FDA Says Varenicline (Chantix) May Increase Risk of CV Events 2

The FDA said that the anti-smoking drug varenicline (Chantix) may increase the risk of cardiovascular events in people who already have cardiovascular disease. The new information will be added to the drug’s label and Medication Guide for patients.

The FDA does not recommend that people with cardiovascular disease discontinue taking varenicline, but says that physicians and patients should weigh the known benefits of varenicline with the potential risks. Pfizer, which manufactures the drug, will be required to conduct a large meta-analysis.

The new action is based on an FDA review of a study of 700 patients with cardiovascular disease who were randomized for 12 weeks to either varenicline or placebo, followed by a 40 week non-treatment period. Use of varenicline compared to placebo was associated with significant improvements in the Continuous Quite Rate during weeks 9-12 (47% vs 14%, p<0.0001) and the continuous abstinence rate from weeks 9 through 52 (19% vs 7%, p<0.0001). However, there were more cardiovascular adverse events in the treated arm than in the placebo arm, although the trial was not powered to detect significant differences. Here is the FDA data:

Adjudicated Cardiovascular Events During the 52-Week Study Period (≥1% in any group)

Varenicline N=353* n (%) Placebo N=350 n (%)
Nonfatal myocardial infarction 7 (2.0) 3 (0.9)
Need for coronary revascularization† 8 (2.3) 3 (0.9)
Hospitalization for angina pectoris 8 (2.3) 8 (2.3)
New diagnosis of peripheral vascular disease (PVD) or admission for a procedure for the treatment of PVD 5 (1.4) 3 (0.9)

*Three patients in the varenicline arm did not meet the protocol-specified definition of stable cardiovascular disease but were included in the safety analysis population.

Patients with need for coronary revascularization in the varenicline arm include 5 patients who are also counted under nonfatal myocardial infarction and/or hospitalization for angina pectoris events. Patients with need for coronary revascularization in the placebo arm include 2 patients who are also counted under nonfatal myocardial infarction and/or hospitalization for angina pectoris.

Editorial note: I’m a bit baffled by the small number of total CV events and the very small difference in events between the arms. The FDA recommends that physicians and patients “weigh the known benefits of Chantix against the potential risks of its use in smokers with cardiovascular disease,” but there’s not nearly enough data included in the safety communication to enable anyone to make a reasonable assessment of the risks and benefits.

Here is the FDA communication:

FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease

Safety Announcement

[6-16-2011] The U.S. Food and Drug Administration (FDA) is notifying the public that the smoking cessation aid Chantix (varenicline) may be associated with a small, increased risk of certain cardiovascular adverse events in patients who have cardiovascular disease. This safety information will be added to theWarnings and Precautions section of the Chantix physician labeling. The patient Medication Guide will also be revised to inform patients about this possible risk.

FDA reviewed a randomized clinical trial of 700 smokers with cardiovascular disease who were treated with Chantix or placebo (see Data Summary below). In this trial, Chantix was effective in helping patients quit smoking and remain abstinent from smoking for as long as one year. Cardiovascular adverse events were infrequent overall, however, certain events, including heart attack, were reported more frequently in patients treated with Chantix than in patients treated with placebo.

Healthcare professionals should be aware that smoking is an independent and major risk factor for cardiovascular disease, and smoking cessation is of particular importance in this patient population. The known benefits of Chantix should be weighed against its potential risks when deciding to use the drug in smokers with cardiovascular disease.

Patients taking Chantix should contact their healthcare professional if they experience new or worsening symptoms of cardiovascular disease.

FDA is continuing to evaluate the cardiovascular safety of Chantix and is requiring the manufacturer to conduct a large, combined analysis (meta-analysis) of randomized, placebo-controlled trials. FDA will update the public when additional information is available.

Additional Information for Patients

  • Smoking is a major risk factor for cardiovascular disease, and Chantix can help you quit smoking.
  • If you have cardiovascular disease, taking Chantix may increase your risk of certain cardiovascular adverse events.
  • Contact your healthcare professional if you experience new or worsening symptoms of cardiovascular disease while taking Chantix, for example:
    • Shortness of breath or trouble breathing
    • New or worsening chest pain
    • New or worse pain in legs when walking
  • Read the Medication Guide you get along with your Chantix prescription. It explains the risks associated with the use of Chantix.
  • Talk to your healthcare professional if you have questions or concerns about Chantix.
  • Report side effects from the use of Chantix to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.

