|Year : 2021 | Volume
| Issue : 2 | Page : 77-80
Comparison of adverse events between ramipril and perindopril in contemporary cardiac practice
Ramesh Sankaran, Nagendraboopathy Senguttuvan, Thoddi Ramamurthy Muralidharan, Vinodkumar Balakrishnan, Shanmugasundaram Sadhanandham, Manokar Panchanatham, Jayanthy Venkata Balasubramaniyan, Preetham Krishnamurthy, Phulgun Badimela
Department of Cardiology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
|Date of Submission||03-Jun-2021|
|Date of Acceptance||02-Jul-2021|
|Date of Web Publication||22-Nov-2021|
Dr. Ramesh Sankaran
Department of Cardiology, Sri Ramachandra Institute of Higher Education and Research, Ramachandra Nagar, Porur, Chennai - 600 116, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Angiotensin-converting enzyme inhibitors (ACEIs) are extensively used for the treatment and management of cardiovascular diseases. Although ACEIs are a well-tolerated medication in high percentage of patients, around 30% can develop adverse reactions like dry cough. Objective: The objective of the study was to capture the incidence of cough in patients with cardiovascular diseases that were prescribed with perindopril and ramipril in an Indian tertiary care hospital. Methods: In this observational study, the incidence of cough in patients with cardiovascular diseases that were prescribed with perindopril and ramipril was estimated. Results: A total of 223 patients were enrolled in this study. Around 50.67% patients received ramipril; among them, 6.02% received 1.25 mg, 78.95% received 2.5 mg, and 13.53% received 5 mg of ramipril. Around 35.9% (n = 80) patients received perindopril. In perindopril group, 31.3% of the patients received 2 mg dose and 68.8% of patients received 4 mg dose. Among perindopril group, the incidence of cough was observed in 10% (n = 8) of the patients, whereas in ramipril group, it was 19.55% (P = 0.00136). Due to cough, in perindopril group, 6.3% (5/80) of the patients discontinued treatment whereas in ramipril group, 9% (12/133) of the patients discontinued treatment medication. Conclusions: Our study has demonstrated that perindopril has been associated with a relatively low incidence of cough compared to ramipril.
Keywords: Angiotensin-converting enzyme inhibitors, cough, perindopril, ramipril
|How to cite this article:|
Sankaran R, Senguttuvan N, Muralidharan TR, Balakrishnan V, Sadhanandham S, Panchanatham M, Balasubramaniyan JV, Krishnamurthy P, Badimela P. Comparison of adverse events between ramipril and perindopril in contemporary cardiac practice. Ann Clin Cardiol 2021;3:77-80
|How to cite this URL:|
Sankaran R, Senguttuvan N, Muralidharan TR, Balakrishnan V, Sadhanandham S, Panchanatham M, Balasubramaniyan JV, Krishnamurthy P, Badimela P. Comparison of adverse events between ramipril and perindopril in contemporary cardiac practice. Ann Clin Cardiol [serial online] 2021 [cited 2022 May 28];3:77-80. Available from: http://www.onlineacc.org/text.asp?2021/3/2/77/336216
| Introduction|| |
Angiotensin-converting enzyme inhibitors (ACEIs) are extensively used for the treatment and management of cardiovascular diseases ranging from hypertension to heart failure, including other comorbidities such as renal failure and diabetic nephropathy., Although ACEIs are a well-tolerated medication in high percentage of patients, around 30% can develop adverse reactions (ARs) such as symptomatic hypotension and dry cough, even more severe ARs, such as angioedema and renal failure in certain cases.,, The incidence of ACEIs-induced dry cough is reported to be approximately 1.5%–11%, with a discontinuation rate of 4% among patients who have been treated with these drugs.,,,,,, In fact, not all previous ACEI trials included cough as an endpoint and lacked long-term follow-up which led to marked differences in reported incidences.,,,,,, Moreover, there is a clear variance in the incidence of cough among individual ACEIs used, and only a few ACEIs have real-world clinical practice data to support findings from randomized trials. Perindopril is an ACEI which has extensive evidence from randomized clinical trials and global real-world observational studies. The incidence of cough was reported to be very low in perindopril prescribed patients according to literature studies.
Ramipril is another ACEI, functionally acts by lowering the conversion of angiotensin I to angiotensin II thereby preventing bradykinin degradation which leading to smooth muscle relaxation in arteriole and a decrease in peripheral resistance. Ramipril has been increasingly prescribed after the publication of the Heart Outcomes Prevention Evaluation (HOPE) trial data (cough incidences reported to be 7.3%), while the growth rates in the use of other ACEIs remain more or less constant., The incidence of cough reported to be 10% in ramipril prescribed patients in an observational study based in India. However, in Indian context, real-world practice data on incidences of cough induced by perindopril and ramipril are still inadequate.
