counts to guide inhaled corticosteroids therapy among patients with COPD: systematic review and meta-analysis. Curr Drug Targets. 2019;20(16):1670-1679. doi:10.2174/1389450120666190808141625
5. Larsson K, Janson C, Lisspers K, et al. Combination of budesonide/formoterol more effective than fluticasone/salmeterol in preventing exacerbations in chronic obstructive pulmonary disease: the PATHOS study. J Intern Med. 2013;273(6):584-594. doi:10.1111/joim.12067
6. West Virginia Department of Health and Human Resources, Division of Health Promotion and Chronic Disease. Statistics about the population of West Virginia. 2018. Accessed January 22, 2024. https://dhhr.wv.gov/hpcd/data_reports/ Pages/Fast-Facts.aspx
7. Fidler L, Green S, Wintemute K. Pressurized metered-dose inhalers and their impact on climate change. CMAJ. 2022;194(12):E460. doi:10.1503/cmaj.211747
8. Blais L, Forget A, Ramachandran S. Relative effectiveness of budesonide/formoterol and fluticasone propionate/salmeterol in a 1-year, population-based, matched cohort study of patients with chronic obstructive pulmonary disease (COPD): Effect on COPD-related exacerbations, emergency department visits and hospitalizations, medication utilization, and treatment adherence. Clin Ther. 2010;32(7):1320-1328. doi:10.1016/j.clinthera.2010.06.022
9. Wheaton AG, Cunningham TJ, Ford ES, Croft JB; Centers for Disease Control and Prevention (CDC). Employment and activity limitations among adults with chronic obstructive pulmonary disease — United States, 2013. MMWR Morb Mortal Wkly Rep. 2015:64(11):289-295.
10. Bamonti PM, Robinson SA, Wan ES, Moy ML. Improving physiological, physical, and psychological health outcomes: a narrative review in US veterans with COPD. Int J Chron Obstruct Pulmon Dis. 2022;17:1269-1283. doi:10.2147/COPD.S339323
11. Czeisler MÉ, Marynak K, Clarke KEN, et al. Delay or avoidance of medical care because of COVID-19–related concerns - United States, June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(36):1250-1257. doi:10.15585/mmwr.mm6936a4
Chronic obstructive pulmonary disease (COPD) is a respiratory disorder associated with slowly progressive systemic inflammation. It includes emphysema, chronic bronchitis, and small airway disease. Patients with COPD have an incomplete reversibility of airway obstruction, the key differentiating factor between it and asthma.1
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend a combination inhaler consisting of a long-acting β-2 agonist (LABA) and inhaled corticosteroid (ICS) for patients with a history of COPD exacerbations.2 Blood eosinophil count is another marker for the initiation of an ICS in patients with COPD. According to the 2023 GOLD Report, ICS therapy is appropriate for patients who experience frequent exacerbations and have a blood eosinophil count > 100 cells/μL, while on maximum tolerated inhaler therapy.3 A 2019 meta-analysis found an overall reduction in the risk of exacerbations in patients with blood eosinophil counts ≥ 100 cells/µL after initiating an ICS.4
Common ICS-LABA inhalers include the combination of budesonide/formoterol as well as fluticasone/salmeterol. Though these combinations are within the same therapeutic class, they have different delivery systems: budesonide/formoterol is a metered dose inhaler, while fluticasone/salmeterol is a dry powder inhaler. The PATHOS study compared the exacerbation rates for the 2 inhalers in primary care patients with COPD. Patients treated long-term with the budesonide/formoterol inhaler were significantly less likely to experience a COPD exacerbation than those treated with the fluticasone/salmeterol inhaler.5
In 2021, The Veteran Health Administration transitioned patients from budesonide/formoterol inhalers to fluticasone/salmeterol inhalers through a formulary conversion. The purpose of this study was to examine the outcomes for patients undergoing the transition.
Methods
A retrospective chart review was conducted on patients at the Hershel “Woody” Williams Veterans Affairs Medical Center in Huntington, West Virginia, with COPD and prescriptions for both budesonide/formoterol and fluticasone/salmeterol inhalers between February 1, 2021, and May 30, 2022. In 2018, the prevalence of COPD in West Virginia was 13.9%, highest in the US.6 Data was obtained through the US Department of Veteran Affairs (VA) Corporate Data Warehouse and stored on a VA Informatics and Computing Infrastructure server. Patients were randomly selected from this cohort and included if they were aged 18 to 89 years, prescribed both inhalers, and had a confirmed COPD diagnosis. Patients were excluded if they also had an asthma diagnosis, if they had an interstitial lung disease, or any tracheostomy tubes. The date of transition from a budesonide/formoterol inhaler to a fluticasone/salmeterol inhaler was collected to establish a timeline of 6 months before and 6 months after the transition.
The primary endpoint was to assess clinical outcomes such as the number of COPD exacerbations and hospitalizations within 6 months of the transition for patients affected by the formulary conversion. Secondary outcomes included the incidence of adverse effects (AEs), treatment failure, tobacco use, and systemic corticosteroid/antimicrobial utilization.
Statistical analyses were performed using STATA v.15. Numerical data was analyzed using a Wilcoxon signed rank test. Categorical data was analyzed by a logistic regression analysis.
Results
Of 1497 included patients who transitioned from budesonide/formoterol to fluticasone/salmeterol inhalers, 165 were randomly selected and 100 patients were included in this analysis. Of the 100 patients, 99 were male with a mean (SEM) age of 71 (0.69) years (range, 54-87) (Table).
The transition from budesonide/formoterol to fluticasone/salmeterol inhalers did not have a statistically significant impact on exacerbations (P = .56). Thirty patients had ≥ 1 exacerbation: 12 had an exacerbation before the transition, 10 had an exacerbation after the transition, and 8 had exacerbations before and after the transition. In the 6 months prior to the transition while on a budesonide/formoterol inhaler, there were 24 exacerbations among 20 patients. Five patients had > 1 exacerbation, accounting for 11 of the 24 exacerbations. There were 29 exacerbations among 19 patients while on a fluticasone/salmeterol inhaler in the 6 months after the transition. Four of these patients had > 1 exacerbation, accounting for 14 of 29 exacerbations (Figure).
Secondary endpoints showed 3 patients experienced an AE related to fluticasone/salmeterol, including thrush, coughing and throat irritation, and dyspnea. Eighteen fluticasone/salmeterol therapeutic failures were indicated by related prior authorization medication requests in the electronic health record. Twelve of 18 patients experienced no difference in exacerbations before vs after the transition to budesonide/formoterol. Twenty-three patients transitioned from fluticasone/salmeterol to a different ICS-LABA therapy; 20 of those 23 patients transitioned back to a budesonide/formoterol inhaler.
There were 48 documented active tobacco users in the study. There was no statistically significant correlation (P = .52) when comparing tobacco use at time of conversion and exacerbation frequency, although the coefficient showed a negative correlation of -0.387. In the 6 months prior to the transition, there were 17 prescriptions for systemic corticosteroids and 24 for antibiotics to treat COPD exacerbations. Following the transition, there were only 12 prescriptions for systemic corticosteroids and 23 for antibiotics. Fifty-two patients had an active prescription for a fluticasone/salmeterol inhaler at the time of the data review (November to December 2022); of the 48 patients who did not, 10 were no longer active due to patient death between the study period and data retrieval.
Discussion
Patients who transitioned from budesonide/formoterol to fluticasone/salmeterol inhalers did not show a significant difference in clinical COPD outcomes. While the total number of exacerbations increased after switching to the fluticasone/salmeterol inhaler, fewer patients had exacerbations during fluticasone/salmeterol therapy when compared with budesonide/fluticasone therapy. The number of patients receiving systemic corticosteroids and antibiotics to treat exacerbations before and after the transition were similar.
The frequency of treatment failures and AEs to the fluticasone/salmeterol inhaler could be due to the change of the inhaler delivery systems. Budesonide/formoterol is a metered dose inhaler (MDI). It is equipped with a pressurized canister that allows a spacer to be used to maximize benefit. Spacers can assist in preventing oral candidiasis by reducing the amount of medication that touches the back of the throat. Spacers are an option for patients, but not all use them for their MDIs, which can result in a less effective administered dose. Fluticasone/salmeterol is a dry powder inhaler, which requires a deep, fast breath to maximize the benefit, and spacers cannot be used with them. MDIs have been shown to be responsible for a negative impact on climate change, which can be reduced by switching to a dry powder inhaler.7
Tobacco cessation is very important in limiting the progression of COPD. As shown with the negative coefficient correlation, not being an active tobacco user at the time of transition correlated (although not significantly) with less frequent exacerbations. When comparing this study to similar research, such as the PATHOS study, several differences are observed.5 The PATHOS study compared long term treatment (> 1 year) of budesonide/formoterol or fluticasone/salmeterol, a longer period than this study. It regarded similar outcomes for the definition of an exacerbation, such as antibiotic/steroid use or hospital admission. While the current study showed no significant difference between the 2 inhalers and their effect on exacerbations, the PATHOS study found that those treated with a budesonide/formoterol inhaler were less likely to experience COPD-related exacerbations than those treated with the fluticasone/salmeterol inhaler. The PATHOS study had a larger mainly Scandinavian sample (N = 5500). This population could exhibit baseline differences from a study of US veterans.5 A similar Canadian matched cohort study of 2262 patients compared the 2 inhalers to assess their relative effectiveness. It found that COPD exacerbations did not differ between the 2 groups, but the budesonide/formoterol group was significantly less likely to have an emergency department visit compared to the fluticasone salmeterol group.8 Like the PATHOS study, the Canadian study had a larger sample size and longer timeframe than did our study.
Limitations
There are various limitations to this study. It was a retrospective, single-center study and the patient population was relatively homogenous, with only 1 female and a mean age of 71 years. As a study conducted in a veteran population in West Virginia, the findings may not be representative of the general population with COPD, which includes more women and more racial diversity.9 The American Lung Association discusses how environmental exposures to hazardous conditions increase the risks of pulmonary diseases for veterans.10 It has been reported that the prevalence of COPD is higher among veterans compared to the general population, but it is not different in terms of disease manifestation.10
Another limitation is the short time frame. Clinical guidelines, including the GOLD Report, typically track the number of exacerbations for 1 year to escalate therapy.3 Six months was a relatively short time frame, and it is possible that more exacerbations may have occurred beyond the study time frame. Ten patients in the sample died between the end of the study period and data retrieval, which might have been caught by a longer study period. An additional limitation was the inability to measure adherence. As this was a formulary conversion, many patients had been mailed a 30- or 90-day prescription of the budesonide/formoterol inhaler when transitioned to the fluticasone/salmeterol inhaler. There was no way to accurately determine when the patient made the switch to the fluticasone/salmeterol inhaler. This study also had a small sample group (a pre-post analysis of the same group), a limitation when evaluating the impact of this formulary change on a small percentage of the population transitioned.
This formulary conversion occurred during the COVID-19 pandemic, and some exacerbations could have been the result of a misdiagnosed COVID-19 infection. Respiratory infections, including COVID-19, are common causes of exacerbations. It is also possible that some patients elected not to receive medical care for symptoms of an exacerbation during the pandemic.11
Conclusions
Switching from the budesonide/formoterol inhaler to the fluticasone/salmeterol inhaler through formulary conversion did not have a significant impact on the clinical outcomes in patients with COPD. This study found that although the inhalers contain different active ingredients, products within the same therapeutic class yielded nonsignificant changes. When conducting formulary conversions, intolerances and treatment failures should be expected when switching from different inhaler delivery systems. This study further justifies the ability to be cost effective by making formulary conversions within the same therapeutic class within a veterans population.
Acknowledgments
The authors would like to acknowledge James Brown, PharmD, PhD.
Chronic obstructive pulmonary disease (COPD) is a respiratory disorder associated with slowly progressive systemic inflammation. It includes emphysema, chronic bronchitis, and small airway disease. Patients with COPD have an incomplete reversibility of airway obstruction, the key differentiating factor between it and asthma.1
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend a combination inhaler consisting of a long-acting β-2 agonist (LABA) and inhaled corticosteroid (ICS) for patients with a history of COPD exacerbations.2 Blood eosinophil count is another marker for the initiation of an ICS in patients with COPD. According to the 2023 GOLD Report, ICS therapy is appropriate for patients who experience frequent exacerbations and have a blood eosinophil count > 100 cells/μL, while on maximum tolerated inhaler therapy.3 A 2019 meta-analysis found an overall reduction in the risk of exacerbations in patients with blood eosinophil counts ≥ 100 cells/µL after initiating an ICS.4
Common ICS-LABA inhalers include the combination of budesonide/formoterol as well as fluticasone/salmeterol. Though these combinations are within the same therapeutic class, they have different delivery systems: budesonide/formoterol is a metered dose inhaler, while fluticasone/salmeterol is a dry powder inhaler. The PATHOS study compared the exacerbation rates for the 2 inhalers in primary care patients with COPD. Patients treated long-term with the budesonide/formoterol inhaler were significantly less likely to experience a COPD exacerbation than those treated with the fluticasone/salmeterol inhaler.5
In 2021, The Veteran Health Administration transitioned patients from budesonide/formoterol inhalers to fluticasone/salmeterol inhalers through a formulary conversion. The purpose of this study was to examine the outcomes for patients undergoing the transition.
Methods
A retrospective chart review was conducted on patients at the Hershel “Woody” Williams Veterans Affairs Medical Center in Huntington, West Virginia, with COPD and prescriptions for both budesonide/formoterol and fluticasone/salmeterol inhalers between February 1, 2021, and May 30, 2022. In 2018, the prevalence of COPD in West Virginia was 13.9%, highest in the US.6 Data was obtained through the US Department of Veteran Affairs (VA) Corporate Data Warehouse and stored on a VA Informatics and Computing Infrastructure server. Patients were randomly selected from this cohort and included if they were aged 18 to 89 years, prescribed both inhalers, and had a confirmed COPD diagnosis. Patients were excluded if they also had an asthma diagnosis, if they had an interstitial lung disease, or any tracheostomy tubes. The date of transition from a budesonide/formoterol inhaler to a fluticasone/salmeterol inhaler was collected to establish a timeline of 6 months before and 6 months after the transition.
The primary endpoint was to assess clinical outcomes such as the number of COPD exacerbations and hospitalizations within 6 months of the transition for patients affected by the formulary conversion. Secondary outcomes included the incidence of adverse effects (AEs), treatment failure, tobacco use, and systemic corticosteroid/antimicrobial utilization.
Statistical analyses were performed using STATA v.15. Numerical data was analyzed using a Wilcoxon signed rank test. Categorical data was analyzed by a logistic regression analysis.
Results
Of 1497 included patients who transitioned from budesonide/formoterol to fluticasone/salmeterol inhalers, 165 were randomly selected and 100 patients were included in this analysis. Of the 100 patients, 99 were male with a mean (SEM) age of 71 (0.69) years (range, 54-87) (Table).
The transition from budesonide/formoterol to fluticasone/salmeterol inhalers did not have a statistically significant impact on exacerbations (P = .56). Thirty patients had ≥ 1 exacerbation: 12 had an exacerbation before the transition, 10 had an exacerbation after the transition, and 8 had exacerbations before and after the transition. In the 6 months prior to the transition while on a budesonide/formoterol inhaler, there were 24 exacerbations among 20 patients. Five patients had > 1 exacerbation, accounting for 11 of the 24 exacerbations. There were 29 exacerbations among 19 patients while on a fluticasone/salmeterol inhaler in the 6 months after the transition. Four of these patients had > 1 exacerbation, accounting for 14 of 29 exacerbations (Figure).
Secondary endpoints showed 3 patients experienced an AE related to fluticasone/salmeterol, including thrush, coughing and throat irritation, and dyspnea. Eighteen fluticasone/salmeterol therapeutic failures were indicated by related prior authorization medication requests in the electronic health record. Twelve of 18 patients experienced no difference in exacerbations before vs after the transition to budesonide/formoterol. Twenty-three patients transitioned from fluticasone/salmeterol to a different ICS-LABA therapy; 20 of those 23 patients transitioned back to a budesonide/formoterol inhaler.
There were 48 documented active tobacco users in the study. There was no statistically significant correlation (P = .52) when comparing tobacco use at time of conversion and exacerbation frequency, although the coefficient showed a negative correlation of -0.387. In the 6 months prior to the transition, there were 17 prescriptions for systemic corticosteroids and 24 for antibiotics to treat COPD exacerbations. Following the transition, there were only 12 prescriptions for systemic corticosteroids and 23 for antibiotics. Fifty-two patients had an active prescription for a fluticasone/salmeterol inhaler at the time of the data review (November to December 2022); of the 48 patients who did not, 10 were no longer active due to patient death between the study period and data retrieval.
Discussion
Patients who transitioned from budesonide/formoterol to fluticasone/salmeterol inhalers did not show a significant difference in clinical COPD outcomes. While the total number of exacerbations increased after switching to the fluticasone/salmeterol inhaler, fewer patients had exacerbations during fluticasone/salmeterol therapy when compared with budesonide/fluticasone therapy. The number of patients receiving systemic corticosteroids and antibiotics to treat exacerbations before and after the transition were similar.
The frequency of treatment failures and AEs to the fluticasone/salmeterol inhaler could be due to the change of the inhaler delivery systems. Budesonide/formoterol is a metered dose inhaler (MDI). It is equipped with a pressurized canister that allows a spacer to be used to maximize benefit. Spacers can assist in preventing oral candidiasis by reducing the amount of medication that touches the back of the throat. Spacers are an option for patients, but not all use them for their MDIs, which can result in a less effective administered dose. Fluticasone/salmeterol is a dry powder inhaler, which requires a deep, fast breath to maximize the benefit, and spacers cannot be used with them. MDIs have been shown to be responsible for a negative impact on climate change, which can be reduced by switching to a dry powder inhaler.7
Tobacco cessation is very important in limiting the progression of COPD. As shown with the negative coefficient correlation, not being an active tobacco user at the time of transition correlated (although not significantly) with less frequent exacerbations. When comparing this study to similar research, such as the PATHOS study, several differences are observed.5 The PATHOS study compared long term treatment (> 1 year) of budesonide/formoterol or fluticasone/salmeterol, a longer period than this study. It regarded similar outcomes for the definition of an exacerbation, such as antibiotic/steroid use or hospital admission. While the current study showed no significant difference between the 2 inhalers and their effect on exacerbations, the PATHOS study found that those treated with a budesonide/formoterol inhaler were less likely to experience COPD-related exacerbations than those treated with the fluticasone/salmeterol inhaler. The PATHOS study had a larger mainly Scandinavian sample (N = 5500). This population could exhibit baseline differences from a study of US veterans.5 A similar Canadian matched cohort study of 2262 patients compared the 2 inhalers to assess their relative effectiveness. It found that COPD exacerbations did not differ between the 2 groups, but the budesonide/formoterol group was significantly less likely to have an emergency department visit compared to the fluticasone salmeterol group.8 Like the PATHOS study, the Canadian study had a larger sample size and longer timeframe than did our study.
Limitations
There are various limitations to this study. It was a retrospective, single-center study and the patient population was relatively homogenous, with only 1 female and a mean age of 71 years. As a study conducted in a veteran population in West Virginia, the findings may not be representative of the general population with COPD, which includes more women and more racial diversity.9 The American Lung Association discusses how environmental exposures to hazardous conditions increase the risks of pulmonary diseases for veterans.10 It has been reported that the prevalence of COPD is higher among veterans compared to the general population, but it is not different in terms of disease manifestation.10
Another limitation is the short time frame. Clinical guidelines, including the GOLD Report, typically track the number of exacerbations for 1 year to escalate therapy.3 Six months was a relatively short time frame, and it is possible that more exacerbations may have occurred beyond the study time frame. Ten patients in the sample died between the end of the study period and data retrieval, which might have been caught by a longer study period. An additional limitation was the inability to measure adherence. As this was a formulary conversion, many patients had been mailed a 30- or 90-day prescription of the budesonide/formoterol inhaler when transitioned to the fluticasone/salmeterol inhaler. There was no way to accurately determine when the patient made the switch to the fluticasone/salmeterol inhaler. This study also had a small sample group (a pre-post analysis of the same group), a limitation when evaluating the impact of this formulary change on a small percentage of the population transitioned.
This formulary conversion occurred during the COVID-19 pandemic, and some exacerbations could have been the result of a misdiagnosed COVID-19 infection. Respiratory infections, including COVID-19, are common causes of exacerbations. It is also possible that some patients elected not to receive medical care for symptoms of an exacerbation during the pandemic.11
Conclusions
Switching from the budesonide/formoterol inhaler to the fluticasone/salmeterol inhaler through formulary conversion did not have a significant impact on the clinical outcomes in patients with COPD. This study found that although the inhalers contain different active ingredients, products within the same therapeutic class yielded nonsignificant changes. When conducting formulary conversions, intolerances and treatment failures should be expected when switching from different inhaler delivery systems. This study further justifies the ability to be cost effective by making formulary conversions within the same therapeutic class within a veterans population.
Acknowledgments
The authors would like to acknowledge James Brown, PharmD, PhD.
1. US Department of Veterans Affairs. VA/DOD Clinical Practice Guideline. Management of Outpatient Chronic Obstructive Pulmonary Disease. 2021. Accessed January 22, 2024. https://www.healthquality.va.gov/guidelines/cd/copd/
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD Report. 2022. Accessed January 22, 2024. https://goldcopd.org/2022-gold-reports/
3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis management, and prevention of chronic obstructive pulmonary disease 2023 report. Accessed January 26, 2024. https://goldcopd.org/wp-content/uploads/2023/03/GOLD-2023-ver-1.3-17Feb2023_WMV.pdf
4. Oshagbemi OA, Odiba JO, Daniel A, Yunusa I. Absolute blood eosinophil counts to guide inhaled corticosteroids therapy among patients with COPD: systematic review and meta-analysis. Curr Drug Targets. 2019;20(16):1670-1679. doi:10.2174/1389450120666190808141625
5. Larsson K, Janson C, Lisspers K, et al. Combination of budesonide/formoterol more effective than fluticasone/salmeterol in preventing exacerbations in chronic obstructive pulmonary disease: the PATHOS study. J Intern Med. 2013;273(6):584-594. doi:10.1111/joim.12067
6. West Virginia Department of Health and Human Resources, Division of Health Promotion and Chronic Disease. Statistics about the population of West Virginia. 2018. Accessed January 22, 2024. https://dhhr.wv.gov/hpcd/data_reports/ Pages/Fast-Facts.aspx
7. Fidler L, Green S, Wintemute K. Pressurized metered-dose inhalers and their impact on climate change. CMAJ. 2022;194(12):E460. doi:10.1503/cmaj.211747
8. Blais L, Forget A, Ramachandran S. Relative effectiveness of budesonide/formoterol and fluticasone propionate/salmeterol in a 1-year, population-based, matched cohort study of patients with chronic obstructive pulmonary disease (COPD): Effect on COPD-related exacerbations, emergency department visits and hospitalizations, medication utilization, and treatment adherence. Clin Ther. 2010;32(7):1320-1328. doi:10.1016/j.clinthera.2010.06.022
9. Wheaton AG, Cunningham TJ, Ford ES, Croft JB; Centers for Disease Control and Prevention (CDC). Employment and activity limitations among adults with chronic obstructive pulmonary disease — United States, 2013. MMWR Morb Mortal Wkly Rep. 2015:64(11):289-295.
10. Bamonti PM, Robinson SA, Wan ES, Moy ML. Improving physiological, physical, and psychological health outcomes: a narrative review in US veterans with COPD. Int J Chron Obstruct Pulmon Dis. 2022;17:1269-1283. doi:10.2147/COPD.S339323
11. Czeisler MÉ, Marynak K, Clarke KEN, et al. Delay or avoidance of medical care because of COVID-19–related concerns - United States, June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(36):1250-1257. doi:10.15585/mmwr.mm6936a4
1. US Department of Veterans Affairs. VA/DOD Clinical Practice Guideline. Management of Outpatient Chronic Obstructive Pulmonary Disease. 2021. Accessed January 22, 2024. https://www.healthquality.va.gov/guidelines/cd/copd/
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD Report. 2022. Accessed January 22, 2024. https://goldcopd.org/2022-gold-reports/
3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis management, and prevention of chronic obstructive pulmonary disease 2023 report. Accessed January 26, 2024. https://goldcopd.org/wp-content/uploads/2023/03/GOLD-2023-ver-1.3-17Feb2023_WMV.pdf
4. Oshagbemi OA, Odiba JO, Daniel A, Yunusa I. Absolute blood eosinophil counts to guide inhaled corticosteroids therapy among patients with COPD: systematic review and meta-analysis. Curr Drug Targets. 2019;20(16):1670-1679. doi:10.2174/1389450120666190808141625
5. Larsson K, Janson C, Lisspers K, et al. Combination of budesonide/formoterol more effective than fluticasone/salmeterol in preventing exacerbations in chronic obstructive pulmonary disease: the PATHOS study. J Intern Med. 2013;273(6):584-594. doi:10.1111/joim.12067
6. West Virginia Department of Health and Human Resources, Division of Health Promotion and Chronic Disease. Statistics about the population of West Virginia. 2018. Accessed January 22, 2024. https://dhhr.wv.gov/hpcd/data_reports/ Pages/Fast-Facts.aspx
7. Fidler L, Green S, Wintemute K. Pressurized metered-dose inhalers and their impact on climate change. CMAJ. 2022;194(12):E460. doi:10.1503/cmaj.211747
8. Blais L, Forget A, Ramachandran S. Relative effectiveness of budesonide/formoterol and fluticasone propionate/salmeterol in a 1-year, population-based, matched cohort study of patients with chronic obstructive pulmonary disease (COPD): Effect on COPD-related exacerbations, emergency department visits and hospitalizations, medication utilization, and treatment adherence. Clin Ther. 2010;32(7):1320-1328. doi:10.1016/j.clinthera.2010.06.022
9. Wheaton AG, Cunningham TJ, Ford ES, Croft JB; Centers for Disease Control and Prevention (CDC). Employment and activity limitations among adults with chronic obstructive pulmonary disease — United States, 2013. MMWR Morb Mortal Wkly Rep. 2015:64(11):289-295.
10. Bamonti PM, Robinson SA, Wan ES, Moy ML. Improving physiological, physical, and psychological health outcomes: a narrative review in US veterans with COPD. Int J Chron Obstruct Pulmon Dis. 2022;17:1269-1283. doi:10.2147/COPD.S339323
11. Czeisler MÉ, Marynak K, Clarke KEN, et al. Delay or avoidance of medical care because of COVID-19–related concerns - United States, June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(36):1250-1257. doi:10.15585/mmwr.mm6936a4
A Cross-sectional Analysis of Regional Trends in Medicare Reimbursement for Phototherapy Services From 2010 to 2023
To the Editor:
Phototherapy regularly is utilized in the outpatient setting to address various skin pathologies, including atopic dermatitis, psoriasis, pruritus, vitiligo, and mycosis fungoides.1,2 Phototherapy is broadly defined by the measured administration of nonionizing radiation within the UV range including wavelengths within the UVA (eg, psoralen sensitizer plus UVA-1) and UVB (eg, broadband UVB, narrowband UVB) spectrums.1,3 Generally, the mechanism of action is derived from effects on inflammatory components of cutaneous disorders and the induction of apoptosis, both precipitating numerous downstream events.4
From 2015 to 2018, there were more than 1.3 million outpatient phototherapy visits in the United States, with the most common procedural indications being dermatitis not otherwise specified, atopic dermatitis, and pruritus.5 From 2000 to 2015, the quantity of phototherapy services billed to Medicare trended upwards by an average of 5% per year, increasing from 334,670 in the year 2000 to 692,093 in 2015.6 Therefore, an illustration of associated costs would be beneficial. Additionally, because total cost and physician reimbursement fluctuate from year to year, studies demonstrating overall trends can inform both US policymakers and physicians. There is a paucity of research on geographical trends for procedural reimbursements in dermatology for phototherapy. Understanding geographic trends of reimbursement could duly serve to optimize dermatologist practice patterns involving access to viable and quality care for patients seeking treatment as well as draw health policymakers’ attention to striking adjustments in physician fees. Therefore, in this study we aimed to illustrate the most recent regional payment trends in phototherapy procedures for Medicare B patients.
