Smoking cessation agents don’t raise serious CVD risks

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Consider population as well as individual risks

Smoking cessation has benefits that extend well beyond cardiovascular disease, both for the individual patient and for the general public, said Dr. Jonathan M. Samet.

Any increased risk for minor cardiovascular events associated with nicotine replacement therapy must be viewed against "the declines in risk for CVD and other diseases that follow successful cessation," he said.

"Even with the assumption of [an excess CVD] risk associated with nicotine replacement therapy, the population-level benefits far exceed the estimated increase."

Dr. Samet is in the department of preventive medicine and the Institute for Global Health at the University of Southern California, Los Angeles. His work is supported by the National Cancer Institute and the FDA Center for Tobacco Products. These remarks were taken from his editorial accompanying Dr. Mills’ report (Circulation 2013 Dec. 9 [doi:10.1161/circulationaha.113.006928]).



The three smoking cessation agents bupropion, varenicline, and nicotine replacement therapy did not raise the risk of serious adverse cardiovascular events in a network meta-analysis of 63 randomized clinical trials reported online Dec. 9 in Circulation.

This finding held true in the main analysis that included 30,508 patients attempting to quit smoking, in a subgroup analysis of the highest-risk patients who had a history of conditions predisposing them to cardiovascular events, and in a sensitivity analysis that broke down cardiovascular events by type and seriousness.


The three smoking cessation agents bupropion, varenicline, and nicotine replacement therapy did not raise the risk of serious adverse cardiovascular events in a network meta-analysis of 63 randomized clinical trials reported in the study.

"Given the current findings of low risk of serious CVD events attributed to smoking cessation pharmacotherapies, combined with the well-established CVD and mortality risks of continued smoking, the benefits of use would seem to outweigh the risks," said Edward J. Mills, Ph.D., of the Stanford (Calif.) Prevention Research Center, and his associates.

The investigators performed the meta-analysis because recent reports have raised concerns that these agents may raise cardiovascular risks. They used a statistical technique known as network meta-analysis to examine both direct, head-to-head comparison studies and indirect evidence, "thus increasing the power and interpretability of a comparative analysis."

They included any randomized clinical trial of any of the three pharmacotherapies that were of any duration and that reported on any cardiovascular events. Dr. Mills and his colleagues then considered two separate definitions of cardiovascular events: the first was any such event, including minor occurrences such as palpitations, and the second was only major adverse cardiovascular events as defined by the Food and Drug Administration, which is "considered to be a more stringent definition of important patient outcomes."

A total of 19 of the randomized clinical trials assessed nicotine replacement therapy against placebo, 27 assessed bupropion against placebo, 18 assessed varenicline against placebo, 1 assessed high-dose nicotine replacement therapy against placebo, 1 assessed combination nicotine replacement therapy against a control condition, 2 assessed bupropion against varenicline, 3 assessed bupropion against nicotine replacement therapy, and 1 assessed varenicline against nicotine replacement therapy.

Both a pairwise meta-analysis and the network meta-analysis demonstrated that none of the three pharmacotherapies raised the risk of major adverse cardiovascular events. Bupropion appeared to exert a protective effect against both minor and major events, while varenicline showed no harmful or beneficial effect at all concerning minor or major cardiovascular events.

"Nicotine replacement therapy, the most widely used pharmacotherapy for smoking cessation, was associated with an increase in cardiovascular events that was driven by lower-risk events" such as palpitations and tachycardia, which are "well known and largely benign" effects of nicotine replacement, Dr. Mills and his associates said (Circulation 2013 Dec. 9 [doi:10.1161/circulationaha.113.003961]).

"Concerns about adverse cardiovascular events need to be balanced with the consistent evidence for the benefit of smoking cessation, and patients should be counseled about what adverse events may be associated with smoking cessation therapies, the symptoms associated with the withdrawal period from cigarettes, and symptoms that may be due to existing cardiovascular diseases," the investigators added.

This study was supported by the Canadian Institutes of Health Research, the U.S. National Institutes of Health, and the California Tobacco-Related Disease Research Program. Dr. Mills reported ties to Merck; Pfizer, maker of Chantix (varenicline); Novartis; Takeda; and GlaxoSmithKline, maker of Zyban (bupropion); and his associates reported ties to Pfizer.

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