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Counseling is a must with this smoking cessation aid
Inform patients who are interested in taking varenicline (Chantix) that there is a small cardiovascular (CV) risk associated with it, as well as neuropsychiatric risks—and consider recommending that smokers with a history of cardiovascular disease (CVD) use nicotine replacement therapy (NRT) or bupropion instead.1
STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis.
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;183:1359-1366.
ILLUSTRATIVE CASE
A 53-year-old man asks you to prescribe Chantix to help him stop smoking. He has made several attempts to quit in the past, but never managed to stop for more than 6 months— and has smoked a pack a day for 30 years. The patient does not have a history of heart disease, but he is on statin therapy for hyperlipidemia. What should you tell him about varenicline’s potential benefits and risks?
Tobacco use remains the largest preventable contributor to death and disease in the United States.2 In smokers with coronary heart disease, smoking cessation is associated with a 36% reduction in all-cause mortality (relative risk [RR], 0.64; 95% confidence interval [CI], 0.58-0.71)—a risk reduction greater than that of statins (29%), aspirin (15%), beta-blockers (23%), or ACE inhibitors (23%).3
Varenicline now has 2 black box warnings
In its 2009 update on recommendations for smoking cessation, the United States Preventive Services Task Force cited NRT and controlled-release bupropion, as well as varenicline, as effective smoking cessation aids.4 Varenicline received US Food and Drug Administration (FDA) approval in 2006. In 2009, the FDA added a black box warning based on evidence of its adverse neuropsychiatric effects, including suicidality.5
In July 2011, the FDA required another label change,6 based on a double-blind RCT published in 2010 showing that for patients with CVD, varenicline is associated with an increased risk.7 As a partial nicotine agonist, varenicline could confer some of the CV risk associated with nicotine abuse.8 The FDA has asked its manufacturer, Pfizer Inc, to conduct further studies.6 The meta-analysis reviewed below—which was not associated with Pfizer or the FDA—was published in September 2011, just a couple of months after the label change.1
STUDY SUMMARY: Risk of ischemic or arrhythmic event is small but significant
Singh et al searched for double-blind RCTs that tested varenicline against a control in tobacco users.1 All included studies had to have reported adverse CV events. The primary outcome was any ischemic or arrhythmic CV event.
The researchers found 15 such studies (n=8216), which ranged in duration from 7 to 52 weeks. Most used a placebo control, but some included bupropion or NRT. The researchers used a Peto odds ratio (OR) for the meta-analysis, useful when combining uncommon events and including studies with no events.9
Compared with placebo, varenicline significantly increased the risk of CV events (odds ratio [OR], 1.72; 95% CI, 1.09-2.71). The incidence of CV events was 1.06% (52 of 4908) among varenicline users vs 0.82% (27 of 3308) in the controls (number needed to harm [NNH]=417).
The limited number of deaths (1.4% among patients taking varenicline vs 2.1% in the placebo groups) prevented analysis of mortality risk. The study with the most statistical power, which accounted for 57% of the overall effect, was the only one that included patients with known stable CV disease. (None included patients with unstable CV disease, whose risk may be greater.) Even when this study was removed, however, the outcome (OR, 2.54; 95% CI, 1.26-5.12) was consistent with the primary result for CV events. A sensitivity analysis comparing the risk associated with varenicline with that of either NRT or bupropion yielded similar results (OR, 1.67; 95% CI, 1.07-26.2). For a higher risk population with stable CVD (5.6% annual risk at baseline), the authors estimated an overall NNH of 28 per year (95% CI, 13-213).
WHAT’S NEW: Evidence of CV risk is cause for concern
This meta-analysis provides evidence that varenicline is associated with a small but significant harmful effect on CV outcomes. The methods Singh et al used for review and article selection appear to be sound, and analysis of the included studies reveals little likelihood of publication bias.
CAVEATS: For many, benefits of quitting outweigh the risks
The absolute risk of a CV event found in this meta-analysis was small—just 0.24%. What’s more, the primary outcome was a composite of a diverse group of outcomes, some more serious than others. And, when compared with the highly positive effects of smoking cessation, the benefit-harm analysis still appears to favor varenicline for most patients. The estimated number needed to treat to get one person to stop smoking for ≥24 weeks is about 10 (95% CI, 8-13).8
CHALLENGES TO IMPLEMENTATION: Finding time to educate patients
The additional time needed to discuss the CV and neuropsychiatric risks of varenicline will be a challenge to physicians working in busy outpatient settings. Proper documentation of this discussion is prudent, however, given the increase in risk with this medication.
