Introduction: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improve outcomes but are underutilized in patients with chronic kidney disease (CKD). Little is known about reasons for discontinuation and lack of reinitiating these medications. We aimed to explore clinicians’ and patients’ experiences and perceptions of ACEI/ARB use in CKD. Methods: A multi-profession sample of health care clinicians and patients with documented ACEI/ARB-associated side effects in the past 6 months. Participants were recruited from 2 Veterans Affairs healthcare systems in Texas and Tennessee. A total of 15 clinicians and 10 patients completed interviews. We used inductive and deductive qualitative data analysis approaches to identify themes related to clinician and patient experiences with ACEI/ARB. Thematic analysis focused on prescribing decisions and practices, clinical guidelines, and perception of side effects. Data were analyzed as they amassed, and recruitment was stopped at the point of thematic saturation. Results: Clinicians prescribe ACEI/ARB for blood pressure control and kidney protection and underscored the importance of these medications in patients with diabetes. While clinicians described providing comprehensive patient education about ACEI/ARB in CKD, patient interviews revealed significant knowledge gaps about CKD and ACEI/ARB use. Many patients were unaware of their CKD status, and some did not know why they were prescribed ACEI/ARB. Clinicians’ drug management strategies varied widely, as did their understanding of prescribing guidelines. They identified structural and patient-level barriers to prescribing and many endorsed the development of a decision support tool to facilitate ACEI/ARB prescribing and management. Discussion/Conclusion: Our qualitative study of clinicians and providers identified key target areas for improvement to increase ACEI/ARB utilization in patients with CKD with the goal to improve long-term outcomes in high-risk patients. These findings will also inform the development of a decision support tool to assist with prescribing ACEI/ARBs for patients with CKD.

Chronic kidney disease (CKD) affects 14% of the general adult population, with 130,522 people reaching end-stage kidney disease (ESKD) in 2020 [1, 2]. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improve cardiovascular outcomes, decrease proteinuria, and slow the progression of CKD [3‒8]. The 2020 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend initiating ACEI/ARB as the first-line therapy in patients with diabetes, hypertension, and albuminuria [9]. Unfortunately, these medications are underutilized and frequently discontinued [10‒12], such that only 66% of patients with CKD stage 3 and 61% with CKD stage 4 receive an ACEI/ARB [13]. These agents are often discontinued due to adverse effects such as cough, acute kidney injury, or hyperkalemia [11, 12, 14]. Once they are discontinued, failure to appropriately reinitiate treatment is a major contributor to overall underutilization [12, 15]. This points to a potential knowledge gap for clinicians who are not certain when to prescribe or how to reinitiate an ACEI/ARB for patients with CKD. There is also a potential knowledge gap for patients, who may not be aware of their CKD diagnosis or that ACEI/ARBs are important kidney protective medicines [16], which limits their ability to self-advocate. However, no prior studies have ascertained the experiences of clinicians and patients to identify barriers to ACEI/ARB utilization.

In this qualitative study, we evaluated reasons for ACEI/ARB underutilization. We used semi-structured interviews with clinicians to explore their experiences prescribing and managing ACEI/ARB for patients with CKD. We also interviewed patients with CKD to understand their perceptions and experiences using ACEI/ARB with the intent that these results will inform the development of a communication aid to assist clinicians in appropriately prescribing and managing ACEI/ARB and to engage patients in informed conversations about these medications.

Study Design and Setting

The reporting of our research methods aligns with the consolidated criteria for reporting qualitative research (COREQ) guidelines [17]. We conducted in-depth qualitative interviews with 15 primary care clinicians and 10 patients sampled from Veterans Affairs (VA) healthcare systems in Southeast Texas and Tennessee. We used our professional network to recruit clinician participants. The study team approached potential participants via email to describe the study and solicit participation. We invited physicians (cardiologists, geriatricians, endocrinologists, internists), nurse practitioners, physician assistants, and clinical pharmacists (pharmacists who prescribe and monitor pharmaceutical interventions) to participate in a one-time, one-on-one, telephone interview to share their experiences prescribing and managing ACEI/ARB for patients with kidney disease. We used chain referral sampling to recruit a sample of 15 clinicians to participate in interviews. This recruitment technique involves requesting names of potential interview participants from those who have already participated in the study. Clinician participants did not receive incentives for their participation.

Patients were recruited via opt-out mailings. We used a population screening approach of eligibility (inclusion and exclusion) criteria from a computer-generated randomized list identified in the EMR for each VA site. We sought to recruit patients aged 18–80 years old, CKD with an eGFR of <60 mL/min/1.73 m2 but >20 mL/min/1.73 m2 and a history of ACEI/ARB-associated side effects in the past 6 months to avoid recall bias. Out of 48 invitation letters mailed, 10 patients enrolled and completed interviews. Letters invited patients to participate in a one-time, one-on-one telephone interview to discuss experiences with ACEI/ARB medication, including side effects, discontinuation, and reinitiation of the medication. Each patient participant received a $40 payment.

Ethics Approval

This study was evaluated and approved by Institutional Review Boards at Baylor College of Medicine and Affiliated Hospitals (Protocol H-47583) and VA Tennessee Valley Healthcare System (Protocol H-47583).

Patient and Public Involvement

Patients or the public were not involved in our research’s design, conduct, reporting, or dissemination plans.

