Cardiovascular Risk of Varenicline for Smoking Cessation
Cardiovascular Risk of Varenicline for Smoking Cessation
Objective To investigate whether varenicline is associated with an increased risk of serious cardiovascular events compared with another drug used for smoking cessation, bupropion.
Design Nationwide historical cohort study.
Setting Denmark, 2007-10.
Participants New users of varenicline (n=17,926) and bupropion (n=17,926).
Main outcome measures Individual level data on dispensed drug prescriptions, cardiovascular events, and potential confounders were linked between registries. Cox regression was used to estimate hazard ratios of cardiovascular events in analyses matched for propensity score. The primary outcomes at six months after start of treatment were acute coronary syndrome, ischaemic stroke, and cardiovascular death analysed individually and as a composite of any major event.
Results There were 57 major cardiovascular events among varenicline users (6.9 cases per 1000 person years) compared with 60 events among bupropion users (7.1 cases per 1000 person years); the hazard ratio for any major event was 0.96 (95% confidence interval 0.67 to 1.39). Varenicline use was not associated with an increased risk of acute coronary syndrome (1.20, 0.75 to 1.91), ischaemic stroke (0.77, 0.40 to 1.48), and cardiovascular death (0.51, 0.13 to 2.02). In subgroup analyses, the risk of any major cardiovascular event was not significantly different between patients with and without a history of cardiovascular disease (1.24 (0.72 to 2.12) and 0.83 (0.51 to 1.36), respectively; P=0.29).
Conclusions This cohort study found no increased risk of major cardiovascular events associated with use of varenicline compared with bupropion for smoking cessation. On the basis of the upper confidence limit, the data allowed the exclusion of a 40% increased risk of the composite outcome of any major cardiovascular event. While the estimates were less precise for specific outcomes, any differences would be small in absolute terms.
Smoking is a major threat to public health globally and represents the number one preventable cause of mortality worldwide. Consequently, any intervention that helps people to stop smoking will have a huge impact on mortality by reducing the burden of associated disease.
Varenicline, a partial agonist at the α4β2 nicotinic acetylcholine receptor, is more efficacious for smoking cessation than placebo and bupropion, and at least equally efficacious as nicotine replacement products. Recent findings, however, have raised concerns about its cardiovascular safety. A randomised controlled trial examining efficacy and safety of varenicline in patients with stable cardiovascular disease found somewhat higher rates of non-fatal myocardial infarction, need for coronary revascularisation, and peripheral vascular disease among patients receiving varenicline compared with placebo. Although the differences were not significant, these findings prompted the United States Food and Drug Administration to issue a drug safety communication about a possible increased risk of certain adverse cardiovascular events associated with varenicline. A subsequent meta-analysis of 14 randomised controlled trials found a significantly increased risk of adverse cardiovascular events in users of varenicline compared with placebo (odds ratio 1.72, 95% confidence interval 1.09 to 2.71), although absolute differences between the groups were small (event rate 1.06% in the varenicline group and 0.82% in the placebo group). In contrast, a more recent meta-analysis of randomised controlled trials found no significantly increased risk of cardiovascular events (relative risk 1.40, 0.82 to 2.39; event rate 0.63% in the varenicline group and 0.47% in the placebo group; risk difference 0.27%, -0.10 to 0.63). Potential mechanisms for an association between varenicline and cardiovascular events include modulation of parasymphathetic output from the brainstem to the heart, release of catecholamines, or a prothrombotic effect.
An increased risk of cardiovascular events associated with varenicline would have important implications for the care of the many patients who want to stop smoking and specifically for the millions of patients who are prescribed varenicline each year. Concerns about cardiovascular risk would add to previous safety concerns regarding neuropsychiatric adverse events, as indicated by spontaneous reporting. The reports suggesting an increased cardiovascular risk from varenicline are based on limited data; while the randomised trial of patients with cardiovascular disease was underpowered to detect specific cardiovascular events and the meta-analysis was a post hoc analysis of efficacy trials and relied on a broad non-specific definitions of cardiovascular events. The meta-analysis that did not find an increased risk of cardiovascular events had relatively low power and, given the upper confidence limits, was able to exclude only an increase in risk of 140% or more. To date, no controlled observational studies of adverse cardiovascular events among real world varenicline users have been published. With adequate sources of data and by applying comprehensive confounder control, observational studies can provide clinically useful evidence regarding concerns about drug safety, not least because they reflect effects of drugs in real world users outside the controlled environment of clinical trials. Within the setting of a large nationwide registry based cohort study in Denmark, we investigated whether varenicline use was associated with increased risk of serious cardiovascular events compared with use of another drug used for smoking cessation, bupropion.