Acknowledgement
The Purls Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
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;183:1359-1366.
2. Centers for Disease Control and Prevention. Smoking-attributable mortality, years of potential life lost, and productivity Losses-United States, 2000-2004. MMWR Morbidity and Mortality Weekly Report. 2008;57:1226-1228.
3. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease. JAMA. 2003;290:86-97.
4. US Preventive Services Task Force. Counseling and interventions to prevent tobacco use and tobacco-caused disease in adults and pregnant women. Ann Intern Med. 2009;150:551-555.
5. US Food and Drug Administration. Boxed warning on serious mental health events to be required for Chantix and Zyban [press release]. July 1, 2009. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170100.htm#.Ttab-ZCbYtE. Accessed January 21, 2012.
6. US Food and Drug Administration. Chantix (varenicline): label change - risk of certain cardiovascular adverse events. 2011. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm259469.htm. Accessed January 21, 2012.
7. Rigotti NA, Pipe AL, Benowitz NL, et al. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010;121:221-229.
8. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.
9. Singh S, Loke YK, Spangler JG, et al. Authors’ response. CMAJ. 2011;183:1405, 1407.
Inform patients who are interested in taking varenicline (Chantix) that there is a small cardiovascular (CV) risk associated with it, as well as neuropsychiatric risks—and consider recommending that smokers with a history of cardiovascular disease (CVD) use nicotine replacement therapy (NRT) or bupropion instead.1
STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis.
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;183:1359-1366.
ILLUSTRATIVE CASE
A 53-year-old man asks you to prescribe Chantix to help him stop smoking. He has made several attempts to quit in the past, but never managed to stop for more than 6 months— and has smoked a pack a day for 30 years. The patient does not have a history of heart disease, but he is on statin therapy for hyperlipidemia. What should you tell him about varenicline’s potential benefits and risks?
Tobacco use remains the largest preventable contributor to death and disease in the United States.2 In smokers with coronary heart disease, smoking cessation is associated with a 36% reduction in all-cause mortality (relative risk [RR], 0.64; 95% confidence interval [CI], 0.58-0.71)—a risk reduction greater than that of statins (29%), aspirin (15%), beta-blockers (23%), or ACE inhibitors (23%).3
Varenicline now has 2 black box warnings
In its 2009 update on recommendations for smoking cessation, the United States Preventive Services Task Force cited NRT and controlled-release bupropion, as well as varenicline, as effective smoking cessation aids.4 Varenicline received US Food and Drug Administration (FDA) approval in 2006. In 2009, the FDA added a black box warning based on evidence of its adverse neuropsychiatric effects, including suicidality.5
In July 2011, the FDA required another label change,6 based on a double-blind RCT published in 2010 showing that for patients with CVD, varenicline is associated with an increased risk.7 As a partial nicotine agonist, varenicline could confer some of the CV risk associated with nicotine abuse.8 The FDA has asked its manufacturer, Pfizer Inc, to conduct further studies.6 The meta-analysis reviewed below—which was not associated with Pfizer or the FDA—was published in September 2011, just a couple of months after the label change.1
STUDY SUMMARY: Risk of ischemic or arrhythmic event is small but significant
Singh et al searched for double-blind RCTs that tested varenicline against a control in tobacco users.1 All included studies had to have reported adverse CV events. The primary outcome was any ischemic or arrhythmic CV event.
The researchers found 15 such studies (n=8216), which ranged in duration from 7 to 52 weeks. Most used a placebo control, but some included bupropion or NRT. The researchers used a Peto odds ratio (OR) for the meta-analysis, useful when combining uncommon events and including studies with no events.9
Compared with placebo, varenicline significantly increased the risk of CV events (odds ratio [OR], 1.72; 95% CI, 1.09-2.71). The incidence of CV events was 1.06% (52 of 4908) among varenicline users vs 0.82% (27 of 3308) in the controls (number needed to harm [NNH]=417).