We queried the Centers for Medicare & Medicaid Services Medicare Physician Fee Schedule (MPFS) database (https://www.cms.gov/medicare/payment/fee-schedules/physician/lookup-tool) for the years 2010 to 2023 for Current Procedural Terminology (CPT) codes common to phototherapy procedures: actinotherapy (96900); photochemotherapy by Goeckerman treatment or using petrolatum and UVB (96910); photochemotherapy using psoralen plus UVA (96912); and photochemotherapy of severe dermatoses requiring a minimum of 4 hours of care under direct physician supervision (96913). Nonfacility prices for these procedures were analyzed. For 2010, due to midyear alterations to Medicare reimbursement (owed to bills HR 3962 and HR 4872), the mean price data of MPFS files 2010A and 2010B were used. All dollar values were converted to January 2023 US dollars using corresponding consumer price index inflation data. The Medicare Administrative Contractors were used to group state pricing information by region in accordance with established US Census Bureau subdivisions (https://www.census.gov/programs-surveys/economic-census/guidance-geographies/levels.html). Weighted percentage change in reimbursement rate was calculated using physician (MD or DO) utilization (procedure volume) data available in the 2020 Physician and Other Practitioners Public Use File (https://data.cms.gov/provider-summary-by-type-of-service/medicare-physician-other-practitioners/medicare-physician-other-practitioners-by-provider-and-service). All descriptive statistics and visualization were generated using R software (v4.2.2)(R Development Core Team).
Table 1 provides physician utilization data and the corresponding number of Part B beneficiaries for phototherapy procedures in 2020. There were 65,045 services of actinotherapy provided to a total of 6855 unique Part B beneficiaries, 173,979 services of photochemotherapy by Goeckerman treatment or using petrolatum and UVB provided to 13,122 unique Part B beneficiaries, 2524 services of photochemotherapy using psoralen plus UVA provided to a total of 357 unique Part B beneficiaries, and 37 services of photochemotherapy of severe dermatoses requiring a minimum of 4 hours of care under direct physician supervision provided to a total of 27 unique Part B beneficiaries.
On average (unweighted), phototherapy reimbursement rates in the North increased by 0.68% between 2010 and 2023 (Table 2). After weighting for 2020 physician utilization, the average change in reimbursement rate was +19.37%. During this time period, CPT code 96910 reported the greatest adjusted increase in reimbursement (+31.45%)($98.12 to $128.98; compound annual growth rate [CAGR], +0.0213), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−12.76%)($126.09 to $109.97; CAGR, −0.0105). For CPT code 96900, the reported adjusted decrease in reimbursement was −11.68% ($30.21 to $26.68; CAGR, −0.0095), and for CPT code 96913, the reported adjusted decrease in reimbursement was −4.27% ($174.03 to $166.60; CAGR, −0.0034).
On average (unweighted), phototherapy reimbursement rates in the Midwest increased by 8.40% between 2010 and 2023 (Table 3). After weighting for 2020 physician utilization, the average change in reimbursement rate was +28.53%. During this time period, CPT code 96910 reported the greatest adjusted change in reimbursement (+41.48%)($80.42 to $113.78; CAGR, +0.0270), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−6.14%)($103.28 to $97.03; CAGR, −0.0049). For CPT code 96900, the reported adjusted decrease in reimbursement was −4.73% ($24.69 to $23.52; CAGR, −0.0037), and for CPT code 96913, the reported adjusted increase in reimbursement was +2.99% ($142.72 to $146.99; CAGR, +0.0023).
On average (unweighted), phototherapy reimbursement rates in the South decreased by 2.62% between 2010 and 2023 (Table 4). After weighting for 2020 physician utilization, the average change in reimbursement rate was +15.41%. During this time period, CPT code 96910 reported the greatest adjusted change in reimbursement (+27.26%)($90.40 to $115.04 USD; CAGR, +0.0187), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−15.50%)($116.08 to $98.09; CAGR, −0.0129). For CPT code 96900, the reported adjusted decrease in reimbursement was −15.06% ($28.02 to $23.80; CAGR, −0.0125), and for CPT code 96913, the reported adjusted decrease in reimbursement was −7.19% ($160.11 to $148.61; CAGR, −0.0057).
On average (unweighted), phototherapy reimbursement rates in the West increased by 27.53% between 2010 and 2023 (Table 5). After weighting for 2020 physician utilization, the average change in reimbursement rate was +51.16%. Reimbursement for all analyzed procedures increased in the western United States. During this time period, CPT code 96910 reported the greatest adjusted increase in reimbursement (+66.56%)($80.84 to $134.65; CAGR, +0.0400), and CPT code 96912 reported the lowest adjusted increase in reimbursement (+10.64%)($103.88 to $114.93; CAGR, +0.0078). For CPT code 96900, the reported adjusted increase in reimbursement was 11.54% ($24.88 to $27.75; CAGR, +0.0084), and for CPT code 96913, the reported adjusted increase in reimbursement was 21.38% ($143.39 to $174.04; CAGR, +0.0150).
In this study evaluating geographical payment trends for phototherapy from 2010 to 2023, we demonstrated regional inconsistency in mean inflation-adjusted Medicare reimbursement rates. We found that all phototherapy procedures had increased reimbursement in the western United States, whereas all other regions reported cuts in reimbursement rates for at least half of the analyzed procedures. After adjusting for procedure utilization by physicians, weighted mean reimbursement for phototherapy increased in all US regions.
In a cross-sectional study that explored trends in the geographic distribution of dermatologists from 2012 to 2017, dermatologists in the northeastern and western United States were more likely to be located in higher-income zip codes, whereas dermatologists in the southern United States were more likely to be located in lower-income zip codes,7 suggesting that payment rate changes are not concordant with cost of living. Additionally, Lauck and colleagues8 observed that 75% of the top 20 most common procedures performed by dermatologists had decreased reimbursement (mean change, −10.8%) from 2011 to 2021. Other studies on Medicare reimbursement trends over the last 2 decades have reported major decreases within other specialties, suggesting that declining Medicare reimbursements are not unique to dermatology.9,10 It is critical to monitor these developments, as the Centers for Medicare & Medicaid Services emphasized health care policy changes aimed at increasing reimbursements for evaluation and management services with compensatory payment cuts in billing for procedural services.11
Mazmudar et al12 previously reported a mean reimbursement decrease of −6.6% for laser/phototherapy procedures between 2007 and 2021, but these data did not include the heavily utilized Goeckerman treatment. Changes in reimbursement pose major ramifications for dermatologists—for practice size, scope, and longevity—as rates influence changes in commercial insurance reimbursements.13 Medicare plays a major role in the US health care system as the second largest expenditure14; indeed, between 2000 and 2015, Part B billing volume for phototherapy procedures increased 5% annually. However, phototherapy remains inaccessible in many locations due to unequal regional distribution of phototherapy clinics.6 Moreover, home phototherapy units are not yet widely utilized because of safety and efficacy concerns, lack of physician oversight, and difficulty obtaining insurance coverage.15 Acknowledgment and consideration of these geographical trends may persuasively allow policymakers, hospitals, and physicians to facilitate cost-effective phototherapy reimbursements that ensure continued access to quality and sustainable dermatologic care in the United States that tailor to regional needs.
In sum, this analysis reveals regional trends in Part B physician reimbursement for phototherapy procedures, with all US regions reporting a mean increase in phototherapy reimbursement after adjusting for utilization, albeit to varying degrees. Mean reimbursement for photochemotherapy by Goeckerman treatment or using petrolatum and UVB increased most among phototherapy procedures. Mean reimbursement for both actinotherapy and photochemotherapy using psoralen plus UVA decreased in all regions except the western United States.
Limitations include the restriction to Part B MPFS and the reliance on single-year (2020) physician utilization data to compute weighted changes in average reimbursement across a multiyear range, effectively restricting sweeping conclusions. Still, this study puts forth actionable insights for dermatologists and policymakers alike to appreciate and consider.
- Rathod DG, Muneer H, Masood S. Phototherapy. StatPearls. StatPearls Publishing; 2002.
- Branisteanu DE, Dirzu DS, Toader MP, et al. Phototherapy in dermatological maladies (Review). Exp Ther Med. 2022;23:259. doi:10.3892/etm.2022.11184
- Barros NM, Sbroglio LL, Buffara MO, et al. Phototherapy. An Bras Dermatol. 2021;96:397-407. doi:10.1016/j.abd.2021.03.001
- Vieyra-Garcia PA, Wolf P. A deep dive into UV-based phototherapy: mechanisms of action and emerging molecular targets in inflammation and cancer. Pharmacol Ther. 2021;222:107784. doi:10.1016/j.pharmthera.2020.107784
- Oulee A, Javadi SS, Martin A, et al. Phototherapy trends in dermatology 2015-2018. J Dermatolog Treat. 2022;33:2545-2546. doi:10.1080/09546634.2021.2019660
- Tan SY, Buzney E, Mostaghimi A. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015. J Am Acad Dermatol. 2018;79:672-679. doi:10.1016/j.jaad.2018.03.018
- Benlagha I, Nguyen BM. Changes in dermatology practice characteristics in the United States from 2012 to 2017. JAAD Int. 2021;3:92-101. doi:10.1016/j.jdin.2021.03.005
- Lauck K, Nguyen QB, Hebert A. Trends in Medicare reimbursement within dermatology: 2011-2021. Skin. 2022;6:122-131. doi:10.25251/skin.6.2.5
- Smith JF, Moore ML, Pollock JR, et al. National and geographic trends in Medicare reimbursement rates for orthopedic shoulder and upper extremity surgery from 2000 to 2020. J Shoulder Elbow Surg. 2022;31:860-867. doi:10.1016/j.jse.2021.09.001
- Haglin JM, Eltorai AEM, Richter KR, et al. Medicare reimbursement for general surgery procedures: 2000 to 2018. Ann Surg. 2020;271:17-22. doi:10.1097/SLA.0000000000003289
- Fleishon HB. Evaluation and management coding initiative. J Am Coll Radiol. 2020;17:1539-1540. doi:10.1016/j.jacr.2020.09.057
- Mazmudar RS, Sheth A, Tripathi R, et al. Inflation-adjusted trends in Medicare reimbursement for common dermatologic procedures, 2007-2021. JAMA Dermatol. 2021;157:1355-1358. doi:10.1001/jamadermatol.2021.3453
- Clemens J, Gottlieb JD. In the shadow of a giant: Medicare’s influence on private physician payments. J Polit Econ. 2017;125:1-39. doi:10.1086/689772
- Ya J, Ezaldein HH, Scott JF. Trends in Medicare utilization by dermatologists, 2012-2015. JAMA Dermatol. 2019;155:471-474. doi:10.1001/jamadermatol.2018.4212
- Rajpara AN, O’Neill JL, Nolan BV, et al. Review of home phototherapy. Dermatol Online J. 2010;16:2.
To the Editor:
Phototherapy regularly is utilized in the outpatient setting to address various skin pathologies, including atopic dermatitis, psoriasis, pruritus, vitiligo, and mycosis fungoides.1,2 Phototherapy is broadly defined by the measured administration of nonionizing radiation within the UV range including wavelengths within the UVA (eg, psoralen sensitizer plus UVA-1) and UVB (eg, broadband UVB, narrowband UVB) spectrums.1,3 Generally, the mechanism of action is derived from effects on inflammatory components of cutaneous disorders and the induction of apoptosis, both precipitating numerous downstream events.4
From 2015 to 2018, there were more than 1.3 million outpatient phototherapy visits in the United States, with the most common procedural indications being dermatitis not otherwise specified, atopic dermatitis, and pruritus.5 From 2000 to 2015, the quantity of phototherapy services billed to Medicare trended upwards by an average of 5% per year, increasing from 334,670 in the year 2000 to 692,093 in 2015.6 Therefore, an illustration of associated costs would be beneficial. Additionally, because total cost and physician reimbursement fluctuate from year to year, studies demonstrating overall trends can inform both US policymakers and physicians. There is a paucity of research on geographical trends for procedural reimbursements in dermatology for phototherapy. Understanding geographic trends of reimbursement could duly serve to optimize dermatologist practice patterns involving access to viable and quality care for patients seeking treatment as well as draw health policymakers’ attention to striking adjustments in physician fees. Therefore, in this study we aimed to illustrate the most recent regional payment trends in phototherapy procedures for Medicare B patients.
We queried the Centers for Medicare & Medicaid Services Medicare Physician Fee Schedule (MPFS) database (https://www.cms.gov/medicare/payment/fee-schedules/physician/lookup-tool) for the years 2010 to 2023 for Current Procedural Terminology (CPT) codes common to phototherapy procedures: actinotherapy (96900); photochemotherapy by Goeckerman treatment or using petrolatum and UVB (96910); photochemotherapy using psoralen plus UVA (96912); and photochemotherapy of severe dermatoses requiring a minimum of 4 hours of care under direct physician supervision (96913). Nonfacility prices for these procedures were analyzed. For 2010, due to midyear alterations to Medicare reimbursement (owed to bills HR 3962 and HR 4872), the mean price data of MPFS files 2010A and 2010B were used. All dollar values were converted to January 2023 US dollars using corresponding consumer price index inflation data. The Medicare Administrative Contractors were used to group state pricing information by region in accordance with established US Census Bureau subdivisions (https://www.census.gov/programs-surveys/economic-census/guidance-geographies/levels.html). Weighted percentage change in reimbursement rate was calculated using physician (MD or DO) utilization (procedure volume) data available in the 2020 Physician and Other Practitioners Public Use File (https://data.cms.gov/provider-summary-by-type-of-service/medicare-physician-other-practitioners/medicare-physician-other-practitioners-by-provider-and-service). All descriptive statistics and visualization were generated using R software (v4.2.2)(R Development Core Team).
Table 1 provides physician utilization data and the corresponding number of Part B beneficiaries for phototherapy procedures in 2020. There were 65,045 services of actinotherapy provided to a total of 6855 unique Part B beneficiaries, 173,979 services of photochemotherapy by Goeckerman treatment or using petrolatum and UVB provided to 13,122 unique Part B beneficiaries, 2524 services of photochemotherapy using psoralen plus UVA provided to a total of 357 unique Part B beneficiaries, and 37 services of photochemotherapy of severe dermatoses requiring a minimum of 4 hours of care under direct physician supervision provided to a total of 27 unique Part B beneficiaries.
On average (unweighted), phototherapy reimbursement rates in the North increased by 0.68% between 2010 and 2023 (Table 2). After weighting for 2020 physician utilization, the average change in reimbursement rate was +19.37%. During this time period, CPT code 96910 reported the greatest adjusted increase in reimbursement (+31.45%)($98.12 to $128.98; compound annual growth rate [CAGR], +0.0213), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−12.76%)($126.09 to $109.97; CAGR, −0.0105). For CPT code 96900, the reported adjusted decrease in reimbursement was −11.68% ($30.21 to $26.68; CAGR, −0.0095), and for CPT code 96913, the reported adjusted decrease in reimbursement was −4.27% ($174.03 to $166.60; CAGR, −0.0034).
On average (unweighted), phototherapy reimbursement rates in the Midwest increased by 8.40% between 2010 and 2023 (Table 3). After weighting for 2020 physician utilization, the average change in reimbursement rate was +28.53%. During this time period, CPT code 96910 reported the greatest adjusted change in reimbursement (+41.48%)($80.42 to $113.78; CAGR, +0.0270), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−6.14%)($103.28 to $97.03; CAGR, −0.0049). For CPT code 96900, the reported adjusted decrease in reimbursement was −4.73% ($24.69 to $23.52; CAGR, −0.0037), and for CPT code 96913, the reported adjusted increase in reimbursement was +2.99% ($142.72 to $146.99; CAGR, +0.0023).
On average (unweighted), phototherapy reimbursement rates in the South decreased by 2.62% between 2010 and 2023 (Table 4). After weighting for 2020 physician utilization, the average change in reimbursement rate was +15.41%. During this time period, CPT code 96910 reported the greatest adjusted change in reimbursement (+27.26%)($90.40 to $115.04 USD; CAGR, +0.0187), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−15.50%)($116.08 to $98.09; CAGR, −0.0129). For CPT code 96900, the reported adjusted decrease in reimbursement was −15.06% ($28.02 to $23.80; CAGR, −0.0125), and for CPT code 96913, the reported adjusted decrease in reimbursement was −7.19% ($160.11 to $148.61; CAGR, −0.0057).
On average (unweighted), phototherapy reimbursement rates in the West increased by 27.53% between 2010 and 2023 (Table 5). After weighting for 2020 physician utilization, the average change in reimbursement rate was +51.16%. Reimbursement for all analyzed procedures increased in the western United States. During this time period, CPT code 96910 reported the greatest adjusted increase in reimbursement (+66.56%)($80.84 to $134.65; CAGR, +0.0400), and CPT code 96912 reported the lowest adjusted increase in reimbursement (+10.64%)($103.88 to $114.93; CAGR, +0.0078). For CPT code 96900, the reported adjusted increase in reimbursement was 11.54% ($24.88 to $27.75; CAGR, +0.0084), and for CPT code 96913, the reported adjusted increase in reimbursement was 21.38% ($143.39 to $174.04; CAGR, +0.0150).
In this study evaluating geographical payment trends for phototherapy from 2010 to 2023, we demonstrated regional inconsistency in mean inflation-adjusted Medicare reimbursement rates. We found that all phototherapy procedures had increased reimbursement in the western United States, whereas all other regions reported cuts in reimbursement rates for at least half of the analyzed procedures. After adjusting for procedure utilization by physicians, weighted mean reimbursement for phototherapy increased in all US regions.
In a cross-sectional study that explored trends in the geographic distribution of dermatologists from 2012 to 2017, dermatologists in the northeastern and western United States were more likely to be located in higher-income zip codes, whereas dermatologists in the southern United States were more likely to be located in lower-income zip codes,7 suggesting that payment rate changes are not concordant with cost of living. Additionally, Lauck and colleagues8 observed that 75% of the top 20 most common procedures performed by dermatologists had decreased reimbursement (mean change, −10.8%) from 2011 to 2021. Other studies on Medicare reimbursement trends over the last 2 decades have reported major decreases within other specialties, suggesting that declining Medicare reimbursements are not unique to dermatology.9,10 It is critical to monitor these developments, as the Centers for Medicare & Medicaid Services emphasized health care policy changes aimed at increasing reimbursements for evaluation and management services with compensatory payment cuts in billing for procedural services.11
Mazmudar et al12 previously reported a mean reimbursement decrease of −6.6% for laser/phototherapy procedures between 2007 and 2021, but these data did not include the heavily utilized Goeckerman treatment. Changes in reimbursement pose major ramifications for dermatologists—for practice size, scope, and longevity—as rates influence changes in commercial insurance reimbursements.13 Medicare plays a major role in the US health care system as the second largest expenditure14; indeed, between 2000 and 2015, Part B billing volume for phototherapy procedures increased 5% annually. However, phototherapy remains inaccessible in many locations due to unequal regional distribution of phototherapy clinics.6 Moreover, home phototherapy units are not yet widely utilized because of safety and efficacy concerns, lack of physician oversight, and difficulty obtaining insurance coverage.15 Acknowledgment and consideration of these geographical trends may persuasively allow policymakers, hospitals, and physicians to facilitate cost-effective phototherapy reimbursements that ensure continued access to quality and sustainable dermatologic care in the United States that tailor to regional needs.
In sum, this analysis reveals regional trends in Part B physician reimbursement for phototherapy procedures, with all US regions reporting a mean increase in phototherapy reimbursement after adjusting for utilization, albeit to varying degrees. Mean reimbursement for photochemotherapy by Goeckerman treatment or using petrolatum and UVB increased most among phototherapy procedures. Mean reimbursement for both actinotherapy and photochemotherapy using psoralen plus UVA decreased in all regions except the western United States.
Limitations include the restriction to Part B MPFS and the reliance on single-year (2020) physician utilization data to compute weighted changes in average reimbursement across a multiyear range, effectively restricting sweeping conclusions. Still, this study puts forth actionable insights for dermatologists and policymakers alike to appreciate and consider.
To the Editor:
Phototherapy regularly is utilized in the outpatient setting to address various skin pathologies, including atopic dermatitis, psoriasis, pruritus, vitiligo, and mycosis fungoides.1,2 Phototherapy is broadly defined by the measured administration of nonionizing radiation within the UV range including wavelengths within the UVA (eg, psoralen sensitizer plus UVA-1) and UVB (eg, broadband UVB, narrowband UVB) spectrums.1,3 Generally, the mechanism of action is derived from effects on inflammatory components of cutaneous disorders and the induction of apoptosis, both precipitating numerous downstream events.4
From 2015 to 2018, there were more than 1.3 million outpatient phototherapy visits in the United States, with the most common procedural indications being dermatitis not otherwise specified, atopic dermatitis, and pruritus.5 From 2000 to 2015, the quantity of phototherapy services billed to Medicare trended upwards by an average of 5% per year, increasing from 334,670 in the year 2000 to 692,093 in 2015.6 Therefore, an illustration of associated costs would be beneficial. Additionally, because total cost and physician reimbursement fluctuate from year to year, studies demonstrating overall trends can inform both US policymakers and physicians. There is a paucity of research on geographical trends for procedural reimbursements in dermatology for phototherapy. Understanding geographic trends of reimbursement could duly serve to optimize dermatologist practice patterns involving access to viable and quality care for patients seeking treatment as well as draw health policymakers’ attention to striking adjustments in physician fees. Therefore, in this study we aimed to illustrate the most recent regional payment trends in phototherapy procedures for Medicare B patients.
We queried the Centers for Medicare & Medicaid Services Medicare Physician Fee Schedule (MPFS) database (https://www.cms.gov/medicare/payment/fee-schedules/physician/lookup-tool) for the years 2010 to 2023 for Current Procedural Terminology (CPT) codes common to phototherapy procedures: actinotherapy (96900); photochemotherapy by Goeckerman treatment or using petrolatum and UVB (96910); photochemotherapy using psoralen plus UVA (96912); and photochemotherapy of severe dermatoses requiring a minimum of 4 hours of care under direct physician supervision (96913). Nonfacility prices for these procedures were analyzed. For 2010, due to midyear alterations to Medicare reimbursement (owed to bills HR 3962 and HR 4872), the mean price data of MPFS files 2010A and 2010B were used. All dollar values were converted to January 2023 US dollars using corresponding consumer price index inflation data. The Medicare Administrative Contractors were used to group state pricing information by region in accordance with established US Census Bureau subdivisions (https://www.census.gov/programs-surveys/economic-census/guidance-geographies/levels.html). Weighted percentage change in reimbursement rate was calculated using physician (MD or DO) utilization (procedure volume) data available in the 2020 Physician and Other Practitioners Public Use File (https://data.cms.gov/provider-summary-by-type-of-service/medicare-physician-other-practitioners/medicare-physician-other-practitioners-by-provider-and-service). All descriptive statistics and visualization were generated using R software (v4.2.2)(R Development Core Team).
Table 1 provides physician utilization data and the corresponding number of Part B beneficiaries for phototherapy procedures in 2020. There were 65,045 services of actinotherapy provided to a total of 6855 unique Part B beneficiaries, 173,979 services of photochemotherapy by Goeckerman treatment or using petrolatum and UVB provided to 13,122 unique Part B beneficiaries, 2524 services of photochemotherapy using psoralen plus UVA provided to a total of 357 unique Part B beneficiaries, and 37 services of photochemotherapy of severe dermatoses requiring a minimum of 4 hours of care under direct physician supervision provided to a total of 27 unique Part B beneficiaries.
On average (unweighted), phototherapy reimbursement rates in the North increased by 0.68% between 2010 and 2023 (Table 2). After weighting for 2020 physician utilization, the average change in reimbursement rate was +19.37%. During this time period, CPT code 96910 reported the greatest adjusted increase in reimbursement (+31.45%)($98.12 to $128.98; compound annual growth rate [CAGR], +0.0213), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−12.76%)($126.09 to $109.97; CAGR, −0.0105). For CPT code 96900, the reported adjusted decrease in reimbursement was −11.68% ($30.21 to $26.68; CAGR, −0.0095), and for CPT code 96913, the reported adjusted decrease in reimbursement was −4.27% ($174.03 to $166.60; CAGR, −0.0034).
On average (unweighted), phototherapy reimbursement rates in the Midwest increased by 8.40% between 2010 and 2023 (Table 3). After weighting for 2020 physician utilization, the average change in reimbursement rate was +28.53%. During this time period, CPT code 96910 reported the greatest adjusted change in reimbursement (+41.48%)($80.42 to $113.78; CAGR, +0.0270), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−6.14%)($103.28 to $97.03; CAGR, −0.0049). For CPT code 96900, the reported adjusted decrease in reimbursement was −4.73% ($24.69 to $23.52; CAGR, −0.0037), and for CPT code 96913, the reported adjusted increase in reimbursement was +2.99% ($142.72 to $146.99; CAGR, +0.0023).
On average (unweighted), phototherapy reimbursement rates in the South decreased by 2.62% between 2010 and 2023 (Table 4). After weighting for 2020 physician utilization, the average change in reimbursement rate was +15.41%. During this time period, CPT code 96910 reported the greatest adjusted change in reimbursement (+27.26%)($90.40 to $115.04 USD; CAGR, +0.0187), and CPT code 96912 reported the greatest adjusted decrease in reimbursement (−15.50%)($116.08 to $98.09; CAGR, −0.0129). For CPT code 96900, the reported adjusted decrease in reimbursement was −15.06% ($28.02 to $23.80; CAGR, −0.0125), and for CPT code 96913, the reported adjusted decrease in reimbursement was −7.19% ($160.11 to $148.61; CAGR, −0.0057).
On average (unweighted), phototherapy reimbursement rates in the West increased by 27.53% between 2010 and 2023 (Table 5). After weighting for 2020 physician utilization, the average change in reimbursement rate was +51.16%. Reimbursement for all analyzed procedures increased in the western United States. During this time period, CPT code 96910 reported the greatest adjusted increase in reimbursement (+66.56%)($80.84 to $134.65; CAGR, +0.0400), and CPT code 96912 reported the lowest adjusted increase in reimbursement (+10.64%)($103.88 to $114.93; CAGR, +0.0078). For CPT code 96900, the reported adjusted increase in reimbursement was 11.54% ($24.88 to $27.75; CAGR, +0.0084), and for CPT code 96913, the reported adjusted increase in reimbursement was 21.38% ($143.39 to $174.04; CAGR, +0.0150).
In this study evaluating geographical payment trends for phototherapy from 2010 to 2023, we demonstrated regional inconsistency in mean inflation-adjusted Medicare reimbursement rates. We found that all phototherapy procedures had increased reimbursement in the western United States, whereas all other regions reported cuts in reimbursement rates for at least half of the analyzed procedures. After adjusting for procedure utilization by physicians, weighted mean reimbursement for phototherapy increased in all US regions.
In a cross-sectional study that explored trends in the geographic distribution of dermatologists from 2012 to 2017, dermatologists in the northeastern and western United States were more likely to be located in higher-income zip codes, whereas dermatologists in the southern United States were more likely to be located in lower-income zip codes,7 suggesting that payment rate changes are not concordant with cost of living. Additionally, Lauck and colleagues8 observed that 75% of the top 20 most common procedures performed by dermatologists had decreased reimbursement (mean change, −10.8%) from 2011 to 2021. Other studies on Medicare reimbursement trends over the last 2 decades have reported major decreases within other specialties, suggesting that declining Medicare reimbursements are not unique to dermatology.9,10 It is critical to monitor these developments, as the Centers for Medicare & Medicaid Services emphasized health care policy changes aimed at increasing reimbursements for evaluation and management services with compensatory payment cuts in billing for procedural services.11
Mazmudar et al12 previously reported a mean reimbursement decrease of −6.6% for laser/phototherapy procedures between 2007 and 2021, but these data did not include the heavily utilized Goeckerman treatment. Changes in reimbursement pose major ramifications for dermatologists—for practice size, scope, and longevity—as rates influence changes in commercial insurance reimbursements.13 Medicare plays a major role in the US health care system as the second largest expenditure14; indeed, between 2000 and 2015, Part B billing volume for phototherapy procedures increased 5% annually. However, phototherapy remains inaccessible in many locations due to unequal regional distribution of phototherapy clinics.6 Moreover, home phototherapy units are not yet widely utilized because of safety and efficacy concerns, lack of physician oversight, and difficulty obtaining insurance coverage.15 Acknowledgment and consideration of these geographical trends may persuasively allow policymakers, hospitals, and physicians to facilitate cost-effective phototherapy reimbursements that ensure continued access to quality and sustainable dermatologic care in the United States that tailor to regional needs.
