Guest Post: Chantix and Cardiovascular Risk: Another Weak Safety Study

Editor’s Note: The following is a guest post by Joseph Ross, an assistant professor at the Mt Sinai School of Medicine. This post originally appeared on CardioExchange, an online cardiology community in the early stages of development by the New England Journal of Medicine. The editor-in-chief of CardioExchange is Harlan Krumholz, who frequently collaborates with Ross. CardioBrief’s Larry Husten is the news editor of CardioExchange.

Chantix and Cardiovascular Risk: Another Weak Safety Study

by Joseph S. Ross, MD, MHS

In 2008, Dr. John Spangler of the Wake Forest University School of Medicine wrote a letter to the editor of Current Medical Research and Opinion expressing concern about a Pfizer-funded, randomized, placebo-controlled trial of the smoking-cessation drug varenicline (Chantix). By 1 year, the varenicline group had experienced a higher rate of serious adverse events than the placebo group; many were cardiovascular (CV) events. The difference was not statistically significant, but Spangler considered it clinically significant and deserving of further study.

When I initially read Spangler’s letter and reviewed the varenicline trial data, I was equally concerned. CardioExchange editor-in-chief Dr. Harlan Krumholz and I approached Pfizer about performing a pooled, subject-level meta-analysis of all clinical trial data on varenicline, to fully evaluate its CV safety using methods we were then applying to our investigation of rofecoxib. Pfizer assured us that the meta-analysis was unnecessary because CV-safety concerns about varenicline were being addressed in a forthcoming randomized trial.

That Pfizer-funded trial has now been published in Circulation. The investigators randomized 714 smokers with stable CV disease to receive varenicline or placebo for 12 weeks. The rate of adjudicated CV events at 1 year was 7.1% in the varenicline group and 5.7% in the placebo group, again a statistically nonsignificant difference. The authors conclude that “varenicline treatment did not increase the risk of cardiovascular events . . . However, trial size and duration preclude a definitive conclusion about the safety of varenicline.”

I applaud the authors’ candor about the limitations of their trial, but I have difficulty understanding its design given the goal of investigating CV safety. Three main areas concern me:

1. The trial excluded smokers who had undergone a CV procedure or exhibited CV instability, including myocardial infarction or unstable angina, in the previous 2 months. Those are precisely the patients who have the greatest motivation to quit smoking and are at the highest risk for CV events.

2. Varenicline use was examined over only 12 weeks, and serious adverse events were followed out to 1 year, consistent with previous trials. However, given that quit rates are below 50% at 12 weeks, it’s reasonable to expect that many patients will use the drug for longer than that.

3. My biggest (but also most technical) concern has to do with the 1.4% CV-event difference. Only a trial involving nearly 10,000 subjects could find such a difference to be statistically significant (at 80% power). A similarly powered trial involving about 700 subjects could detect a statistically significant difference only if the CV-event difference were at least 6.2% between the groups. That would be essentially double the CV-event rate — and would exceed the CV risk from smoking!

So what do I make of another underpowered safety study? My overall instinct is that varenicline is safe, particularly when I weigh the anticipated CV benefits from smoking cessation against the potential CV risk from the drug. But I would prefer to have stronger evidence on which to base my decision.

Are you concerned about varenicline’s CV risk? Do the findings from the new trial make you less concerned or persuade you to change how you view the drug in clinical practice? For your patients at highest CV risk, are you more inclined to use other smoking-cessation drugs (which have lower efficacy rates) or varenicline as first-line therapy? Please share your thoughts with your fellow clinicians here on CardioExchange.


  1. Thank you for pursuing this. My biggest concern about the Williams study in Current Research and Medical Opinion is that now it is broadly quoted in the medical literature.

    The study derived safety and efficacy inferences, but the authors themselves stated that they did not carry out inferntial statistics.

