The anti-smoking drug varenicline (Chantix, Pfizer) is associated with an increased risk of serious adverse cardiovascular events, according to a new meta-analysis published in CMAJ.
In the meta-analysis, Sonal Singh and colleagues analyzed data from 14 double-blind randomized trials including 8216 subjects. The rate of serious adverse cardiovascular events was 1.06% (52/4908) in the varenicline patients versus 0.82% (27/3308) patients in the placebo patients (OR 1.72, CI 1.09-2.71). The authors, led by Curt Furberg, estimated the number needed to treat with varenicline for one additional person to successfully quit smoking was 10, while the number needed to cause on additional serious CV event was 28. The authors also noted that varenicline already has a black box warning about adverse neuropsychiatric symptoms.
In an associated commentary, Taylor Hays, who has performed research on varenicline with funding from Pfizer, writes that "the small absolute risk of cardiovascular events associated with varenicline treatment is outweighed by the enormous benefit for reducing cardiovascular morbidity and mortality that can be achieved with successful smoking abstinence."
The CMAJ paper follows a statement issued by the FDA on June 16, which warned that the drug might increase the risk of cardiovascular events in people who already have cardiovascular disease. “This would have raised a red flag for us if the flag hadn’t already been flying,” said the FDA's Celia Winchell, in an interview with the New York Times.
The Times also quoted Furberg, who has served as an expert witness in cases against Pfizer: “We have known for many years that Chantix is one of the most harmful prescription drugs on the U.S. market, based on the number of serious adverse effects reported to the FDA. It causes loss of consciousness, visual disturbances, suicides, violence, depression and worsening of diabetes. To this list we now can add serious cardiovascular events.”
In a press release, Pfizer said the meta-analysis was unreliable and said that "the currently available safety data on Chantix... do not support an increased cardiovascular risk associated with Chantix.”
Here is the press release from the CMAJ:
Varenicline for smoking cessation linked to increased risk of serious harmful cardiac events
The use of varenicline to stop smoking is associated with a 72% increased risk of a serious adverse cardiovascular event, states an article in CMAJ (Canadian Medical Association Journal).
Heart disease is a common cause of serious illness and death in smokers and is often a reason for people to stop smoking. Varenicline is one of the most commonly used drugs to help people quit smoking worldwide. When varenicline was launched in 2006, the US Food and Drug Administration (FDA) safety reviewers reported that existing data indicated it could raise the risk of adverse cardiac events. The FDA recently updated the label for Chantix based on a small increased risk of cardiovascular events among smokers with heart disease.
A team of researchers from Johns Hopkins University School of Medicine, Baltimore, Maryland; the University of East Anglia, Norwich, United Kingdom; and Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, sought to investigate the serious cardiac effects of varenicline in tobacco users (smokers or smokeless tobacco users) compared with placebos in clinical trials. They looked at 14 trials that included 8216 patients (4908 people on varenicline and 3308 taking placebos). All trials except one excluded people with a history of heart disease.
In the study, 52 of 4908 (1.06%) participants taking varenicline had adverse events compared with 27 of 3308 (0.82%) participants on placebo. Seven of the 4908 people taking varenicline died compared with 7 of 3308 receiving placebo.
"Among tobacco users varenicline use was associated with a significantly increased risk of serious adverse cardiovascular events greater than 72%," writes Dr. Sonal Singh, Johns Hopkins University School of Medicine, Baltimore, Maryland, with coauthors.
"However, despite achieving more than twofold higher rates of abstinence in the trials, which should potentially induce a cardiovascular benefit, the participants allocated to varenicline experienced an increase in the risk of serious adverse cardiovascular events," they write. "These increased risks of adverse cardiovascular events are seen in smokers with or without heart disease," according to the authors.
They note additional risks of depression, agitation and suicidal thoughts which resulted in the FDA issuing a boxed warning - the highest level of warning - for the drug.
Despite study limitations such as variable data and lack of statistical strength, the researchers conclude that "clinicians should carefully balance the risk of serious cardiovascular events and other serious neuropsychiatric adverse events associated with varenicline against their known benefits on smoking cessation."
In a related commentary, Dr. Taylor Hays from the Mayo Clinic writes, "Although these results suggest a measure of caution should be taken in prescribing varenicline for tobacco dependence treatment, the small absolute risk of cardiovascular events associated with varenicline treatment is outweighed by the enormous benefit for reducing cardiovascular morbidity and mortality that can be achieved with successful smoking abstinence."
"The risk for cardiovascular events is low and is far outweighed by the benefits of diminishing the truly "heartbreaking" effects of cigarette smoking," he concludes.