In sum, this analysis reveals regional trends in Part B physician reimbursement for phototherapy procedures, with all US regions reporting a mean increase in phototherapy reimbursement after adjusting for utilization, albeit to varying degrees. Mean reimbursement for photochemotherapy by Goeckerman treatment or using petrolatum and UVB increased most among phototherapy procedures. Mean reimbursement for both actinotherapy and photochemotherapy using psoralen plus UVA decreased in all regions except the western United States.
Limitations include the restriction to Part B MPFS and the reliance on single-year (2020) physician utilization data to compute weighted changes in average reimbursement across a multiyear range, effectively restricting sweeping conclusions. Still, this study puts forth actionable insights for dermatologists and policymakers alike to appreciate and consider.
- Rathod DG, Muneer H, Masood S. Phototherapy. StatPearls. StatPearls Publishing; 2002.
- Branisteanu DE, Dirzu DS, Toader MP, et al. Phototherapy in dermatological maladies (Review). Exp Ther Med. 2022;23:259. doi:10.3892/etm.2022.11184
- Barros NM, Sbroglio LL, Buffara MO, et al. Phototherapy. An Bras Dermatol. 2021;96:397-407. doi:10.1016/j.abd.2021.03.001
- Vieyra-Garcia PA, Wolf P. A deep dive into UV-based phototherapy: mechanisms of action and emerging molecular targets in inflammation and cancer. Pharmacol Ther. 2021;222:107784. doi:10.1016/j.pharmthera.2020.107784
- Oulee A, Javadi SS, Martin A, et al. Phototherapy trends in dermatology 2015-2018. J Dermatolog Treat. 2022;33:2545-2546. doi:10.1080/09546634.2021.2019660
- Tan SY, Buzney E, Mostaghimi A. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015. J Am Acad Dermatol. 2018;79:672-679. doi:10.1016/j.jaad.2018.03.018
- Benlagha I, Nguyen BM. Changes in dermatology practice characteristics in the United States from 2012 to 2017. JAAD Int. 2021;3:92-101. doi:10.1016/j.jdin.2021.03.005
- Lauck K, Nguyen QB, Hebert A. Trends in Medicare reimbursement within dermatology: 2011-2021. Skin. 2022;6:122-131. doi:10.25251/skin.6.2.5
- Smith JF, Moore ML, Pollock JR, et al. National and geographic trends in Medicare reimbursement rates for orthopedic shoulder and upper extremity surgery from 2000 to 2020. J Shoulder Elbow Surg. 2022;31:860-867. doi:10.1016/j.jse.2021.09.001
- Haglin JM, Eltorai AEM, Richter KR, et al. Medicare reimbursement for general surgery procedures: 2000 to 2018. Ann Surg. 2020;271:17-22. doi:10.1097/SLA.0000000000003289
- Fleishon HB. Evaluation and management coding initiative. J Am Coll Radiol. 2020;17:1539-1540. doi:10.1016/j.jacr.2020.09.057
- Mazmudar RS, Sheth A, Tripathi R, et al. Inflation-adjusted trends in Medicare reimbursement for common dermatologic procedures, 2007-2021. JAMA Dermatol. 2021;157:1355-1358. doi:10.1001/jamadermatol.2021.3453
- Clemens J, Gottlieb JD. In the shadow of a giant: Medicare’s influence on private physician payments. J Polit Econ. 2017;125:1-39. doi:10.1086/689772
- Ya J, Ezaldein HH, Scott JF. Trends in Medicare utilization by dermatologists, 2012-2015. JAMA Dermatol. 2019;155:471-474. doi:10.1001/jamadermatol.2018.4212
- Rajpara AN, O’Neill JL, Nolan BV, et al. Review of home phototherapy. Dermatol Online J. 2010;16:2.
- Rathod DG, Muneer H, Masood S. Phototherapy. StatPearls. StatPearls Publishing; 2002.
- Branisteanu DE, Dirzu DS, Toader MP, et al. Phototherapy in dermatological maladies (Review). Exp Ther Med. 2022;23:259. doi:10.3892/etm.2022.11184
- Barros NM, Sbroglio LL, Buffara MO, et al. Phototherapy. An Bras Dermatol. 2021;96:397-407. doi:10.1016/j.abd.2021.03.001
- Vieyra-Garcia PA, Wolf P. A deep dive into UV-based phototherapy: mechanisms of action and emerging molecular targets in inflammation and cancer. Pharmacol Ther. 2021;222:107784. doi:10.1016/j.pharmthera.2020.107784
- Oulee A, Javadi SS, Martin A, et al. Phototherapy trends in dermatology 2015-2018. J Dermatolog Treat. 2022;33:2545-2546. doi:10.1080/09546634.2021.2019660
- Tan SY, Buzney E, Mostaghimi A. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015. J Am Acad Dermatol. 2018;79:672-679. doi:10.1016/j.jaad.2018.03.018
- Benlagha I, Nguyen BM. Changes in dermatology practice characteristics in the United States from 2012 to 2017. JAAD Int. 2021;3:92-101. doi:10.1016/j.jdin.2021.03.005
- Lauck K, Nguyen QB, Hebert A. Trends in Medicare reimbursement within dermatology: 2011-2021. Skin. 2022;6:122-131. doi:10.25251/skin.6.2.5
- Smith JF, Moore ML, Pollock JR, et al. National and geographic trends in Medicare reimbursement rates for orthopedic shoulder and upper extremity surgery from 2000 to 2020. J Shoulder Elbow Surg. 2022;31:860-867. doi:10.1016/j.jse.2021.09.001
- Haglin JM, Eltorai AEM, Richter KR, et al. Medicare reimbursement for general surgery procedures: 2000 to 2018. Ann Surg. 2020;271:17-22. doi:10.1097/SLA.0000000000003289
- Fleishon HB. Evaluation and management coding initiative. J Am Coll Radiol. 2020;17:1539-1540. doi:10.1016/j.jacr.2020.09.057
- Mazmudar RS, Sheth A, Tripathi R, et al. Inflation-adjusted trends in Medicare reimbursement for common dermatologic procedures, 2007-2021. JAMA Dermatol. 2021;157:1355-1358. doi:10.1001/jamadermatol.2021.3453
- Clemens J, Gottlieb JD. In the shadow of a giant: Medicare’s influence on private physician payments. J Polit Econ. 2017;125:1-39. doi:10.1086/689772
- Ya J, Ezaldein HH, Scott JF. Trends in Medicare utilization by dermatologists, 2012-2015. JAMA Dermatol. 2019;155:471-474. doi:10.1001/jamadermatol.2018.4212
- Rajpara AN, O’Neill JL, Nolan BV, et al. Review of home phototherapy. Dermatol Online J. 2010;16:2.
Practice Points
- After weighting for procedure utilization, mean reimbursement for phototherapy increased across all US regions from 2010 to 2023 (mean change, +28.62%), yet with marked regional diversity.
- The southern United States reported the least growth in weighted mean reimbursement (+15.41%), and the western United States reported the greatest growth in weighted mean reimbursement (+51.16%).
- Region- and procedure-specific payment changes are especially valuable to dermatologists and policymakers alike, potentially reinvigorating payment reform discussions.
The Impact of a Paracentesis Clinic on Internal Medicine Resident Procedural Competency
Competency in paracentesis is an important procedural skill for medical practitioners caring for patients with decompensated liver cirrhosis. Paracentesis is performed to drain ascitic fluid for both diagnosis and/or therapeutic purposes.1 While this procedure can be performed without the use of ultrasound, it is preferable to use ultrasound to identify an area of fluid that is away from dangerous anatomy including bowel loops, the liver, and spleen. After prepping the area, lidocaine is administered locally. A catheter is then inserted until fluid begins flowing freely. The catheter is connected to a suction canister or collection kit, and the patient is monitored until the flow ceases. Samples can be sent for analysis to determine the etiology of ascites, identify concerns for infection, and more.
Paracentesis is a very common procedure. Barsuk and colleagues noted that between 2010 and 2012, 97,577 procedures were performed across 120 academic medical centers and 290 affiliated hospitals.2 Patients undergo paracentesis in a variety of settings including the emergency department, inpatient hospitalizations, and clinics. Some patients may require only 1 paracentesis procedure while others may require it regularly.
Due to the rising need for paracentesis in the Central Texas Veterans Affairs Hospital (CTVAH) in Temple, a paracentesis clinic was started in February 2018. The goal of the paracentesis clinic was multifocal—to reduce hospital admissions, improve access to regularly scheduled procedures, decrease wait times, and increase patient satisfaction.3 Through the CTVAH affiliation with the Texas A&M internal medicine residency program, the paracentesis clinic started involving and training residents on this procedure. Up to 3 residents are on weekly rotation and can perform up to 6 paracentesis procedures in a week. The purpose of this article was to evaluate resident competency in paracentesis after completion of the paracentesis clinic.
Methods
The paracentesis clinic schedules up to 3 patients on Tuesdays and Thursdays between 8
A survey was sent via email to all categorical internal medicine residents across all 3 program years at the time of data collection. Competency for paracentesis sign-off was defined as completing and logging 5 procedures supervised by a competent physician who confirmed that all portions of the procedure were performed correctly. Residents were also asked to answer questions on a scale from 1 to 10, with 1 representing no confidence and 10 representing strong confidence to practice independently (Table).
We also evaluated the number of procedures performed by internal medicine residents 3 years before the clinic was started in 2015 up to the completion of 2022. The numbers were obtained by examining procedural log data for each year for all internal medicine residents.
Results
Thirty-three residents completed the survey: 10 first-year internal medicine residents (PGY1), 12 second-year residents (PGY2), and 11 third-year residents (PGY3). The mean participation was 4.8 paracentesis sessions per person for the duration of the study. The range of paracentesis procedures performed varied based on PGY year: PGY1s performed 1 to > 10 procedures, PGY2s performed 2 to > 10 procedures, and PGY3s performed 5 to > 10 procedures. Thirty-six percent of residents completed > 10 procedures in the paracentesis clinic; 82% of PGY3s had completed > 10 procedures by December of their third year. Twenty-six residents (79%) were credentialed to perform paracentesis procedures independently after performing > 5 procedures, and 7 residents were not yet cleared for procedural independence.
In the survey, residents rated their comfort with performing paracentesis procedures independently at a mean of 7.9. The mean comfort reported by PGY1s was 7.2, PGY2s was 7.3, and PGY3s was 9.3. Residents also rated their opinion on whether or not the paracentesis clinic adequately prepared them for paracentesis procedural independence; the mean was 8.9 across all residents.
The total number of procedures performed by residents at CTVAH also increased. Starting in 2015, 3 years before the clinic was started, 38 procedures were performed by internal medicine residents, followed by 72 procedures in 2016; 76 in 2017; 58 in 2018; 94 in 2019; 88 in 2020; 136 in 2021; and 188 in 2022.
Discussion
Paracentesis is a simple but invasive procedure to relieve ascites, often relieving patients’ symptoms, preventing hospital admission, and increasing patient satisfaction.4 The CTVAH does not have the capacity to perform outpatient paracentesis effectively in its emergency or radiology departments. Furthermore, the use of the emergency or radiology departments for routine paracentesis may not be feasible due to the acuity of care being provided, as these procedures can be time consuming and can draw away critical resources and time from patients that need emergent care. The paracentesis clinic was then formed to provide veterans access to the procedural care they need, while also preparing residents to ably and confidently perform the procedure independently.
Based on our study, most residents were cleared to independently perform paracentesis procedures across all 3 years, with 79% of residents having completed the required 5 supervised procedures to independently practice. A study assessing unsupervised practice standards showed that paracentesis skill declines as soon as 3 months after training. However, retraining was shown to potentially interrupt this skill decline.5 Studies have shown that procedure-driven electives or services significantly improved paracentesis certification rates and total logged procedures, with minimal funding or scheduling changes required.6 Our clinic showed a significant increase in the number of procedures logged starting with the minimum of 38 procedures in 2015 and ending with 188 procedures logged at the end of 2022.
By allowing residents to routinely return to the paracentesis clinic across all 3 years, residents were more likely to feel comfortable independently performing the procedure, with residents reporting a mean comfort score of 7.9. The spaced repetition and ability to work with the clinic during elective time allows regular opportunities to undergo supervised training in a controlled environment and created scheduled retraining opportunities. Future studies should evaluate residents prior to each paracentesis clinic to ascertain if skill decline is occurring at a slower rate.
The inpatient effect of the clinic is also multifocal. Pham and colleagues showed that integrating paracentesis into timely training can reduce paracentesis delay and delays in care.7 By increasing the volume of procedures each resident performs and creating a sense of confidence amongst residents, the clinic increases the number of residents able and willing to perform inpatient procedures, thus reducing the number of unnecessary consultations and hospital resources. One of the reasons the paracentesis clinic was started was to allow patients to have scheduled times to remove fluid from their abdomen, thus cutting down on emergency department procedures and unnecessary admissions. Additionally, the benefits of early paracentesis procedural performance by residents and internal medicine physicians have been demonstrated in the literature. A study by Gaetano and colleagues noted that patients undergoing early paracentesis had reduced mortality of 5.5% vs 7.5% in those undergoing late paracentesis.8 This study also showed the in-hospital mortality rate was decreased with paracentesis (6.3%) vs without paracentesis (8.9%).8 By offering residents a chance to participate in the clinic, we have shown that regular opportunities to perform paracentesis may increase the number of physicians capable of independently practicing, improve procedural competency, and improve patient access to this procedure.
Limitations
Our study was not free of bias and has potential weaknesses. The survey was sent to all current residents who have participated in the paracentesis clinic, but not every resident filled out the survey (55% of all residents across 3 years completed the survey, 68.7% who had done clinic that year completed the survey). There is a possibility that those not signed off avoided doing the survey, but we are unable to confirm this. The survey also depended on resident recall of the number of paracenteses completed or looking at their procedure log. It is possible that some procedures were not documented, changing the true number. Additionally, rating comfortability with procedures is subjective, which may also create a source of potential weakness. Future projects should include a baseline survey for residents, followed by a repeat survey a year later to show changes from baseline competency.
Conclusions
A dedicated paracentesis clinic with internal medicine resident involvement may increase resident paracentesis procedural independence, the number of procedures available and performed, and procedural comfort level.
1. Aponte EM, O’Rourke MC, Katta S. Paracentesis. StatPearls [internet]. September 5, 2022. Accessed December 11, 2023. https://www.ncbi.nlm.nih.gov/books/NBK435998
2. Barsuk JH, Feinglass J, Kozmic SE, Hohmann SF, Ganger D, Wayne DB. Specialties performing paracentesis procedures at university hospitals: implications for training and certification. J Hosp Med. 2014;9(3):162-168. doi:10.1002/jhm.2153
3. Cheng Y-W, Sandrasegaran K, Cheng K, et al. A dedicated paracentesis clinic decreases healthcare utilization for serial paracenteses in decompensated cirrhosis. Abdominal Radiology. 2017;43(8):2190-2197. doi:10.1007/s00261-017-1406-y
4. Wang J, Khan S, Wyer P, et al. The role of ultrasound-guided therapeutic paracentesis in an outpatient transitional care program: A case series. Am J Hospice Palliat Med. 2018;35(9):1256-1260. doi:10.1177/1049909118755378
5. Sall D, Warm EJ, Kinnear B, Kelleher M, Jandarov R, O’Toole J. See one, do one, forget one: early skill decay after paracentesis training. J Gen Int Med. 2020;36(5):1346-1351. doi:10.1007/s11606-020-06242-x
6. Berger M, Divilov V, Paredes H, Kesar V, Sun E. Improving resident paracentesis certification rates by using an innovative resident driven procedure service. Am J Gastroenterol. 2018;113(suppl). doi:10.14309/00000434-201810001-00980
7. Pham C, Xu A, Suaez MG. S1250 a pilot study to improve resident paracentesis training and reduce paracentesis delay in admitted patients with cirrhosis. Am J Gastroenterol. 2022;117(10S). doi:10.14309/01.ajg.0000861640.53682.93
8. Gaetano JN, Micic D, Aronsohn A, et al. The benefit of paracentesis on hospitalized adults with cirrhosis and ascites. J Gastroenterol Hepatol. 2016;31(5):1025-1030. doi:10.1111/jgh.13255
Competency in paracentesis is an important procedural skill for medical practitioners caring for patients with decompensated liver cirrhosis. Paracentesis is performed to drain ascitic fluid for both diagnosis and/or therapeutic purposes.1 While this procedure can be performed without the use of ultrasound, it is preferable to use ultrasound to identify an area of fluid that is away from dangerous anatomy including bowel loops, the liver, and spleen. After prepping the area, lidocaine is administered locally. A catheter is then inserted until fluid begins flowing freely. The catheter is connected to a suction canister or collection kit, and the patient is monitored until the flow ceases. Samples can be sent for analysis to determine the etiology of ascites, identify concerns for infection, and more.
Paracentesis is a very common procedure. Barsuk and colleagues noted that between 2010 and 2012, 97,577 procedures were performed across 120 academic medical centers and 290 affiliated hospitals.2 Patients undergo paracentesis in a variety of settings including the emergency department, inpatient hospitalizations, and clinics. Some patients may require only 1 paracentesis procedure while others may require it regularly.
Due to the rising need for paracentesis in the Central Texas Veterans Affairs Hospital (CTVAH) in Temple, a paracentesis clinic was started in February 2018. The goal of the paracentesis clinic was multifocal—to reduce hospital admissions, improve access to regularly scheduled procedures, decrease wait times, and increase patient satisfaction.3 Through the CTVAH affiliation with the Texas A&M internal medicine residency program, the paracentesis clinic started involving and training residents on this procedure. Up to 3 residents are on weekly rotation and can perform up to 6 paracentesis procedures in a week. The purpose of this article was to evaluate resident competency in paracentesis after completion of the paracentesis clinic.
Methods
The paracentesis clinic schedules up to 3 patients on Tuesdays and Thursdays between 8
A survey was sent via email to all categorical internal medicine residents across all 3 program years at the time of data collection. Competency for paracentesis sign-off was defined as completing and logging 5 procedures supervised by a competent physician who confirmed that all portions of the procedure were performed correctly. Residents were also asked to answer questions on a scale from 1 to 10, with 1 representing no confidence and 10 representing strong confidence to practice independently (Table).
We also evaluated the number of procedures performed by internal medicine residents 3 years before the clinic was started in 2015 up to the completion of 2022. The numbers were obtained by examining procedural log data for each year for all internal medicine residents.
Results
Thirty-three residents completed the survey: 10 first-year internal medicine residents (PGY1), 12 second-year residents (PGY2), and 11 third-year residents (PGY3). The mean participation was 4.8 paracentesis sessions per person for the duration of the study. The range of paracentesis procedures performed varied based on PGY year: PGY1s performed 1 to > 10 procedures, PGY2s performed 2 to > 10 procedures, and PGY3s performed 5 to > 10 procedures. Thirty-six percent of residents completed > 10 procedures in the paracentesis clinic; 82% of PGY3s had completed > 10 procedures by December of their third year. Twenty-six residents (79%) were credentialed to perform paracentesis procedures independently after performing > 5 procedures, and 7 residents were not yet cleared for procedural independence.
In the survey, residents rated their comfort with performing paracentesis procedures independently at a mean of 7.9. The mean comfort reported by PGY1s was 7.2, PGY2s was 7.3, and PGY3s was 9.3. Residents also rated their opinion on whether or not the paracentesis clinic adequately prepared them for paracentesis procedural independence; the mean was 8.9 across all residents.
The total number of procedures performed by residents at CTVAH also increased. Starting in 2015, 3 years before the clinic was started, 38 procedures were performed by internal medicine residents, followed by 72 procedures in 2016; 76 in 2017; 58 in 2018; 94 in 2019; 88 in 2020; 136 in 2021; and 188 in 2022.
Discussion
Paracentesis is a simple but invasive procedure to relieve ascites, often relieving patients’ symptoms, preventing hospital admission, and increasing patient satisfaction.4 The CTVAH does not have the capacity to perform outpatient paracentesis effectively in its emergency or radiology departments. Furthermore, the use of the emergency or radiology departments for routine paracentesis may not be feasible due to the acuity of care being provided, as these procedures can be time consuming and can draw away critical resources and time from patients that need emergent care. The paracentesis clinic was then formed to provide veterans access to the procedural care they need, while also preparing residents to ably and confidently perform the procedure independently.
Based on our study, most residents were cleared to independently perform paracentesis procedures across all 3 years, with 79% of residents having completed the required 5 supervised procedures to independently practice. A study assessing unsupervised practice standards showed that paracentesis skill declines as soon as 3 months after training. However, retraining was shown to potentially interrupt this skill decline.5 Studies have shown that procedure-driven electives or services significantly improved paracentesis certification rates and total logged procedures, with minimal funding or scheduling changes required.6 Our clinic showed a significant increase in the number of procedures logged starting with the minimum of 38 procedures in 2015 and ending with 188 procedures logged at the end of 2022.
By allowing residents to routinely return to the paracentesis clinic across all 3 years, residents were more likely to feel comfortable independently performing the procedure, with residents reporting a mean comfort score of 7.9. The spaced repetition and ability to work with the clinic during elective time allows regular opportunities to undergo supervised training in a controlled environment and created scheduled retraining opportunities. Future studies should evaluate residents prior to each paracentesis clinic to ascertain if skill decline is occurring at a slower rate.
The inpatient effect of the clinic is also multifocal. Pham and colleagues showed that integrating paracentesis into timely training can reduce paracentesis delay and delays in care.7 By increasing the volume of procedures each resident performs and creating a sense of confidence amongst residents, the clinic increases the number of residents able and willing to perform inpatient procedures, thus reducing the number of unnecessary consultations and hospital resources. One of the reasons the paracentesis clinic was started was to allow patients to have scheduled times to remove fluid from their abdomen, thus cutting down on emergency department procedures and unnecessary admissions. Additionally, the benefits of early paracentesis procedural performance by residents and internal medicine physicians have been demonstrated in the literature. A study by Gaetano and colleagues noted that patients undergoing early paracentesis had reduced mortality of 5.5% vs 7.5% in those undergoing late paracentesis.8 This study also showed the in-hospital mortality rate was decreased with paracentesis (6.3%) vs without paracentesis (8.9%).8 By offering residents a chance to participate in the clinic, we have shown that regular opportunities to perform paracentesis may increase the number of physicians capable of independently practicing, improve procedural competency, and improve patient access to this procedure.
Limitations
Our study was not free of bias and has potential weaknesses. The survey was sent to all current residents who have participated in the paracentesis clinic, but not every resident filled out the survey (55% of all residents across 3 years completed the survey, 68.7% who had done clinic that year completed the survey). There is a possibility that those not signed off avoided doing the survey, but we are unable to confirm this. The survey also depended on resident recall of the number of paracenteses completed or looking at their procedure log. It is possible that some procedures were not documented, changing the true number. Additionally, rating comfortability with procedures is subjective, which may also create a source of potential weakness. Future projects should include a baseline survey for residents, followed by a repeat survey a year later to show changes from baseline competency.
Conclusions
A dedicated paracentesis clinic with internal medicine resident involvement may increase resident paracentesis procedural independence, the number of procedures available and performed, and procedural comfort level.
Competency in paracentesis is an important procedural skill for medical practitioners caring for patients with decompensated liver cirrhosis. Paracentesis is performed to drain ascitic fluid for both diagnosis and/or therapeutic purposes.1 While this procedure can be performed without the use of ultrasound, it is preferable to use ultrasound to identify an area of fluid that is away from dangerous anatomy including bowel loops, the liver, and spleen. After prepping the area, lidocaine is administered locally. A catheter is then inserted until fluid begins flowing freely. The catheter is connected to a suction canister or collection kit, and the patient is monitored until the flow ceases. Samples can be sent for analysis to determine the etiology of ascites, identify concerns for infection, and more.
Paracentesis is a very common procedure. Barsuk and colleagues noted that between 2010 and 2012, 97,577 procedures were performed across 120 academic medical centers and 290 affiliated hospitals.2 Patients undergo paracentesis in a variety of settings including the emergency department, inpatient hospitalizations, and clinics. Some patients may require only 1 paracentesis procedure while others may require it regularly.
Due to the rising need for paracentesis in the Central Texas Veterans Affairs Hospital (CTVAH) in Temple, a paracentesis clinic was started in February 2018. The goal of the paracentesis clinic was multifocal—to reduce hospital admissions, improve access to regularly scheduled procedures, decrease wait times, and increase patient satisfaction.3 Through the CTVAH affiliation with the Texas A&M internal medicine residency program, the paracentesis clinic started involving and training residents on this procedure. Up to 3 residents are on weekly rotation and can perform up to 6 paracentesis procedures in a week. The purpose of this article was to evaluate resident competency in paracentesis after completion of the paracentesis clinic.
Methods
The paracentesis clinic schedules up to 3 patients on Tuesdays and Thursdays between 8
A survey was sent via email to all categorical internal medicine residents across all 3 program years at the time of data collection. Competency for paracentesis sign-off was defined as completing and logging 5 procedures supervised by a competent physician who confirmed that all portions of the procedure were performed correctly. Residents were also asked to answer questions on a scale from 1 to 10, with 1 representing no confidence and 10 representing strong confidence to practice independently (Table).
We also evaluated the number of procedures performed by internal medicine residents 3 years before the clinic was started in 2015 up to the completion of 2022. The numbers were obtained by examining procedural log data for each year for all internal medicine residents.
Results
Thirty-three residents completed the survey: 10 first-year internal medicine residents (PGY1), 12 second-year residents (PGY2), and 11 third-year residents (PGY3). The mean participation was 4.8 paracentesis sessions per person for the duration of the study. The range of paracentesis procedures performed varied based on PGY year: PGY1s performed 1 to > 10 procedures, PGY2s performed 2 to > 10 procedures, and PGY3s performed 5 to > 10 procedures. Thirty-six percent of residents completed > 10 procedures in the paracentesis clinic; 82% of PGY3s had completed > 10 procedures by December of their third year. Twenty-six residents (79%) were credentialed to perform paracentesis procedures independently after performing > 5 procedures, and 7 residents were not yet cleared for procedural independence.
In the survey, residents rated their comfort with performing paracentesis procedures independently at a mean of 7.9. The mean comfort reported by PGY1s was 7.2, PGY2s was 7.3, and PGY3s was 9.3. Residents also rated their opinion on whether or not the paracentesis clinic adequately prepared them for paracentesis procedural independence; the mean was 8.9 across all residents.
The total number of procedures performed by residents at CTVAH also increased. Starting in 2015, 3 years before the clinic was started, 38 procedures were performed by internal medicine residents, followed by 72 procedures in 2016; 76 in 2017; 58 in 2018; 94 in 2019; 88 in 2020; 136 in 2021; and 188 in 2022.
Discussion
Paracentesis is a simple but invasive procedure to relieve ascites, often relieving patients’ symptoms, preventing hospital admission, and increasing patient satisfaction.4 The CTVAH does not have the capacity to perform outpatient paracentesis effectively in its emergency or radiology departments. Furthermore, the use of the emergency or radiology departments for routine paracentesis may not be feasible due to the acuity of care being provided, as these procedures can be time consuming and can draw away critical resources and time from patients that need emergent care. The paracentesis clinic was then formed to provide veterans access to the procedural care they need, while also preparing residents to ably and confidently perform the procedure independently.
