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ACE inhibitor-related coughing shown substantially higher than labeling indicates
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A new meta-analysis of 125 studies has found that ACE inhibitor-associated coughing was nearly ninefold higher than the reported rate in the Physicians’ Desk Reference/drug label, which represents a “sweeping under the rug” of side effects that could potentially apply to more serious adverse events, according to study researcher Franz H. Messerli, MD.
The impetus for the study was a study published last year in The New England Journal of Medicine that found that not all of the information put out by the FDA is actually reaching practicing physicians, said Messerli, who is the medical director in the division of research at St. Luke’s Roosevelt Hospital, New York, and a Cardiology Today Editorial Board member.
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“What immediately came to my mind when I read this was the issue with ACE inhibitor-associated cough,” Messerli told Cardiology Today. The PDR/drug label rate of cough of 1.3% was never changed when enalapril came to the market, he said, even after a study comparing losartan (Cozaar, Merck) with enalapril reported a cough incidence of about 10% in the enalapril arm vs. 0% in the losartan arm.
To bring further clarification to this issue, Sripal Bangalore, MD, Harvard Medical School, Boston, and the study’s principal investigator, as well as Sunil Kumar, MD, from St. Luke’s Roosevelt Hospital, and Messerli searched for randomized clinical trials of ACE inhibitors that included a sample size of at least 100 patients in the ACE inhibitor arm, had a follow-up of at least 3 months and reported the rate of cough. The final study group featured 198,130 patients from 125 studies, with 111,798 patients randomly assigned to ACE inhibitors and 86,437 to other treatments, including placebo.
Their analysis resulted in a pooled weighted coughing incidence for enalapril of 11.48% (95% CI, 9.54-13.41), which was ninefold greater than the reported rate in the PDR/drug label of 1.3%. An even larger discrepancy was noted in the pooled withdrawal rate due to cough for enalapril, which was 31-fold greater than the reported rate in the PDR/drug label (3.08% vs. 0.1%).
A possible explanation for such oversights such as the one witnessed with enalapril-related coughing and the PDR/drug label, Messerli said, may stem from the consequences of performing research.
“The investigator’s foremost goal is to keep the patient in the study,” he said. “Therefore, investigators are all a tad evasive when it comes to writing down side effects because you need to fill out a form, send it to the study center, etc. So, by and large, if it’s a nuisance side effect, like cough, most researchers don’t care too much about them.”
Although the rate of coughing is often dismissed as nothing more than a nuisance side effect, Messerli said the implications may go well beyond improper documentation of small scale adverse events. “Our suspicion is that if this game goes on with adverse events that are not of major consequence, how much more is actually hidden in side effects that are more consequential. When you look at carcinogenesis and other serious effects, I hope that the reporting there is more accurate than it is with coughs,” he said.
Although his ultimate goal of the FDA requiring companies to update the frequency of adverse events on a regular basis to ensure that it is still accurate is not yet in place, Messerli suggested how physicians can best apply this information for the benefit of their patients.
“In a nut shell, take package insert information with a grain of salt. Don’t base your therapeutic decisions solely on package insert information,” he said. – by Brian Ellis
For more information:
- Bangalore S. Am J Med. 2010;doi:10.1016/j.amjmed.2010.06.014.
- Schwartz L. N Engl J Med. 2009;361:1717-1720.