The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease

doi:10.1016/j.ijcard.2014.07.108

International Journal of Cardiology

Volume 176, Issue 3, 20 October 2014, Pages 718-723

https://doi.org/10.1016/j.ijcard.2014.07.108 Get rights and content

Highlights

•
The overall incidence of ACE-inhibitor induced cough is 3.9% which is lower as compared to literature.
•
Clinical determinants of dry cough are older age, female gender and concomitant use of lipid-lowering agents.
•
In contrast, racial differences were not related to the incidence of dry cough.
•
Especially, no difference in the incidence of ACE-inhibitor induced dry cough was found between Caucasians and Asians patients.
•
We found no evidence for a dose-dependent relation between cough and higher doses of ACE-inhibitors.
•
Considering our findings, the rate of switching to angiotensin-receptor antagonists (ARB) for reason of ACE-inhibitor cough according to the international guidelines, as the second best alternative, should be around 4%.

Abstract

Objectives

Our objective was to investigate the actual incidence and clinical determinants of cough leading to discontinuation of ACE-inhibitors. Cough is the most frequent reason to stop ACE-inhibitor treatment.

Methods

We studied 27,492 ACE-inhibitor naïve patients randomized to the ACE-inhibitor perindopril or placebo using individual data of 3 clinical trials. Multivariate logistic regression analysis was used to study the incidence of cough in relation to baseline clinical characteristics including racial background.

Results

In 27,492 patients with cardiovascular disease, 1076 patients discontinued ACE-inhibitor perindopril due to cough (3.9%), 703 patients during run-in period of 4 weeks and 373 patients during a mean four years of follow-up. Significant determinants of cough were female gender (OR 1.92 95% CI 1.68–2.18), age above 65 years (OR 1.53 95% CI 1.35–1.73), and concomitant use of lipid-lowering agents (OR 1.37; 95% CI 1.18–1.59). A simple clinical risk score composed of these 3 predictors of cough mounted to an odds ratio of 4.4 (95% CI 3.1–5.4) in the subjects with highest score (i.e. all determinants present). Racial background was not related to a differential incidence of cough in patients of Caucasian or Asian descendent (OR 1.11 95% CI 0.92–1.39).

Conclusion

This large combined analysis of randomized clinical trials in 27,492 patients showed an overall lower incidence of cough leading to discontinuation of ACE-inhibitors (3.9%) as compared to literature. Clinical determinants of such cough are older age, female gender and concomitant use of lipid-lowering agents. In contrast, racial differences were not related to the incidence of cough.

Introduction

The angiotensin-converting enzyme (ACE) inhibitors are a keystone in the treatment of cardiovascular disease (CVD). The effectiveness of ACE-inhibitors in reducing CVD risk has been consistently established by several large clinical trials in a broad variety of patients at different levels of risk, from patients with overt heart failure to patients at relatively low-risk with stable coronary artery disease (CAD) and preserved left ventricular function [1], [2], [3], [4], [5], [6], [7], [8]. The consistent body of evidence for the use of ACE-inhibitors in these patient groups has led to their widespread implementation in clinical practice [1], [2], [3], [4], [5], [6], [7], [8]. Nowadays, the use of ACE inhibitors is recommended in international guidelines of the European Society of Cardiology (ESC), American heart Association (AHA) and American College of Cardiology (ACC) on the management of patients with hypertension, stable CAD, myocardial infarction, and heart failure [9], [10], [11]. Worldwide, tens of millions of patients are using ACE-inhibitors.

Common side effects of ACE-inhibitors include dry cough, hypotension, hyperkalemia, headache, dizziness and renal impairment [8]. A persistent dry cough is the most common adverse effect of ACE-inhibitors which is believed to be related to an increased production in bradykinin [11], [12], [13]. In a recent review, the incidence of dry cough in patients using ACE-inhibitors varied from 10% to as high as 35% [11], [12], [13]. Dry cough usually develops in the first week or 1 month after starting the drug and is assumed to be more frequent in women and in Asian people [11], [12], [13]. Once ACE-inhibitor therapy is stopped, cough usually disappears within 1 week. Patients who experience this dry cough are often switched to angiotensin-II receptor antagonists (ARB), in agreement with ESC guidelines recommendations [9], [10], [11].

Prior studies assessing risk of cough are severely limited by small sample size, short follow-up and low number of events, which explains the large differences in reported incidences [14], [15], [16]. As dry cough is a frequent reason to switch therapy it is clinically highly relevant to study the extent of this side-effect as well as its clinical determinants. We performed a large scale meta-analysis with access to individual data to assess the incidence and clinical predictors of cough leading to discontinuation in patients with cardiovascular disease treated with the ACE-inhibitor perindopril, which is one of the most potent ACE-inhibitors also when considering the effect on bradykinin levels [8].

Section snippets

Methods

The methodological principles that lie behind a combined analysis of randomized clinical trials based on data from individual patient have been described in detail [17], [18]. We therefore only briefly describe the applied methods of trial selection, data-management, endpoint definitions and statistical analysis [18].