Based on our study, most residents were cleared to independently perform paracentesis procedures across all 3 years, with 79% of residents having completed the required 5 supervised procedures to independently practice. A study assessing unsupervised practice standards showed that paracentesis skill declines as soon as 3 months after training. However, retraining was shown to potentially interrupt this skill decline.5 Studies have shown that procedure-driven electives or services significantly improved paracentesis certification rates and total logged procedures, with minimal funding or scheduling changes required.6 Our clinic showed a significant increase in the number of procedures logged starting with the minimum of 38 procedures in 2015 and ending with 188 procedures logged at the end of 2022.
By allowing residents to routinely return to the paracentesis clinic across all 3 years, residents were more likely to feel comfortable independently performing the procedure, with residents reporting a mean comfort score of 7.9. The spaced repetition and ability to work with the clinic during elective time allows regular opportunities to undergo supervised training in a controlled environment and created scheduled retraining opportunities. Future studies should evaluate residents prior to each paracentesis clinic to ascertain if skill decline is occurring at a slower rate.
The inpatient effect of the clinic is also multifocal. Pham and colleagues showed that integrating paracentesis into timely training can reduce paracentesis delay and delays in care.7 By increasing the volume of procedures each resident performs and creating a sense of confidence amongst residents, the clinic increases the number of residents able and willing to perform inpatient procedures, thus reducing the number of unnecessary consultations and hospital resources. One of the reasons the paracentesis clinic was started was to allow patients to have scheduled times to remove fluid from their abdomen, thus cutting down on emergency department procedures and unnecessary admissions. Additionally, the benefits of early paracentesis procedural performance by residents and internal medicine physicians have been demonstrated in the literature. A study by Gaetano and colleagues noted that patients undergoing early paracentesis had reduced mortality of 5.5% vs 7.5% in those undergoing late paracentesis.8 This study also showed the in-hospital mortality rate was decreased with paracentesis (6.3%) vs without paracentesis (8.9%).8 By offering residents a chance to participate in the clinic, we have shown that regular opportunities to perform paracentesis may increase the number of physicians capable of independently practicing, improve procedural competency, and improve patient access to this procedure.
Limitations
Our study was not free of bias and has potential weaknesses. The survey was sent to all current residents who have participated in the paracentesis clinic, but not every resident filled out the survey (55% of all residents across 3 years completed the survey, 68.7% who had done clinic that year completed the survey). There is a possibility that those not signed off avoided doing the survey, but we are unable to confirm this. The survey also depended on resident recall of the number of paracenteses completed or looking at their procedure log. It is possible that some procedures were not documented, changing the true number. Additionally, rating comfortability with procedures is subjective, which may also create a source of potential weakness. Future projects should include a baseline survey for residents, followed by a repeat survey a year later to show changes from baseline competency.
Conclusions
A dedicated paracentesis clinic with internal medicine resident involvement may increase resident paracentesis procedural independence, the number of procedures available and performed, and procedural comfort level.
1. Aponte EM, O’Rourke MC, Katta S. Paracentesis. StatPearls [internet]. September 5, 2022. Accessed December 11, 2023. https://www.ncbi.nlm.nih.gov/books/NBK435998
2. Barsuk JH, Feinglass J, Kozmic SE, Hohmann SF, Ganger D, Wayne DB. Specialties performing paracentesis procedures at university hospitals: implications for training and certification. J Hosp Med. 2014;9(3):162-168. doi:10.1002/jhm.2153
3. Cheng Y-W, Sandrasegaran K, Cheng K, et al. A dedicated paracentesis clinic decreases healthcare utilization for serial paracenteses in decompensated cirrhosis. Abdominal Radiology. 2017;43(8):2190-2197. doi:10.1007/s00261-017-1406-y
4. Wang J, Khan S, Wyer P, et al. The role of ultrasound-guided therapeutic paracentesis in an outpatient transitional care program: A case series. Am J Hospice Palliat Med. 2018;35(9):1256-1260. doi:10.1177/1049909118755378
5. Sall D, Warm EJ, Kinnear B, Kelleher M, Jandarov R, O’Toole J. See one, do one, forget one: early skill decay after paracentesis training. J Gen Int Med. 2020;36(5):1346-1351. doi:10.1007/s11606-020-06242-x
6. Berger M, Divilov V, Paredes H, Kesar V, Sun E. Improving resident paracentesis certification rates by using an innovative resident driven procedure service. Am J Gastroenterol. 2018;113(suppl). doi:10.14309/00000434-201810001-00980
7. Pham C, Xu A, Suaez MG. S1250 a pilot study to improve resident paracentesis training and reduce paracentesis delay in admitted patients with cirrhosis. Am J Gastroenterol. 2022;117(10S). doi:10.14309/01.ajg.0000861640.53682.93
8. Gaetano JN, Micic D, Aronsohn A, et al. The benefit of paracentesis on hospitalized adults with cirrhosis and ascites. J Gastroenterol Hepatol. 2016;31(5):1025-1030. doi:10.1111/jgh.13255
1. Aponte EM, O’Rourke MC, Katta S. Paracentesis. StatPearls [internet]. September 5, 2022. Accessed December 11, 2023. https://www.ncbi.nlm.nih.gov/books/NBK435998
2. Barsuk JH, Feinglass J, Kozmic SE, Hohmann SF, Ganger D, Wayne DB. Specialties performing paracentesis procedures at university hospitals: implications for training and certification. J Hosp Med. 2014;9(3):162-168. doi:10.1002/jhm.2153
3. Cheng Y-W, Sandrasegaran K, Cheng K, et al. A dedicated paracentesis clinic decreases healthcare utilization for serial paracenteses in decompensated cirrhosis. Abdominal Radiology. 2017;43(8):2190-2197. doi:10.1007/s00261-017-1406-y
4. Wang J, Khan S, Wyer P, et al. The role of ultrasound-guided therapeutic paracentesis in an outpatient transitional care program: A case series. Am J Hospice Palliat Med. 2018;35(9):1256-1260. doi:10.1177/1049909118755378
5. Sall D, Warm EJ, Kinnear B, Kelleher M, Jandarov R, O’Toole J. See one, do one, forget one: early skill decay after paracentesis training. J Gen Int Med. 2020;36(5):1346-1351. doi:10.1007/s11606-020-06242-x
6. Berger M, Divilov V, Paredes H, Kesar V, Sun E. Improving resident paracentesis certification rates by using an innovative resident driven procedure service. Am J Gastroenterol. 2018;113(suppl). doi:10.14309/00000434-201810001-00980
7. Pham C, Xu A, Suaez MG. S1250 a pilot study to improve resident paracentesis training and reduce paracentesis delay in admitted patients with cirrhosis. Am J Gastroenterol. 2022;117(10S). doi:10.14309/01.ajg.0000861640.53682.93
8. Gaetano JN, Micic D, Aronsohn A, et al. The benefit of paracentesis on hospitalized adults with cirrhosis and ascites. J Gastroenterol Hepatol. 2016;31(5):1025-1030. doi:10.1111/jgh.13255
Piperacillin/Tazobactam Use vs Cefepime May Be Associated With Acute Decompensated Heart Failure
Piperacillin/tazobactam (PTZ) is a combination IV antibiotic comprised of the semisynthetic antipseudomonal β-lactam, piperacillin sodium, and the β-lactamase inhibitor, tazobactam sodium.1 PTZ is extensively prescribed in the hospital setting for a multitude of infections including but not limited to the US Food and Drug Administration–approved indications: intra-abdominal infection, skin and skin structure infection (SSTI), urinary tract infection (UTI), and pneumonia. Given its broad spectrum of activity and relative safety profile, PTZ is a mainstay of many empiric IV antibiotic regimens. The primary elimination pathway for PTZ is renal excretion, and dosage adjustments are recommended with reduced creatinine clearance. Additionally, PTZ use has been associated with acute renal injury and delayed renal recovery.1-3
There are various mechanisms through which medications can contribute to acute decomopensated heart failure (ADHF).4 These mechanisms include direct cardiotoxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; sodium loading; and drug-drug interactions that limit the benefits of heart failure (HF) medications. One potentially overlooked constituent of PTZ is the sodium content, with the standard formulation containing 65 mg of sodium per gram of piperacillin.1-3 Furthermore, PTZ must be diluted in 50 to 150 mL of diluent, commonly 0.9% sodium chloride, which can contribute an additional 177 to 531 mg of sodium per dose. PTZ prescribing information advises caution for use in patients with decreased renal, hepatic, and/or cardiac function and notes that geriatric patients, particularly with HF, may be at risk of impaired natriuresis in the setting of large sodium doses.
It is estimated that roughly 6.2 million adults in the United States have HF and prevalence continues to rise.5,6 Mortality rates after hospitalization due to HF are 20% to 25% at 1 year. Health care expenditures for the management of HF surpass $30 billion per year in the US, with most of this cost attributed to hospitalizations. Consequently, it is important to continue to identify and practice preventative strategies when managing patients with HF.
Methods
This single-center, retrospective, cohort study was conducted at James H. Quillen Veterans Affairs Medical Center (JHQVAMC) in Mountain Home, Tennessee, a 174-bed tertiary medical center. The purpose of this study was to compare the incidence of ADHF in patients who received PTZ vs cefepime (CFP). This project was reviewed by the JHQVAMC Institutional Review Board and deemed exempt as a clinical process improvement operations activity.
The antimicrobial stewardship team at JHQVAMC reviewed the use of PTZ in veterans between January 1, 2018, to December 31, 2019, and compared baseline demographics, history of HF, and outcomes in patients receiving analogous broad-spectrum empiric antibiotic therapy with CFP.
Statistical Analysis
Analysis was conducted with R Software. Pearson χ2 and t tests were used to compare baseline demographics, length of stay, readmission, and mortality. Significance used was α = .05.
Results
A retrospective chart review was performed on 389 veterans. Of the 389, 204 patients received at least 24 hours of PTZ, and 185 patients received CFP. The mean age in both groups was 75 years. Patients in the PTZ group were more likely to have been admitted with the diagnosis of pneumonia (105 vs 49, P < .001). However, 29 patients (15.7%) in the CFP group were admitted with a UTI diagnosis compared with 6 patients (2.9%) in the PTZ group (P < .001) and 62 patients (33.5%) in the CFP group were admitted with a SSTI diagnosis compared with 48 patients (23.5%) in the PTZ group (P = .03). Otherwise, there were no differences between other admitting diagnoses. Additionally, there was no difference in prior history of HF between groups (Table 1).
Twenty-five patients (12.3%) in the PTZ group and 4 patients (2.2%) in the CFP group were subsequently diagnosed with ADHF (P < .001). Hospital readmissions due to HF were higher in the PTZ group compared with the CFP group (11 vs 2, P = .02). Hospital readmission due to other causes was not significantly different between groups. Hospital readmission due to infection occurred in 18 patients who received PTZ and 25 who received CFP (8.8% vs 13.5%, P = .14). Hospital readmission due to any other indication occurred in 24 patients who received PTZ and 24 who received CFP (11.8% vs 13.0%, P = .72). There was no statistically significant difference in all-cause mortality during the associated admission or within 6 months of discharge between groups, with 59 total deaths in the PTZ group and 50 in the CFP group (28.9% vs 27.0%, P = .63).
There was no difference in length of stay outcomes between patients receiving PTZ compared with CFP. Twenty-eight patients in the PTZ group and 20 in the CFP group had a length of stay duration of < 3 days (13.7% vs 10.8%, P = .46). Seventy-three patients in the PTZ group and 76 in the CFP group had a length of stay duration of 4 to 6 days (36.3% vs 41.1%, P = .28). One hundred three patients in the PTZ group and 89 in the CFP group had a length of stay duration ≥ 7 days (50.5% vs 48.1%, P = .78). Table 2 includes a complete overview of primary and secondary endpoint results.
Discussion
The American Heart Association (AHA) lists PTZ as a medication that may cause or exacerbate HF, though no studies have identified a clear association between PTZ use and ADHF.4 Sodium restriction is consistently recommended as an important strategy for the prevention of ADHF. Accordingly, PTZ prescribing information and the AHA advise careful consideration with PTZ use in this patient population.1,4
The specific mechanism responsible for the association of PTZ with cardiac-related adverse outcomes is unclear. It is easy to presume that the sodium content of PTZ is solely responsible; however, other antibiotic regimens not included as agents of concern by the AHA, such as meropenem, can approach similar overall daily sodium amounts.4,7 Additionally, total sodium and volume can also be contributed by various IV medications and fluids. This study did not evaluate total sodium intake from all sources, but it is notable that this study identified a possible trend toward the risk of ADHF with PTZ use in a routine practice environment. It is reasonable to postulate additional intrinsic properties of PTZ may be contributing to the development of ADHF, such as its association with renal injury possibly resulting in increased fluid retainment and subsequent fluid volume overload.1,2,4 Other hypothesized mechanisms may include those previously described, such as direct myocardial toxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; and drug-drug interactions that limit the benefits of HF medications, although these have not been overtly associated with PTZ in the literature to date.4,8
ADHF can present similarly to other acute pulmonary conditions, including pneumonia.9,10 It is important to acknowledge the challenge this creates for diagnosticians to differentiate between these conditions rapidly and precisely. As a result, this patient population is likely at increased risk of IV antibiotic exposure. Other studies have identified worse outcomes in patients who receive potentially unwarranted IV antibiotics in patients with ADHF.9,10 The results of this study further emphasize the importance of careful considerate antibiotic selection and overall avoidance of unnecessary antibiotic exposure to limit potential adverse outcomes.
Limitations
There are various limitations to this study. Firstly, no women were included due to the predominantly male population within the Veterans Health Administration system. Secondly, this study was retrospective in design and was therefore limited to the completeness and accuracy of the available data collected. Additionally, this study evaluated any ADHF episode during the associated hospitalization as the primary endpoint. The time to diagnosis of ADHF in relation to PTZ initiation was not evaluated, which may have helped better elucidate this possible association. Furthermore, while a significant statistical difference was identified, the smaller sample size may have limited the ability to accurately identify differences in lower event rate outcomes.
Conclusions
This study identifies an association between PTZ use and significant cardiac-related adverse outcomes, including increased incidence of ADHF and readmission due to HF exacerbation. While more research is needed to define the exact mechanisms by which PTZ may precipitate acute decompensation in patients with HF, it is judicious to consider close monitoring or the avoidance of PTZ when appropriate antibiotic alternatives are available in patients with a known history of HF.
1. Zosyn. Package insert. Wyeth Pharmaceuticals; 2020.
2. Jensen JU, Hein L, Lundgren B, et al. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial. BMJ Open. 2012;2(2):e000635. Published 2012 Mar 11. doi:10.1136/bmjopen-2011-000635
3. Kadomura S, Takekuma Y, Sato Y, et al. Higher incidence of acute kidney injury in patients treated with piperacillin/tazobactam than in patients treated with cefepime: a single-center retrospective cohort study. J Pharm Health Care Sci. 2019;5:13. Published 2019 Jun 12. doi:10.1186/s40780-019-0142-6
4. Page RL 2nd, O’Bryant CL, Cheng D, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134(6):e32-e69. doi:10.1161/CIR.0000000000000426
5. Bozkurt B, Hershberger RE, Butler J, et al. 2021 ACC/AHA key data elements and definitions for heart failure: a report of the American College of Cardiology/American Heart Association task force on clinical data standards. J Am Coll Cardiol. 2021;77(16):2053-2150.
6. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation. 2021;143(8):e254-e743. doi:10.1161/CIR.0000000000000950
7. Merrem. Package insert. Pfizer Labs; 2021.
8. Keller GA, Alvarez PA, Ponte ML, et al. Drug-induced QTc interval prolongation: a multicenter study to detect drugs and clinical factors involved in every day practice. Curr Drug Saf. 2016;11(1):86-98. doi:10.2174/1574886311207040262
9. Wu S, Alikhil M, Forsyth R, Allen B. Impact of potentially unwarranted intravenous antibiotics targeting pulmonary infections in acute decompensated heart failure. J Pharm Technol. 2021;37(6):298-303. doi:10.1177/87551225211038020
10. Frisbee J, Heidel RH, Rasnake MS. Adverse outcomes associated with potentially inappropriate antibiotic use in heart failure admissions. Open Forum Infect Dis. 2019;6(6):ofz220. doi:10.1093/ofid/ofz220
Piperacillin/tazobactam (PTZ) is a combination IV antibiotic comprised of the semisynthetic antipseudomonal β-lactam, piperacillin sodium, and the β-lactamase inhibitor, tazobactam sodium.1 PTZ is extensively prescribed in the hospital setting for a multitude of infections including but not limited to the US Food and Drug Administration–approved indications: intra-abdominal infection, skin and skin structure infection (SSTI), urinary tract infection (UTI), and pneumonia. Given its broad spectrum of activity and relative safety profile, PTZ is a mainstay of many empiric IV antibiotic regimens. The primary elimination pathway for PTZ is renal excretion, and dosage adjustments are recommended with reduced creatinine clearance. Additionally, PTZ use has been associated with acute renal injury and delayed renal recovery.1-3
There are various mechanisms through which medications can contribute to acute decomopensated heart failure (ADHF).4 These mechanisms include direct cardiotoxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; sodium loading; and drug-drug interactions that limit the benefits of heart failure (HF) medications. One potentially overlooked constituent of PTZ is the sodium content, with the standard formulation containing 65 mg of sodium per gram of piperacillin.1-3 Furthermore, PTZ must be diluted in 50 to 150 mL of diluent, commonly 0.9% sodium chloride, which can contribute an additional 177 to 531 mg of sodium per dose. PTZ prescribing information advises caution for use in patients with decreased renal, hepatic, and/or cardiac function and notes that geriatric patients, particularly with HF, may be at risk of impaired natriuresis in the setting of large sodium doses.
It is estimated that roughly 6.2 million adults in the United States have HF and prevalence continues to rise.5,6 Mortality rates after hospitalization due to HF are 20% to 25% at 1 year. Health care expenditures for the management of HF surpass $30 billion per year in the US, with most of this cost attributed to hospitalizations. Consequently, it is important to continue to identify and practice preventative strategies when managing patients with HF.
Methods
This single-center, retrospective, cohort study was conducted at James H. Quillen Veterans Affairs Medical Center (JHQVAMC) in Mountain Home, Tennessee, a 174-bed tertiary medical center. The purpose of this study was to compare the incidence of ADHF in patients who received PTZ vs cefepime (CFP). This project was reviewed by the JHQVAMC Institutional Review Board and deemed exempt as a clinical process improvement operations activity.
The antimicrobial stewardship team at JHQVAMC reviewed the use of PTZ in veterans between January 1, 2018, to December 31, 2019, and compared baseline demographics, history of HF, and outcomes in patients receiving analogous broad-spectrum empiric antibiotic therapy with CFP.
Statistical Analysis
Analysis was conducted with R Software. Pearson χ2 and t tests were used to compare baseline demographics, length of stay, readmission, and mortality. Significance used was α = .05.
Results
A retrospective chart review was performed on 389 veterans. Of the 389, 204 patients received at least 24 hours of PTZ, and 185 patients received CFP. The mean age in both groups was 75 years. Patients in the PTZ group were more likely to have been admitted with the diagnosis of pneumonia (105 vs 49, P < .001). However, 29 patients (15.7%) in the CFP group were admitted with a UTI diagnosis compared with 6 patients (2.9%) in the PTZ group (P < .001) and 62 patients (33.5%) in the CFP group were admitted with a SSTI diagnosis compared with 48 patients (23.5%) in the PTZ group (P = .03). Otherwise, there were no differences between other admitting diagnoses. Additionally, there was no difference in prior history of HF between groups (Table 1).
Twenty-five patients (12.3%) in the PTZ group and 4 patients (2.2%) in the CFP group were subsequently diagnosed with ADHF (P < .001). Hospital readmissions due to HF were higher in the PTZ group compared with the CFP group (11 vs 2, P = .02). Hospital readmission due to other causes was not significantly different between groups. Hospital readmission due to infection occurred in 18 patients who received PTZ and 25 who received CFP (8.8% vs 13.5%, P = .14). Hospital readmission due to any other indication occurred in 24 patients who received PTZ and 24 who received CFP (11.8% vs 13.0%, P = .72). There was no statistically significant difference in all-cause mortality during the associated admission or within 6 months of discharge between groups, with 59 total deaths in the PTZ group and 50 in the CFP group (28.9% vs 27.0%, P = .63).
There was no difference in length of stay outcomes between patients receiving PTZ compared with CFP. Twenty-eight patients in the PTZ group and 20 in the CFP group had a length of stay duration of < 3 days (13.7% vs 10.8%, P = .46). Seventy-three patients in the PTZ group and 76 in the CFP group had a length of stay duration of 4 to 6 days (36.3% vs 41.1%, P = .28). One hundred three patients in the PTZ group and 89 in the CFP group had a length of stay duration ≥ 7 days (50.5% vs 48.1%, P = .78). Table 2 includes a complete overview of primary and secondary endpoint results.
Discussion
The American Heart Association (AHA) lists PTZ as a medication that may cause or exacerbate HF, though no studies have identified a clear association between PTZ use and ADHF.4 Sodium restriction is consistently recommended as an important strategy for the prevention of ADHF. Accordingly, PTZ prescribing information and the AHA advise careful consideration with PTZ use in this patient population.1,4
The specific mechanism responsible for the association of PTZ with cardiac-related adverse outcomes is unclear. It is easy to presume that the sodium content of PTZ is solely responsible; however, other antibiotic regimens not included as agents of concern by the AHA, such as meropenem, can approach similar overall daily sodium amounts.4,7 Additionally, total sodium and volume can also be contributed by various IV medications and fluids. This study did not evaluate total sodium intake from all sources, but it is notable that this study identified a possible trend toward the risk of ADHF with PTZ use in a routine practice environment. It is reasonable to postulate additional intrinsic properties of PTZ may be contributing to the development of ADHF, such as its association with renal injury possibly resulting in increased fluid retainment and subsequent fluid volume overload.1,2,4 Other hypothesized mechanisms may include those previously described, such as direct myocardial toxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; and drug-drug interactions that limit the benefits of HF medications, although these have not been overtly associated with PTZ in the literature to date.4,8
ADHF can present similarly to other acute pulmonary conditions, including pneumonia.9,10 It is important to acknowledge the challenge this creates for diagnosticians to differentiate between these conditions rapidly and precisely. As a result, this patient population is likely at increased risk of IV antibiotic exposure. Other studies have identified worse outcomes in patients who receive potentially unwarranted IV antibiotics in patients with ADHF.9,10 The results of this study further emphasize the importance of careful considerate antibiotic selection and overall avoidance of unnecessary antibiotic exposure to limit potential adverse outcomes.
Limitations
There are various limitations to this study. Firstly, no women were included due to the predominantly male population within the Veterans Health Administration system. Secondly, this study was retrospective in design and was therefore limited to the completeness and accuracy of the available data collected. Additionally, this study evaluated any ADHF episode during the associated hospitalization as the primary endpoint. The time to diagnosis of ADHF in relation to PTZ initiation was not evaluated, which may have helped better elucidate this possible association. Furthermore, while a significant statistical difference was identified, the smaller sample size may have limited the ability to accurately identify differences in lower event rate outcomes.
Conclusions
This study identifies an association between PTZ use and significant cardiac-related adverse outcomes, including increased incidence of ADHF and readmission due to HF exacerbation. While more research is needed to define the exact mechanisms by which PTZ may precipitate acute decompensation in patients with HF, it is judicious to consider close monitoring or the avoidance of PTZ when appropriate antibiotic alternatives are available in patients with a known history of HF.
Piperacillin/tazobactam (PTZ) is a combination IV antibiotic comprised of the semisynthetic antipseudomonal β-lactam, piperacillin sodium, and the β-lactamase inhibitor, tazobactam sodium.1 PTZ is extensively prescribed in the hospital setting for a multitude of infections including but not limited to the US Food and Drug Administration–approved indications: intra-abdominal infection, skin and skin structure infection (SSTI), urinary tract infection (UTI), and pneumonia. Given its broad spectrum of activity and relative safety profile, PTZ is a mainstay of many empiric IV antibiotic regimens. The primary elimination pathway for PTZ is renal excretion, and dosage adjustments are recommended with reduced creatinine clearance. Additionally, PTZ use has been associated with acute renal injury and delayed renal recovery.1-3
There are various mechanisms through which medications can contribute to acute decomopensated heart failure (ADHF).4 These mechanisms include direct cardiotoxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; sodium loading; and drug-drug interactions that limit the benefits of heart failure (HF) medications. One potentially overlooked constituent of PTZ is the sodium content, with the standard formulation containing 65 mg of sodium per gram of piperacillin.1-3 Furthermore, PTZ must be diluted in 50 to 150 mL of diluent, commonly 0.9% sodium chloride, which can contribute an additional 177 to 531 mg of sodium per dose. PTZ prescribing information advises caution for use in patients with decreased renal, hepatic, and/or cardiac function and notes that geriatric patients, particularly with HF, may be at risk of impaired natriuresis in the setting of large sodium doses.
It is estimated that roughly 6.2 million adults in the United States have HF and prevalence continues to rise.5,6 Mortality rates after hospitalization due to HF are 20% to 25% at 1 year. Health care expenditures for the management of HF surpass $30 billion per year in the US, with most of this cost attributed to hospitalizations. Consequently, it is important to continue to identify and practice preventative strategies when managing patients with HF.
Methods
This single-center, retrospective, cohort study was conducted at James H. Quillen Veterans Affairs Medical Center (JHQVAMC) in Mountain Home, Tennessee, a 174-bed tertiary medical center. The purpose of this study was to compare the incidence of ADHF in patients who received PTZ vs cefepime (CFP). This project was reviewed by the JHQVAMC Institutional Review Board and deemed exempt as a clinical process improvement operations activity.
The antimicrobial stewardship team at JHQVAMC reviewed the use of PTZ in veterans between January 1, 2018, to December 31, 2019, and compared baseline demographics, history of HF, and outcomes in patients receiving analogous broad-spectrum empiric antibiotic therapy with CFP.
Statistical Analysis
Analysis was conducted with R Software. Pearson χ2 and t tests were used to compare baseline demographics, length of stay, readmission, and mortality. Significance used was α = .05.
Results
A retrospective chart review was performed on 389 veterans. Of the 389, 204 patients received at least 24 hours of PTZ, and 185 patients received CFP. The mean age in both groups was 75 years. Patients in the PTZ group were more likely to have been admitted with the diagnosis of pneumonia (105 vs 49, P < .001). However, 29 patients (15.7%) in the CFP group were admitted with a UTI diagnosis compared with 6 patients (2.9%) in the PTZ group (P < .001) and 62 patients (33.5%) in the CFP group were admitted with a SSTI diagnosis compared with 48 patients (23.5%) in the PTZ group (P = .03). Otherwise, there were no differences between other admitting diagnoses. Additionally, there was no difference in prior history of HF between groups (Table 1).
Twenty-five patients (12.3%) in the PTZ group and 4 patients (2.2%) in the CFP group were subsequently diagnosed with ADHF (P < .001). Hospital readmissions due to HF were higher in the PTZ group compared with the CFP group (11 vs 2, P = .02). Hospital readmission due to other causes was not significantly different between groups. Hospital readmission due to infection occurred in 18 patients who received PTZ and 25 who received CFP (8.8% vs 13.5%, P = .14). Hospital readmission due to any other indication occurred in 24 patients who received PTZ and 24 who received CFP (11.8% vs 13.0%, P = .72). There was no statistically significant difference in all-cause mortality during the associated admission or within 6 months of discharge between groups, with 59 total deaths in the PTZ group and 50 in the CFP group (28.9% vs 27.0%, P = .63).
There was no difference in length of stay outcomes between patients receiving PTZ compared with CFP. Twenty-eight patients in the PTZ group and 20 in the CFP group had a length of stay duration of < 3 days (13.7% vs 10.8%, P = .46). Seventy-three patients in the PTZ group and 76 in the CFP group had a length of stay duration of 4 to 6 days (36.3% vs 41.1%, P = .28). One hundred three patients in the PTZ group and 89 in the CFP group had a length of stay duration ≥ 7 days (50.5% vs 48.1%, P = .78). Table 2 includes a complete overview of primary and secondary endpoint results.