Data Collection

Clinicians and patients were asked about their experiences with and perceptions of ACEI and ARB medications. Clinicians were asked about their perspectives on the value of ACEI/ARBs in patients with CKD, reasons for discontinuation of ACEI or ARBs, current management strategies when considering the reinitiation of ACEI/ARB in patients with CKD, and suggestions to inform the development of a communication aid to assist in prescribing decisions and management of ACEI and ARB medications. Patients were asked about their experiences using ACEI or ARB medication, challenges that keep them from taking the medication as prescribed, clinical discussions about risks and benefits of these medications, and any side effects resulting from the medications. These goals were communicated to participants at the beginning of the interviews. Interview guides were informed by the Consolidated Framework for Implementation Research [18], which facilitates the organization of themes by the key domains to inform communication aid development. Following interviews, participants were not contacted again.

Interview guides were revised throughout the interviewing process to reflect emergent findings and clarify developing areas of interest (interview guides available as supplemental files). Content in earlier interviews informed areas of inquiry and probing in subsequent interviews. All interviews were included in the analyses. All interviews were conducted by J.A., a medical sociologist trained in qualitative methods. The interviewer is a non-Hispanic, White female with a Ph.D. in Sociology. She has extensive experience conducting qualitative interviews with clinicians and patients, analyzing qualitative data, and presenting qualitative findings. Interviews with clinicians took place from September 2021 to October 2022 and patient interviews from July 2022 to February 2023. Interviews with both clinicians and patients ranged from 13 to 45 min in duration (average of 27 min). Participants gave verbal informed consent twice – before recording and then again after recording started for documentation. With participants’ permission, interviews were audio recorded, transcribed verbatim, and pseudonymized for analysis.

Data Analysis

Data were analyzed as they amassed, and emerging findings informed areas of focus for subsequent interviews. Analysis was guided by principles of framework analysis [19], which allowed for a deductive approach to derive themes from the Consolidated Framework for Implementation Research as well as an inductive approach to identify emergent themes in participants’ narratives. During data collection and analysis, the qualitative interviewer met weekly to discuss progress with the multidisciplinary research team that included internists, nephrologists, and cardiologists. Meetings included discussion of early analysis, emerging interview themes, and the interviewer’s own experiences, beliefs, and potential biases. This reflexivity allowed the researchers to minimize the effects of biases and enhance the credibility and rigor of the findings. Several analytic team members reviewed early transcripts, created memos, and used a constant comparative method to create a preliminary codebook [20]. Codes were anchored in interview guide questions as well as emergent findings. Codebooks were piloted and revised, with additional codes added as necessary. Two team members (J.A. and M.A.H.) independently coded all transcripts. Coding discrepancies were resolved in weekly team meetings. Coding was performed using Atlas.ti (version 23). After initial coding, all codes were collapsed into broader categories, which team members then summarized, highlighting themes that spanned across interviews. The entire study team participated in the integration of codes into themes describing decisions and experiences driving ACEI/ARB utilization and discontinuation. Recruitment was stopped at the point of thematic saturation [21], defined as the point when two independent coders agreed that no new thematic concepts emerged from subsequent interviews.

Participant Characteristics

We conducted semi-structured interviews with 15 clinicians and 10 veterans with a history of ACEI/ARB use (Table 1). The sample of clinicians included 11 women and 4 men representing multiple specializations, including physicians (53%), nurse practitioners and physicians’ assistants (20%), and clinical pharmacists (27%). The sample of patients included 6 women and 4 men. Patients ranged in age from 49 to 84 years, with a mean of 68.8 years. All patient participants had at least a high school education, and the majority (60%) had completed college or an advanced degree. Patients in the sample had a documented eGFR ranging from <60 mL/min/1.73 m2 but >20 mL/min/1.73 m2.

Table 1.

Demographic characteristics of the study population

AttributeValue
Clinicians, n = 15  
Age, mean (range), years 42.8 (28–53) 
Clinical role, n (%) 
 Physician 8 (53) 
 Nurse practitioner/physician assistant 3 (20) 
 Clinical pharmacist 4 (27) 
Years in current role, n (%) 
 Less than 1 year 3 (20) 
 1–5 years 1 (7) 
 5–9 years 5 (33) 
 10–19 years 5 (33) 
 20–30 years 1 (7) 
Gender, n (%) 
 Male 4 (27) 
 Female 11 (73) 
Race/ethnicity, n (%) 
 White/Caucasian 8 (53) 
 African American 3 (20) 
 Asian 3 (20) 
 Native Hawaiian/Pacific Islander 1 (7) 
Patients, n = 10  
Age, mean (range), years 68.8 (49–84) 
Gender, n (%) 
 Male 4 (40) 
 Female 6 (60) 
Race/ethnicity, n (%) 
 White/Caucasian 7 (70) 
 African American 2 (20) 
 Declined to respond 1 (10) 
Education completed, n (%) 
 High school graduate or equivalent 3 (30) 
 Some college 1 (10) 
 College graduate 4 (40) 
 Graduate degree 2 (20) 
AttributeValue
Clinicians, n = 15  
Age, mean (range), years 42.8 (28–53) 
Clinical role, n (%) 
 Physician 8 (53) 
 Nurse practitioner/physician assistant 3 (20) 
 Clinical pharmacist 4 (27) 
Years in current role, n (%) 
 Less than 1 year 3 (20) 
 1–5 years 1 (7) 
 5–9 years 5 (33) 
 10–19 years 5 (33) 
 20–30 years 1 (7) 
Gender, n (%) 
 Male 4 (27) 
 Female 11 (73) 
Race/ethnicity, n (%) 
 White/Caucasian 8 (53) 
 African American 3 (20) 
 Asian 3 (20) 
 Native Hawaiian/Pacific Islander 1 (7) 
Patients, n = 10  
Age, mean (range), years 68.8 (49–84) 
Gender, n (%) 
 Male 4 (40) 
 Female 6 (60) 
Race/ethnicity, n (%) 
 White/Caucasian 7 (70) 
 African American 2 (20) 
 Declined to respond 1 (10) 
Education completed, n (%) 
 High school graduate or equivalent 3 (30) 
 Some college 1 (10) 
 College graduate 4 (40) 
 Graduate degree 2 (20) 

Analyses of patient and clinician interviews revealed three themes pertaining to use of ACEI/ARB medications in patients with CKD: (1) prescribing decisions and practices, (2) reliance on and uncertainty about prescribing guidelines, (3) perception of side effects. Within each theme, we emphasize clinicians’ preferences for a communication aid to facilitate appropriate ACEI/ARB prescribing (see Fig. 1). Each theme and related subthemes are as follows. Illustrative quotations for each theme and subtheme are outlined in Table 2.