Trial selection

We obtained data from the ADVANCE, EUROPA, and PROGRESS studies that are the three main large randomized clinical trials with a regimen based primarily on the ACE-inhibitor perindopril [7], [19], [20]. Since all trials studied a regimen based on the same agent, perindopril, we had the opportunity to include individual data in this combined analysis, which enabled important subgroup analyses at patient level. The types of patients included in these studies were different with respect to their

Outcome

The primary outcome variable was the incidence of ACE-inhibitor induced dry cough which was defined as the occurrence of dry cough which leads to the discontinuation of study treatment. The incidence of cough refers to “discontinuing of treatment by the ACE-inhibitor perindopril due to cough” throughout the manuscript. During the run-in period of all three trials, patients were prescribed the ACE-inhibitor perindopril in up-titrating dose to 4 mg (ADVANCE, PROGRESS) or 8 mg (EUROPA). The

Statistical analysis

Summary statistics for continuous variables are presented as mean ± 1 standard deviation. Categorical data are summarized as frequencies and percentages. One-way analysis of variance and Pearson chi-square tests were used to calculate p values. Univariate and multivariate logistic regression analyses were applied to examine the association between baseline variables and ACE-inhibitor cough. In multivariable analysis, we adjusted for the following (potentially) confounding baseline

Results

The baseline characteristics of the total study population (n = 27,492 ACE-inhibitor naive patients) have been summarized in Table 1. The mean (SD) age was 62.7 (9.1) years, 26.9% were female, 37.3% hypertensives, 36.1% diabetics, and 35.9% had experienced a previous MI. Mean blood pressure was 141/82 mm Hg. 73.8% were taking anti-platelet agents, 40.0% beta-blockers, 38.9% lipid-lowering agents and 32.3% calcium antagonists. Of the 27,492 ACE-inhibitor naive patients at the start of the run-in

Discussion

The current meta-analysis with individual data of 27,492 patients with (cardio-)vascular disease treated with ACE-inhibitors, showed an overall incidence of ACE-inhibitor induced cough of 3.9%, which is lower as compared to previous reports in literature. Clinical determinants of ACE-inhibitor dry cough are female gender, older age and the use of lipid-lowering agents in multivariate analysis. No difference in the incidence of ACE-inhibitor induced dry cough was found between Caucasians and

Funding

This combined analysis was initiated by the authors and was designed, conducted, interpreted, and reported independently of the original sponsor. The current study had no funding source or any with a participating role in data collection, outcome assessment, or writing of the manuscript. All authors had joint responsibility for the decision to submit for publication.

Conflict of interest

J.J.B., A.H., J.D., K.A., F.Z., K.C., E.B., and K.A. have declared no conflict of interest. J.C., S.M., M.B., W.R., K.F., R.F., F.M. and M.L.S. have received research grants and fees from Servier. KF is an NIHR Senior Investigator supported by the NIHR Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital

Acknowledgments

All authors contributed to the analysis of the data and writing of the report. All authors approved the final version of the manuscript. Dr J.J.B. and Dr H.A. merged individual data from the trials and had full access to the total data sets of all three trials. Dr J.J.B. performed the statistical analyses.

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Of 642,336 new users of ACEI, 6.4% had active asthma. The hazard of switching to ARB was greater in people with asthma (HR = 1.16; 95% confidence interval [CI], 1.14-1.18; P ≤ .001) and highest in those at BTS step 3 or greater (HR = 1.35, 95% CI, 1.32-1.39; and HR = 1.18, 95% CI, 1.15-1.22, P ≤ .001 for patients aged ≥60 and <60 years, respectively). Hazard was highest with enalapril (HR = 1.25, 95% CI, 1.18-1.34, P ≤ .001; HR = 1.44, 95% CI, 1.32-1.58, P ≤ .001 for BTS step 3 or greater asthma). No increased hazard was observed in chronic obstructive pulmonary disease or those younger than age 60 years at BTS step 1/2. The number needed to treat varied by age, sex, and body mass index (BMI), ranging between 21 and 4, and was lowest in older women with a BMI of 25 or greater.
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View full text

The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease

Highlights

Abstract

Objectives

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Trial selection

Outcome

Statistical analysis

Results

Discussion

Funding

Conflict of interest

Acknowledgments

Lancet

Lancet

J Am Coll Cardiol

Chest

J Clin Epidemiol

J Mol Cell Cardiol

SAVE investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction and myocardial infarction: results of the survival and ventricular enlargement trial

N Engl J Med

Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure

N Engl J Med

Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

N Engl J Med

Angiotensin-converting-enzyme inhibition in stable coronary artery disease

N Engl J Med

Efficacy of perindopril in reduction of cardiovascular events in stable coronary artery disease: randomized, double-blind, placebo controlled, multicentre trial (the EUROPA study)

Lancet

Angiotensin-converting enzyme inhibition by perindopril in the treatment of cardiovascular disease

Expert Rev Cardiovasc

The task force on the management of stable angina pectoris of the European Society of Cardiology. Guidelines on the management of stable angina pectoris

Eur Heart J