Discussion
The American Heart Association (AHA) lists PTZ as a medication that may cause or exacerbate HF, though no studies have identified a clear association between PTZ use and ADHF.4 Sodium restriction is consistently recommended as an important strategy for the prevention of ADHF. Accordingly, PTZ prescribing information and the AHA advise careful consideration with PTZ use in this patient population.1,4
The specific mechanism responsible for the association of PTZ with cardiac-related adverse outcomes is unclear. It is easy to presume that the sodium content of PTZ is solely responsible; however, other antibiotic regimens not included as agents of concern by the AHA, such as meropenem, can approach similar overall daily sodium amounts.4,7 Additionally, total sodium and volume can also be contributed by various IV medications and fluids. This study did not evaluate total sodium intake from all sources, but it is notable that this study identified a possible trend toward the risk of ADHF with PTZ use in a routine practice environment. It is reasonable to postulate additional intrinsic properties of PTZ may be contributing to the development of ADHF, such as its association with renal injury possibly resulting in increased fluid retainment and subsequent fluid volume overload.1,2,4 Other hypothesized mechanisms may include those previously described, such as direct myocardial toxicity; negative inotropic, lusitropic, or chronotropic effects; exacerbating hypertension; and drug-drug interactions that limit the benefits of HF medications, although these have not been overtly associated with PTZ in the literature to date.4,8
ADHF can present similarly to other acute pulmonary conditions, including pneumonia.9,10 It is important to acknowledge the challenge this creates for diagnosticians to differentiate between these conditions rapidly and precisely. As a result, this patient population is likely at increased risk of IV antibiotic exposure. Other studies have identified worse outcomes in patients who receive potentially unwarranted IV antibiotics in patients with ADHF.9,10 The results of this study further emphasize the importance of careful considerate antibiotic selection and overall avoidance of unnecessary antibiotic exposure to limit potential adverse outcomes.
Limitations
There are various limitations to this study. Firstly, no women were included due to the predominantly male population within the Veterans Health Administration system. Secondly, this study was retrospective in design and was therefore limited to the completeness and accuracy of the available data collected. Additionally, this study evaluated any ADHF episode during the associated hospitalization as the primary endpoint. The time to diagnosis of ADHF in relation to PTZ initiation was not evaluated, which may have helped better elucidate this possible association. Furthermore, while a significant statistical difference was identified, the smaller sample size may have limited the ability to accurately identify differences in lower event rate outcomes.
Conclusions
This study identifies an association between PTZ use and significant cardiac-related adverse outcomes, including increased incidence of ADHF and readmission due to HF exacerbation. While more research is needed to define the exact mechanisms by which PTZ may precipitate acute decompensation in patients with HF, it is judicious to consider close monitoring or the avoidance of PTZ when appropriate antibiotic alternatives are available in patients with a known history of HF.
1. Zosyn. Package insert. Wyeth Pharmaceuticals; 2020.
2. Jensen JU, Hein L, Lundgren B, et al. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial. BMJ Open. 2012;2(2):e000635. Published 2012 Mar 11. doi:10.1136/bmjopen-2011-000635
3. Kadomura S, Takekuma Y, Sato Y, et al. Higher incidence of acute kidney injury in patients treated with piperacillin/tazobactam than in patients treated with cefepime: a single-center retrospective cohort study. J Pharm Health Care Sci. 2019;5:13. Published 2019 Jun 12. doi:10.1186/s40780-019-0142-6
4. Page RL 2nd, O’Bryant CL, Cheng D, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134(6):e32-e69. doi:10.1161/CIR.0000000000000426
5. Bozkurt B, Hershberger RE, Butler J, et al. 2021 ACC/AHA key data elements and definitions for heart failure: a report of the American College of Cardiology/American Heart Association task force on clinical data standards. J Am Coll Cardiol. 2021;77(16):2053-2150.
6. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation. 2021;143(8):e254-e743. doi:10.1161/CIR.0000000000000950
7. Merrem. Package insert. Pfizer Labs; 2021.
8. Keller GA, Alvarez PA, Ponte ML, et al. Drug-induced QTc interval prolongation: a multicenter study to detect drugs and clinical factors involved in every day practice. Curr Drug Saf. 2016;11(1):86-98. doi:10.2174/1574886311207040262
9. Wu S, Alikhil M, Forsyth R, Allen B. Impact of potentially unwarranted intravenous antibiotics targeting pulmonary infections in acute decompensated heart failure. J Pharm Technol. 2021;37(6):298-303. doi:10.1177/87551225211038020
10. Frisbee J, Heidel RH, Rasnake MS. Adverse outcomes associated with potentially inappropriate antibiotic use in heart failure admissions. Open Forum Infect Dis. 2019;6(6):ofz220. doi:10.1093/ofid/ofz220
1. Zosyn. Package insert. Wyeth Pharmaceuticals; 2020.
2. Jensen JU, Hein L, Lundgren B, et al. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial. BMJ Open. 2012;2(2):e000635. Published 2012 Mar 11. doi:10.1136/bmjopen-2011-000635
3. Kadomura S, Takekuma Y, Sato Y, et al. Higher incidence of acute kidney injury in patients treated with piperacillin/tazobactam than in patients treated with cefepime: a single-center retrospective cohort study. J Pharm Health Care Sci. 2019;5:13. Published 2019 Jun 12. doi:10.1186/s40780-019-0142-6
4. Page RL 2nd, O’Bryant CL, Cheng D, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134(6):e32-e69. doi:10.1161/CIR.0000000000000426
5. Bozkurt B, Hershberger RE, Butler J, et al. 2021 ACC/AHA key data elements and definitions for heart failure: a report of the American College of Cardiology/American Heart Association task force on clinical data standards. J Am Coll Cardiol. 2021;77(16):2053-2150.
6. Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation. 2021;143(8):e254-e743. doi:10.1161/CIR.0000000000000950
7. Merrem. Package insert. Pfizer Labs; 2021.
8. Keller GA, Alvarez PA, Ponte ML, et al. Drug-induced QTc interval prolongation: a multicenter study to detect drugs and clinical factors involved in every day practice. Curr Drug Saf. 2016;11(1):86-98. doi:10.2174/1574886311207040262
9. Wu S, Alikhil M, Forsyth R, Allen B. Impact of potentially unwarranted intravenous antibiotics targeting pulmonary infections in acute decompensated heart failure. J Pharm Technol. 2021;37(6):298-303. doi:10.1177/87551225211038020
10. Frisbee J, Heidel RH, Rasnake MS. Adverse outcomes associated with potentially inappropriate antibiotic use in heart failure admissions. Open Forum Infect Dis. 2019;6(6):ofz220. doi:10.1093/ofid/ofz220
Association Between LDL-C and Androgenetic Alopecia Among Female Patients in a Specialty Alopecia Clinic
To the Editor:
Female pattern hair loss (FPHL), or androgenetic alopecia (AGA), is the most common form of alopecia worldwide and is characterized by a reduction of hair follicles spent in the anagen phase of growth as well as progressive terminal hair loss.1 It is caused by an excessive response to androgens and leads to the characteristic distribution of hair loss in both sexes. Studies have shown a notable association between AGA and markers of metabolic syndrome such as dyslipidemia, insulin resistance, and obesity in age- and sex-matched controls.2,3 However, research describing the relationship between AGA severity and these markers is scarce.
To understand the relationship between FPHL severity and abnormal cholesterol levels, we performed a retrospective chart review of patients diagnosed with FPHL at a specialty alopecia clinic from June 2022 to December 2022. Patient age and age at onset of FPHL were collected. The severity of FPHL was measured using the Sinclair scale (score range, 1–5) and unidentifiable patient photographs. Laboratory values were collected; abnormal cholesterol was defined by the American Heart Association as having a low-density lipoprotein cholesterol (LDL-C) level of 100 mg/dL or higher.4 Finally, data on medication use were noted to understand patient treatment status (Table).
We identified 54 female patients with FPHL with an average age of 59 years (range, 34–80 years). Thirty-three females (61.11%) had a normal LDL-C level and 21 (38.89%) had an abnormal level. The mean (SD) LDL-C level was 66.02 (15.20) mg/dL (range, 29–92 mg/dL) in the group with normal levels and 138.81 (29.90) mg/dL (range, 100–193 mg/dL) in the group with abnormal levels. Patients with abnormal LDL-C had significantly higher Sinclair scale scores compared to those with normal levels (2.43 vs 1.91; P=.01). There were no significant differences in patient age (58.71 vs 59.70 years; P=.39), age at onset of AGA (47.75 vs 47.65 years; P=.49), history of polycystic ovary syndrome (9.52% vs 6.06%; P=.64), or statin use (38.09% vs 36.36%; P=.89) between patients with abnormal and normal LDL-C levels, respectively. There also were no significant differences in ferritin (96.42 vs 91.54 ng/mL; P=.40), vitamin D (42.35 vs 48.96 ng/mL; P=.09), or hemoglobin A1c levels (5.60 ng/mL vs 5.38 ng/mL; P=.06)—variables that could have confounded this relationship. Triglycerides were within reference range in both groups (121.36 vs 116.16 mg/dL; P=.32), while total cholesterol was mildly elevated in both groups but not significantly different (213.19 vs 201.21 mg/dL; P=.13). Use of hair loss treatments such as topical minoxidil (14.29% vs 21.21%; P=.53), oral low-dose minoxidil (57.14% vs 66.67%; P=.48), oral spironolactone (47.62% vs 57.58%; P=.47), and platelet-rich plasma injections (47.62% vs 27.27%; P=.90) were not significantly different across both groups.
The data suggest a significant (P<.05) association between abnormal LDL-C and hair loss severity in FPHL patients. Our study was limited by its small sample size and lack of causality; however, it coincides with and reiterates the findings established in the literature. The mechanism of the association between hyperlipidemia and AGA is not well understood but is thought to stem from the homology between cholesterol and androgens. Increased cholesterol release from dermal adipocytes and subsequent absorption into hair follicle cell populations may increase hair follicle steroidogenesis, thereby accelerating the anagen-catagen transition and inducing AGA. Alternatively, impaired cholesterol homeostasis may disrupt normal hair follicle cycling by interrupting signaling pathways in follicle proliferation and differentiation.5 Adequate control and monitoring of LDL-C levels may be important, particularly in patients with more severe FPHL.
- Herskovitz I, Tosti A. Female pattern hair loss. Int J Endocrinol Metab. 2013;11:E9860. doi:10.5812/ijem.9860
- El Sayed MH, Abdallah MA, Aly DG, et al. Association of metabolic syndrome with female pattern hair loss in women: a case-control study. Int J Dermatol. 2016;55:1131-1137. doi:10.1111/ijd.13303
- Kim MW, Shin IS, Yoon HS, et al. Lipid profile in patients with androgenetic alopecia: a meta-analysis. J Eur Acad Dermatol Venereol. 2017;31:942-951. doi:10.1111/jdv.14000
- Birtcher KK, Ballantyne CM. Cardiology patient page. measurement of cholesterol: a patient perspective. Circulation. 2004;110:E296-E297. doi:10.1161/01.CIR.0000141564.89465.4E
- Palmer MA, Blakeborough L, Harries M, et al. Cholesterol homeostasis: links to hair follicle biology and hair disorders. Exp Dermatol. 2020;29:299-311. doi:10.1111/exd.13993
To the Editor:
Female pattern hair loss (FPHL), or androgenetic alopecia (AGA), is the most common form of alopecia worldwide and is characterized by a reduction of hair follicles spent in the anagen phase of growth as well as progressive terminal hair loss.1 It is caused by an excessive response to androgens and leads to the characteristic distribution of hair loss in both sexes. Studies have shown a notable association between AGA and markers of metabolic syndrome such as dyslipidemia, insulin resistance, and obesity in age- and sex-matched controls.2,3 However, research describing the relationship between AGA severity and these markers is scarce.
To understand the relationship between FPHL severity and abnormal cholesterol levels, we performed a retrospective chart review of patients diagnosed with FPHL at a specialty alopecia clinic from June 2022 to December 2022. Patient age and age at onset of FPHL were collected. The severity of FPHL was measured using the Sinclair scale (score range, 1–5) and unidentifiable patient photographs. Laboratory values were collected; abnormal cholesterol was defined by the American Heart Association as having a low-density lipoprotein cholesterol (LDL-C) level of 100 mg/dL or higher.4 Finally, data on medication use were noted to understand patient treatment status (Table).
We identified 54 female patients with FPHL with an average age of 59 years (range, 34–80 years). Thirty-three females (61.11%) had a normal LDL-C level and 21 (38.89%) had an abnormal level. The mean (SD) LDL-C level was 66.02 (15.20) mg/dL (range, 29–92 mg/dL) in the group with normal levels and 138.81 (29.90) mg/dL (range, 100–193 mg/dL) in the group with abnormal levels. Patients with abnormal LDL-C had significantly higher Sinclair scale scores compared to those with normal levels (2.43 vs 1.91; P=.01). There were no significant differences in patient age (58.71 vs 59.70 years; P=.39), age at onset of AGA (47.75 vs 47.65 years; P=.49), history of polycystic ovary syndrome (9.52% vs 6.06%; P=.64), or statin use (38.09% vs 36.36%; P=.89) between patients with abnormal and normal LDL-C levels, respectively. There also were no significant differences in ferritin (96.42 vs 91.54 ng/mL; P=.40), vitamin D (42.35 vs 48.96 ng/mL; P=.09), or hemoglobin A1c levels (5.60 ng/mL vs 5.38 ng/mL; P=.06)—variables that could have confounded this relationship. Triglycerides were within reference range in both groups (121.36 vs 116.16 mg/dL; P=.32), while total cholesterol was mildly elevated in both groups but not significantly different (213.19 vs 201.21 mg/dL; P=.13). Use of hair loss treatments such as topical minoxidil (14.29% vs 21.21%; P=.53), oral low-dose minoxidil (57.14% vs 66.67%; P=.48), oral spironolactone (47.62% vs 57.58%; P=.47), and platelet-rich plasma injections (47.62% vs 27.27%; P=.90) were not significantly different across both groups.
The data suggest a significant (P<.05) association between abnormal LDL-C and hair loss severity in FPHL patients. Our study was limited by its small sample size and lack of causality; however, it coincides with and reiterates the findings established in the literature. The mechanism of the association between hyperlipidemia and AGA is not well understood but is thought to stem from the homology between cholesterol and androgens. Increased cholesterol release from dermal adipocytes and subsequent absorption into hair follicle cell populations may increase hair follicle steroidogenesis, thereby accelerating the anagen-catagen transition and inducing AGA. Alternatively, impaired cholesterol homeostasis may disrupt normal hair follicle cycling by interrupting signaling pathways in follicle proliferation and differentiation.5 Adequate control and monitoring of LDL-C levels may be important, particularly in patients with more severe FPHL.
To the Editor:
Female pattern hair loss (FPHL), or androgenetic alopecia (AGA), is the most common form of alopecia worldwide and is characterized by a reduction of hair follicles spent in the anagen phase of growth as well as progressive terminal hair loss.1 It is caused by an excessive response to androgens and leads to the characteristic distribution of hair loss in both sexes. Studies have shown a notable association between AGA and markers of metabolic syndrome such as dyslipidemia, insulin resistance, and obesity in age- and sex-matched controls.2,3 However, research describing the relationship between AGA severity and these markers is scarce.
To understand the relationship between FPHL severity and abnormal cholesterol levels, we performed a retrospective chart review of patients diagnosed with FPHL at a specialty alopecia clinic from June 2022 to December 2022. Patient age and age at onset of FPHL were collected. The severity of FPHL was measured using the Sinclair scale (score range, 1–5) and unidentifiable patient photographs. Laboratory values were collected; abnormal cholesterol was defined by the American Heart Association as having a low-density lipoprotein cholesterol (LDL-C) level of 100 mg/dL or higher.4 Finally, data on medication use were noted to understand patient treatment status (Table).
We identified 54 female patients with FPHL with an average age of 59 years (range, 34–80 years). Thirty-three females (61.11%) had a normal LDL-C level and 21 (38.89%) had an abnormal level. The mean (SD) LDL-C level was 66.02 (15.20) mg/dL (range, 29–92 mg/dL) in the group with normal levels and 138.81 (29.90) mg/dL (range, 100–193 mg/dL) in the group with abnormal levels. Patients with abnormal LDL-C had significantly higher Sinclair scale scores compared to those with normal levels (2.43 vs 1.91; P=.01). There were no significant differences in patient age (58.71 vs 59.70 years; P=.39), age at onset of AGA (47.75 vs 47.65 years; P=.49), history of polycystic ovary syndrome (9.52% vs 6.06%; P=.64), or statin use (38.09% vs 36.36%; P=.89) between patients with abnormal and normal LDL-C levels, respectively. There also were no significant differences in ferritin (96.42 vs 91.54 ng/mL; P=.40), vitamin D (42.35 vs 48.96 ng/mL; P=.09), or hemoglobin A1c levels (5.60 ng/mL vs 5.38 ng/mL; P=.06)—variables that could have confounded this relationship. Triglycerides were within reference range in both groups (121.36 vs 116.16 mg/dL; P=.32), while total cholesterol was mildly elevated in both groups but not significantly different (213.19 vs 201.21 mg/dL; P=.13). Use of hair loss treatments such as topical minoxidil (14.29% vs 21.21%; P=.53), oral low-dose minoxidil (57.14% vs 66.67%; P=.48), oral spironolactone (47.62% vs 57.58%; P=.47), and platelet-rich plasma injections (47.62% vs 27.27%; P=.90) were not significantly different across both groups.
The data suggest a significant (P<.05) association between abnormal LDL-C and hair loss severity in FPHL patients. Our study was limited by its small sample size and lack of causality; however, it coincides with and reiterates the findings established in the literature. The mechanism of the association between hyperlipidemia and AGA is not well understood but is thought to stem from the homology between cholesterol and androgens. Increased cholesterol release from dermal adipocytes and subsequent absorption into hair follicle cell populations may increase hair follicle steroidogenesis, thereby accelerating the anagen-catagen transition and inducing AGA. Alternatively, impaired cholesterol homeostasis may disrupt normal hair follicle cycling by interrupting signaling pathways in follicle proliferation and differentiation.5 Adequate control and monitoring of LDL-C levels may be important, particularly in patients with more severe FPHL.
- Herskovitz I, Tosti A. Female pattern hair loss. Int J Endocrinol Metab. 2013;11:E9860. doi:10.5812/ijem.9860
- El Sayed MH, Abdallah MA, Aly DG, et al. Association of metabolic syndrome with female pattern hair loss in women: a case-control study. Int J Dermatol. 2016;55:1131-1137. doi:10.1111/ijd.13303
- Kim MW, Shin IS, Yoon HS, et al. Lipid profile in patients with androgenetic alopecia: a meta-analysis. J Eur Acad Dermatol Venereol. 2017;31:942-951. doi:10.1111/jdv.14000
- Birtcher KK, Ballantyne CM. Cardiology patient page. measurement of cholesterol: a patient perspective. Circulation. 2004;110:E296-E297. doi:10.1161/01.CIR.0000141564.89465.4E
- Palmer MA, Blakeborough L, Harries M, et al. Cholesterol homeostasis: links to hair follicle biology and hair disorders. Exp Dermatol. 2020;29:299-311. doi:10.1111/exd.13993
- Herskovitz I, Tosti A. Female pattern hair loss. Int J Endocrinol Metab. 2013;11:E9860. doi:10.5812/ijem.9860
- El Sayed MH, Abdallah MA, Aly DG, et al. Association of metabolic syndrome with female pattern hair loss in women: a case-control study. Int J Dermatol. 2016;55:1131-1137. doi:10.1111/ijd.13303
- Kim MW, Shin IS, Yoon HS, et al. Lipid profile in patients with androgenetic alopecia: a meta-analysis. J Eur Acad Dermatol Venereol. 2017;31:942-951. doi:10.1111/jdv.14000
- Birtcher KK, Ballantyne CM. Cardiology patient page. measurement of cholesterol: a patient perspective. Circulation. 2004;110:E296-E297. doi:10.1161/01.CIR.0000141564.89465.4E
- Palmer MA, Blakeborough L, Harries M, et al. Cholesterol homeostasis: links to hair follicle biology and hair disorders. Exp Dermatol. 2020;29:299-311. doi:10.1111/exd.13993
Practice Points
- Associations have been shown between hair loss and markers of bad health such as insulin resistance and high cholesterol. Research has not yet shown the relationship between hair loss severity and these markers, particularly cholesterol.
Analysis of Nail Excision Practice Patterns in the Medicare Provider Utilization and Payment Database 2012-2017
To the Editor:
Partial or total nail plate excisions commonly are used for the treatment of onychocryptosis and nail spicules. Procedures involving the nail unit require advanced technical skills to achieve optimal functional and aesthetic outcomes, avoid complications, and minimize health care costs. Data on the frequency of nail plate excisions performed by dermatologists and their relative frequency compared to other medical providers are limited. The objective of our study was to analyze trends in nail excision practice patterns among medical providers in the United States.
A retrospective analysis on nail excisions using the Current Procedural Terminology (CPT) code 11750 (excision of nail and nail matrix, partial or complete [eg, ingrown or deformed nail] for permanent removal), which is distinct from code 11755 (biopsy of nail unit [eg, plate, bed, matrix, hyponychium, proximal and lateral nail folds][separate procedure]), was performed using data from the Medicare Provider Utilization and Payment Database 2012-2017.1,2 This file also is used by Peck et al3 in an article submitted to the Journal of the American Podiatric Medical Association and currently under consideration for publication. Procedures were recorded by year and provider type—dermatologist, podiatrist, physician assistant (PA)/nurse practitioner (NP), nondermatologist physician—and subcategorized by provider specialty (Table). Practice locations subcategorized by provider type were mapped using Tableau Software (Salesforce)(Figure). Descriptive statistics including number of providers, mean and median excisions per provider, and minimum/maximum nail excisions were calculated (Table). Practice types of PAs/NPs and specialization of nondermatologist physicians were determined using provider name, identification number, and practice address. This study did not require institutional review board review, as only publicly available data were utilized in our analysis.
A total of 6936 podiatrists, 58 nondermatologist physicians, 25 PAs/NPs, and 4 dermatologists performed 10 or more nail excisions annually under CPT code 11750 from January 2012 to December 2017 with annual means of 31, 31, 25, and 34, respectively (Table). No PAs/NPs included in the dataset worked in dermatology practices during the study period. Physician assistants and NPs most often practiced in podiatry and family medicine (FM) settings (both 40% [10/25]). Nondermatologist physicians most often specialized in FM (40% [23/58])(Table). The greatest number of providers practiced in 3 of the 4 most-populous states: California, Texas, and Florida; the fewest number practiced in 3 of the 10 least-populous states: Alaska, Hawaii, and Vermont. Vermont, Wyoming, and North Dakota—3 of the 5 least-populous states—had the fewest practitioners among the contiguous United States (Figure).
Our study showed that from January 2012 to December 2017, fewer dermatologists performed nail excisions than any other provider type (0.06%, 4 dermatologists of 7023 total providers), and dermatologists performed 1734-fold fewer nail excisions than podiatrists (99%, 6936 podiatrists of 7023 total providers). Only dermatologists practicing in California, Georgia, Indiana, and Oklahoma performed nail excisions. Conversely, podiatrists were more geographically distributed across the United States and other territories, with representation in all 50 states as well as the District of Columbia, Puerto Rico, and Guam.
Reasons for these large discrepancies in practice between dermatologists and other providers likely are multifactorial, encompassing a lack of emphasis on nail procedures in dermatology training, patient perception of the scope of dermatologic practice, and nail excision reimbursement patterns. Most dermatologists likely lack experience in performing nail procedures. The Accreditation Council for Graduate Medical Education requirements mandate that dermatology residents observe or perform 3 nail procedures over 3 years of residency, including 1 that may be performed on a human cadaver.4 In contrast, podiatry trainees must gain competency in toenail avulsion (both partial and complete), participate in anesthesia workshops, and become proficient in administering lower extremity blocks by the end of their training.5 Therefore, incorporating aspects of podiatric surgical training into dermatology residency requirements may increase the competency and comfort of dermatologists in performing nail excisions and practicing as nail experts as attending physicians.
It is likely that US patients do not perceive dermatologists as nail specialists and instead primarily consult podiatrists or FM and/or internal medicine physicians for treatment; for example, nail disease was one of the least common reasons for consulting a dermatologist (5%) in a German nationwide survey-based study (N=1015).6 Therefore, increased efforts are needed to educate the general public about the expertise of dermatologists in the diagnosis and management of nail conditions.
Reimbursement also may be a barrier to dermatologists performing nail procedures as part of their scope of practice; for example, in a retrospective study of nail biopsies using the Medicare Provider Utilization and Payment Database, there was no statistically significant difference in reimbursements for nail biopsies vs skin biopsies from 2012 to 2017 (P=0.69).7 Similar to nail biopsies, nail excisions typically are much more time consuming and technically demanding than skin biopsies, which may discourage dermatologists from routinely performing nail excision procedures.
Our study is subject to a number of limitations. The data reflected only US-based practice patterns and may not be applicable to nail procedures globally. There also is the potential for miscoding of procedures in the Medicare database. The data included only Part B Medicare fee-for-service and excludes non-Medicare insured, uninsured, and self-pay patients, as well as aggregated records from 10 or fewer Medicare beneficiaries.
Dermatologists rarely perform nail excisions and perform fewer nail excisions than any other provider type in the United States. There currently is an unmet need for comprehensive nail surgery education in US-based dermatology residency programs. We hope that our study fosters interdisciplinary collegiality and training between podiatrists and dermatologists and promotes expanded access to care across the United States to serve patients with nail disorders.
- Centers for Medicare & Medicaid Services. Medicare Fee-For-Service Provider Utilization & Payment Data Physician and Other Supplier Public Use File: A Methodological Overview . Updated September 22, 2020. Accessed January 5, 2024. https://www.cms.gov/research-statistics-data-and-systems/statistics-trends-and-reports/medicare-provider-charge-data/downloads/medicare-physician-and-other-supplier-puf-methodology.pdf
- Centers for Medicare and Medicaid Services. Billing and Coding: Surgical Treatment of Nails. Updated November 9, 2023. Accessed January 8, 2024. https://www.cms.gov/medicare-coverage-database/view/article.aspx?articleID=52998#:~:text=The%20description%20of%20CPT%20codes,date%20of%20service%20(DOS).
- Peck GM, Vlahovic TC, Hill R, et al. Senior podiatrists in solo practice are high performers of nail excisions. JAPMA. In press.
- Accreditation Council for Graduate Medical Education. Case log minimums. review committee for dermatology. Published May 2019. Accessed January 5, 2024. https://www.acgme.org/Portals/0/PFAssets/ProgramResources/CaseLogMinimums.pdf?ver=2018-04-03-102751-650
- Council on Podiatric Medical Education. Standards and Requirements for Approval of Podiatric Medicine and Surgery Residencies. Published July 2023. Accessed January 17, 2024. https://www.cpme.org/files/320%20Council%20Approved%20October%202022%20-%20April%202023%20edits.pdf
- Augustin M, Eissing L, Elsner P, et al. Perception and image of dermatology in the German general population 2002-2014. J Eur Acad Dermatol Venereol. 2017;31:2124-2130.
- Wang Y, Lipner SR. Retrospective analysis of nail biopsies performed using the Medicare provider utilization and payment database 2012 to 2017. Dermatol Ther. 2021;34:E14928.
To the Editor:
Partial or total nail plate excisions commonly are used for the treatment of onychocryptosis and nail spicules. Procedures involving the nail unit require advanced technical skills to achieve optimal functional and aesthetic outcomes, avoid complications, and minimize health care costs. Data on the frequency of nail plate excisions performed by dermatologists and their relative frequency compared to other medical providers are limited. The objective of our study was to analyze trends in nail excision practice patterns among medical providers in the United States.