Fig. 1.

Perspectives of clinicians and patients about side of ACEI/ARB use and potential solutions to overcome therapeutic inertia.

Fig. 1.

Perspectives of clinicians and patients about side of ACEI/ARB use and potential solutions to overcome therapeutic inertia.

Close modal
Table 2.

Representative quotations

Theme 1: Prescribing decisions and practices 
 Reasons for prescribing 
  “It’s for control of their blood pressure or…for kidney protection and also for cardiovascular protection” (39-year-old physician with 5- to 9-year experience in CKD) 
  “In patients with diabetes, to reduce the risk of kidney disease. For my patients with hypertension, to reduce the risk of cardiovascular disease. And then…patients with heart failure, to improve their outcomes with heart failure.” (49-year-old physician with 10- to 19-year experience in CKD) 
  “They have a lot of upside with minimal downsides. They’re great medicines…I prescribe them for my hypertensive patients, for my CHF patients, to slow the progression of chronic kidney disease…They’re renal protective, so if they’re diabetic…and their kidneys are doing well, I wanna make them stay well. I wanna protect their kidneys long-term, so that would be a another good reason to have those agents on board. And they’re really good at bringing down blood pressure.” (30-year-old physician assistant with less than 1-year experience in CKD) 
  “The main reason that we prescribe them…is for the added renal protection…We don’t really like it as a blood pressure medication because…we don’t feel like it works that well, but usually it’s one of our first-line therapies that we put them on, especially if they have any proteinuria.” (41-year-old nurse practitioner with 1- to 4-year experience in CKD) 
 Educating patients about ACEI/ARB 
  “I educate them first on the natural course of whatever disease we’re dealing with such as hypertension or diabetes or heart disease, cardiovascular disease, or stroke…Once I explain the natural course of that disease, I tie it in with the renal portion…and let them know how the kidneys can be stressed.” (47-year-old physician with 5- to 9-year experience in CKD) 
  “You don’t have high blood pressure. This is a blood pressure medication, but that’s not the reason we’re giving it to you. We want to prevent kidney disease in the long run. We want to keep your kidneys functioning well.” (51-year-old physician with 5-year experience in CKD) 
  “Your disease can create more stress for your kidneys and when your kidneys are stressed, this can make you urinate more protein than you’re supposed to. We can check for protein levels and it helps us understand if your kidneys are stressed. This medication, ACE or ARB, can decrease that stress level on kidneys.” (47-year-old physician with 5- to 9-year experience in CKD) 
  “Usually I tell them it’s very well tolerated, that we’re gonna bring them back in a few weeks to check their potassium and their electrolytes and make sure that looks good and to let me know if they have a cough.” (48-year-old physician with 10- to 19-year experience in CKD) 
  “It was just to help bring my blood pressure down…I don’t have any other problem that it was supposed to address.” (67-year-old female patient) 
  “I don’t take any medication for kidney disease because I didn’t know I had kidney disease.” (59-year-old female patient) 
  “I was having a lot of hypertension issues, and so….the losartan…was for…protecting my kidneys.” (49-year-old female patient) 
 Strategies for managing ACEI/ARB 
  “I would start them on medication and then follow-up with labs and then titrate as tolerated.” (39-year-old Physician with 5- to 9-year experience in CKD) 
  “Once we put a patient on an ACE or ARB, we usually check labs within 2 weeks…just to make sure their creatinine is stable, and they don’t have any hyperkalemia issues…And then…we titrate it up…and repeat labs in 2 weeks.” (41-year-old nurse practitioner with 1- to 4-year experience in CKD) 
  “I would just make sure the creatinine doesn’t increase by about 30%, and as long as I’m not freaked out about renal artery stenosis, we’re going up on the ARBs and ACE inhibitors.” (30-year-old physician assistant with less than 1-year experience in CKD) 
Theme 2: Prescribing guidelines 
 Knowledge of guidelines and decision support tools 
  “The diabetes guidelines…American Heart Association…we go with the kidney guidelines too, but mostly the AHA guidelines.” (47-year-old physician with 10- to 19-year experience in CKD) 
  “I just got my training to start all diabetics on an ACE inhibitor.” (48-year-old physician with 10- to 19-year experience in CKD) 
  “I primarily follow the ADA diabetes guidelines, and then I’ll look at the VA hypertension guidelines…sometimes I look at the American Heart Association.” (53-year-old clinical pharmacist with 20- to 29-year experience in CKD) 
  “There isn’t a guideline that I can say that I specifically follow…I’m just basically going on guidelines and stuff that I’ve learned through my training…But if there’s updates I’m always open to updates…But I will be honest that it is kinda hard and you get in your little bubble… I do try to keep up as much as possible.” (46-year-old clinical pharmacist with 10- to 19-year experience in CKD) 
 Challenges to guideline concordant prescribing 
  “I think it’s far under prescribed. I think people get really nervous about the bump in creatinine or maybe hyperkalemia or things like that.” (30-year-old physician assistant with less than 1-year experience in CKD) 
  “Logistically it’s hard because it requires the patients to be coming in regularly for me to find an appointment and the time to see them.” (39-year-old physician with 5- to 9-year experience in CKD) 
  “Given the pandemic, given the environment where we’re doing more telephone versus in person, the last few years I’ve been very low likely at prescribing. Whereas in the past I would have.” (46-year-old clinical pharmacist with 10- to 19-year experience in CKD) 
  “If the blood pressure is normal, kidney function is normal, but they are diabetic, do we start them [on an ACE inhibitor]? How do we convince the patient that they have to be n an ACE or an ARB and when is the correct time to start them on it?” (47-year-old physician with 10- to 19-year experience in CKD) 
Theme 3: Perception of side effects 
 Frequency and response to side effects 