Additional Information for Healthcare Professionals

  • Smoking is an independent and major risk factor for cardiovascular disease, and Chantix is effective in helping patients quit smoking.
  • Be aware that a small, increased risk of certain cardiovascular adverse events was reported in a study of patients with cardiovascular disease receiving Chantix. The events included angina pectoris, nonfatal myocardial infarction, need for coronary revascularization, and new diagnosis of peripheral vascular disease or admission for a procedure for the treatment of peripheral vascular disease.
  • Weigh the known benefits of Chantix against the potential risks of its use in smokers with cardiovascular disease.
  • Counsel patients to seek medical attention if they experience new or worsening symptoms of cardiovascular disease while taking Chantix.
  • Encourage patients to read the Medication Guide they receive along with their Chantix prescription.
  • Report adverse events involving Chantix to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of this page.

Data Summary

FDA reviewed a randomized, double-blind, placebo-controlled clinical trial designed to assess the efficacy and safety of Chantix for smoking cessation in 700 patients aged 35 to 75 years with stable, documented cardiovascular disease (other than, or in addition to, hypertension) that had been diagnosed at least two months prior to the screening visit. Patients were randomized to treatment with Chantix 1 mg twice daily (n=350) or placebo (n=350). The study consisted of a 12-week treatment period that was followed by a 40-week non-treatment period. Patients also received smoking cessation counseling throughout the study. The 4-week Continuous Quit Rate (CQR) for Weeks 9 through 12 was obtained through weekly reports of cigarette or other nicotine use since the last study visit, and confirmed by measurement of end-expiratory exhaled carbon monoxide ≤10 ppm.

The results showed a statistically significantly higher 4-week CQR in the Chantix arm compared with the placebo arm (47% versus 14%, respectively; p<0.0001). The continuous abstinence rate from Week 9 through Week 52 of the study was also significantly higher in the Chantix group compared with the placebo group (19% versus 7%, respectively; p<0.0001).

Certain cardiovascular adverse events were reported in more patients treated with Chantix than patients treated with placebo. These included angina pectoris, nonfatal myocardial infarction, need for coronary revascularization, and new diagnosis of peripheral vascular disease or admission for a procedure for the treatment of peripheral vascular disease, as is shown in the table below. These events were reviewed by an independent cardiovascular endpoint committee. Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal myocardial infarction and hospitalization for angina pectoris. The trial was not designed to have statistical power to detect differences between the arms on the safety endpoints.

Adjudicated Cardiovascular Events During the 52-Week Study Period (≥1% in any group)

Varenicline N=353* n (%) Placebo N=350 n (%)
Nonfatal myocardial infarction 7 (2.0) 3 (0.9)
Need for coronary revascularization† 8 (2.3) 3 (0.9)
Hospitalization for angina pectoris 8 (2.3) 8 (2.3)
New diagnosis of peripheral vascular disease (PVD) or admission for a procedure for the treatment of PVD 5 (1.4) 3 (0.9)

*Three patients in the varenicline arm did not meet the protocol-specified definition of stable cardiovascular disease but were included in the safety analysis population.

Patients with need for coronary revascularization in the varenicline arm include 5 patients who are also counted under nonfatal myocardial infarction and/or hospitalization for angina pectoris events. Patients with need for coronary revascularization in the placebo arm include 2 patients who are also counted under nonfatal myocardial infarction and/or hospitalization for angina pectoris.

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2 comments

  1. That is a pretty small number of events and I suspect many occurred after participants were off of varenicline. This finding may be due to chance (note the absence of p values for the CVD events), but I am glad the FDA is paying close attention.

    Although it is well-established that smoking cessation reduces risk of MI, CHD death, and all-cause mortality, more research is needed to understand the magnitude of the risks of continued smoking and the magnitude and timing of the benefits of smoking cessation. This is especially true for modern smokers, who are more overweight, more likely to use pharmacotherapy when they try to quit, smoke fewer cigarettes, and have other socio-demographic features than make them different than historical cohorts.

  2. Pingback: FDA and EMA Issue Updates on Dronedarone, Varenicline, and Pioglitazone « CardioBrief

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