Clinical research study
Angiotensin-Converting Enzyme Inhibitor Associated Cough: Deceptive Information from the Physicians' Desk Reference

https://doi.org/10.1016/j.amjmed.2010.06.014Get rights and content

Abstract

Background

Dry cough is a common, annoying adverse effect of all angiotensin-converting enzyme (ACE) inhibitors. The present study was designed to compare the rate of coughs reported in the literature with reported rates in the Physicians' Desk Reference (PDR)/drug label.

Methods

We searched MEDLINE/EMBASE/CENTRAL for articles published from 1990 to the present about randomized clinical trials (RCTs) of ACE inhibitors with a sample size of at least 100 patients in the ACE inhibitors arm with follow-up for at least 3 months and reporting the incidence or withdrawal rates due to cough. Baseline characteristics, cohort enrolled, metrics used to assess cough, incidence, and withdrawal rates due to cough were abstracted.

Results

One hundred twenty-five studies that satisfied our inclusion criteria enrolled 198,130 patients. The pooled weighted incidence of cough for enalapril was 11.48% (95% confidence interval [CI], 9.54% to 13.41%), which was ninefold greater compared to the reported rate in the PDR/drug label (1.3%). The pooled weighted withdrawal rate due to cough for enalapril was 2.57% (95% CI, 2.40-2.74), which was 31-fold greater compared to the reported rate in the PDR/drug label (0.1%). The incidence of cough has increased progressively over the last 2 decades with accumulating data, but it has been reported consistently several-fold less in the PDR compared to the RCTs. The results were similar for most other ACE inhibitors.

Conclusion

The incidence of ACE inhibitor-associated cough and the withdrawal rate (the more objective metric) due to cough is significantly greater in the literature than reported in the PDR/drug label and is likely to be even greater in the real world when compared with the data from RCTs. There exists a gap between the data available from the literature and that which is presented to the consumers (prescribing physicians and patients).

Section snippets

Search Strategy and Selection of Studies

We conducted PUBMED/EMBASE/CENTRAL searches from 1990 to February 2010 for studies using the terms: ‘angiotensin-converting enzyme inhibitors’ and by using the names of individual ACE inhibitors (Enalapril, lisinopril, perindopril, moexipril, ramipril, trandalopril, and fosinopril). We limited our search to studies in humans from 1990 to February 2010. We checked the reference lists of review articles, meta-analyses, and original studies identified by the electronic search to find other

Study Selection

We identified 2811 RCTs through electronic and hand searches, of which 125 trials (159 comparison arms) fulfilled the inclusion criteria and were chosen for this analysis (Figure 1). We excluded trials that involved a combination of ACE inhibitors and angiotensin receptor blockers (ARBs; example: ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint [ONTARGET] Trial), and studies that only enrolled patients with known intolerance to ACE inhibitors. However, studies using a

Discussion

The results of the present analysis of nearly 200,000 patients suggests that the rate of a common nuisance adverse effect with ACE inhibitors, cough, is grossly under-reported in the PDR/drug label and is several folds greater in the literature.

Conclusions

In this largest meta-analysis to date involving nearly 200,000 patients, the incidence of ACE inhibitor-associated cough and the withdrawal rate (the more objective metric) due to cough is several-fold greater in the literature than reported in the PDR (and the drug label) and is likely greater in the real-world compared to data from RCTs presented here. Action must be taken to ensure that the drug labeling is regularly updated both for safety and for medication-specific adverse effects.

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    Funding: This study was supported by a grant from Boehringer Ingelheim.

    Conflict of Interest: Drs. Bangalore and Kumar do not have any potential conflicts of interest to disclose. Dr. Messerli is on the speaker's bureau or ad hoc consulting for Pfizer, Abbott, Takeda, Nicox, Boehringer Ingelheim, Merck, Novartis, and Daiichi-Sankyo.

    Authorship: All authors have read and approved the manuscript. All authors met the criteria for authorship, had access to data, and played an important role in writing the manuscript. All activities and decisions involved in the meta-analysis and preparation of the manuscript were performed completely independently with no input or review by Boehringer Ingelheim.

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