  “The cough, well, that just depends on the patient…If they think it’s mild and it’s not botherin” “em any, then I wouldn’t do anything. But if it’s bothersome for the patient then I would change” “em to an ARB.” (51-year-old clinical pharmacist with 10- to 19-year experience in CKD) 
  “So I actually haven’t seen any side effects from ACE or ARBs.” (29-year-old Clinical Pharmacist with less than 1-year experience in CKD) 
  “Usually it’s just very mild intolerances, like they have a headache or nausea, or they notice they have some swelling in the legs…Those are more mild, so I’ll try to work through those or back off the dosing, but I won’t remove the medication.” (43-year-old physician assistant with 5- to 9-year experience in CKD) 
  “If it’s less than 30% increase in creatinine, I’m not worried about it whatsoever. If it’s more than 30% increase, I might wanna do a renal ultrasound. I might want to cut the dose in half.” (30-year-old Physician Assistant with less than 1-year experience in CKD) 
  “The main component I would like to see [in a decision aid] is guidance on…side effects. If they have hyperkalemia or their creatinine is bumping up or GFR is getting less, do we stop? Something to alert us that you can continue it, or you can…reduce the dose, hold off, and restart, repeat.” (51-year-old Physician with 5- to 9-year experience in CKD) 
 Discontinued and reinitiating ACEI/ARB therapy 
  “I think for me the biggest challenge has been restarting them after an acute kidney injury…knowing when to restart it.” (39-year-old physician with 5- to 9-year experience in CKD) 
  “I see [ACE inhibitor discontinued] all the time. I think people see a bump in creatinine, and they’re like okay, can’t do that medication anymore. They’re not tolerating it well, or it’s burning their kidneys, but a bump in creatinine is to be expected…as long as…you recheck their labs again 3 months after that visit or 6 months, the creatinine will probably stabilize. But I think people give up too easily.” (30-year-old Physician Assistant with less than 1-year experience in CKD) 
  “[A decision aid] should have when to initially consider it, when to consider a change, when to stop. And if we’re restarting it, like after they had AKI, then very clear guidelines and how much should we wait, anything else we need to consider.” (39-year-old physician with 5- to 9-year experience in CKD) 
 Alternatives to ACEI/ARB 
  “I don’t think there are any out for kidney protection…There are definitely other categories of medication that I have those patients on, but they serve for protection and treatment of other areas. But I don’t know of any that are for renal protection other than ACEs and ARBs…Of course, we can definitely treat hypertension with other agents that do act on the kidney like diuretics but nothing that offers the type of protection that the ACEs and ARBs do.” (47-year-old physician with 5- to 9-year experience in CKD) 
  “The main thing with kidney disease is control of the risk factors…So mainly control of high blood pressure, control of diabetes, put them on a statin.” (48-year-old physician with 10- to 19-year experience in CKD) 
  “In our diabetic patients, we’re loving [empagliflozin], so we try to use that as much as possible…I have had some patients who have had hyperkalemia in the past on an ACE and ARB, and they can’t tolerate either one of them, so we’ve added the empa…to help with renal and cardio protection.” (41-year-old nurse practitioner with 1- to 4-year experience in CKD) 
Theme 1: Prescribing decisions and practices 
 Reasons for prescribing 
  “It’s for control of their blood pressure or…for kidney protection and also for cardiovascular protection” (39-year-old physician with 5- to 9-year experience in CKD) 
  “In patients with diabetes, to reduce the risk of kidney disease. For my patients with hypertension, to reduce the risk of cardiovascular disease. And then…patients with heart failure, to improve their outcomes with heart failure.” (49-year-old physician with 10- to 19-year experience in CKD) 
  “They have a lot of upside with minimal downsides. They’re great medicines…I prescribe them for my hypertensive patients, for my CHF patients, to slow the progression of chronic kidney disease…They’re renal protective, so if they’re diabetic…and their kidneys are doing well, I wanna make them stay well. I wanna protect their kidneys long-term, so that would be a another good reason to have those agents on board. And they’re really good at bringing down blood pressure.” (30-year-old physician assistant with less than 1-year experience in CKD) 
  “The main reason that we prescribe them…is for the added renal protection…We don’t really like it as a blood pressure medication because…we don’t feel like it works that well, but usually it’s one of our first-line therapies that we put them on, especially if they have any proteinuria.” (41-year-old nurse practitioner with 1- to 4-year experience in CKD) 
 Educating patients about ACEI/ARB 
  “I educate them first on the natural course of whatever disease we’re dealing with such as hypertension or diabetes or heart disease, cardiovascular disease, or stroke…Once I explain the natural course of that disease, I tie it in with the renal portion…and let them know how the kidneys can be stressed.” (47-year-old physician with 5- to 9-year experience in CKD) 
  “You don’t have high blood pressure. This is a blood pressure medication, but that’s not the reason we’re giving it to you. We want to prevent kidney disease in the long run. We want to keep your kidneys functioning well.” (51-year-old physician with 5-year experience in CKD) 
  “Your disease can create more stress for your kidneys and when your kidneys are stressed, this can make you urinate more protein than you’re supposed to. We can check for protein levels and it helps us understand if your kidneys are stressed. This medication, ACE or ARB, can decrease that stress level on kidneys.” (47-year-old physician with 5- to 9-year experience in CKD) 
  “Usually I tell them it’s very well tolerated, that we’re gonna bring them back in a few weeks to check their potassium and their electrolytes and make sure that looks good and to let me know if they have a cough.” (48-year-old physician with 10- to 19-year experience in CKD) 
  “It was just to help bring my blood pressure down…I don’t have any other problem that it was supposed to address.” (67-year-old female patient) 
  “I don’t take any medication for kidney disease because I didn’t know I had kidney disease.” (59-year-old female patient) 