The limited number of deaths (1.4% among patients taking varenicline vs 2.1% in the placebo groups) prevented analysis of mortality risk. The study with the most statistical power, which accounted for 57% of the overall effect, was the only one that included patients with known stable CV disease. (None included patients with unstable CV disease, whose risk may be greater.) Even when this study was removed, however, the outcome (OR, 2.54; 95% CI, 1.26-5.12) was consistent with the primary result for CV events. A sensitivity analysis comparing the risk associated with varenicline with that of either NRT or bupropion yielded similar results (OR, 1.67; 95% CI, 1.07-26.2). For a higher risk population with stable CVD (5.6% annual risk at baseline), the authors estimated an overall NNH of 28 per year (95% CI, 13-213).
WHAT’S NEW: Evidence of CV risk is cause for concern
This meta-analysis provides evidence that varenicline is associated with a small but significant harmful effect on CV outcomes. The methods Singh et al used for review and article selection appear to be sound, and analysis of the included studies reveals little likelihood of publication bias.
CAVEATS: For many, benefits of quitting outweigh the risks
The absolute risk of a CV event found in this meta-analysis was small—just 0.24%. What’s more, the primary outcome was a composite of a diverse group of outcomes, some more serious than others. And, when compared with the highly positive effects of smoking cessation, the benefit-harm analysis still appears to favor varenicline for most patients. The estimated number needed to treat to get one person to stop smoking for ≥24 weeks is about 10 (95% CI, 8-13).8
CHALLENGES TO IMPLEMENTATION: Finding time to educate patients
The additional time needed to discuss the CV and neuropsychiatric risks of varenicline will be a challenge to physicians working in busy outpatient settings. Proper documentation of this discussion is prudent, however, given the increase in risk with this medication.
Acknowledgement
The Purls Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
Inform patients who are interested in taking varenicline (Chantix) that there is a small cardiovascular (CV) risk associated with it, as well as neuropsychiatric risks—and consider recommending that smokers with a history of cardiovascular disease (CVD) use nicotine replacement therapy (NRT) or bupropion instead.1
STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis.
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;183:1359-1366.
ILLUSTRATIVE CASE
A 53-year-old man asks you to prescribe Chantix to help him stop smoking. He has made several attempts to quit in the past, but never managed to stop for more than 6 months— and has smoked a pack a day for 30 years. The patient does not have a history of heart disease, but he is on statin therapy for hyperlipidemia. What should you tell him about varenicline’s potential benefits and risks?
Tobacco use remains the largest preventable contributor to death and disease in the United States.2 In smokers with coronary heart disease, smoking cessation is associated with a 36% reduction in all-cause mortality (relative risk [RR], 0.64; 95% confidence interval [CI], 0.58-0.71)—a risk reduction greater than that of statins (29%), aspirin (15%), beta-blockers (23%), or ACE inhibitors (23%).3
Varenicline now has 2 black box warnings
In its 2009 update on recommendations for smoking cessation, the United States Preventive Services Task Force cited NRT and controlled-release bupropion, as well as varenicline, as effective smoking cessation aids.4 Varenicline received US Food and Drug Administration (FDA) approval in 2006. In 2009, the FDA added a black box warning based on evidence of its adverse neuropsychiatric effects, including suicidality.5
In July 2011, the FDA required another label change,6 based on a double-blind RCT published in 2010 showing that for patients with CVD, varenicline is associated with an increased risk.7 As a partial nicotine agonist, varenicline could confer some of the CV risk associated with nicotine abuse.8 The FDA has asked its manufacturer, Pfizer Inc, to conduct further studies.6 The meta-analysis reviewed below—which was not associated with Pfizer or the FDA—was published in September 2011, just a couple of months after the label change.1
STUDY SUMMARY: Risk of ischemic or arrhythmic event is small but significant
Singh et al searched for double-blind RCTs that tested varenicline against a control in tobacco users.1 All included studies had to have reported adverse CV events. The primary outcome was any ischemic or arrhythmic CV event.
The researchers found 15 such studies (n=8216), which ranged in duration from 7 to 52 weeks. Most used a placebo control, but some included bupropion or NRT. The researchers used a Peto odds ratio (OR) for the meta-analysis, useful when combining uncommon events and including studies with no events.9
Compared with placebo, varenicline significantly increased the risk of CV events (odds ratio [OR], 1.72; 95% CI, 1.09-2.71). The incidence of CV events was 1.06% (52 of 4908) among varenicline users vs 0.82% (27 of 3308) in the controls (number needed to harm [NNH]=417).