A retrospective analysis on nail excisions using the Current Procedural Terminology (CPT) code 11750 (excision of nail and nail matrix, partial or complete [eg, ingrown or deformed nail] for permanent removal), which is distinct from code 11755 (biopsy of nail unit [eg, plate, bed, matrix, hyponychium, proximal and lateral nail folds][separate procedure]), was performed using data from the Medicare Provider Utilization and Payment Database 2012-2017.1,2 This file also is used by Peck et al3 in an article submitted to the Journal of the American Podiatric Medical Association and currently under consideration for publication. Procedures were recorded by year and provider type—dermatologist, podiatrist, physician assistant (PA)/nurse practitioner (NP), nondermatologist physician—and subcategorized by provider specialty (Table). Practice locations subcategorized by provider type were mapped using Tableau Software (Salesforce)(Figure). Descriptive statistics including number of providers, mean and median excisions per provider, and minimum/maximum nail excisions were calculated (Table). Practice types of PAs/NPs and specialization of nondermatologist physicians were determined using provider name, identification number, and practice address. This study did not require institutional review board review, as only publicly available data were utilized in our analysis.
A total of 6936 podiatrists, 58 nondermatologist physicians, 25 PAs/NPs, and 4 dermatologists performed 10 or more nail excisions annually under CPT code 11750 from January 2012 to December 2017 with annual means of 31, 31, 25, and 34, respectively (Table). No PAs/NPs included in the dataset worked in dermatology practices during the study period. Physician assistants and NPs most often practiced in podiatry and family medicine (FM) settings (both 40% [10/25]). Nondermatologist physicians most often specialized in FM (40% [23/58])(Table). The greatest number of providers practiced in 3 of the 4 most-populous states: California, Texas, and Florida; the fewest number practiced in 3 of the 10 least-populous states: Alaska, Hawaii, and Vermont. Vermont, Wyoming, and North Dakota—3 of the 5 least-populous states—had the fewest practitioners among the contiguous United States (Figure).
Our study showed that from January 2012 to December 2017, fewer dermatologists performed nail excisions than any other provider type (0.06%, 4 dermatologists of 7023 total providers), and dermatologists performed 1734-fold fewer nail excisions than podiatrists (99%, 6936 podiatrists of 7023 total providers). Only dermatologists practicing in California, Georgia, Indiana, and Oklahoma performed nail excisions. Conversely, podiatrists were more geographically distributed across the United States and other territories, with representation in all 50 states as well as the District of Columbia, Puerto Rico, and Guam.
Reasons for these large discrepancies in practice between dermatologists and other providers likely are multifactorial, encompassing a lack of emphasis on nail procedures in dermatology training, patient perception of the scope of dermatologic practice, and nail excision reimbursement patterns. Most dermatologists likely lack experience in performing nail procedures. The Accreditation Council for Graduate Medical Education requirements mandate that dermatology residents observe or perform 3 nail procedures over 3 years of residency, including 1 that may be performed on a human cadaver.4 In contrast, podiatry trainees must gain competency in toenail avulsion (both partial and complete), participate in anesthesia workshops, and become proficient in administering lower extremity blocks by the end of their training.5 Therefore, incorporating aspects of podiatric surgical training into dermatology residency requirements may increase the competency and comfort of dermatologists in performing nail excisions and practicing as nail experts as attending physicians.
It is likely that US patients do not perceive dermatologists as nail specialists and instead primarily consult podiatrists or FM and/or internal medicine physicians for treatment; for example, nail disease was one of the least common reasons for consulting a dermatologist (5%) in a German nationwide survey-based study (N=1015).6 Therefore, increased efforts are needed to educate the general public about the expertise of dermatologists in the diagnosis and management of nail conditions.
Reimbursement also may be a barrier to dermatologists performing nail procedures as part of their scope of practice; for example, in a retrospective study of nail biopsies using the Medicare Provider Utilization and Payment Database, there was no statistically significant difference in reimbursements for nail biopsies vs skin biopsies from 2012 to 2017 (P=0.69).7 Similar to nail biopsies, nail excisions typically are much more time consuming and technically demanding than skin biopsies, which may discourage dermatologists from routinely performing nail excision procedures.
Our study is subject to a number of limitations. The data reflected only US-based practice patterns and may not be applicable to nail procedures globally. There also is the potential for miscoding of procedures in the Medicare database. The data included only Part B Medicare fee-for-service and excludes non-Medicare insured, uninsured, and self-pay patients, as well as aggregated records from 10 or fewer Medicare beneficiaries.
Dermatologists rarely perform nail excisions and perform fewer nail excisions than any other provider type in the United States. There currently is an unmet need for comprehensive nail surgery education in US-based dermatology residency programs. We hope that our study fosters interdisciplinary collegiality and training between podiatrists and dermatologists and promotes expanded access to care across the United States to serve patients with nail disorders.
To the Editor:
Partial or total nail plate excisions commonly are used for the treatment of onychocryptosis and nail spicules. Procedures involving the nail unit require advanced technical skills to achieve optimal functional and aesthetic outcomes, avoid complications, and minimize health care costs. Data on the frequency of nail plate excisions performed by dermatologists and their relative frequency compared to other medical providers are limited. The objective of our study was to analyze trends in nail excision practice patterns among medical providers in the United States.
A retrospective analysis on nail excisions using the Current Procedural Terminology (CPT) code 11750 (excision of nail and nail matrix, partial or complete [eg, ingrown or deformed nail] for permanent removal), which is distinct from code 11755 (biopsy of nail unit [eg, plate, bed, matrix, hyponychium, proximal and lateral nail folds][separate procedure]), was performed using data from the Medicare Provider Utilization and Payment Database 2012-2017.1,2 This file also is used by Peck et al3 in an article submitted to the Journal of the American Podiatric Medical Association and currently under consideration for publication. Procedures were recorded by year and provider type—dermatologist, podiatrist, physician assistant (PA)/nurse practitioner (NP), nondermatologist physician—and subcategorized by provider specialty (Table). Practice locations subcategorized by provider type were mapped using Tableau Software (Salesforce)(Figure). Descriptive statistics including number of providers, mean and median excisions per provider, and minimum/maximum nail excisions were calculated (Table). Practice types of PAs/NPs and specialization of nondermatologist physicians were determined using provider name, identification number, and practice address. This study did not require institutional review board review, as only publicly available data were utilized in our analysis.
A total of 6936 podiatrists, 58 nondermatologist physicians, 25 PAs/NPs, and 4 dermatologists performed 10 or more nail excisions annually under CPT code 11750 from January 2012 to December 2017 with annual means of 31, 31, 25, and 34, respectively (Table). No PAs/NPs included in the dataset worked in dermatology practices during the study period. Physician assistants and NPs most often practiced in podiatry and family medicine (FM) settings (both 40% [10/25]). Nondermatologist physicians most often specialized in FM (40% [23/58])(Table). The greatest number of providers practiced in 3 of the 4 most-populous states: California, Texas, and Florida; the fewest number practiced in 3 of the 10 least-populous states: Alaska, Hawaii, and Vermont. Vermont, Wyoming, and North Dakota—3 of the 5 least-populous states—had the fewest practitioners among the contiguous United States (Figure).
Our study showed that from January 2012 to December 2017, fewer dermatologists performed nail excisions than any other provider type (0.06%, 4 dermatologists of 7023 total providers), and dermatologists performed 1734-fold fewer nail excisions than podiatrists (99%, 6936 podiatrists of 7023 total providers). Only dermatologists practicing in California, Georgia, Indiana, and Oklahoma performed nail excisions. Conversely, podiatrists were more geographically distributed across the United States and other territories, with representation in all 50 states as well as the District of Columbia, Puerto Rico, and Guam.
Reasons for these large discrepancies in practice between dermatologists and other providers likely are multifactorial, encompassing a lack of emphasis on nail procedures in dermatology training, patient perception of the scope of dermatologic practice, and nail excision reimbursement patterns. Most dermatologists likely lack experience in performing nail procedures. The Accreditation Council for Graduate Medical Education requirements mandate that dermatology residents observe or perform 3 nail procedures over 3 years of residency, including 1 that may be performed on a human cadaver.4 In contrast, podiatry trainees must gain competency in toenail avulsion (both partial and complete), participate in anesthesia workshops, and become proficient in administering lower extremity blocks by the end of their training.5 Therefore, incorporating aspects of podiatric surgical training into dermatology residency requirements may increase the competency and comfort of dermatologists in performing nail excisions and practicing as nail experts as attending physicians.
It is likely that US patients do not perceive dermatologists as nail specialists and instead primarily consult podiatrists or FM and/or internal medicine physicians for treatment; for example, nail disease was one of the least common reasons for consulting a dermatologist (5%) in a German nationwide survey-based study (N=1015).6 Therefore, increased efforts are needed to educate the general public about the expertise of dermatologists in the diagnosis and management of nail conditions.
Reimbursement also may be a barrier to dermatologists performing nail procedures as part of their scope of practice; for example, in a retrospective study of nail biopsies using the Medicare Provider Utilization and Payment Database, there was no statistically significant difference in reimbursements for nail biopsies vs skin biopsies from 2012 to 2017 (P=0.69).7 Similar to nail biopsies, nail excisions typically are much more time consuming and technically demanding than skin biopsies, which may discourage dermatologists from routinely performing nail excision procedures.
Our study is subject to a number of limitations. The data reflected only US-based practice patterns and may not be applicable to nail procedures globally. There also is the potential for miscoding of procedures in the Medicare database. The data included only Part B Medicare fee-for-service and excludes non-Medicare insured, uninsured, and self-pay patients, as well as aggregated records from 10 or fewer Medicare beneficiaries.
Dermatologists rarely perform nail excisions and perform fewer nail excisions than any other provider type in the United States. There currently is an unmet need for comprehensive nail surgery education in US-based dermatology residency programs. We hope that our study fosters interdisciplinary collegiality and training between podiatrists and dermatologists and promotes expanded access to care across the United States to serve patients with nail disorders.
- Centers for Medicare & Medicaid Services. Medicare Fee-For-Service Provider Utilization & Payment Data Physician and Other Supplier Public Use File: A Methodological Overview . Updated September 22, 2020. Accessed January 5, 2024. https://www.cms.gov/research-statistics-data-and-systems/statistics-trends-and-reports/medicare-provider-charge-data/downloads/medicare-physician-and-other-supplier-puf-methodology.pdf
- Centers for Medicare and Medicaid Services. Billing and Coding: Surgical Treatment of Nails. Updated November 9, 2023. Accessed January 8, 2024. https://www.cms.gov/medicare-coverage-database/view/article.aspx?articleID=52998#:~:text=The%20description%20of%20CPT%20codes,date%20of%20service%20(DOS).
- Peck GM, Vlahovic TC, Hill R, et al. Senior podiatrists in solo practice are high performers of nail excisions. JAPMA. In press.
- Accreditation Council for Graduate Medical Education. Case log minimums. review committee for dermatology. Published May 2019. Accessed January 5, 2024. https://www.acgme.org/Portals/0/PFAssets/ProgramResources/CaseLogMinimums.pdf?ver=2018-04-03-102751-650
- Council on Podiatric Medical Education. Standards and Requirements for Approval of Podiatric Medicine and Surgery Residencies. Published July 2023. Accessed January 17, 2024. https://www.cpme.org/files/320%20Council%20Approved%20October%202022%20-%20April%202023%20edits.pdf
- Augustin M, Eissing L, Elsner P, et al. Perception and image of dermatology in the German general population 2002-2014. J Eur Acad Dermatol Venereol. 2017;31:2124-2130.
- Wang Y, Lipner SR. Retrospective analysis of nail biopsies performed using the Medicare provider utilization and payment database 2012 to 2017. Dermatol Ther. 2021;34:E14928.
- Centers for Medicare & Medicaid Services. Medicare Fee-For-Service Provider Utilization & Payment Data Physician and Other Supplier Public Use File: A Methodological Overview . Updated September 22, 2020. Accessed January 5, 2024. https://www.cms.gov/research-statistics-data-and-systems/statistics-trends-and-reports/medicare-provider-charge-data/downloads/medicare-physician-and-other-supplier-puf-methodology.pdf
- Centers for Medicare and Medicaid Services. Billing and Coding: Surgical Treatment of Nails. Updated November 9, 2023. Accessed January 8, 2024. https://www.cms.gov/medicare-coverage-database/view/article.aspx?articleID=52998#:~:text=The%20description%20of%20CPT%20codes,date%20of%20service%20(DOS).
- Peck GM, Vlahovic TC, Hill R, et al. Senior podiatrists in solo practice are high performers of nail excisions. JAPMA. In press.
- Accreditation Council for Graduate Medical Education. Case log minimums. review committee for dermatology. Published May 2019. Accessed January 5, 2024. https://www.acgme.org/Portals/0/PFAssets/ProgramResources/CaseLogMinimums.pdf?ver=2018-04-03-102751-650
- Council on Podiatric Medical Education. Standards and Requirements for Approval of Podiatric Medicine and Surgery Residencies. Published July 2023. Accessed January 17, 2024. https://www.cpme.org/files/320%20Council%20Approved%20October%202022%20-%20April%202023%20edits.pdf
- Augustin M, Eissing L, Elsner P, et al. Perception and image of dermatology in the German general population 2002-2014. J Eur Acad Dermatol Venereol. 2017;31:2124-2130.
- Wang Y, Lipner SR. Retrospective analysis of nail biopsies performed using the Medicare provider utilization and payment database 2012 to 2017. Dermatol Ther. 2021;34:E14928.
Practice Points
- Dermatologists are considered nail experts but perform nail excisions less frequently than their podiatric counterparts and physicians in other specialties.
- Aspects of podiatric surgical training should be incorporated into dermatology residency to increase competency and comfort of dermatologists in nail excision procedures.
- Dermatologists may not be perceived as nail experts by the public, indicating a need for increased community education on the role of dermatologists in treating nail disease.
PRAME Expression in Melanocytic Proliferations in Special Sites
The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.1 Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.1,2
When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture3; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.1 If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.
Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.4 It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.5 PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site5; therefore, expressing PRAME allows lesional cells a substantial growth advantage.
PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.6-10 Although PRAME has been studied in acral nevi,11 the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.
Methods
We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.
The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry7: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.
Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).
Results
Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.
Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10-12).
Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.
Comment
The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.
Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases.
Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.
Conclusion
Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.
Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.
- VandenBoom T, Gerami P. Melanocytic nevi of special sites. In: Pathology of Melanocytic Tumors. Elsevier; 2019:90-100. doi:10.1016/B978-0-323-37457-6.00007-9
- Hosler GA, Moresi JM, Barrett TL. Nevi with site-related atypia: a review of melanocytic nevi with atypical histologic features based on anatomic site. J Cutan Pathol. 2008;35:889-898. doi:10.1111/j.1600-0560.2008.01041.x.
- Brenn T. Melanocytic lesions—staying out of trouble. Ann Diagn Pathol. 2018;37:91-102. doi:10.1016/j.anndiagpath.2018.09.010
- Ikeda H, Lethé B, Lehmann F, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6:199-208. doi:10.1016/s1074-7613(00)80426-4
- Epping MT, Wang L, Edel MJ, et al. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 2005;122:835-847. doi:10.1016/j.cell.2005.07.003
- Alomari AK, Tharp AW, Umphress B, et al. The utility of PRAME immunohistochemistry in the evaluation of challenging melanocytic tumors. J Cutan Pathol. 2021;48:1115-1123. doi:10.1111/cup.14000
- Lezcano C, Jungbluth AA, Nehal KS, et al. PRAME expression in melanocytic tumors. Am J Surg Pathol. 2018;42:1456-1465. doi:10.1097/PAS.0000000000001134
- Gill P, Prieto VG, Austin MT, et al. Diagnostic utility of PRAME in distinguishing proliferative nodules from melanoma in giant congenital melanocytic nevi. J Cutan Pathol. 2021;48:1410-1415. doi:10.1111/cup.14091
- Googe PB, Flanigan KL, Miedema JR. Preferentially expressed antigen in melanoma immunostaining in a series of melanocytic neoplasms. Am J Dermatopathol. 2021;43):794-800. doi:10.1097/DAD.0000000000001885
- Raghavan SS, Wang JY, Kwok S, et al. PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features. J Cutan Pathol. 2020;47:1123-1131. doi:10.1111/cup.13818
- McBride JD, McAfee JL, Piliang M, et al. Preferentially expressed antigen in melanoma and p16 expression in acral melanocytic neoplasms. J Cutan Pathol. 2022;49:220-230. doi:10.1111/cup.14130
The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.1 Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.1,2
When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture3; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.1 If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.
Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.4 It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.5 PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site5; therefore, expressing PRAME allows lesional cells a substantial growth advantage.
PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.6-10 Although PRAME has been studied in acral nevi,11 the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.
Methods
We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.
The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry7: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.
Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).
Results
Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.
Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10-12).
Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.
Comment
The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.
Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases.
Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.
Conclusion
Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.
Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.
The assessment and diagnosis of melanocytic lesions can present a formidable challenge to even a seasoned pathologist, which is especially true when dealing with the subset of nevi occurring at special sites—where baseline variations inherent to particular locations on the body can preclude the use of features routinely used to diagnose malignancy elsewhere. These so-called special-site nevi previously have been described in the literature along with suggested criteria for differentiating malignant lesions from their benign counterparts.1 Locations generally considered to be special sites include the acral skin, anogenital region, breast, ear, and flexural regions.1,2
When evaluating non–special-site melanocytic lesions, general characteristics associated with a malignant diagnosis include confluence or pagetoid spread of melanocytes, nuclear pleomorphism, cytologic atypia, and irregular architecture3; however, these features can be compatible with a benign diagnosis in special-site nevi depending on their extent and the site in question. Although they can be atypical, special-site nevi tend to have the bulk of their architectural distortion and cytologic atypia in the center of the lesion as opposed to the edges.1 If a given lesion is from a special site but lacks this reassuring feature, special care should be taken to rule out malignancy.
Preferentially expressed antigen in melanoma (PRAME) is an antigen first identified in tumor-reactive T-cell populations in patients with malignant melanoma. It is the product of an oncogene that frequently is overexpressed in melanomas, lung squamous cell carcinomas, sarcomas, and acute leukemias.4 It functions as an antagonist of the retinoic acid signaling pathway, which normally serves to induce further cell differentiation, senescence, or apoptosis.5 PRAME inhibits retinoid signaling by forming a complex with both the ligand-bound retinoic acid holoreceptor and the polycomb protein EZH2, which blocks retinoid-dependent gene expression by encouraging chromatin condensation at the RARβ promoter site5; therefore, expressing PRAME allows lesional cells a substantial growth advantage.
PRAME expression has been extensively characterized in non–special-site nevi and has filled the need for a rather specific marker of melanoma.6-10 Although PRAME has been studied in acral nevi,11 the expression pattern in nevi of special sites has yet to be elucidated. Herein, we present a dataset characterizing PRAME expression in these challenging lesions.
Methods
We performed a retrospective case review at the University of Virginia (Charlottesville, Virginia) and collected a panel of 36 special-site nevi that previously were diagnosed as benign by a trained dermatopathologist from January 2020 through December 2022. Special-site nevi were identified using a natural language filter for the following terms: acral, palm, sole, ear, auricular, lip, axilla, armpit, breast, groin, labia, vulva, umbilicus, and penis. This study was approved by the University of Virginia institutional review board.
The original hematoxylin and eosin slides used for primary diagnosis were re-examined to verify the prior diagnosis of benign nevus at a special site. We performed a detailed microscopic examination of all benign nevi in our cohort to determine the frequency of various characteristics at each special site. Sections were prepared from the formalin-fixed and paraffin-embedded tissue blocks and stained with a commercial PRAME antibody (#219650 [Abcam] at a 1:50 dilution) and counterstain. A trained dermatopathologist (S.S.R.) examined the stained sections and recorded the percentage of tumor cells with nuclear PRAME staining. We reported our results using previously established criteria for scoring PRAME immunohistochemistry7: 0 for no expression, 1+ for 1% to 25% expression, 2+ for 26% to 50% expression, 3+ for 51% to 75% expression, and 4+ for diffuse or 76% to 100% expression. Only strong clonal expression within a population of cells was graded.
Data handling and statistical testing were performed using the R Project for Statistical Computing (https://www.r-project.org/). Significance testing was performed using the Fisher exact test. Plot construction was performed using ggplot2 (https://ggplot2.tidyverse.org/).
Results
Our study cohort included 36 special-site nevi, and the control cohort comprised 25 melanoma in situ (MIS) or invasive melanoma (IM) lesions occurring at special sites. Table 1 provides a breakdown of the study and control cohorts by lesion site. Table 2 details the results of our microscopic examination, describing frequency of various characteristics of special-site nevi stratified by site.
Of the 36 special-site nevi in our cohort, 20 (56%) had no staining (0) for PRAME, 11 (31%) demonstrated 1+ PRAME expression, 3 (8%) demonstrated 2+ PRAME expression, and 2 (6%) demonstrated 3+ PRAME expression. No nevi showed 4+ expression. In the control cohort, 24 of 25 (96%) MIS and IM showed 3+ or 4+ expression, with 21 (84%) demonstrating diffuse/4+ expression. One control case (4%) demonstrated 0 PRAME expression. These data are summarized in Table 3 and Figure 1. There is a significant difference in diffuse (4+) PRAME expression between special-site nevi and MIS/IM occurring at special sites (P=1.039×10-12).
Based on our cohort, a positivity threshold of 3+ for PRAME expression for the diagnosis of melanoma in a special-site lesion would have a sensitivity of 96% and a specificity of 94%, while a positivity threshold of 4+ for PRAME expression would have a sensitivity of 84% and a specificity of 100%. Figures 2 through 4 show photomicrographs of a special-site nevus of the breast, which appropriately does not stain for PRAME; Figures 5 and 6 show an MIS at a special site that appropriately stains for PRAME.
Comment
The distinction between benign and malignant pigmented lesions at special sites presents a fair challenge for pathologists due to the larger degree of leniency for architectural distortion and cytologic atypia in benign lesions at these sites. The presence of architectural distortion or cytologic atypia at the lesion’s edge makes rendering a benign diagnosis especially difficult, and the need for a validated immunohistochemical stain is apparent. In our cohort, strong clonal PRAME expression provided a reliable immunohistochemical marker, allowing for the distinction of malignant lesions from benign nevi at special sites. Diffuse faint PRAME expression was present in several benign nevi within our cohort, and these lesions were considered negative (0) in our analysis.
Given the described test characteristics, we support the implementation of PRAME immunohistochemistry with a positivity threshold of 4+ expression as an ancillary test supporting the diagnosis of IM or MIS in special sites, which would allow clinicians to leverage the high specificity of 4+ PRAME expression to distinguish an IM or MIS from a benign nevus occurring at a special site. We do not recommend the use of 4+ PRAME expression as a screening test for melanoma or MIS among special-site nevi due to its comparatively low sensitivity; however, no one marker is always reliable, and we recommend continued clinicopathologic correlation for all cases.
Although our case series included nevi and MIS/IM from all special sites, we were limited in the number of acrogenital and ear nevi included due to a relative paucity of biopsied benign nevi from these locations at the University of Virginia. Additionally, although the magnitude of the difference in PRAME expression between the study and control groups is sufficient to demonstrate statistical significance, the overall strength of our argument would be increased with a larger study group. We were limited by the number of cases available at our institution, which did not utilize PRAME during the initial diagnosis of the case; including these cases in the study group would have undermined the integrity of our argument because the differentiation of benign vs malignant initially was made using PRAME immunohistochemistry.
Conclusion
Due to their atypical features, special-site nevi can be challenging to assess. In this study, we showed that PRAME expression can be a reliable marker to distinguish benign from malignant lesions. Our results showed that 100% of benign special-site nevi demonstrated 3+ expression or less, with 56% (20/36) demonstrating no expression at all. The presence of diffuse PRAME expression (4+ PRAME staining) appears to be a specific indicator of a malignant lesion, but results should always be interpreted with respect to the patient’s clinical history and the lesion’s histomorphologic features. Further study of a larger sample size would allow refinement of the sensitivity and specificity of diffuse PRAME expression in the determination of malignancy for special-site lesions.
Acknowledgment—The authors thank the pathologistsat the University of Virginia Biorepository and Tissue Research Facility (Charlottesville, Virginia) for their skill and expertise in performing immunohistochemical staining for this study.
- VandenBoom T, Gerami P. Melanocytic nevi of special sites. In: Pathology of Melanocytic Tumors. Elsevier; 2019:90-100. doi:10.1016/B978-0-323-37457-6.00007-9
- Hosler GA, Moresi JM, Barrett TL. Nevi with site-related atypia: a review of melanocytic nevi with atypical histologic features based on anatomic site. J Cutan Pathol. 2008;35:889-898. doi:10.1111/j.1600-0560.2008.01041.x.
- Brenn T. Melanocytic lesions—staying out of trouble. Ann Diagn Pathol. 2018;37:91-102. doi:10.1016/j.anndiagpath.2018.09.010
- Ikeda H, Lethé B, Lehmann F, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6:199-208. doi:10.1016/s1074-7613(00)80426-4
- Epping MT, Wang L, Edel MJ, et al. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 2005;122:835-847. doi:10.1016/j.cell.2005.07.003
- Alomari AK, Tharp AW, Umphress B, et al. The utility of PRAME immunohistochemistry in the evaluation of challenging melanocytic tumors. J Cutan Pathol. 2021;48:1115-1123. doi:10.1111/cup.14000
- Lezcano C, Jungbluth AA, Nehal KS, et al. PRAME expression in melanocytic tumors. Am J Surg Pathol. 2018;42:1456-1465. doi:10.1097/PAS.0000000000001134
- Gill P, Prieto VG, Austin MT, et al. Diagnostic utility of PRAME in distinguishing proliferative nodules from melanoma in giant congenital melanocytic nevi. J Cutan Pathol. 2021;48:1410-1415. doi:10.1111/cup.14091
- Googe PB, Flanigan KL, Miedema JR. Preferentially expressed antigen in melanoma immunostaining in a series of melanocytic neoplasms. Am J Dermatopathol. 2021;43):794-800. doi:10.1097/DAD.0000000000001885
- Raghavan SS, Wang JY, Kwok S, et al. PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features. J Cutan Pathol. 2020;47:1123-1131. doi:10.1111/cup.13818
- McBride JD, McAfee JL, Piliang M, et al. Preferentially expressed antigen in melanoma and p16 expression in acral melanocytic neoplasms. J Cutan Pathol. 2022;49:220-230. doi:10.1111/cup.14130
- VandenBoom T, Gerami P. Melanocytic nevi of special sites. In: Pathology of Melanocytic Tumors. Elsevier; 2019:90-100. doi:10.1016/B978-0-323-37457-6.00007-9
- Hosler GA, Moresi JM, Barrett TL. Nevi with site-related atypia: a review of melanocytic nevi with atypical histologic features based on anatomic site. J Cutan Pathol. 2008;35:889-898. doi:10.1111/j.1600-0560.2008.01041.x.
- Brenn T. Melanocytic lesions—staying out of trouble. Ann Diagn Pathol. 2018;37:91-102. doi:10.1016/j.anndiagpath.2018.09.010
- Ikeda H, Lethé B, Lehmann F, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6:199-208. doi:10.1016/s1074-7613(00)80426-4
- Epping MT, Wang L, Edel MJ, et al. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 2005;122:835-847. doi:10.1016/j.cell.2005.07.003
- Alomari AK, Tharp AW, Umphress B, et al. The utility of PRAME immunohistochemistry in the evaluation of challenging melanocytic tumors. J Cutan Pathol. 2021;48:1115-1123. doi:10.1111/cup.14000
- Lezcano C, Jungbluth AA, Nehal KS, et al. PRAME expression in melanocytic tumors. Am J Surg Pathol. 2018;42:1456-1465. doi:10.1097/PAS.0000000000001134
- Gill P, Prieto VG, Austin MT, et al. Diagnostic utility of PRAME in distinguishing proliferative nodules from melanoma in giant congenital melanocytic nevi. J Cutan Pathol. 2021;48:1410-1415. doi:10.1111/cup.14091
- Googe PB, Flanigan KL, Miedema JR. Preferentially expressed antigen in melanoma immunostaining in a series of melanocytic neoplasms. Am J Dermatopathol. 2021;43):794-800. doi:10.1097/DAD.0000000000001885
- Raghavan SS, Wang JY, Kwok S, et al. PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features. J Cutan Pathol. 2020;47:1123-1131. doi:10.1111/cup.13818
- McBride JD, McAfee JL, Piliang M, et al. Preferentially expressed antigen in melanoma and p16 expression in acral melanocytic neoplasms. J Cutan Pathol. 2022;49:220-230. doi:10.1111/cup.14130
Practice Points
- Special-site nevi are benign melanocytic proliferations at special anatomic sites. Although cytologic atypia and architectural distortion may be present, they are centrally located and should not be present at the borders of the lesion.