  “I was having a lot of hypertension issues, and so….the losartan…was for…protecting my kidneys.” (49-year-old female patient) 
 Strategies for managing ACEI/ARB 
  “I would start them on medication and then follow-up with labs and then titrate as tolerated.” (39-year-old Physician with 5- to 9-year experience in CKD) 
  “Once we put a patient on an ACE or ARB, we usually check labs within 2 weeks…just to make sure their creatinine is stable, and they don’t have any hyperkalemia issues…And then…we titrate it up…and repeat labs in 2 weeks.” (41-year-old nurse practitioner with 1- to 4-year experience in CKD) 
  “I would just make sure the creatinine doesn’t increase by about 30%, and as long as I’m not freaked out about renal artery stenosis, we’re going up on the ARBs and ACE inhibitors.” (30-year-old physician assistant with less than 1-year experience in CKD) 
Theme 2: Prescribing guidelines 
 Knowledge of guidelines and decision support tools 
  “The diabetes guidelines…American Heart Association…we go with the kidney guidelines too, but mostly the AHA guidelines.” (47-year-old physician with 10- to 19-year experience in CKD) 
  “I just got my training to start all diabetics on an ACE inhibitor.” (48-year-old physician with 10- to 19-year experience in CKD) 
  “I primarily follow the ADA diabetes guidelines, and then I’ll look at the VA hypertension guidelines…sometimes I look at the American Heart Association.” (53-year-old clinical pharmacist with 20- to 29-year experience in CKD) 
  “There isn’t a guideline that I can say that I specifically follow…I’m just basically going on guidelines and stuff that I’ve learned through my training…But if there’s updates I’m always open to updates…But I will be honest that it is kinda hard and you get in your little bubble… I do try to keep up as much as possible.” (46-year-old clinical pharmacist with 10- to 19-year experience in CKD) 
 Challenges to guideline concordant prescribing 
  “I think it’s far under prescribed. I think people get really nervous about the bump in creatinine or maybe hyperkalemia or things like that.” (30-year-old physician assistant with less than 1-year experience in CKD) 
  “Logistically it’s hard because it requires the patients to be coming in regularly for me to find an appointment and the time to see them.” (39-year-old physician with 5- to 9-year experience in CKD) 
  “Given the pandemic, given the environment where we’re doing more telephone versus in person, the last few years I’ve been very low likely at prescribing. Whereas in the past I would have.” (46-year-old clinical pharmacist with 10- to 19-year experience in CKD) 
  “If the blood pressure is normal, kidney function is normal, but they are diabetic, do we start them [on an ACE inhibitor]? How do we convince the patient that they have to be n an ACE or an ARB and when is the correct time to start them on it?” (47-year-old physician with 10- to 19-year experience in CKD) 
Theme 3: Perception of side effects 
 Frequency and response to side effects 
  “The cough, well, that just depends on the patient…If they think it’s mild and it’s not botherin” “em any, then I wouldn’t do anything. But if it’s bothersome for the patient then I would change” “em to an ARB.” (51-year-old clinical pharmacist with 10- to 19-year experience in CKD) 
  “So I actually haven’t seen any side effects from ACE or ARBs.” (29-year-old Clinical Pharmacist with less than 1-year experience in CKD) 
  “Usually it’s just very mild intolerances, like they have a headache or nausea, or they notice they have some swelling in the legs…Those are more mild, so I’ll try to work through those or back off the dosing, but I won’t remove the medication.” (43-year-old physician assistant with 5- to 9-year experience in CKD) 
  “If it’s less than 30% increase in creatinine, I’m not worried about it whatsoever. If it’s more than 30% increase, I might wanna do a renal ultrasound. I might want to cut the dose in half.” (30-year-old Physician Assistant with less than 1-year experience in CKD) 
  “The main component I would like to see [in a decision aid] is guidance on…side effects. If they have hyperkalemia or their creatinine is bumping up or GFR is getting less, do we stop? Something to alert us that you can continue it, or you can…reduce the dose, hold off, and restart, repeat.” (51-year-old Physician with 5- to 9-year experience in CKD) 
 Discontinued and reinitiating ACEI/ARB therapy 
  “I think for me the biggest challenge has been restarting them after an acute kidney injury…knowing when to restart it.” (39-year-old physician with 5- to 9-year experience in CKD) 
  “I see [ACE inhibitor discontinued] all the time. I think people see a bump in creatinine, and they’re like okay, can’t do that medication anymore. They’re not tolerating it well, or it’s burning their kidneys, but a bump in creatinine is to be expected…as long as…you recheck their labs again 3 months after that visit or 6 months, the creatinine will probably stabilize. But I think people give up too easily.” (30-year-old Physician Assistant with less than 1-year experience in CKD) 
  “[A decision aid] should have when to initially consider it, when to consider a change, when to stop. And if we’re restarting it, like after they had AKI, then very clear guidelines and how much should we wait, anything else we need to consider.” (39-year-old physician with 5- to 9-year experience in CKD) 
 Alternatives to ACEI/ARB 
  “I don’t think there are any out for kidney protection…There are definitely other categories of medication that I have those patients on, but they serve for protection and treatment of other areas. But I don’t know of any that are for renal protection other than ACEs and ARBs…Of course, we can definitely treat hypertension with other agents that do act on the kidney like diuretics but nothing that offers the type of protection that the ACEs and ARBs do.” (47-year-old physician with 5- to 9-year experience in CKD) 
  “The main thing with kidney disease is control of the risk factors…So mainly control of high blood pressure, control of diabetes, put them on a statin.” (48-year-old physician with 10- to 19-year experience in CKD) 
  “In our diabetic patients, we’re loving [empagliflozin], so we try to use that as much as possible…I have had some patients who have had hyperkalemia in the past on an ACE and ARB, and they can’t tolerate either one of them, so we’ve added the empa…to help with renal and cardio protection.” (41-year-old nurse practitioner with 1- to 4-year experience in CKD) 