It is rational to use ACEIs that induce cough less frequently. Hence, we conducted a real-world observational study to capture the incidence of cough in patients with cardiovascular diseases that were prescribed with perindopril and ramipril in an Indian tertiary care hospital.
| Methods|| |
The participated center/hospital in this prospective study had obtained approval from their local ethics committees. All hypertensive patients provided a written informed consent before enrolling in this study. This study was conducted by adhering to the Declaration of Helsinki ethics principles, International Council for Harmonization-Good Clinical Practice (GCP) guidelines, Indian Council of Medical Research, and the Indian GCP guidelines.
Study design and participants
This is a cross-sectional observational study conducted at SRIHER from July 2019 to December 2019. Patients who were on stable antihypertensive dose for ≥8 weeks and who were on ACEI medication (perindopril or ramipril once-daily regimen) for 4 weeks were included, and visited cardiology outpatient department was included in the study. Hypertension was defined as a high brachial blood pressure (BP) (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) as per International Society of Hypertension guidelines. Patients with liver dysfunction, signs and symptoms of heart failure, chronic kidney disease, or systemic inflammation and infection were excluded from the study.
These incidences of cough were compared in patients who were receiving ACEIs.
Descriptive statistics were performed on all demographic and clinical measurements. Baseline patient characteristics were reported as percentages for categorical variables and mean ± standard deviation for continuous variables. Data involving comparison of proportions were conducted using Chi-square-test (Microsoft excel). All P < 0.05 were considered statistically significant.
| Results|| |
A total of 223 patients were enrolled in this study. Majority patients were male (78.5%). Mean age of the patients was 58.81 ± 10.97 years. Among all patients, history of hypertension and diabetes mellitus was observed in 15.7% and 9.4% patients, respectively. Left ventricular ejection fraction (LVEF) was measured in all the participated hypertensive patients, and mean LVEF (%) was found to be 50.3 ± 10.36 [Table 1].
Around 58.74% (n = 131) received ramipril; among them, 6.02% received 1.25 mg, 78.95% received 2.5 mg, and 13.53% received 5 mg dose of ramipril. Around 35.87% (n = 80) patients were received perindopril. In perindopril group, 31.25% of the patients received 2 mg dose and 68.75% of patients received 4 mg dose of perindopril [Figure 1].
Patients enrolled in this study were observed for ACEIs-induced cough. Among perindopril group, 10.38% (n = 8) of the patients developed cough, whereas in ramipril group, the incidence of cough was observed in 19.55% (n = 26, P = 0.00136) of patients [Figure 2]a. Among cough patients in perindopril group, 71.42% (n = 5) of the patients discontinued treatment medication and 28.57% (n = 2) continued despite cough. Whereas in case of cough patients of ramipril group, 15.38% (n = 4) continued ramipril therapy despite cough, and 80.76% (n = 21) of the patients discontinued treatment. Among discontinued patients, 34.61% (n = 9) switched to telmisartan treatment. Dose of ramipril was reduced for 3.84% (n = 1) of the patients [Figure 2]b.
|Figure 2: (a) Incidence of cough in patients (b) Course of action in case of cough|
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| Discussion|| |
ACEIs are the first-line therapy for hypertension. Impaired therapeutic adherence due to side effect of dry cough can negatively impact treatment. Therefore, in this cross-sectional study, the incidence of ACEIs-induced cough in a cohort of hypertensive patients was estimated. Two ACEIs, perindopril and ramipril were prescribed as a treatment medication for two groups of hypertensive patients separately. The incidence of cough was more in ramipril prescribed group (19.55%; P = 0.00136) compared to perindopril group (10%).
The incidences of cough vary among ACEIs due to the lack of long-term follow-up studies and real-world data, and also, the incidence of cough induced by ACEIs was observed more in certain ethic groups. Perindopril is one of the ACEIs which has extensive real-world evidence for incidence of cough in hypertensive patients. PAINT, PIANIST, and PETRA reported very low incidence of cough (ranged from 0.04% to 0.8%) in hypertensive patients that were prescribed with perindopril even with the use of higher doses.,, In line with previous studies, even in our study, we observed less incidences of cough in perindopril group compared to ramipril group. Data from couple of Indian observational studies demonstrated an incidence rate of cough to be 3.7% and 3.6% in perindopril treated hypertensive patients., Previous studies from Reisin and Schneeweiss demonstrated a phenomenon of spontaneous disappearance of cough after 2–8 months of ACEI therapy despite continued and unaltered administration.,
In a study by Singh et al., the incidence of cough in ramipril prescribed patients was reported to be 24.3%. In a randomized clinical trial on Korean population, the incidence of cough was persisted in 22.7% of the patients. In this study, the incidence of cough in ramipril prescribed group was 19.55%.
Previous Indian-based studies reported a discontinuation rate of 0.4%–1.6% with perindopril as a monotherapy or in combination with other ACEIs.,, In this study, 6.3% of the patients discontinued treatment in perindopril group. With respect to ramipril, in HOPE trial, 7% of the patients discontinued therapy due to the incidence of cough whereas in an observational study conducted by Wyskida et al., around 28.2% of patients discontinued the use of ramipril because of cough. In this study, 9% of the patients discontinued the use of ramipril medication.