Abstract and Introduction
Abstract
Objective To investigate whether varenicline is associated with an increased risk of serious cardiovascular events compared with another drug used for smoking cessation, bupropion.
Design Nationwide historical cohort study.
Setting Denmark, 2007-10.
Participants New users of varenicline (n=17,926) and bupropion (n=17,926).
Main outcome measures Individual level data on dispensed drug prescriptions, cardiovascular events, and potential confounders were linked between registries. Cox regression was used to estimate hazard ratios of cardiovascular events in analyses matched for propensity score. The primary outcomes at six months after start of treatment were acute coronary syndrome, ischaemic stroke, and cardiovascular death analysed individually and as a composite of any major event.
Results There were 57 major cardiovascular events among varenicline users (6.9 cases per 1000 person years) compared with 60 events among bupropion users (7.1 cases per 1000 person years); the hazard ratio for any major event was 0.96 (95% confidence interval 0.67 to 1.39). Varenicline use was not associated with an increased risk of acute coronary syndrome (1.20, 0.75 to 1.91), ischaemic stroke (0.77, 0.40 to 1.48), and cardiovascular death (0.51, 0.13 to 2.02). In subgroup analyses, the risk of any major cardiovascular event was not significantly different between patients with and without a history of cardiovascular disease (1.24 (0.72 to 2.12) and 0.83 (0.51 to 1.36), respectively; P=0.29).
Conclusions This cohort study found no increased risk of major cardiovascular events associated with use of varenicline compared with bupropion for smoking cessation. On the basis of the upper confidence limit, the data allowed the exclusion of a 40% increased risk of the composite outcome of any major cardiovascular event. While the estimates were less precise for specific outcomes, any differences would be small in absolute terms.
Introduction
Smoking is a major threat to public health globally and represents the number one preventable cause of mortality worldwide. Consequently, any intervention that helps people to stop smoking will have a huge impact on mortality by reducing the burden of associated disease.
Varenicline, a partial agonist at the α4β2 nicotinic acetylcholine receptor, is more efficacious for smoking cessation than placebo and bupropion, and at least equally efficacious as nicotine replacement products. Recent findings, however, have raised concerns about its cardiovascular safety. A randomised controlled trial examining efficacy and safety of varenicline in patients with stable cardiovascular disease found somewhat higher rates of non-fatal myocardial infarction, need for coronary revascularisation, and peripheral vascular disease among patients receiving varenicline compared with placebo. Although the differences were not significant, these findings prompted the United States Food and Drug Administration to issue a drug safety communication about a possible increased risk of certain adverse cardiovascular events associated with varenicline. A subsequent meta-analysis of 14 randomised controlled trials found a significantly increased risk of adverse cardiovascular events in users of varenicline compared with placebo (odds ratio 1.72, 95% confidence interval 1.09 to 2.71), although absolute differences between the groups were small (event rate 1.06% in the varenicline group and 0.82% in the placebo group). In contrast, a more recent meta-analysis of randomised controlled trials found no significantly increased risk of cardiovascular events (relative risk 1.40, 0.82 to 2.39; event rate 0.63% in the varenicline group and 0.47% in the placebo group; risk difference 0.27%, -0.10 to 0.63). Potential mechanisms for an association between varenicline and cardiovascular events include modulation of parasymphathetic output from the brainstem to the heart, release of catecholamines, or a prothrombotic effect.
An increased risk of cardiovascular events associated with varenicline would have important implications for the care of the many patients who want to stop smoking and specifically for the millions of patients who are prescribed varenicline each year. Concerns about cardiovascular risk would add to previous safety concerns regarding neuropsychiatric adverse events, as indicated by spontaneous reporting. The reports suggesting an increased cardiovascular risk from varenicline are based on limited data; while the randomised trial of patients with cardiovascular disease was underpowered to detect specific cardiovascular events and the meta-analysis was a post hoc analysis of efficacy trials and relied on a broad non-specific definitions of cardiovascular events. The meta-analysis that did not find an increased risk of cardiovascular events had relatively low power and, given the upper confidence limits, was able to exclude only an increase in risk of 140% or more. To date, no controlled observational studies of adverse cardiovascular events among real world varenicline users have been published. With adequate sources of data and by applying comprehensive confounder control, observational studies can provide clinically useful evidence regarding concerns about drug safety, not least because they reflect effects of drugs in real world users outside the controlled environment of clinical trials. Within the setting of a large nationwide registry based cohort study in Denmark, we investigated whether varenicline use was associated with increased risk of serious cardiovascular events compared with use of another drug used for smoking cessation, bupropion.