Recent Warnings About Varenicline Cite Cardiovascular Risk

Two family physicians who are experts on smoking cessation said in interviews with AAFP News Now that new information regarding an increased cardiovascular risk associated with the tobacco cessation drug varenicline has not discouraged them from prescribing the medication, which is marketed as Chantix. They agree, however, that heightened vigilance -- even further investigation -- is warranted.

"Are we to stop using varenicline -- the most effective pharmacological intervention for smoking cessation -- because of a small statistically (as opposed to clinically) significant effect? I would think not," said Carlos Jaén, M.D., Ph.D., a member of the AAFP's Tobacco Cessation Advisory Committee and Dr. John M. Smith Jr. endowed professor and chairman of family and community medicine and professor of epidemiology and biostatistics at the University of Texas Health Science Center at San Antonio. "I would recommend continuing to use it but to keep vigilance similar to that required for psychiatric problems and have a low threshold for intervention."

The FDA, which previously reviewed varenicline after it was linked to suicidal ideation and suicidal behavior in 2007, issued a safety alert June 16 to notify physicians and patients that the "Warnings and Precautions" section of the drug's prescribing information and its accompanying patient medication guide will be updated to include information about a "small, increased risk of certain cardiovascular events in patients who have cardiovascular disease."

The FDA's action was based on the results of a randomized, double-blind, placebo-controlled clinical trial designed to assess the efficacy and safety of varenicline for smoking cessation in 700 patients with stable, documented cardiovascular disease.

Meanwhile, a systematic review and meta-analysis of 14 controlled trials involving more than 8,200 participants that recently was published in the Canadian Medical Association Journal, or CMAJ, found what authors termed a "significantly increased risk" for cardiovascular events in tobacco users both with and without existing cardiovascular disease. In that study, 52 of 4,908 patients (1.06 percent) taking varenicline suffered cardiovascular events compared with 27 of 3,308 patients (0.82 percent) taking a placebo.

The authors of the CMAJ study acknowledged that their findings need to be "interpreted in the context of other studies and the overall benefit-risk profile of varenicline."

Tom Houston, M.D., chair of the AAFP's Tobacco Cessation Advisory Committee and clinical professor of family medicine and public health at The Ohio State University, Columbus, said he, too, will not stop prescribing varenicline to his patients and would like to see additional research.

"As the authors (of the CMAJ meta-analysis) point out, there are limitations to the paper, including whether the cardiovascular complications were clinical diagnoses, or exactly how the events were defined," Houston said. "We also don't have any idea about the length of time these patients were on varenicline and whether there is any relationship between the duration of treatment and the adverse events, which could point to more worry about a causal problem."

The FDA said in its June 16 safety alert that it is continuing to evaluate the cardiovascular safety of varenicline, and the agency is requiring manufacturer Pfizer Inc. to conduct a large meta-analysis of randomized, placebo-controlled trials.

The agency also noted that smoking is an independent and leading risk factor for cardiovascular disease, and varenicline is effective in helping patients quit smoking.

Houston, who disclosed receiving educational grants from Pfizer and serving as a consultant in the manufacturer's international tobacco cessation education program, told AAFP News Now that "the risk of cardiac disease and other health problems from continuing smoking is higher than the risk of using varenicline."

In the study reviewed by the FDA, the group of patients taking varenicline had a continuous smoking abstinence rate of 47 percent at four weeks compared with 14 percent in the placebo group. From week nine to week 52, the varenicline group had a continuous abstinence rate of 19 percent, compared with 7 percent in the placebo group.

"There is clear evidence that varenicline has the best outcome, particularly when paired with counseling interventions," said Jaén, who also is an adjunct professor of public health at the University of Texas School of Public Health's San Antonio regional campus and co-director of the health science center's Center for Research in Family Medicine and Primary Care.

However, Jaén said, bupropion, which is marketed for smoking cessation as Zyban, and other nicotine replacement therapies (2-page PDF; About PDFs) also are effective.

"My patients have the best success when they are ready to quit and use the best available treatment -- pharmacotherapy and counseling," he said.

Houston said combining a transdermal nicotine patch with a short-acting nicotine replacement product also has been proven effective. Like Jaén, he emphasized that counseling -- whether in-person or through a quitline (2-page PDF; About PDFs) -- is critical to success.

The AAFP offers members tobacco cessation resources through its Ask and Act program, which encourages family physicians to ask all patients about tobacco use, then act to help them quit.