Prescribing Decisions and Practices

Reasons for Prescribing

Clinicians characterized ACEI/ARB medications as very effective with few risks and viewed them as very effective in the prevention of cardiovascular disease or to manage hypertension. ACEI/ARB therapy is frequently prescribed in patients with diabetes with the goal of decreasing progression to CKD. Several clinicians expressed that all of their diabetes patients should be on ACEI/ARB and that most of those patients are. One clinician indicated that ACEI/ARB should be used in patients with proteinuria, especially if they have a diagnosis of hyperglycemia and/or metabolic syndrome. One clinician described ACEI/ARB as “first-line therapies” for renal protection. A clinician referred to these as “great medicines” and remarked on their broad utility and effectiveness. Though clinicians commonly supported prescribing ACEI/ARB therapy for all diabetic patients, one outlier explained that if the patient’s blood pressure is controlled and their kidneys are functioning normally, they will not prescribe the medication.

Educating Patients about ACEI/ARB

Adding an ACEI or ARB medication to a patient’s drug regimen provides an opportunity to educate patients about their health conditions and the intended effects of the medication. Some clinicians begin by educating the patient on the natural course of their disease – cardiovascular disease or diabetes – and then explaining how the ACEI/ARB helps address the disease. The conversation also includes discussion of common side effects, like cough and gastrointestinal upset, and particularly dangerous side effects, like angioedema. Clinicians notify patients about upcoming laboratory tests and the potential for abnormalities in laboratory testing.

As ACEI/ARB therapy is often prescribed for renal protection, clinicians are faced with the task of presenting the ACEI/ARB as a preventative medication. This can be challenging, as patients may be reluctant to take medication for a condition they do not have. Clinicians expressed the desire for a communication aid to assist them in that conversation.

Our interviews with patients revealed knowledge gaps about health status, as many of the patients were unaware they had CKD, despite documented eGFR indicative of CKD. Patients who were aware of their kidney disease had limited information about it, did not think they were being treated for it, and expressed a desire to know how their kidney disease will progress. Almost all of the patients understood that they were prescribed ACEI/ARB to manage their blood pressure, but they did not link use of the medication with kidney function. One patient understood that she was using the ACEI/ARB to address a high protein level (proteinuria), and another said he was never told why he’d been prescribed this medication.

Strategies for Managing ACEI/ARB

For many clinicians, management of ACEI/ARB begins with introducing a low dose of the medication, following up with laboratory testing, and then titrating the dose as tolerated. All clinicians expressed that they expect an initial increase in creatinine but responses to that increase and level at which they were concerned varied. One clinician said that he tries to “white knuckle it and ignore an initial increase in creatinine.” Others stated that they will reduce the medication dose in response to a 30% or higher increase in creatinine. Some clinicians expressed uncertainty about appropriate responses to specific laboratory readings; this is an area in which clinicians would like more guidance.

Clinicians expressed preference for a decision aid with an easy-to-follow algorithm to assist them in managing ACEI/ARB therapy. They would benefit from an algorithm that would help identify patients appropriate for ACEI/ARB therapy and provide guidance on whether to start ACEI or ARB first, along with recommended initial dosing. Clinicians noted that such a tool could help them make decisions about particular situations that may be unclear, such as prescribing decisions in diabetic patients with normal blood pressure and kidney function. Clinicians also expressed interest in a communication aid to assist with follow-up criteria. Specifically, they desire guidance on when to consider a change of medication, how to titrate effectively, or when to reduce the dose. Some expressed need for specific cutoffs for various laboratories (increases in creatinine, decreases in GFR, hyperkalemia), guidance on when it is safe to continue the medication and when to reduce or stop the medication.

Reliance on and Uncertainty about Prescribing Guidelines

Knowledge of Guidelines and Decision Support Tools

Some clinicians rely on treatment guidelines from such sources as Kidney Disease Improving Global Outcomes (KDIGO), American Diabetes Association, Department of Veterans Affairs, Department of Defense, and American Heart Association. Prescribing decisions may be informed by up-to-date, which, as one clinician noted, offers “good decision trees.” Others mentioned DynaMed, Epocrates, and Lexicon as decision support tools. Some clinicians said that they do not follow any guidelines in particular; rather, they just prescribe based on their training or their clinical experience.

While several clinicians believe their patients are prescribed ACEI/ARB therapy as recommended by guidelines, some disagreed, expressing that “not many at all” are prescribed ACEI/ARBs as recommended by clinical guidelines. Others admitted uncertainty about current treatment guidelines. One clinical pharmacist acknowledged that it is difficult to keep abreast of updates. She said, “I hope that information finds me.”