The limited number of deaths (1.4% among patients taking varenicline vs 2.1% in the placebo groups) prevented analysis of mortality risk. The study with the most statistical power, which accounted for 57% of the overall effect, was the only one that included patients with known stable CV disease. (None included patients with unstable CV disease, whose risk may be greater.) Even when this study was removed, however, the outcome (OR, 2.54; 95% CI, 1.26-5.12) was consistent with the primary result for CV events. A sensitivity analysis comparing the risk associated with varenicline with that of either NRT or bupropion yielded similar results (OR, 1.67; 95% CI, 1.07-26.2). For a higher risk population with stable CVD (5.6% annual risk at baseline), the authors estimated an overall NNH of 28 per year (95% CI, 13-213).
WHAT’S NEW: Evidence of CV risk is cause for concern
This meta-analysis provides evidence that varenicline is associated with a small but significant harmful effect on CV outcomes. The methods Singh et al used for review and article selection appear to be sound, and analysis of the included studies reveals little likelihood of publication bias.
CAVEATS: For many, benefits of quitting outweigh the risks
The absolute risk of a CV event found in this meta-analysis was small—just 0.24%. What’s more, the primary outcome was a composite of a diverse group of outcomes, some more serious than others. And, when compared with the highly positive effects of smoking cessation, the benefit-harm analysis still appears to favor varenicline for most patients. The estimated number needed to treat to get one person to stop smoking for ≥24 weeks is about 10 (95% CI, 8-13).8
CHALLENGES TO IMPLEMENTATION: Finding time to educate patients
The additional time needed to discuss the CV and neuropsychiatric risks of varenicline will be a challenge to physicians working in busy outpatient settings. Proper documentation of this discussion is prudent, however, given the increase in risk with this medication.
Acknowledgement
The Purls Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
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;183:1359-1366.
2. Centers for Disease Control and Prevention. Smoking-attributable mortality, years of potential life lost, and productivity Losses-United States, 2000-2004. MMWR Morbidity and Mortality Weekly Report. 2008;57:1226-1228.
3. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease. JAMA. 2003;290:86-97.
4. US Preventive Services Task Force. Counseling and interventions to prevent tobacco use and tobacco-caused disease in adults and pregnant women. Ann Intern Med. 2009;150:551-555.
5. US Food and Drug Administration. Boxed warning on serious mental health events to be required for Chantix and Zyban [press release]. July 1, 2009. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170100.htm#.Ttab-ZCbYtE. Accessed January 21, 2012.
6. US Food and Drug Administration. Chantix (varenicline): label change - risk of certain cardiovascular adverse events. 2011. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm259469.htm. Accessed January 21, 2012.
7. Rigotti NA, Pipe AL, Benowitz NL, et al. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010;121:221-229.
8. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.
9. Singh S, Loke YK, Spangler JG, et al. Authors’ response. CMAJ. 2011;183:1405, 1407.
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;183:1359-1366.
2. Centers for Disease Control and Prevention. Smoking-attributable mortality, years of potential life lost, and productivity Losses-United States, 2000-2004. MMWR Morbidity and Mortality Weekly Report. 2008;57:1226-1228.
3. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease. JAMA. 2003;290:86-97.
4. US Preventive Services Task Force. Counseling and interventions to prevent tobacco use and tobacco-caused disease in adults and pregnant women. Ann Intern Med. 2009;150:551-555.
5. US Food and Drug Administration. Boxed warning on serious mental health events to be required for Chantix and Zyban [press release]. July 1, 2009. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170100.htm#.Ttab-ZCbYtE. Accessed January 21, 2012.
6. US Food and Drug Administration. Chantix (varenicline): label change - risk of certain cardiovascular adverse events. 2011. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm259469.htm. Accessed January 21, 2012.
7. Rigotti NA, Pipe AL, Benowitz NL, et al. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010;121:221-229.
8. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.
9. Singh S, Loke YK, Spangler JG, et al. Authors’ response. CMAJ. 2011;183:1405, 1407.
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