Increased CV risk with smoking cessation drug varenicline: New meta-analysis
July 4, 2011 | Sue Hughes|
Baltimore, MD and Winston-Salem, NC - A new meta-analysis is raising fresh concerns about the cardiovascular risk associated with the smoking cessation drug varenicline (Chantix, Pfizer) .
The meta-analysis, published online today in the Canadian Medical Association Journal, was conducted by a team led by Drs Sonal Singh (Johns Hopkins University School of Medicine, Baltimore, MD) and Curt Furberg (Wake Forest Baptist Medical Center, Winston-Salem, NC).
Furberg is calling for varenicline to be taken off the market. He commented to heartwire: "This increase in cardiovascular events adds to the large amount of central nervous system (CNS) reactions reported with varenicline, and highlights yet again how dangerous this drug is. It has only a very modest benefit. But it is associated with some very real and scary side effects, and there are other things available to help people stop smoking."
But others are not convinced, arguing that the benefits of stopping smoking vastly outweigh any side effects of a drug that is only taken short term. In an accompanying editorial , Dr Taylor Hays (Mayo Clinic, Rochester, MN), who has been involved in clinical trials of varenicline, 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."
Independent observer Dr Robert Bonow (Northwestern University, Chicago, IL) tended to side with Hays. He commented to heartwire: "The effects of smoking are so horrific that the benefits of stopping outweigh the risks of this drug in my view."
Furberg explained to heartwire that at the time of approval, the US FDA review of varenicline showed a trend towards an increased rate of cardiovascular events with the drug. To look at this further, he and his colleagues conducted a meta-analysis of randomized trials of varenicline versus placebo in smokers that reported on cardiovascular events. The meta-analysis included 14 trials with a total of 8216 participants. The trials ranged in duration from 7 to 52 weeks, and all except one excluded people with a history of heart disease.
Results showed that varenicline was associated with a significantly increased risk of serious adverse cardiovascular events compared with placebo. There were too few deaths to allow meaningful comparisons of mortality.
This meta-analysis follows a recent safety communication from the FDA warning that varenicline may be associated with a small increased risk of cardiovascular events in patients with cardiovascular disease.
Singh explained to heartwire that the FDA warning was based on a trial by Rigotti et al in 700 patients with heart disease. He said: "We have updated all the previous analyses with extra studies and found this cardiovascular risk occurs both in patients with heart disease and those without heart disease. Most of the studies in our meta-analysis included patients without heart disease. No population is immune to the effect."
Singh notes that while 1 in 10 people on Chantix quit smoking, the number needed to harm is 28. "There is not a great difference there." He added: "We don't know if the cardiovascular risk with Chantix stops after the drug has been discontinued. We have only looked at one-year's data-when the patients were actually taking the drug. And we showed a 72% increased risk of cardiovascular events. We don't know what happens later on." He also noted that the actual cardiovascular risk with Chantix may be even greater as more people in the Chantix arm stopped smoking and so should have had an immediate reduction in risk.
"We all know the harms of smoking, and I am not disputing the need to quit. But I would advocate using a different method to help you quit. There are lots of other aids out there that work without increasing cardiovascular risk."
Benefit only modest
"The efficacy is weak. And the adverse events are piling up"
Furberg reinforces this view. He commented to heartwire: "Quitting smoking is exceedingly important. If Chantix was very effective at getting people to quit smoking, you might argue in favor of its continued use, but it is only modestly effective. With Chantix, for every 10 people who take it, 9 have relapsed after a year. And we don't know what happens to the 10th person after a year. So the efficacy is weak. And the adverse events are piling up."
CNS effects a particular worry
Furberg is particularly worried about the CNS effects of the drug. He notes that MedWatch data show it is one of the worst drugs on the market in terms of side effects. "It is associated with sudden loss of consciousness, which has led it to be banned from use in pilots and truck drivers, and the Department of Defense has discouraged its use in army personnel working with missiles. But what about all the people who drive cars every day? It also has the most reports of aggression, hostility and violence of any drug marketed, and these are only the reactions that have actually been reported to the FDA, so just represent the tip of the iceberg." His next focus is on reports of suicide and self-inflicted injury with the drug, with a paper on this subject currently in review.
"It is an exceedingly potent drug which blocks nerve impulses in the brain"
Noting that France has stopped reimbursing varenicline, Furberg is urging the FDA to follow a similar path. "It is an exceedingly potent drug which blocks nerve impulses in the brain. There are other options for smoking cessation." He believes counseling should be the main method to help people quit smoking. "People need moral support to keep their willpower, but physicians are not trained to do this. It is hugely time consuming and not reimbursed. It is much more convenient just to prescribe a pill. It would be great if it worked, but unfortunately it doesn't".
CV risk small
But Hays and Bonow can still see a place for varenicline.
In his editorial, Hays notes that the increased risk of cardiovascular events must be tempered by the rarity of these events (around 1%), and the absolute difference between varenicline and placebo is only 0.24%. He also points out that in most of the studies included in the meta-analysis the rate of participants lost to follow-up was greater in the placebo than the treatment arm, which introduces bias, and that cardiac events were not adjudicated. "These results represent a significant degree of uncertainty about the relative good or harm from varenicline, leaving the issue unsettled," he writes.
Commenting on the study for heartwire, Bonow agreed that the absolute cardiovascular risk appeared low. "I don't want to minimize the risks. I think they're there but they are small. But even if this drug just enables 1 in 10 to give up smoking, I think that is OK, if it avoids the downstream risks associated with smoking."
"I think that is OK, if it avoids the downstream risks associated with smoking"
Bonow appeared more worried about the CNS effects than the cardiovascular effects of the drug. "Clearly, the CNS effects are real. I would hesitate to prescribe this drug to anyone with mental health issues, and I would be careful to discuss these risks with patients, or the parents/spouses of patients to make them alert for any changes in emotional status."
In a statement, Pfizer said it disagreed with the interpretation of the data by Singh et al, which the company emphasized was based on a small number of events, "which raises concerns about the reliability of the authors' conclusion." It added that the FDA has asked Pfizer to conduct its own meta-analysis of cardiovascular events in the whole database on the drug.
On the CNS side effects, Pfizer told heartwire that "there is no reliable scientific evidence to say these events are caused by Chantix." It added, however, that it is planning a large trial of varenicline in smokers with and without mental health disorders to look at this further.
The company adds that: "The health benefits of quitting smoking are immediate and substantial" and that "each year, an estimated 5.4 million people worldwide die from smoking-related causes."
Furberg was paid by plaintiffs for expert testimony on Pfizer's COX-2 inhibitors. Hays has received grant funding from Pfizer to conduct a trial of varenicline.
1. Singh S, Loke YK, Spangler JG, et al. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ 2011. Available at: http://www.cmaj.ca
2. Hays JT. Varenicline for smoking cessation: Is it a heartbreaker? CMAJ 2011.
Available at: http://www.cmaj.ca
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