- Strong expression of the preferentially expressed antigen in melanoma (PRAME) via immunohistochemistry provides a reliable indicator for benignity in differentiating a special-site nevus from a malignant melanoma occurring at a special site.
Association Between Atopic Dermatitis and Chronic Obstructive Pulmonary Disease Among US Adults in the 1999-2006 NHANES Survey
To the Editor:
Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.1 Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.2 In 2020, Smirnova et al3 reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.4
We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).
Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).
Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.5 Additionally, Harazin et al6 discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.6
Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.
- Chiesa Fuxench ZC, Block JK, Boguniewicz M, et al. Atopic Dermatitis in America Study: a cross-sectional study examining the prevalence and disease burden of atopic dermatitis in the US adult population. J Invest Dermatol. 2019;139:583-590. doi:10.1016/j.jid.2018.08.028
- Darlenski R, Kazandjieva J, Hristakieva E, et al. Atopic dermatitis as a systemic disease. Clin Dermatol. 2014;32:409-413. doi:10.1016/j.clindermatol.2013.11.007
- Smirnova J, Montgomery S, Lindberg M, et al. Associations of self-reported atopic dermatitis with comorbid conditions in adults: a population-based cross-sectional study. BMC Dermatol. 2020;20:23. doi:10.1186/s12895-020-00117-8
- National Center for Health Statistics. NHANES questionnaires, datasets, and related documentation. Centers for Disease Control and Prevention website. Accessed February 1, 2023. https://wwwn.cdc.gov/nchs/nhanes/
- Kawayama T, Okamoto M, Imaoka H, et al. Interleukin-18 in pulmonary inflammatory diseases. J Interferon Cytokine Res. 2012;32:443-449. doi:10.1089/jir.2012.0029
- Harazin M, Parwez Q, Petrasch-Parwez E, et al. Variation in the COL29A1 gene in German patients with atopic dermatitis, asthma and chronic obstructive pulmonary disease. J Dermatol. 2010;37:740-742. doi:10.1111/j.1346-8138.2010.00923.x
To the Editor:
Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.1 Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.2 In 2020, Smirnova et al3 reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.4
We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).
Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).
Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.5 Additionally, Harazin et al6 discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.6
Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.
To the Editor:
Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.1 Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.2 In 2020, Smirnova et al3 reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.4
We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).
Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).
Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.5 Additionally, Harazin et al6 discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.6
Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.
- Chiesa Fuxench ZC, Block JK, Boguniewicz M, et al. Atopic Dermatitis in America Study: a cross-sectional study examining the prevalence and disease burden of atopic dermatitis in the US adult population. J Invest Dermatol. 2019;139:583-590. doi:10.1016/j.jid.2018.08.028
- Darlenski R, Kazandjieva J, Hristakieva E, et al. Atopic dermatitis as a systemic disease. Clin Dermatol. 2014;32:409-413. doi:10.1016/j.clindermatol.2013.11.007
- Smirnova J, Montgomery S, Lindberg M, et al. Associations of self-reported atopic dermatitis with comorbid conditions in adults: a population-based cross-sectional study. BMC Dermatol. 2020;20:23. doi:10.1186/s12895-020-00117-8
- National Center for Health Statistics. NHANES questionnaires, datasets, and related documentation. Centers for Disease Control and Prevention website. Accessed February 1, 2023. https://wwwn.cdc.gov/nchs/nhanes/
- Kawayama T, Okamoto M, Imaoka H, et al. Interleukin-18 in pulmonary inflammatory diseases. J Interferon Cytokine Res. 2012;32:443-449. doi:10.1089/jir.2012.0029
- Harazin M, Parwez Q, Petrasch-Parwez E, et al. Variation in the COL29A1 gene in German patients with atopic dermatitis, asthma and chronic obstructive pulmonary disease. J Dermatol. 2010;37:740-742. doi:10.1111/j.1346-8138.2010.00923.x
- Chiesa Fuxench ZC, Block JK, Boguniewicz M, et al. Atopic Dermatitis in America Study: a cross-sectional study examining the prevalence and disease burden of atopic dermatitis in the US adult population. J Invest Dermatol. 2019;139:583-590. doi:10.1016/j.jid.2018.08.028
- Darlenski R, Kazandjieva J, Hristakieva E, et al. Atopic dermatitis as a systemic disease. Clin Dermatol. 2014;32:409-413. doi:10.1016/j.clindermatol.2013.11.007
- Smirnova J, Montgomery S, Lindberg M, et al. Associations of self-reported atopic dermatitis with comorbid conditions in adults: a population-based cross-sectional study. BMC Dermatol. 2020;20:23. doi:10.1186/s12895-020-00117-8
- National Center for Health Statistics. NHANES questionnaires, datasets, and related documentation. Centers for Disease Control and Prevention website. Accessed February 1, 2023. https://wwwn.cdc.gov/nchs/nhanes/
- Kawayama T, Okamoto M, Imaoka H, et al. Interleukin-18 in pulmonary inflammatory diseases. J Interferon Cytokine Res. 2012;32:443-449. doi:10.1089/jir.2012.0029
- Harazin M, Parwez Q, Petrasch-Parwez E, et al. Variation in the COL29A1 gene in German patients with atopic dermatitis, asthma and chronic obstructive pulmonary disease. J Dermatol. 2010;37:740-742. doi:10.1111/j.1346-8138.2010.00923.x
Practice Points
- Various comorbidities are associated with atopic dermatitis (AD). Currently, research exploring the association between AD and chronic obstructive pulmonary disease is limited.
- Understanding the systemic diseases associated with inflammatory skin diseases can assist with adequate patient management.
Thiazide Diuretic Utilization Within the VA
Hypertension is one of the most common cardiovascular disease (CVD) states, affecting nearly half of all adults in the United States.1 Numerous classes of antihypertensives are available for blood pressure (BP) management, including thiazide diuretics, which contain both thiazide and thiazide-like agents. Thiazide diuretics available in the US include hydrochlorothiazide (HCTZ), chlorthalidone, metolazone, and indapamide. These agents are commonly used and recommended as first-line treatment in the current 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the prevention, detection, evaluation, and management of high BP in adults.2
The ACC/AHA guideline recommends chlorthalidone as the preferred thiazide diuretic.2 This recommendation is based on its prolonged half-life compared with other thiazide agents, as well as the reduction of CVD seen with chlorthalidone in previous trials. The main evidence supporting chlorthalidone use comes from the ALLHAT trial, which compared chlorthalidone, amlodipine, and lisinopril in patients with hypertension. The primary composite outcome of fatal coronary artery disease or nonfatal myocardial infarction was not significantly different between groups. However, when looking at the incidence of heart failure, chlorthalidone was superior to both amlodipine and lisinopril.3 In the TOMHS trial, chlorthalidone was more effective in reducing left ventricular hypertrophy than amlodipine, enalapril, doxazosin, or acebutolol.4 Furthermore, both a systematic review and a retrospective cohort analysis suggested that chlorthalidone may be associated with improved CVD outcomes compared with HCTZ.5,6 However, prospective randomized trial data is needed to confirm the superiority of chlorthalidone over other thiazide diuretics.
HCTZ has historically been the most common thiazide diuretic.7 However, with the available evidence and 2017 ACC/AHA BP guideline recommendations, it is unclear whether this trend continues and what impact it may have on CVD outcomes. It is unclear which thiazide diuretic is most commonly used in the US Department of Veterans Affairs (VA) health care system. The purpose of this project was to evaluate current thiazide diuretic utilization within the VA.
Methods
This retrospective, observational study evaluated the prescribing pattern of thiazide diuretics from all VA health care systems from January 1, 2016, to January 21, 2022. Thiazide diuretic agents included in this study were HCTZ, chlorthalidone, indapamide, and any combination antihypertensive products that included these 3 thiazide diuretics. Metolazone was excluded as it is commonly used in the setting of diuretic resistance with heart failure. Data was obtained from the VA Corporate Data Warehouse (CDW) and divided into 2 cohorts: the active and historic cohorts. The active cohort was of primary interest and included any active VA thiazide diuretic prescriptions on January 21, 2022. The historic cohort included thiazide prescriptions assessed at yearly intervals from January 1, 2016, to December 31, 2021. This date range was selected to assess what impact the 2017 ACC/AHA BP guideline had on clinician preferences and thiazide diuretic prescribing rates.
Within the active cohort, demographic data, vital information, and concomitant potassium or magnesium supplementation were collected. Baseline characteristics included were age, sex, race and ethnicity, and BP. Patients with > 1 race or ethnicity reported were categorized as other. The first BP reading documented after the active thiazide diuretic initiation date was included for analysis to capture on-therapy BPs while limiting confounding factors due to other potential antihypertensive changes. This project was ruled exempt from institutional review board review by the West Palm Beach VA Healthcare System Research and Development Committee.
The primary outcome was the evaluation of utilization rates of each thiazide in the active cohort, reported as a proportion of overall thiazide class utilization within the VA. Secondary outcomes in the active thiazide cohort included concomitant potassium or magnesium supplement utilization rates in each of the thiazide groups, BP values, and BP control rates. BP control was defined as a systolic BP < 130 mm Hg and a diastolic BP < 80 mm Hg. Finally, the change in thiazide diuretic utilization patterns from January 1, 2016, to December 31, 2021, was evaluated in the historic cohort.
Statistical Analysis
Data collection and analysis were completed using the CDW analyzed with Microsoft SQL Server Management Studio 18 and Microsoft Excel. All exported data to Microsoft Excel was kept in a secure network drive that was only accessible to the authors. Protected health information remained confidential per VA policy and the Health Insurance Portability and Accountability Act.
Baseline demographics were evaluated across thiazide arms using descriptive statistics. The primary outcome was assessed and a χ2 test with a single comparison α level of 0.05 with Bonferroni correction to adjust for multiple comparisons when appropriate. For the secondary outcomes, analysis of continuous data was assessed using analysis of variance (ANOVA), and nominal data were assessed with a χ2 test with a single comparison α level of 0.05 and Bonferroni correction to adjust for multiple comparisons where appropriate. When comparing all 3 thiazide groups, after the Bonferroni correction, P < .01667 was considered statistically significant to avoid a type 1 error in a family of statistical tests.
Results
As of January 21, 2022, the active thiazide cohort yielded 628,994 thiazide prescriptions within the VA nationwide. Most patients were male, with female patients representing 8.4%, 6.6%, and 5.6% of the HCTZ, chlorthalidone, and indapamide arms, respectively (Table 1). Utilization rates were significantly different between thiazide groups (P < .001). HCTZ was the most prescribed thiazide diuretic (84.6%) followed by chlorthalidone (14.9%) and indapamide (0.5%) (Table 2).
BP values documented after prescription initiation date were available for few individuals in the HCTZ, chlorthalidone, and indapamide groups (0.3%, 0.2%, and 0.5%, respectively). Overall, the mean BP values were similar among thiazide groups: 135/79 mm Hg for HCTZ, 137/78 mm Hg for chlorthalidone, and 133/79 mm Hg for indapamide (P = .32). BP control was also similar with control rates of 26.0%, 27.1%, and 33.3% for those on HCTZ, chlorthalidone, and indapamide, respectively (P = .75). The use of concomitant potassium or magnesium supplementation was significantly different between thiazide groups with rates of 12.4%, 22.6%, and 27.1% for HCTZ, chlorthalidone, and indapamide, respectively (P < .001). When comparing chlorthalidone to HCTZ, there was a significantly higher rate of concomitant supplementation with chlorthalidone (P < .001) (Table 3).
In the historic cohort, HCTZ utilization decreased from 90.2% to 83.5% (P < .001) and chlorthalidone utilization increased significantly from 9.3% to 16.0% (P < .001) (Figure). There was no significant change in the use of indapamide during this period (P = .73). Yearly trends from 2016 to 2021 are listed in Table 4.
Discussion
The findings of our evaluation demonstrate that despite the 2017 ACC/AHA BP guideline recommendations for using chlorthalidone, HCTZ predominates as the most prescribed thiazide diuretic within the VA. However, since the publication of this guideline, there has been an increase in chlorthalidone prescribing and a decrease in HCTZ prescribing within the VA.
A 2010 study by Ernst and colleagues revealed a similar trend to what was seen in our study. At that time, HCTZ was the most prescribed thiazide encompassing 95% of total thiazide utilization; however, chlorthalidone utilization increased from 1.1% in 2003 to 2.4% in 2008.8 In comparing our chlorthalidone utilization rates with these results, 9.3% in 2016 and 16.0% in 2021, the change in chlorthalidone prescribing from 2003 to 2016 represents a more than linear increase. This trend continued in our study from 2016 to 2021; the expected chlorthalidone utilization would be 21.2% in 2021 if it followed the 2003 to 2016 rate of change. Thus the trend in increasing chlorthalidone use predated the 2017 guideline recommendation. Nonetheless, this change in the thiazide prescribing pattern represents a positive shift in practice.
Our evaluation found a significantly higher rate of concomitant potassium or magnesium supplementation with chlorthalidone and indapamide compared with HCTZ in the active cohort. Electrolyte abnormalities are well documented adverse effects associated with thiazide diuretic use.9 A cross-sectional analysis by Ravioli and colleagues revealed thiazide diuretic use was an independent predictor of both hyponatremia (22.1% incidence) and hypokalemia (19% incidence) and that chlorthalidone was associated with the highest risk of electrolyte abnormalities whereas HCTZ was associated with the lowest risk. Their study also found these electrolyte abnormalities to have a dose-dependent relationship with the thiazide diuretic prescribed.10
While Ravioli and colleagues did not address the incidence of hypomagnesemia with thiazide diuretic use, a cross-sectional analysis by Kieboom and colleagues reported a significant increase in hypomagnesemia in patients prescribed thiazide diuretics.11 Although rates of electrolyte abnormalities are reported in the literature, the rates of concomitant supplementation are unclear, especially when compared across thiazide agents. Our study provides insight into the use of concomitant potassium and magnesium supplementation compared between HCTZ, chlorthalidone, and indapamide. In our active cohort, potassium was more commonly prescribed than magnesium. Interestingly, magnesium supplementation accounted for 25.9% of the total supplement use for HCTZ compared with rates of 22.4% and 21.0% for chlorthalidone and indapamide, respectively. It is unclear if this trend highlights a greater incidence of hypomagnesemia with HCTZ or greater clinician awareness to monitor this agent, but this finding may warrant further investigation. In addition, when considering the overall lower rate of supplementation seen with HCTZ in our study, the use of potassium-sparing diuretics should be considered. These agents, including triamterene, amiloride, eplerenone, and spironolactone, can be supplement-sparing and are available in combination products only with HCTZ.
Low chlorthalidone utilization rates are concerning especially given the literature demonstrating CVD benefit with chlorthalidone and the lack of compelling outcomes data to support HCTZ as the preferred agent.3,4 There are several reasons why HCTZ use may be higher in practice. First is clinical inertia, which is defined as a lack of treatment intensification or lack of changing practice patterns, despite evidence-based goals of care.12 HCTZ has been the most widely prescribed thiazide diuretic for years.7 As a result, converting HCTZ to chlorthalidone for a patient with suboptimal BP control may not be considered and instead clinicians may add on another antihypertensive or titrate doses of current antihypertensives.
There is also a consideration for patient adherence. HCTZ has many more combination products available than chlorthalidone and indapamide. If switching a patient from an HCTZ-containing combination product to chlorthalidone, adherence and patient willingness to take another capsule or tablet must be considered. Finally, there may be clinical controversy and questions around switching patients from HCTZ to chlorthalidone. Although the guidelines do not explicitly recommend switching to chlorthalidone, it may be reasonable in most patients unless they have or are at significant risk of electrolyte or metabolic disturbances that may be exacerbated or triggered with conversion.
When converting from HCTZ to chlorthalidone, it is important to consider dosing. Previous studies have demonstrated that chlorthalidone is 1.5 to 2 times more potent than HCTZ.13,14 Therefore, the conversion from HCTZ to chlorthalidone is not 1:1, but instead 50 mg of HCTZ is approximately equal to25 to 37.5 mg of chlorthalidone.14
Limitations
This study was limited by its retrospective design, gaps in data, duplicate active prescription data, and the assessment of concomitant electrolyte supplementation. As with any retrospective study, there is a potential for confounding and a concern for information bias with missing information. This study relied on proper documentation of prescription and demographic information in the Veterans Health Information Systems and Technology Architecture (VistA), as the CDW compiles information from this electronic health record. Strengths of the VistA include ease in clinical functions, documentation, and the ability for records to be updated from any VA facility nationally. However, there is always the possibility of user error and information to be omitted.
In our study, the documentation of BP values and subsequent analysis of overall BP control were limited. For BP values to be included in this study, they had to be recorded after the active thiazide prescription was written and from an in-person encounter documented in VistA. The COVID-19 pandemic shifted the clinical landscape and many primary care appointments during the active cohort evaluation period were conducted virtually. Therefore, patients may not have had formal vitals recorded. There may also be an aspect of selection bias regarding the chlorthalidone group. Although rates of thiazide switching were not assessed, some patients may have been switched from HCTZ or indapamide to chlorthalidone to achieve additional BP control. Thus, patients receiving chlorthalidone may represent a more difficult-to-control hypertensive population, making a finding of similar BP control rates between HCTZ and chlorthalidone an actual positive finding regarding chlorthalidone. Finally, this study did not assess adherence to medications. As the intent of the study was to analyze prescribing patterns, it is impossible to know if the patient was actively taking the medication at the time of assessment. When considering the rates of BP control, there were limited BP values, a potential for selection bias, and neither adherence nor patient self-reported home BP values were assessed. Therefore, the interpretation of overall BP control must be done with caution.
Additionally, duplicate prescriptions were noted in the active cohort. Rates of duplication were 0.2%, 0.08%, and 0.09% for HCTZ, chlorthalidone, and indapamide, respectively. With these small percentages, we felt this would not have a significant impact on the overall thiazide use trends seen in our study. Patients can receive prescriptions from multiple VA facilities and may have > 1 active prescriptions. This has been mitigated in recent years with the introduction of the OneVA program, allowing pharmacists to access any prescription on file from any VA facility and refill if needed (except controlled substance prescriptions). However, there are certain instances in which duplicate prescriptions may be necessary. These include patients enrolled and receiving care at another VA facility (eg, traveling for part of a year) and patients hospitalized at a different facility and given medications on discharge.
With the overall low rate of duplication prescriptions seen in each thiazide group, we determined that this was not large enough to cause substantial variation in the results of this evaluation and was unlikely to alter the results. This study also does not inform on the incidence of switching between thiazide diuretics. If a patient was switched from HCTZ to chlorthalidone in 2017, for example, a prescription for HCTZ and chlorthalidone would have been reported in this study. We felt that the change in chlorthalidone prescribing from January 1, 2016, to December 31, 2021, would reflect overall utilization rates, which may include switching from HCTZ or indapamide to chlorthalidone in addition to new chlorthalidone prescriptions.
Finally, there are confounders and trends in concomitant potassium or magnesium supplementation that were not accounted for in our study. These include concomitant loop diuretics or other medications that may cause electrolyte abnormalities and the dose-dependent relationship between thiazide diuretics and electrolyte abnormalities.10 Actual laboratory values were not included in this analysis and thus we cannot assess whether supplementation or management of electrolyte disturbances was clinically appropriate.
Conclusions
Thiazide utilization patterns have shifted possibly due to the 2017 ACC/AHA BP guideline recommendations. However, HCTZ continues to be the most widely prescribed thiazide diuretic within the VA. There is a need for future projects and clinician education to increase the implementation of guideline-recommended therapy within the VA, particularly regarding chlorthalidone use.
1. Centers for Disease Control and Prevention. Hypertension cascade: hypertension prevalence, treatment and control estimates among U.S. adults aged 18 years and older applying the criteria from the American College of Cardiology and American Heart Association’s 2017 Hypertension Guideline—NHANES 2015–2018. Updated May 12, 2023. Accessed October 12, 2023. https://millionhearts.hhs.gov/data-reports/hypertension-prevalence.html
2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13-e115. doi:10.1161/HYP.0000000000000065
3. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997. doi:10.1001/jama.288.23.2981
4. Liebson PR, Grandits GA, Dianzumba S, et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation. 1995;91(3):698-706. doi:10.1161/01.cir.91.3.698
5. Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension. 2012;59(6):1110-1117. doi:10.1161/HYPERTENSIONAHA.112.191106
6. Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 2011;57(4):689-694. doi:10.1161/HYPERTENSIONAHA.110.161505
7. Vongpatanasin W. Hydrochlorothiazide is not the most useful nor versatile thiazide diuretic. Curr Opin Cardiol. 2015;30(4):361-365. doi:10.1097/HCO.0000000000000178
8. Ernst ME, Lund BC. Renewed interest in chlorthalidone: evidence from the Veterans Health Administration. J Clin Hypertens (Greenwich). 2010;12(12):927-934. doi:10.1111/j.1751-7176.2010.00373.x
9. Greenberg A. Diuretic complications. Am J Med Sci. 2000;319(1):10-24. doi:10.1016/S0002-9629(15)40676-7
10. Ravioli S, Bahmad S, Funk GC, Schwarz C, Exadaktylos A, Lindner G. Risk of electrolyte disorders, syncope, and falls in patients taking thiazide diuretics: results of a cross-sectional study. Am J Med. 2021;134(9):1148-1154. doi:10.1016/j.amjmed.2021.04.007
11. Kieboom BCT, Zietse R, Ikram MA, Hoorn EJ, Stricker BH. Thiazide but not loop diuretics is associated with hypomagnesaemia in the general population. Pharmacoepidemiol Drug Saf. 2018;27(11):1166-1173. doi:10.1002/pds.4636
12. O’Connor PJ, Sperl-Hillen JAM, Johnson PE, et al. Clinical Inertia and Outpatient Medical Errors. In: Henriksen K, Battles JB, Marks ES, et al, editors. Advances in Patient Safety: From Research to Implementation (Volume 2: Concepts and Methodology). Rockville (MD): Agency for Healthcare Research and Quality (US); 2005. https://www.ncbi.nlm.nih.gov/books/NBK20513/
13. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004;43(1):4-9. doi:10.1161/01.HYP.0000103632.19915.0E
14. Liang W, Ma H, Cao L, Yan W, Yang J. Comparison of thiazide-like diuretics versus thiazide-type diuretics: a meta-analysis. J Cell Mol Med. 2017;21(11):2634-2642. doi:10.1111/jcmm.13205
Hypertension is one of the most common cardiovascular disease (CVD) states, affecting nearly half of all adults in the United States.1 Numerous classes of antihypertensives are available for blood pressure (BP) management, including thiazide diuretics, which contain both thiazide and thiazide-like agents. Thiazide diuretics available in the US include hydrochlorothiazide (HCTZ), chlorthalidone, metolazone, and indapamide. These agents are commonly used and recommended as first-line treatment in the current 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the prevention, detection, evaluation, and management of high BP in adults.2
The ACC/AHA guideline recommends chlorthalidone as the preferred thiazide diuretic.2 This recommendation is based on its prolonged half-life compared with other thiazide agents, as well as the reduction of CVD seen with chlorthalidone in previous trials. The main evidence supporting chlorthalidone use comes from the ALLHAT trial, which compared chlorthalidone, amlodipine, and lisinopril in patients with hypertension. The primary composite outcome of fatal coronary artery disease or nonfatal myocardial infarction was not significantly different between groups. However, when looking at the incidence of heart failure, chlorthalidone was superior to both amlodipine and lisinopril.3 In the TOMHS trial, chlorthalidone was more effective in reducing left ventricular hypertrophy than amlodipine, enalapril, doxazosin, or acebutolol.4 Furthermore, both a systematic review and a retrospective cohort analysis suggested that chlorthalidone may be associated with improved CVD outcomes compared with HCTZ.5,6 However, prospective randomized trial data is needed to confirm the superiority of chlorthalidone over other thiazide diuretics.
HCTZ has historically been the most common thiazide diuretic.7 However, with the available evidence and 2017 ACC/AHA BP guideline recommendations, it is unclear whether this trend continues and what impact it may have on CVD outcomes. It is unclear which thiazide diuretic is most commonly used in the US Department of Veterans Affairs (VA) health care system. The purpose of this project was to evaluate current thiazide diuretic utilization within the VA.
Methods
This retrospective, observational study evaluated the prescribing pattern of thiazide diuretics from all VA health care systems from January 1, 2016, to January 21, 2022. Thiazide diuretic agents included in this study were HCTZ, chlorthalidone, indapamide, and any combination antihypertensive products that included these 3 thiazide diuretics. Metolazone was excluded as it is commonly used in the setting of diuretic resistance with heart failure. Data was obtained from the VA Corporate Data Warehouse (CDW) and divided into 2 cohorts: the active and historic cohorts. The active cohort was of primary interest and included any active VA thiazide diuretic prescriptions on January 21, 2022. The historic cohort included thiazide prescriptions assessed at yearly intervals from January 1, 2016, to December 31, 2021. This date range was selected to assess what impact the 2017 ACC/AHA BP guideline had on clinician preferences and thiazide diuretic prescribing rates.
Within the active cohort, demographic data, vital information, and concomitant potassium or magnesium supplementation were collected. Baseline characteristics included were age, sex, race and ethnicity, and BP. Patients with > 1 race or ethnicity reported were categorized as other. The first BP reading documented after the active thiazide diuretic initiation date was included for analysis to capture on-therapy BPs while limiting confounding factors due to other potential antihypertensive changes. This project was ruled exempt from institutional review board review by the West Palm Beach VA Healthcare System Research and Development Committee.
The primary outcome was the evaluation of utilization rates of each thiazide in the active cohort, reported as a proportion of overall thiazide class utilization within the VA. Secondary outcomes in the active thiazide cohort included concomitant potassium or magnesium supplement utilization rates in each of the thiazide groups, BP values, and BP control rates. BP control was defined as a systolic BP < 130 mm Hg and a diastolic BP < 80 mm Hg. Finally, the change in thiazide diuretic utilization patterns from January 1, 2016, to December 31, 2021, was evaluated in the historic cohort.
Statistical Analysis
Data collection and analysis were completed using the CDW analyzed with Microsoft SQL Server Management Studio 18 and Microsoft Excel. All exported data to Microsoft Excel was kept in a secure network drive that was only accessible to the authors. Protected health information remained confidential per VA policy and the Health Insurance Portability and Accountability Act.
Baseline demographics were evaluated across thiazide arms using descriptive statistics. The primary outcome was assessed and a χ2 test with a single comparison α level of 0.05 with Bonferroni correction to adjust for multiple comparisons when appropriate. For the secondary outcomes, analysis of continuous data was assessed using analysis of variance (ANOVA), and nominal data were assessed with a χ2 test with a single comparison α level of 0.05 and Bonferroni correction to adjust for multiple comparisons where appropriate. When comparing all 3 thiazide groups, after the Bonferroni correction, P < .01667 was considered statistically significant to avoid a type 1 error in a family of statistical tests.
Results
As of January 21, 2022, the active thiazide cohort yielded 628,994 thiazide prescriptions within the VA nationwide. Most patients were male, with female patients representing 8.4%, 6.6%, and 5.6% of the HCTZ, chlorthalidone, and indapamide arms, respectively (Table 1). Utilization rates were significantly different between thiazide groups (P < .001). HCTZ was the most prescribed thiazide diuretic (84.6%) followed by chlorthalidone (14.9%) and indapamide (0.5%) (Table 2).
BP values documented after prescription initiation date were available for few individuals in the HCTZ, chlorthalidone, and indapamide groups (0.3%, 0.2%, and 0.5%, respectively). Overall, the mean BP values were similar among thiazide groups: 135/79 mm Hg for HCTZ, 137/78 mm Hg for chlorthalidone, and 133/79 mm Hg for indapamide (P = .32). BP control was also similar with control rates of 26.0%, 27.1%, and 33.3% for those on HCTZ, chlorthalidone, and indapamide, respectively (P = .75). The use of concomitant potassium or magnesium supplementation was significantly different between thiazide groups with rates of 12.4%, 22.6%, and 27.1% for HCTZ, chlorthalidone, and indapamide, respectively (P < .001). When comparing chlorthalidone to HCTZ, there was a significantly higher rate of concomitant supplementation with chlorthalidone (P < .001) (Table 3).