Challenges to Guideline Concordant Prescribing

Interviews revealed barriers to prescribing. Several clinicians acknowledged that it is a challenge to follow guidelines, particularly guidelines on laboratories and follow-up, because there may not be appointments available to bring patients back as frequently as guidelines recommend. Frequent follow-up increases workload for clinicians, which may deter some clinicians from prescribing an ACEI/ARB. According to one clinical pharmacist, primary care providers often refer patients with diabetes to clinical pharmacists for medication management because of the workload involved in conducting follow-up and monitoring laboratories. In addition to the workload, clinicians acknowledged a knowledge gap concerning when to initiate or reinitiate an ACEI/ARB. They reported uncertainty about the guidelines and concerns about titrating too aggressively. Some clinicians pointed to a patient-level barrier to ACEI/ARB prescribing. Patients who are already reluctant to add new medications to their regimen may decline the ACEI/ARB, particularly if it is being offered to prevent a condition they do not have (like kidney disease). Clinicians acknowledged that it can be difficult to present ACEI/ARB as a preventative medication and suggested a communication aid could assist them in these clinical conversations.

Patients acknowledged that they may not take a medication as prescribed because they forget to renew their prescription, or they simply forget to take the medication. Patients also noted system-level challenges in the VA, specifically that medication renewals within the VA are often “not seamless.”

Perception of Side Effects

Frequency and Response to Side Effects

Clinicians’ perspectives on the frequency of side effects varied. Some clinicians indicated that ACEI/ARB users rarely experience side effects, while other clinicians see side effects quite often. Dry cough was the most frequently mentioned side effect, which is viewed as mild to moderate in severity, given how disruptive it can be for patients. A frequent clinical response to a cough is to discontinue the ACEI and instead initiate an ARB. Severe side effects include hyperkalemia, acute kidney injury, and angioedema. Clinicians indicated that severe side effects are rare, and one clinician noted that hyperkalemia seems to occur more often in patients with advanced kidney disease.

Reported side effects were rare among our patient participants. Among those who experienced side effects, most reported having a cough while taking an ACEI. Consistent with the clinician interviews, these patients reported changing from an ACEI to an ARB medication. One patient discontinued her medication due to gastrointestinal upset, and another patient experienced hypotension, which resulted in a reduced dose.

Reinitiating Discontinued ACEI/ARB Therapy

Patients who have experienced side effects, including cough, electrolyte disturbance, hyperkalemia, or acute kidney injury, may have the medication discontinued. Some clinicians noted that, for many of these patients, ACEI/ARB therapy could probably be reinitiated, but they find it challenging to know when and how to reinitiate therapy. Clinicians expressed interest in a decision aid to assist them in reinitiating ACEI/ARB therapy in patients who have previously experienced side effects. The decision aid should provide guidance on how long to wait after acute kidney injury to reinitiate ACEI/ARB therapy, at what dosing, whether an ACEI or ARB would be preferred, and any other considerations that might affect the decision to reinitiate it. Clinicians also voiced support for a decision aid that would provide e-consult with nephrology and cardiology, along with when they should refer a patient to nephrology.

Alternatives to ACEI/ARB

If a patient does not tolerate ACEI/ARB, some clinicians may choose an alternative medication, depending on the treatment goal. One clinician stated that if the goal is kidney protection, “there are no other medications out there for kidney protection.” In lieu of ACEI/ARB, clinicians may try to “control the risk factors…control high blood pressure.” This might result in choosing a statin or a diuretic, but these aren’t considered as effective as ACEI/ARB. Another clinician stated that they can treat diabetes with medications that improve kidney health in patients with diabetes, and specifically mentioned empagliflozin, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and glucagon-like peptide−1 receptor agonists (GLP-1 RA) as options. For patients who do not tolerate ACEI/ARB for cardiovascular disease prevention, clinicians may choose another antihypertensive agent such as β-blocker or calcium channel blocker as alternatives.

In this qualitative study, we observed that many clinicians are uncertain about how to manage or reinitiate ACEI/ARBs with side effects and that patients were often unaware of their CKD diagnosis, even if this was their indication for receiving an ACEI/ARB. While prior studies identified clinical reasons for treatment discontinuation by chart review, we aimed to ascertain clinicians’ and patients’ experiences to identify barriers to utilization. These findings point to the need for a tool to assist in clinical decisions and conversations.

Previous studies have shown that up to one-third of patients with CKD are not prescribed an ACEI/ARB [11‒13], and treatment discontinuation contributes to a large proportion of total underutilization [12]. Hyperkalemia and acute kidney injury account for the majority of reasons for discontinuation [11]. Patients who did not receive care from a nephrologist were more likely to have their ACEI/ARB stopped. Discontinuation by physicians and lack of knowledge about the disease or medication have both been identified as key barriers to ACEI/ARB use [22]. Given that ACEI/ARB treatment non-initiation or discontinuation is associated with an increased risk of dialysis initiation, death, and cardiovascular events [23‒26], developing a tool to facilitate safe prescription or reinitiation and promote clinician-patient communication is vital for us to potentially improve long-term patient outcomes.

Clinicians provided key suggestions to guide the development of such a tool. They responded favorably to the idea of an algorithm and decision tree to assist them with prescribing ACEI/ARB therapy. Clinicians highlighted particular challenges, including uncertainty about the ideal time to initiate a patient on ACEI/ARB, how to manage side effects related to medication, and when and how to reinitiate it after it is held for adverse effects. Furthermore, only one clinician discussed proteinuria as an indication for ACEI/ARB prescription and none mentioned strategies for mitigating hyperkalemia such as diuretic use or potassium binders, identifying additional specific content areas for intervention. A communication aid should also improve patient engagement by helping clinicians discuss kidney and cardioprotective effects of ACEI/ARB to patients, and by providing guidance on discussing the patient’s health condition and the purpose of the medication. Clinicians also expressed desire for a decision support tool to optimize the dose (increase or reduce the dose with side effects) and when to discontinue treatment.

