Therapeutics
Review: Nicotine replacement therapy increases CVD events; bupropion and varenicline do not
Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ. Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis. Circulation. 2014;129:28-41.
Clinical impact ratings: F ★★★★★✩✩ M ★★★★★★✩ C ★★★★★✩✩ Question
Conclusions
Do smoking cessation therapies (nicotine replacement therapy [NRT], bupropion, and varenicline) increase risk for cardiovascular (CV) events?
Nicotine replacement therapy increases risk for any cardiovascular events but not major adverse cardiovascular events. Bupropion and varenicline do not increase risk for cardiovascular events or major adverse cardiovascular events.
Review scope
Source of funding: No external funding.
Included studies assessed NRT (any marketed dose or combination) or licensed doses of bupropion or varenicline for any duration as cessation therapy in smokers and reported CVD events. Outcomes were any CV event and major adverse CV events (MACE) (CV death, nonfatal myocardial infarction, and nonfatal stroke).
For correspondence: Dr. E.J. Mills, Stanford University School of Medicine, Stanford, CA, USA. E-mail [email protected]. ■
Commentary Smoking increases risk for CV events and death. Stopping smoking reduces these risks, but this is often difficult. Several forms of nicotine replacement are available to help patients quit (gum, patches, and lozenges) as well as medications to reduce nicotine cravings, such as bupropion and varenicline.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane CENTRAL, AMED, CINAHL, TOXNET, Development and Reproductive Toxicology, Hazardous Substances Databank, PsycINFO, Web of Science (all to Mar 2013), reference lists, reviews, and health technology assessments were searched for randomized controlled trials (RCTs). Authors were contacted. 63 RCTs (n = 30 508, median treatment duration 12 wk, median follow-up 12 mo) met the selection criteria. Placebo-controlled trials assessed NRT (19 RCTs), high-dose NRT (1 RCT), bupropion (27 RCTs), and varenicline (18 RCTs); 1 RCT compared NRT with no treatment; head-to-head trials compared bupropion with varenicline (2 RCTs), bupropion with NRT (3 RCTs), and varenicline with NRT (1 RCT). Random sequence generation was clear in 39 RCTs, allocation was clearly concealed in 28 RCTs, 58 RCTs were blinded, and 59 included biological confirmation of smoking cessation.
Main results Meta-analyses of placebo-controlled trials are in the Table. Metaanalyses of head-to-head comparisons showed no increased risks for CV events or MACE.
A meta-analysis found NRT to be safe (1), even when used by persons who are actively smoking, but questions about its risk profile remain. Previous meta-analyses of the effects of varenicline have shown inconsistent results for risk for CV events and death (2, 3). The review by Mills and colleagues found that NRT was associated with a small increase in risk for any CV event compared with placebo (2.8% vs 1.6%). The definition of CV event was broad; sensitivity analysis showed that the increase was due to relatively minor events like tachycardia, bradycardia, or palpitations. Analyses of MACE, however, showed no increased risk with NRT, varenicline, or bupropion. Mills and colleagues also used network meta-analysis, including both direct and indirect comparisons between medications, even when they were not compared in the same study. The network meta-analyses showed that bupropion was associated with fewer MACE than placebo, NRT, or varenicline.
Meta-analyses of pharmacologic smoking cessation therapies in smokers* Outcomes
CV events
MACE‡
Comparators
Number of Weighted event rates At a median 12 mo trials (n) Intervention Control RRI/RRR (95% CI)
NRT vs placebo or no treatment
21 (11 647)
2.8%
1.6%
RRI 81% (35 to 143)†
Bupropion vs placebo
27 (10 402)
0.97%
0.94%
RRI 3% (−29 to 50)
Varenicline vs placebo
18 (8058)
1.4%
1.1%
RRI 24% (−15 to 81)
NRT vs placebo or no treatment
21 (11 647)
0.18%
0.13%
RRI 38% (−42 to 226)
Bupropion vs placebo
27 (10 402)
0.32%
0.56%
RRR 43% (−4 to 69)
Varenicline vs placebo
18 (8058)
0.52%
0.36%
RRI 44% (−27 to 183)
*CV = cardiovascular; MACE = major adverse cardiovascular events; NRT = nicotine replacement therapy; other abbreviations defined in Glossary. Weighted event rates, RRI, RRR, and CI calculated from data in article using a random-effects model.
The review reassures us that smoking cessation aids are safer than the known CV risks of continuing to smoke. Kate Rowland, MD, MS University of Chicago Chicago, Illinois, USA References 1. Moore D, Aveyard P, Connock M, et al. Effectiveness and safety of nicotine replacement therapy assisted reduction to stop smoking: systematic review and meta-analysis. BMJ. 2009;338:b1024. 2. Prochaska JJ, Hilton JF. Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis. BMJ. 2012;344:e2856. 3. Singh S, Loke YK, Spangler JG, Furberg CD. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ. 2011;183:1359-66.
†Number needed to harm 80 (CI 45 to 184). ‡Composite of CV death, nonfatal myocardial infarction, and nonfatal stroke.
© 2014 American College of Physicians JC2 Downloaded From: http://annals.org/ by a University of South Dakota User on 06/06/2014
15 April 2014 | ACP Journal Club | Volume 160 • Number 8
Review: Nicotine replacement therapy increases CVD events; bupropion and varenicline do not
Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ. Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis. Circulation. 2014;129:28-41.