Here is the press release from Pfizer:
Pfizer Affirms CHANTIX/CHAMPIX as Important Treatment Option for Smokers Wanting to Quit
NEW YORK--(BUSINESS WIRE)--Pfizer said today that the reliable science on varenicline (CHANTIX/CHAMPIX), involving more than 14 clinical trials with more than 7,000 smokers, and the medicine’s approval by regulatory authorities around the world, demonstrate the importance of the medicine as an effective and appropriate treatment option for adult smokers wanting to quit. Pfizer stands behind the benefit/risk profile of Chantix.
“estimates are imprecise owing to the low event rates.”
The company expressed concerns about the reliability of the meta-analysis by Singh et al published today in the Canadian Medical Association Journal (CMAJ). These concerns, among others, are related to the appropriateness of the authors' measure of cardiovascular risk, or composite endpoint, which combines events that do not share a common biological cause; the manner in which cardiovascular events were counted and classified; and a small number of events, which forms the authors' conclusions.
The authors themselves acknowledge that the cardiovascular risk “estimates are imprecise owing to the low event rates.”
Notwithstanding these reliability concerns, the difference of 72 percent reported in the Singh analysis also needs to be put into appropriate context. The actual difference in cardiovascular event rates reported in this analysis was less than one quarter of one percent (i.e., 1.06 percent with varenicline versus 0.82 percent with placebo).
“Pfizer scientists and doctors continuously evaluate the benefits and risks of its medicines, including Chantix,” said Dr. Gail Cawkwell, Vice President of Medical Affairs. “The currently available safety data on Chantix, including a pooled analysis of clinical data in 7,375 people trying to quit smoking, do not support an increased cardiovascular risk associated with Chantix.”
Pfizer is discussing with the U.S. Food and Drug Administration (FDA) a protocol to conduct a meta-analysis of Pfizer’s clinical trial data to help further evaluate the cardiovascular safety of Chantix. This meta-analysis will address a number of limitations in the Singh analysis; Pfizer expects that it will be based on a more reliable composite endpoint to measure cardiovascular risk, as well as a validated process to classify, or adjudicate, cardiovascular events that are part of the composite endpoint.
A video addressing the meta-analysis published in the CMAJ was posted to www.pfizer.com.
Each year, an estimated 5.4 million people worldwide die from smoking related causes, including cardiovascular disease.1 Chantix is a proven aid to smoking cessation treatment and an important treatment option that has been prescribed to over 13 million patients worldwide.
Chantix is currently approved for use in 99 countries around the world. Pfizer works with regulators worldwide on a continual basis to review and monitor data for Chantix.
Patients should consult with their health care providers to determine what medications are right for them. Patients should contact their healthcare professional if they experience new or worsening symptoms of cardiovascular disease.
Chantix was approved by the FDA in May 2006 as an aid to smoking cessation treatment in adults 18 and older. Chantix has been shown to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo. Adults who smoke may benefit from quit smoking support programs and/or counseling during their quit attempt. It’s possible that patients might slip up and smoke while taking Chantix . If patients slip up, they can stay on Chantix and keep trying to quit. Nearly 13 million people have been prescribed Chantix worldwide. The prescribing information for Chantix can be obtained at http://labeling.pfizer.com/ShowLabeling.aspx?id=557.
IMPORTANT SAFETY INFORMATION
Some people have had changes in behavior, hostility, agitation, depressed mood, suicidal thoughts or actions while using Chantix to help them quit smoking. Some people had these symptoms when they began taking Chantix , and others developed them after several weeks of treatment or after stopping Chantix. If you, your family or caregiver notice agitation, hostility, depression or changes in behavior, thinking, or mood that are not typical for you, or you develop suicidal thoughts or actions, anxiety, panic, aggression, anger, mania, abnormal sensations, hallucinations, paranoia or confusion, stop taking Chantix and call your doctor right away. Also tell your doctor about any history of depression or other mental health problems before taking Chantix , as these symptoms may worsen while taking Chantix .
Some people can have serious skin reactions while taking Chantix , some of which can become life-threatening. These can include rash, swelling, redness, and peeling of the skin. Some people can have allergic reactions to Chantix, some of which can be life-threatening and include: swelling of the face, mouth, and throat that can cause trouble breathing. If you have these symptoms or have a rash with peeling skin or blisters in your mouth, stop taking Chantix and get medical attention right away.
The most common side effects include nausea (30%), sleep problems, constipation, gas and/or vomiting. If you have side effects that bother you or don’t go away, tell your doctor. You may have trouble sleeping, vivid, unusual or strange dreams while taking Chantix . Use caution driving or operating machinery until you know how Chantix may affect you.
Chantix should not be taken with other quit smoking products. A lower dose of Chantix may be necessary in patients with kidney problems or who get dialysis.
Before starting Chantix , patients should tell their doctors if they are pregnant, plan to become pregnant, or if they take insulin, asthma medicines, or blood thinners. Medicines like these may work differently when patients quit smoking.
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1 Tobacco Free Initiative (TFI), World Health Organization (WHO). Facts and Figures About Tobacco, June 2007