This qualitative assessment of patient and clinicians’ perspectives not only identifies avenues for optimizing ACEI/ARB use but also informs us about developing interventions and tools to potentially increase uptake of novel therapies for CKD. As we enter an era where several novel therapies are being developed and approved for management of kidney disease and its associated complications, increasing their adoption is critical to ultimately improve outcomes. While cardio-kidney protective agents such as SGLT2 inhibitors and GLP-1 RA are recommended by clinical practice guidelines, their use remains low even among high-risk patients [27, 28]. In contrast to ACEI/ARB therapy, understanding the reasons for lack of initiation of these agents early on would prevent us from waiting longer to optimize their use in clinical practice.

Our study has several strengths. To our knowledge, this is the first qualitative analysis evaluating clinicians’ and patients’ experiences with ACEI/ARB to identify barriers to use and inform the development of a tool to improve overall utilization. Our approach allowed us to elicit detailed accounts of patients’ and clinicians’ beliefs and experiences related to ACEI/ARB use [29]. We recruited clinicians and patients from two geographically separated VA healthcare systems to increase the validity of the results. Our sample was representative of women, which is sometimes a challenge in VA studies. Other strengths include detailed data collection, analysis, and rigorous reporting process. A non-clinician researcher conducted interviews and analyzed data. This was important to reduce bias in the study and more accurately reflect the participants’ own prescribing experiences by not asking leading questions. Data were coded by two individuals who met frequently to discuss codes and enhance reliability. Coding and emerging themes were regularly discussed among members of the multidisciplinary research team. This study also has limitations. Our study focused on prescribing behaviors and experiences of patients with eGFR <60; findings may not be applicable to patients with higher degrees of kidney function. The results may not be generalizable outside the VA system since these medications have been available for more than 2 decades, barriers identified are likely to be similar in non-VA setting. While we recorded patients’ education level, we did not assess their health literacy, which may influence perceptions of medication use and health conditions. Further, the results of the study rely on participants’ recall of prior conversations rather than direct observation of patient-clinician conversations and immediate assessment.

The findings of this qualitative study indicate that some clinicians are uncertain about how to start, manage, or reinitiate ACEI/ARB therapy, and support the development of a communication tool to assist with prescribing ACEI/ARB for patients with CKD. Clinicians suggested that an algorithm or decision tree would make it easier to prescribe ACEI/ARB therapy as recommended by clinical practice guidelines. This tool may also facilitate more effective clinical communication and patient education to improve engagement in their care of kidney disease. Further studies evaluating potential impact of such tools are warranted.

The opinions expressed reflect those of the authors and not necessarily those of the Department of Veterans Affairs, NIH or the US government.

This study was evaluated and approved by Institutional Review Boards at Baylor College of Medicine and Affiliated Hospitals (Protocol H-47583) and VA Tennessee Valley Healthcare System (Protocol H-47583). Participants gave verbal informed consent twice – before recording and then again after recording started for documentation. With participants’ permission, interviews were audio recorded, transcribed verbatim, and pseudonymized for analysis.

Dr. Virani has received honoraria from the American College of Cardiology in his role as the Associate Editor for Innovations, acc.org. Dr. Gregg serves as an Editorial Fellow for the Journal of the American Society of Nephrology. Dr. Matheny reported receiving consulting from a VA-DoD-NIH Pain Management Consortium. Outside the submitted work, Dr. Navaneethan reported serving as consultant for ACI clinical, AstraZeneca (Data safety monitoring board), Bayer, Boehringer Ingelheim/Eli Lilly and Co, GSK, Intercept (event adjudication committee) and Vertex (event adjudication committee), and Vifor; and receiving research funding from the Department of Veterans Affairs Health Services Research and Development.

This work was supported by a Department of Veterans Affairs Health Service Research and Development Service Investigator Initiated Grants (IIR 16-072, IIR 19-069), and the Houston VA Health Services Research and Development Center for Innovations grant (CIN13-413). Support for VA/CMS data provided by the Department of Veterans Affairs, VA Health Services Research and Development Service, VA Information Resource Center (Project Numbers SDR 02-237 and 98-004). Dr. Gregg is supported by a VA Clinical Sciences Research and Development Career Development Award (IK2CX002368). Dr. Navaneethan is also supported NIH/NHLBI K24 HL161414-01A). Dr. Navaneethan is also supported by Garabed Eknoyan MD Endowed Professorship. Dr. Virani is supported by research grants from the Department of Veterans Affairs, NIH, and the Tahir and Jooma Family. Dr. Matheny was supported by research grants from the Department of Veteran Affairs HSR&D IIR 16-072, 19-069, and SDR 18-194.

Jennifer Arney, PhD was involved in concept development, data collection, drafting of the manuscript, and critical review of the content for submission and approval. L. Parker Gregg, MD, MSCS and Sheena Wydermyer, MD were involved in critical review of the content and approval for its submission. Michael A. Herrera, MPH worked with data collection and critical review of the content of the manuscript and approval for its submission. Peter A. Richardson, PhD was involved in data collection and critical review of the manuscript. Michael E. Matheny, MD, MS, MPH developed concepts, reviewed data, the drafting of manuscript, and final approval for its submission. Julia M. Akeroyd, MPH and Adriana Hung, MD, MPH critically reviewed the content of the manuscript and approval for its submission. Glenn T Gobbel, DVM, PhD, MS was involved in concept development and critically reviewed content of the manuscript and approval for its submission. Salim S. Virani, MD, PhD and Sankar D. Navaneethan, MD, MS, MPH were involved in concept development, review of data, drafting of manuscript, and final approval for its submission.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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