Clinical impact ratings: F ★★★★★✩✩ M ★★★★★★✩ C ★★★★★✩✩ Question
Conclusions
Do smoking cessation therapies (nicotine replacement therapy [NRT], bupropion, and varenicline) increase risk for cardiovascular (CV) events?
Nicotine replacement therapy increases risk for any cardiovascular events but not major adverse cardiovascular events. Bupropion and varenicline do not increase risk for cardiovascular events or major adverse cardiovascular events.
Review scope
Source of funding: No external funding.
Included studies assessed NRT (any marketed dose or combination) or licensed doses of bupropion or varenicline for any duration as cessation therapy in smokers and reported CVD events. Outcomes were any CV event and major adverse CV events (MACE) (CV death, nonfatal myocardial infarction, and nonfatal stroke).
For correspondence: Dr. E.J. Mills, Stanford University School of Medicine, Stanford, CA, USA. E-mail [email protected]. ■
Commentary Smoking increases risk for CV events and death. Stopping smoking reduces these risks, but this is often difficult. Several forms of nicotine replacement are available to help patients quit (gum, patches, and lozenges) as well as medications to reduce nicotine cravings, such as bupropion and varenicline.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane CENTRAL, AMED, CINAHL, TOXNET, Development and Reproductive Toxicology, Hazardous Substances Databank, PsycINFO, Web of Science (all to Mar 2013), reference lists, reviews, and health technology assessments were searched for randomized controlled trials (RCTs). Authors were contacted. 63 RCTs (n = 30 508, median treatment duration 12 wk, median follow-up 12 mo) met the selection criteria. Placebo-controlled trials assessed NRT (19 RCTs), high-dose NRT (1 RCT), bupropion (27 RCTs), and varenicline (18 RCTs); 1 RCT compared NRT with no treatment; head-to-head trials compared bupropion with varenicline (2 RCTs), bupropion with NRT (3 RCTs), and varenicline with NRT (1 RCT). Random sequence generation was clear in 39 RCTs, allocation was clearly concealed in 28 RCTs, 58 RCTs were blinded, and 59 included biological confirmation of smoking cessation.
Main results Meta-analyses of placebo-controlled trials are in the Table. Metaanalyses of head-to-head comparisons showed no increased risks for CV events or MACE.
A meta-analysis found NRT to be safe (1), even when used by persons who are actively smoking, but questions about its risk profile remain. Previous meta-analyses of the effects of varenicline have shown inconsistent results for risk for CV events and death (2, 3). The review by Mills and colleagues found that NRT was associated with a small increase in risk for any CV event compared with placebo (2.8% vs 1.6%). The definition of CV event was broad; sensitivity analysis showed that the increase was due to relatively minor events like tachycardia, bradycardia, or palpitations. Analyses of MACE, however, showed no increased risk with NRT, varenicline, or bupropion. Mills and colleagues also used network meta-analysis, including both direct and indirect comparisons between medications, even when they were not compared in the same study. The network meta-analyses showed that bupropion was associated with fewer MACE than placebo, NRT, or varenicline.
Meta-analyses of pharmacologic smoking cessation therapies in smokers* Outcomes
CV events
MACE‡
Comparators
Number of Weighted event rates At a median 12 mo trials (n) Intervention Control RRI/RRR (95% CI)
NRT vs placebo or no treatment
21 (11 647)
2.8%
1.6%
RRI 81% (35 to 143)†
Bupropion vs placebo
27 (10 402)
0.97%
0.94%
RRI 3% (−29 to 50)
Varenicline vs placebo
18 (8058)
1.4%
1.1%
RRI 24% (−15 to 81)
NRT vs placebo or no treatment
21 (11 647)
0.18%
0.13%
RRI 38% (−42 to 226)
Bupropion vs placebo
27 (10 402)
0.32%
0.56%
RRR 43% (−4 to 69)
Varenicline vs placebo
18 (8058)
0.52%
0.36%
RRI 44% (−27 to 183)
*CV = cardiovascular; MACE = major adverse cardiovascular events; NRT = nicotine replacement therapy; other abbreviations defined in Glossary. Weighted event rates, RRI, RRR, and CI calculated from data in article using a random-effects model.
The review reassures us that smoking cessation aids are safer than the known CV risks of continuing to smoke. Kate Rowland, MD, MS University of Chicago Chicago, Illinois, USA References 1. Moore D, Aveyard P, Connock M, et al. Effectiveness and safety of nicotine replacement therapy assisted reduction to stop smoking: systematic review and meta-analysis. BMJ. 2009;338:b1024. 2. Prochaska JJ, Hilton JF. Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis. BMJ. 2012;344:e2856. 3. Singh S, Loke YK, Spangler JG, Furberg CD. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ. 2011;183:1359-66.
†Number needed to harm 80 (CI 45 to 184). ‡Composite of CV death, nonfatal myocardial infarction, and nonfatal stroke.
© 2014 American College of Physicians JC2 Downloaded From: http://annals.org/ by a University of South Dakota User on 06/06/2014
15 April 2014 | ACP Journal Club | Volume 160 • Number 8