In the historic cohort, HCTZ utilization decreased from 90.2% to 83.5% (P < .001) and chlorthalidone utilization increased significantly from 9.3% to 16.0% (P < .001) (Figure). There was no significant change in the use of indapamide during this period (P = .73). Yearly trends from 2016 to 2021 are listed in Table 4.
Discussion
The findings of our evaluation demonstrate that despite the 2017 ACC/AHA BP guideline recommendations for using chlorthalidone, HCTZ predominates as the most prescribed thiazide diuretic within the VA. However, since the publication of this guideline, there has been an increase in chlorthalidone prescribing and a decrease in HCTZ prescribing within the VA.
A 2010 study by Ernst and colleagues revealed a similar trend to what was seen in our study. At that time, HCTZ was the most prescribed thiazide encompassing 95% of total thiazide utilization; however, chlorthalidone utilization increased from 1.1% in 2003 to 2.4% in 2008.8 In comparing our chlorthalidone utilization rates with these results, 9.3% in 2016 and 16.0% in 2021, the change in chlorthalidone prescribing from 2003 to 2016 represents a more than linear increase. This trend continued in our study from 2016 to 2021; the expected chlorthalidone utilization would be 21.2% in 2021 if it followed the 2003 to 2016 rate of change. Thus the trend in increasing chlorthalidone use predated the 2017 guideline recommendation. Nonetheless, this change in the thiazide prescribing pattern represents a positive shift in practice.
Our evaluation found a significantly higher rate of concomitant potassium or magnesium supplementation with chlorthalidone and indapamide compared with HCTZ in the active cohort. Electrolyte abnormalities are well documented adverse effects associated with thiazide diuretic use.9 A cross-sectional analysis by Ravioli and colleagues revealed thiazide diuretic use was an independent predictor of both hyponatremia (22.1% incidence) and hypokalemia (19% incidence) and that chlorthalidone was associated with the highest risk of electrolyte abnormalities whereas HCTZ was associated with the lowest risk. Their study also found these electrolyte abnormalities to have a dose-dependent relationship with the thiazide diuretic prescribed.10
While Ravioli and colleagues did not address the incidence of hypomagnesemia with thiazide diuretic use, a cross-sectional analysis by Kieboom and colleagues reported a significant increase in hypomagnesemia in patients prescribed thiazide diuretics.11 Although rates of electrolyte abnormalities are reported in the literature, the rates of concomitant supplementation are unclear, especially when compared across thiazide agents. Our study provides insight into the use of concomitant potassium and magnesium supplementation compared between HCTZ, chlorthalidone, and indapamide. In our active cohort, potassium was more commonly prescribed than magnesium. Interestingly, magnesium supplementation accounted for 25.9% of the total supplement use for HCTZ compared with rates of 22.4% and 21.0% for chlorthalidone and indapamide, respectively. It is unclear if this trend highlights a greater incidence of hypomagnesemia with HCTZ or greater clinician awareness to monitor this agent, but this finding may warrant further investigation. In addition, when considering the overall lower rate of supplementation seen with HCTZ in our study, the use of potassium-sparing diuretics should be considered. These agents, including triamterene, amiloride, eplerenone, and spironolactone, can be supplement-sparing and are available in combination products only with HCTZ.
Low chlorthalidone utilization rates are concerning especially given the literature demonstrating CVD benefit with chlorthalidone and the lack of compelling outcomes data to support HCTZ as the preferred agent.3,4 There are several reasons why HCTZ use may be higher in practice. First is clinical inertia, which is defined as a lack of treatment intensification or lack of changing practice patterns, despite evidence-based goals of care.12 HCTZ has been the most widely prescribed thiazide diuretic for years.7 As a result, converting HCTZ to chlorthalidone for a patient with suboptimal BP control may not be considered and instead clinicians may add on another antihypertensive or titrate doses of current antihypertensives.
There is also a consideration for patient adherence. HCTZ has many more combination products available than chlorthalidone and indapamide. If switching a patient from an HCTZ-containing combination product to chlorthalidone, adherence and patient willingness to take another capsule or tablet must be considered. Finally, there may be clinical controversy and questions around switching patients from HCTZ to chlorthalidone. Although the guidelines do not explicitly recommend switching to chlorthalidone, it may be reasonable in most patients unless they have or are at significant risk of electrolyte or metabolic disturbances that may be exacerbated or triggered with conversion.
When converting from HCTZ to chlorthalidone, it is important to consider dosing. Previous studies have demonstrated that chlorthalidone is 1.5 to 2 times more potent than HCTZ.13,14 Therefore, the conversion from HCTZ to chlorthalidone is not 1:1, but instead 50 mg of HCTZ is approximately equal to25 to 37.5 mg of chlorthalidone.14
Limitations
This study was limited by its retrospective design, gaps in data, duplicate active prescription data, and the assessment of concomitant electrolyte supplementation. As with any retrospective study, there is a potential for confounding and a concern for information bias with missing information. This study relied on proper documentation of prescription and demographic information in the Veterans Health Information Systems and Technology Architecture (VistA), as the CDW compiles information from this electronic health record. Strengths of the VistA include ease in clinical functions, documentation, and the ability for records to be updated from any VA facility nationally. However, there is always the possibility of user error and information to be omitted.
In our study, the documentation of BP values and subsequent analysis of overall BP control were limited. For BP values to be included in this study, they had to be recorded after the active thiazide prescription was written and from an in-person encounter documented in VistA. The COVID-19 pandemic shifted the clinical landscape and many primary care appointments during the active cohort evaluation period were conducted virtually. Therefore, patients may not have had formal vitals recorded. There may also be an aspect of selection bias regarding the chlorthalidone group. Although rates of thiazide switching were not assessed, some patients may have been switched from HCTZ or indapamide to chlorthalidone to achieve additional BP control. Thus, patients receiving chlorthalidone may represent a more difficult-to-control hypertensive population, making a finding of similar BP control rates between HCTZ and chlorthalidone an actual positive finding regarding chlorthalidone. Finally, this study did not assess adherence to medications. As the intent of the study was to analyze prescribing patterns, it is impossible to know if the patient was actively taking the medication at the time of assessment. When considering the rates of BP control, there were limited BP values, a potential for selection bias, and neither adherence nor patient self-reported home BP values were assessed. Therefore, the interpretation of overall BP control must be done with caution.
Additionally, duplicate prescriptions were noted in the active cohort. Rates of duplication were 0.2%, 0.08%, and 0.09% for HCTZ, chlorthalidone, and indapamide, respectively. With these small percentages, we felt this would not have a significant impact on the overall thiazide use trends seen in our study. Patients can receive prescriptions from multiple VA facilities and may have > 1 active prescriptions. This has been mitigated in recent years with the introduction of the OneVA program, allowing pharmacists to access any prescription on file from any VA facility and refill if needed (except controlled substance prescriptions). However, there are certain instances in which duplicate prescriptions may be necessary. These include patients enrolled and receiving care at another VA facility (eg, traveling for part of a year) and patients hospitalized at a different facility and given medications on discharge.
With the overall low rate of duplication prescriptions seen in each thiazide group, we determined that this was not large enough to cause substantial variation in the results of this evaluation and was unlikely to alter the results. This study also does not inform on the incidence of switching between thiazide diuretics. If a patient was switched from HCTZ to chlorthalidone in 2017, for example, a prescription for HCTZ and chlorthalidone would have been reported in this study. We felt that the change in chlorthalidone prescribing from January 1, 2016, to December 31, 2021, would reflect overall utilization rates, which may include switching from HCTZ or indapamide to chlorthalidone in addition to new chlorthalidone prescriptions.
Finally, there are confounders and trends in concomitant potassium or magnesium supplementation that were not accounted for in our study. These include concomitant loop diuretics or other medications that may cause electrolyte abnormalities and the dose-dependent relationship between thiazide diuretics and electrolyte abnormalities.10 Actual laboratory values were not included in this analysis and thus we cannot assess whether supplementation or management of electrolyte disturbances was clinically appropriate.
Conclusions
Thiazide utilization patterns have shifted possibly due to the 2017 ACC/AHA BP guideline recommendations. However, HCTZ continues to be the most widely prescribed thiazide diuretic within the VA. There is a need for future projects and clinician education to increase the implementation of guideline-recommended therapy within the VA, particularly regarding chlorthalidone use.
Hypertension is one of the most common cardiovascular disease (CVD) states, affecting nearly half of all adults in the United States.1 Numerous classes of antihypertensives are available for blood pressure (BP) management, including thiazide diuretics, which contain both thiazide and thiazide-like agents. Thiazide diuretics available in the US include hydrochlorothiazide (HCTZ), chlorthalidone, metolazone, and indapamide. These agents are commonly used and recommended as first-line treatment in the current 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the prevention, detection, evaluation, and management of high BP in adults.2
The ACC/AHA guideline recommends chlorthalidone as the preferred thiazide diuretic.2 This recommendation is based on its prolonged half-life compared with other thiazide agents, as well as the reduction of CVD seen with chlorthalidone in previous trials. The main evidence supporting chlorthalidone use comes from the ALLHAT trial, which compared chlorthalidone, amlodipine, and lisinopril in patients with hypertension. The primary composite outcome of fatal coronary artery disease or nonfatal myocardial infarction was not significantly different between groups. However, when looking at the incidence of heart failure, chlorthalidone was superior to both amlodipine and lisinopril.3 In the TOMHS trial, chlorthalidone was more effective in reducing left ventricular hypertrophy than amlodipine, enalapril, doxazosin, or acebutolol.4 Furthermore, both a systematic review and a retrospective cohort analysis suggested that chlorthalidone may be associated with improved CVD outcomes compared with HCTZ.5,6 However, prospective randomized trial data is needed to confirm the superiority of chlorthalidone over other thiazide diuretics.
HCTZ has historically been the most common thiazide diuretic.7 However, with the available evidence and 2017 ACC/AHA BP guideline recommendations, it is unclear whether this trend continues and what impact it may have on CVD outcomes. It is unclear which thiazide diuretic is most commonly used in the US Department of Veterans Affairs (VA) health care system. The purpose of this project was to evaluate current thiazide diuretic utilization within the VA.
Methods
This retrospective, observational study evaluated the prescribing pattern of thiazide diuretics from all VA health care systems from January 1, 2016, to January 21, 2022. Thiazide diuretic agents included in this study were HCTZ, chlorthalidone, indapamide, and any combination antihypertensive products that included these 3 thiazide diuretics. Metolazone was excluded as it is commonly used in the setting of diuretic resistance with heart failure. Data was obtained from the VA Corporate Data Warehouse (CDW) and divided into 2 cohorts: the active and historic cohorts. The active cohort was of primary interest and included any active VA thiazide diuretic prescriptions on January 21, 2022. The historic cohort included thiazide prescriptions assessed at yearly intervals from January 1, 2016, to December 31, 2021. This date range was selected to assess what impact the 2017 ACC/AHA BP guideline had on clinician preferences and thiazide diuretic prescribing rates.
Within the active cohort, demographic data, vital information, and concomitant potassium or magnesium supplementation were collected. Baseline characteristics included were age, sex, race and ethnicity, and BP. Patients with > 1 race or ethnicity reported were categorized as other. The first BP reading documented after the active thiazide diuretic initiation date was included for analysis to capture on-therapy BPs while limiting confounding factors due to other potential antihypertensive changes. This project was ruled exempt from institutional review board review by the West Palm Beach VA Healthcare System Research and Development Committee.
The primary outcome was the evaluation of utilization rates of each thiazide in the active cohort, reported as a proportion of overall thiazide class utilization within the VA. Secondary outcomes in the active thiazide cohort included concomitant potassium or magnesium supplement utilization rates in each of the thiazide groups, BP values, and BP control rates. BP control was defined as a systolic BP < 130 mm Hg and a diastolic BP < 80 mm Hg. Finally, the change in thiazide diuretic utilization patterns from January 1, 2016, to December 31, 2021, was evaluated in the historic cohort.
Statistical Analysis
Data collection and analysis were completed using the CDW analyzed with Microsoft SQL Server Management Studio 18 and Microsoft Excel. All exported data to Microsoft Excel was kept in a secure network drive that was only accessible to the authors. Protected health information remained confidential per VA policy and the Health Insurance Portability and Accountability Act.
Baseline demographics were evaluated across thiazide arms using descriptive statistics. The primary outcome was assessed and a χ2 test with a single comparison α level of 0.05 with Bonferroni correction to adjust for multiple comparisons when appropriate. For the secondary outcomes, analysis of continuous data was assessed using analysis of variance (ANOVA), and nominal data were assessed with a χ2 test with a single comparison α level of 0.05 and Bonferroni correction to adjust for multiple comparisons where appropriate. When comparing all 3 thiazide groups, after the Bonferroni correction, P < .01667 was considered statistically significant to avoid a type 1 error in a family of statistical tests.
Results
As of January 21, 2022, the active thiazide cohort yielded 628,994 thiazide prescriptions within the VA nationwide. Most patients were male, with female patients representing 8.4%, 6.6%, and 5.6% of the HCTZ, chlorthalidone, and indapamide arms, respectively (Table 1). Utilization rates were significantly different between thiazide groups (P < .001). HCTZ was the most prescribed thiazide diuretic (84.6%) followed by chlorthalidone (14.9%) and indapamide (0.5%) (Table 2).
BP values documented after prescription initiation date were available for few individuals in the HCTZ, chlorthalidone, and indapamide groups (0.3%, 0.2%, and 0.5%, respectively). Overall, the mean BP values were similar among thiazide groups: 135/79 mm Hg for HCTZ, 137/78 mm Hg for chlorthalidone, and 133/79 mm Hg for indapamide (P = .32). BP control was also similar with control rates of 26.0%, 27.1%, and 33.3% for those on HCTZ, chlorthalidone, and indapamide, respectively (P = .75). The use of concomitant potassium or magnesium supplementation was significantly different between thiazide groups with rates of 12.4%, 22.6%, and 27.1% for HCTZ, chlorthalidone, and indapamide, respectively (P < .001). When comparing chlorthalidone to HCTZ, there was a significantly higher rate of concomitant supplementation with chlorthalidone (P < .001) (Table 3).
In the historic cohort, HCTZ utilization decreased from 90.2% to 83.5% (P < .001) and chlorthalidone utilization increased significantly from 9.3% to 16.0% (P < .001) (Figure). There was no significant change in the use of indapamide during this period (P = .73). Yearly trends from 2016 to 2021 are listed in Table 4.
Discussion
The findings of our evaluation demonstrate that despite the 2017 ACC/AHA BP guideline recommendations for using chlorthalidone, HCTZ predominates as the most prescribed thiazide diuretic within the VA. However, since the publication of this guideline, there has been an increase in chlorthalidone prescribing and a decrease in HCTZ prescribing within the VA.
A 2010 study by Ernst and colleagues revealed a similar trend to what was seen in our study. At that time, HCTZ was the most prescribed thiazide encompassing 95% of total thiazide utilization; however, chlorthalidone utilization increased from 1.1% in 2003 to 2.4% in 2008.8 In comparing our chlorthalidone utilization rates with these results, 9.3% in 2016 and 16.0% in 2021, the change in chlorthalidone prescribing from 2003 to 2016 represents a more than linear increase. This trend continued in our study from 2016 to 2021; the expected chlorthalidone utilization would be 21.2% in 2021 if it followed the 2003 to 2016 rate of change. Thus the trend in increasing chlorthalidone use predated the 2017 guideline recommendation. Nonetheless, this change in the thiazide prescribing pattern represents a positive shift in practice.
Our evaluation found a significantly higher rate of concomitant potassium or magnesium supplementation with chlorthalidone and indapamide compared with HCTZ in the active cohort. Electrolyte abnormalities are well documented adverse effects associated with thiazide diuretic use.9 A cross-sectional analysis by Ravioli and colleagues revealed thiazide diuretic use was an independent predictor of both hyponatremia (22.1% incidence) and hypokalemia (19% incidence) and that chlorthalidone was associated with the highest risk of electrolyte abnormalities whereas HCTZ was associated with the lowest risk. Their study also found these electrolyte abnormalities to have a dose-dependent relationship with the thiazide diuretic prescribed.10
While Ravioli and colleagues did not address the incidence of hypomagnesemia with thiazide diuretic use, a cross-sectional analysis by Kieboom and colleagues reported a significant increase in hypomagnesemia in patients prescribed thiazide diuretics.11 Although rates of electrolyte abnormalities are reported in the literature, the rates of concomitant supplementation are unclear, especially when compared across thiazide agents. Our study provides insight into the use of concomitant potassium and magnesium supplementation compared between HCTZ, chlorthalidone, and indapamide. In our active cohort, potassium was more commonly prescribed than magnesium. Interestingly, magnesium supplementation accounted for 25.9% of the total supplement use for HCTZ compared with rates of 22.4% and 21.0% for chlorthalidone and indapamide, respectively. It is unclear if this trend highlights a greater incidence of hypomagnesemia with HCTZ or greater clinician awareness to monitor this agent, but this finding may warrant further investigation. In addition, when considering the overall lower rate of supplementation seen with HCTZ in our study, the use of potassium-sparing diuretics should be considered. These agents, including triamterene, amiloride, eplerenone, and spironolactone, can be supplement-sparing and are available in combination products only with HCTZ.
Low chlorthalidone utilization rates are concerning especially given the literature demonstrating CVD benefit with chlorthalidone and the lack of compelling outcomes data to support HCTZ as the preferred agent.3,4 There are several reasons why HCTZ use may be higher in practice. First is clinical inertia, which is defined as a lack of treatment intensification or lack of changing practice patterns, despite evidence-based goals of care.12 HCTZ has been the most widely prescribed thiazide diuretic for years.7 As a result, converting HCTZ to chlorthalidone for a patient with suboptimal BP control may not be considered and instead clinicians may add on another antihypertensive or titrate doses of current antihypertensives.
There is also a consideration for patient adherence. HCTZ has many more combination products available than chlorthalidone and indapamide. If switching a patient from an HCTZ-containing combination product to chlorthalidone, adherence and patient willingness to take another capsule or tablet must be considered. Finally, there may be clinical controversy and questions around switching patients from HCTZ to chlorthalidone. Although the guidelines do not explicitly recommend switching to chlorthalidone, it may be reasonable in most patients unless they have or are at significant risk of electrolyte or metabolic disturbances that may be exacerbated or triggered with conversion.
When converting from HCTZ to chlorthalidone, it is important to consider dosing. Previous studies have demonstrated that chlorthalidone is 1.5 to 2 times more potent than HCTZ.13,14 Therefore, the conversion from HCTZ to chlorthalidone is not 1:1, but instead 50 mg of HCTZ is approximately equal to25 to 37.5 mg of chlorthalidone.14
Limitations
This study was limited by its retrospective design, gaps in data, duplicate active prescription data, and the assessment of concomitant electrolyte supplementation. As with any retrospective study, there is a potential for confounding and a concern for information bias with missing information. This study relied on proper documentation of prescription and demographic information in the Veterans Health Information Systems and Technology Architecture (VistA), as the CDW compiles information from this electronic health record. Strengths of the VistA include ease in clinical functions, documentation, and the ability for records to be updated from any VA facility nationally. However, there is always the possibility of user error and information to be omitted.
In our study, the documentation of BP values and subsequent analysis of overall BP control were limited. For BP values to be included in this study, they had to be recorded after the active thiazide prescription was written and from an in-person encounter documented in VistA. The COVID-19 pandemic shifted the clinical landscape and many primary care appointments during the active cohort evaluation period were conducted virtually. Therefore, patients may not have had formal vitals recorded. There may also be an aspect of selection bias regarding the chlorthalidone group. Although rates of thiazide switching were not assessed, some patients may have been switched from HCTZ or indapamide to chlorthalidone to achieve additional BP control. Thus, patients receiving chlorthalidone may represent a more difficult-to-control hypertensive population, making a finding of similar BP control rates between HCTZ and chlorthalidone an actual positive finding regarding chlorthalidone. Finally, this study did not assess adherence to medications. As the intent of the study was to analyze prescribing patterns, it is impossible to know if the patient was actively taking the medication at the time of assessment. When considering the rates of BP control, there were limited BP values, a potential for selection bias, and neither adherence nor patient self-reported home BP values were assessed. Therefore, the interpretation of overall BP control must be done with caution.
Additionally, duplicate prescriptions were noted in the active cohort. Rates of duplication were 0.2%, 0.08%, and 0.09% for HCTZ, chlorthalidone, and indapamide, respectively. With these small percentages, we felt this would not have a significant impact on the overall thiazide use trends seen in our study. Patients can receive prescriptions from multiple VA facilities and may have > 1 active prescriptions. This has been mitigated in recent years with the introduction of the OneVA program, allowing pharmacists to access any prescription on file from any VA facility and refill if needed (except controlled substance prescriptions). However, there are certain instances in which duplicate prescriptions may be necessary. These include patients enrolled and receiving care at another VA facility (eg, traveling for part of a year) and patients hospitalized at a different facility and given medications on discharge.
With the overall low rate of duplication prescriptions seen in each thiazide group, we determined that this was not large enough to cause substantial variation in the results of this evaluation and was unlikely to alter the results. This study also does not inform on the incidence of switching between thiazide diuretics. If a patient was switched from HCTZ to chlorthalidone in 2017, for example, a prescription for HCTZ and chlorthalidone would have been reported in this study. We felt that the change in chlorthalidone prescribing from January 1, 2016, to December 31, 2021, would reflect overall utilization rates, which may include switching from HCTZ or indapamide to chlorthalidone in addition to new chlorthalidone prescriptions.
Finally, there are confounders and trends in concomitant potassium or magnesium supplementation that were not accounted for in our study. These include concomitant loop diuretics or other medications that may cause electrolyte abnormalities and the dose-dependent relationship between thiazide diuretics and electrolyte abnormalities.10 Actual laboratory values were not included in this analysis and thus we cannot assess whether supplementation or management of electrolyte disturbances was clinically appropriate.
Conclusions
Thiazide utilization patterns have shifted possibly due to the 2017 ACC/AHA BP guideline recommendations. However, HCTZ continues to be the most widely prescribed thiazide diuretic within the VA. There is a need for future projects and clinician education to increase the implementation of guideline-recommended therapy within the VA, particularly regarding chlorthalidone use.
1. Centers for Disease Control and Prevention. Hypertension cascade: hypertension prevalence, treatment and control estimates among U.S. adults aged 18 years and older applying the criteria from the American College of Cardiology and American Heart Association’s 2017 Hypertension Guideline—NHANES 2015–2018. Updated May 12, 2023. Accessed October 12, 2023. https://millionhearts.hhs.gov/data-reports/hypertension-prevalence.html
2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13-e115. doi:10.1161/HYP.0000000000000065
3. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997. doi:10.1001/jama.288.23.2981
4. Liebson PR, Grandits GA, Dianzumba S, et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation. 1995;91(3):698-706. doi:10.1161/01.cir.91.3.698
5. Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension. 2012;59(6):1110-1117. doi:10.1161/HYPERTENSIONAHA.112.191106
6. Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 2011;57(4):689-694. doi:10.1161/HYPERTENSIONAHA.110.161505
7. Vongpatanasin W. Hydrochlorothiazide is not the most useful nor versatile thiazide diuretic. Curr Opin Cardiol. 2015;30(4):361-365. doi:10.1097/HCO.0000000000000178
8. Ernst ME, Lund BC. Renewed interest in chlorthalidone: evidence from the Veterans Health Administration. J Clin Hypertens (Greenwich). 2010;12(12):927-934. doi:10.1111/j.1751-7176.2010.00373.x
9. Greenberg A. Diuretic complications. Am J Med Sci. 2000;319(1):10-24. doi:10.1016/S0002-9629(15)40676-7
10. Ravioli S, Bahmad S, Funk GC, Schwarz C, Exadaktylos A, Lindner G. Risk of electrolyte disorders, syncope, and falls in patients taking thiazide diuretics: results of a cross-sectional study. Am J Med. 2021;134(9):1148-1154. doi:10.1016/j.amjmed.2021.04.007
11. Kieboom BCT, Zietse R, Ikram MA, Hoorn EJ, Stricker BH. Thiazide but not loop diuretics is associated with hypomagnesaemia in the general population. Pharmacoepidemiol Drug Saf. 2018;27(11):1166-1173. doi:10.1002/pds.4636
12. O’Connor PJ, Sperl-Hillen JAM, Johnson PE, et al. Clinical Inertia and Outpatient Medical Errors. In: Henriksen K, Battles JB, Marks ES, et al, editors. Advances in Patient Safety: From Research to Implementation (Volume 2: Concepts and Methodology). Rockville (MD): Agency for Healthcare Research and Quality (US); 2005. https://www.ncbi.nlm.nih.gov/books/NBK20513/
13. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004;43(1):4-9. doi:10.1161/01.HYP.0000103632.19915.0E
14. Liang W, Ma H, Cao L, Yan W, Yang J. Comparison of thiazide-like diuretics versus thiazide-type diuretics: a meta-analysis. J Cell Mol Med. 2017;21(11):2634-2642. doi:10.1111/jcmm.13205
1. Centers for Disease Control and Prevention. Hypertension cascade: hypertension prevalence, treatment and control estimates among U.S. adults aged 18 years and older applying the criteria from the American College of Cardiology and American Heart Association’s 2017 Hypertension Guideline—NHANES 2015–2018. Updated May 12, 2023. Accessed October 12, 2023. https://millionhearts.hhs.gov/data-reports/hypertension-prevalence.html
2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13-e115. doi:10.1161/HYP.0000000000000065
3. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997. doi:10.1001/jama.288.23.2981
4. Liebson PR, Grandits GA, Dianzumba S, et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation. 1995;91(3):698-706. doi:10.1161/01.cir.91.3.698
5. Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension. 2012;59(6):1110-1117. doi:10.1161/HYPERTENSIONAHA.112.191106
6. Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 2011;57(4):689-694. doi:10.1161/HYPERTENSIONAHA.110.161505
7. Vongpatanasin W. Hydrochlorothiazide is not the most useful nor versatile thiazide diuretic. Curr Opin Cardiol. 2015;30(4):361-365. doi:10.1097/HCO.0000000000000178
8. Ernst ME, Lund BC. Renewed interest in chlorthalidone: evidence from the Veterans Health Administration. J Clin Hypertens (Greenwich). 2010;12(12):927-934. doi:10.1111/j.1751-7176.2010.00373.x
9. Greenberg A. Diuretic complications. Am J Med Sci. 2000;319(1):10-24. doi:10.1016/S0002-9629(15)40676-7
10. Ravioli S, Bahmad S, Funk GC, Schwarz C, Exadaktylos A, Lindner G. Risk of electrolyte disorders, syncope, and falls in patients taking thiazide diuretics: results of a cross-sectional study. Am J Med. 2021;134(9):1148-1154. doi:10.1016/j.amjmed.2021.04.007
11. Kieboom BCT, Zietse R, Ikram MA, Hoorn EJ, Stricker BH. Thiazide but not loop diuretics is associated with hypomagnesaemia in the general population. Pharmacoepidemiol Drug Saf. 2018;27(11):1166-1173. doi:10.1002/pds.4636
12. O’Connor PJ, Sperl-Hillen JAM, Johnson PE, et al. Clinical Inertia and Outpatient Medical Errors. In: Henriksen K, Battles JB, Marks ES, et al, editors. Advances in Patient Safety: From Research to Implementation (Volume 2: Concepts and Methodology). Rockville (MD): Agency for Healthcare Research and Quality (US); 2005. https://www.ncbi.nlm.nih.gov/books/NBK20513/
13. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004;43(1):4-9. doi:10.1161/01.HYP.0000103632.19915.0E
14. Liang W, Ma H, Cao L, Yan W, Yang J. Comparison of thiazide-like diuretics versus thiazide-type diuretics: a meta-analysis. J Cell Mol Med. 2017;21(11):2634-2642. doi:10.1111/jcmm.13205