The major limitation of this study included, it is a cross-sectional single-center study. To confirm our study observations, a multicenter randomized trial is warranted.
| Conclusions|| |
Considering the high burden of cardiovascular diseases in India which is a highly populated country, there is a greater need to find strategies and solutions that improve treatment adherence to ACEIs, and also, it is practical to use ACEIs that induce low incidence of cough. In this regard, our study demonstrated that perindopril has been associated with a relatively low incidence of cough compared to ramipril and has extensive literature evidence supporting its cardiovascular benefits and tolerability.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yılmaz İ. Angiotensin-converting enzyme inhibitors induce cough. Turk Thorac J 2019;20:36-42.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al
. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J 2018;39:3021-104.
Rasmussen ER, von Buchwald C, Wadelius M, Prasad SC, Kamaleswaran S, Ajgeiy KK, et al
. Assessment of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema. Int J Otolaryngol 2017;2017:1476402.
McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. BMJ 2006;332:1177-81.
Caldeira D, David C, Sampaio C. Tolerability of angiotensin-receptor blockers in patients with intolerance to angiotensin-converting enzyme inhibitors: A systematic review and meta-analysis. Am J Cardiovasc Drugs 2012;12:263-77.
Brugts JJ, Arima H, Remme W, Bertrand M, Ferrari R, Fox K, et al
. The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease. Int J Cardiol 2014;176:718-23.
Bangalore S, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: Deceptive information from the Physicians' Desk Reference. Am J Med 2010;123:1016-30.
Wyskida K, Jura-Szołtys E, Smertka M, Owczarek A, Chudek J. Factors that favor the occurrence of cough in patients treated with ramipril – A pharmacoepidemiological study. Med Sci Monit 2012;18:I21-8.
Bahl VK, Jadhav UM, Thacker HP. Management of hypertension with the fixed combination of perindopril and amlodipine in daily clinical practice: Results from the STRONG prospective, observational, multicenter study. Am J Cardiovasc Drugs 2009;9:135-42.
Padma MV, Kaul S. Incidence of recurrent stroke in primary care during preventive treatment based on perindopril with or without indapamide. Neurol India 2007;55:141-4.
] [Full text]
Shankar PK, Vidyasagar S, Adiga S, Naidu MU, Usha Rani P, Rao D, et al
. Efficacy and tolerability of trandolapril in mild to moderate hypertension – A double blind comparative clinical trial with enalapril in Indian population. Indian J Physiol Pharmacol 2006;50:421-6.
Bansal S, Chauhan DK, Ramesh D, Barmare S, Chakraborty S. Blood pressure control and acceptability of perindopril and its fixed dose combinations with amlodipine or indapamide, in younger patients with hypertension. Indian Heart J 2014;66:635-9.
Pinto B, Jadhav U, Singhai P, Sadhanandham S, Shah N. ACEI-induced cough: A review of current evidence and its practical implications for optimal CV risk reduction. Indian Heart J 2020;72:345-50.
Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T, Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol 2007;577:1-6.
Hemels ME, Bennett HA, Bonari L, Han D, Traverso ML, Einarson TR. HOPE study impact on ACE inhibitors use. Ann Pharmacother 2003;37:640-5.
Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, et al
. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53.
Hathial M. Safety and tolerability of ramipril 10 mg in patients at high risk of cardiovascular events: An observational study. Indian Heart J 2008;60:200-4.
Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al
. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension 2020;75:1334-57.
Ng LP, Goh PS. Incidence of discontinuation of angiotensin-converting enzyme inhibitors due to cough, in a primary healthcare centre in Singapore. Singapore Med J 2014;55:146-9.
Tóth K, PIANIST Investigators. Antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: Results of the PIANIST study (Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients). Am J Cardiovasc Drugs 2014;14:137-45.
Páll D, Szántó I, Szabó Z. Triple combination therapy in hypertension: The antihypertensive efficacy of treatment with perindopril, amlodipine, and indapamide SR. Clin Drug Investig 2014;34:701-8.
Ábrahám G, Dézsi CA. The antihypertensive efficacy of the triple fixed combination of perindopril, indapamide, and amlodipine: The results of the PETRA study. Adv Ther 2017;34:1753-63.
Reisin L, Schneeweiss A. Spontaneous disappearance of cough induced by angiotensin-converting enzyme inhibitors (captopril or enalapril). Am J Cardiol 1992;70:398-9.
Reisin L, Schneeweiss A. Complete spontaneous remission of cough induced by ACE inhibitors during chronic therapy in hypertensive patients. J Hum Hypertens 1992;6:333-5.
Singh NP, Uppal M, Anuradha S, Agarwal A, Rizvi SN. Angiotensin converting enzyme inhibitors and cough – A north Indian study. J Assoc Physicians India 1998;46:448-51.
Kim SH, Chung WY, Zo JH, Kim MA, Chang HJ, Cho YS, et al
. Efficacy and tolerability of two formulations of ramipril in Korean adults with mild to moderate essential hypertension: An 8-week, multicenter, prospective, randomized, open-label, parallel-group noninferiority trial. Clin Ther 2009;31:988-98.
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355:253-9.
[Figure 1], [Figure 2]