  2. Melissa Walton-Shirley provided the following comment to CardioBrief:

    My inclination, as you know is that varenicline has never been associated with brain mets, COPD, or myocardial infarction with safety never had been an issue in multiple studies performed to date. Serena Todstadt told me she had performed several trials in the early phase with up to 1000 pts demonstrating safety, plus the overwhelming anectdotal experience she’s had with the drug has been favorable. Of course, I’m happy to see any trial adequately powered to address this issue but I can’t see any plausible physiologic mechanism in which an impact on the nicotine receptor centrally would lead to cardiovascular events. It’s the “tar” chock full of carcinogens, even cyanide contained in cigarettes that cause the prothombotic , vasospastic and pro-oncologic side effects of tobacco utilization. If I were a smoker, I’d be far more concerned about the absolute certainty that smoking kills 5.4 million human beings every year. We are working awfully hard here to find someone that we can say was harmed or killed by Varenicline. A few years ago, before this drug was FDA approved in the US, I predicted to Dr. Tonstadt that veranicline would come under heavy fire in the US because the tobacco companies are embedded here. I jokingly told her when I interviewed her at the ESC in Stockholm a few years back that they will acuse this medicationsof killing patients, making them crazy, causing them to commit suicide and grow three heads. I knew the class action lawyers would be salivating even before they sold their first pill in the U.S. The first three accusastions have already been lodged, I’m just waiting on the National Enquirer to publish the fourth.

  3. Thank you, Dr. Ross, for this thoughtful post. I also am not particularly reassured by the results of this trial, in view of the difference in cardiovascular events between the varenicline and placebo arm, and in light of the fact that more patients quit smoking in the varenicline arm, which would presumably tend to lower event rates in that arm. It would have been more convincing if varenicline had been compared to buproprion or nicotine replacement therapy, and if the trial had been larger.

    Varenicline is thought to achieve its effect through partially blocking and partially stimulating a type of nicotinic acetylcholine receptor. Acetylcholine receptors play many roles throughout the body and are central to muscle contractions, including heart muscle contractions and the tone of the smooth muscles that line blood vessels. Varenicline is thought to be most active against a receptor that affects the release of dopamine in the brain. Dopamine plays a major role in addiction, mood, and muscle movement. So I am not so sure that there is no biologically plausible mechanism in which varenicline could have cardiac effects.

    The Institute for Safe Medication Practices released a report in May 2008 of its review of adverse event reports filed with the FDA on varenicline.(1) The reports included 988 SAEs linked to varenicline during the 4th quarter of 2007, including accidents and injuries, heart rhythm disturbances, MIs, seizures and abnormal muscle spasms or movements, high blood glucose and new onset diabetes, various psychiatric adverse events, skin reactions, and vision disturbances. In the 4th quarter of 2007, varenicline accounted for more reports of SAEs in the U.S. than any other drug. Although the ISMP report notes that adverse event reports do not establish causality, the authors recommend that physicians and patients exercise caution in the use of varenicline and consider alternative methods of quitting smoking.

    The FDA safety reviewer voiced uncertainty as to possible link between varenicline and cardiac events in view of a higher, but nonsignificant, number of events in the patients on varenicline: “The serious adverse event data suggest that varenicline may possibly increase the risk of cardiac events, both ischemic and arrhythmic, particularly over longer treatment periods. This finding is far from definitive.” (2)

    Although varenicline may have slightly higher efficacy than other pharmacological cessation methods, the difference is small. The USPHS smoking cessation guidelines do not recommend any one of the first-line agents over another.(3)

    Moreover, population studies show that a large majority of smokers who permanently stop smoking do so without any form of assistance.(4)

    I continue to have doubts about the safety of varenicline. I believe patients should be advised of the uncertainties and should consider other options before they try varenicline.

    (1) Strong Safety Signal Seen for New Varenicline Risks

    (2) Josefberg H. Clinical Safety Review: Varenicline tartrate. Rockville, MD: U.S. Food and Drug Administration, Center for Drug Evaluation and Research; April 3, 2006.

    (3) Fiore, MC, Jaen, CR, Baker, TB, et al. Treating tobacco use and dependence: 2008 update. US Department of Health and Human Services 2008.

    (4) Chapman, S, MacKenzie, R. (2010) The Global Research Neglect of Unassisted Smoking Cessation: Causes and Consequences. PLoS Med 7(2):e10000216. References 10-15.

  4. Debra McConnell says

    My brother died in 2018 of a heart attack. He was using Chantix and secretly smoking. He was 59. Did this combination kill him? He did not have heart disease. He was deemed healthy the same month he died.

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