Use of Contrave, Naltrexone with Bupropion, Bupropion, or Naltrexone and Major Adverse Cardiovascular Events: A Systematic Literature Review

Figures & data

Figure 1 PRISMA flow diagram detailing study selection, inclusion and exclusion. *Bibliographies of all review articles published in 2021 and a subset of earlier reviews selected based on titles and abstracts were screened for additional relevant articles.

Note: Adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.¹⁵

Table 1 Breakdown of Publications Identified by Treatment of Interest

	Treatment	Contrave^®/N-B	Bupropion	Naltrexone	Total
Total	n	7	32	31	70
Reported CV adverse events	n	7	19	9	35
	%	100	59.4	29	-
	# patients	11,536	3,112,198	9422	3,133,156
Reported zero CV adverse events	n	0	13	22	35
	%	0	40.6	71	-
	# patients	0	3,627	2,766	6,393

Abbreviations: CV, cardiovascular; N, number (of); N-B, naltrexone-bupropion.

Table 2 Breakdown of Studies Reporting CV Events According to Study Design

Treatment		Contrave^®/N-B	Bupropion	Naltrexone
Total Studies		7	19	9
Randomized controlled trial	N	7	8	7
	%	100	42.1	77.8
	Patients*	11,536	17,835	1,118
Observational cohort	N	0	10	1
	%	0	52.6	11.1
	Patients	0	2,768,655	8,226
Other observational study design	N	0	1	1
	%	0	5.3	11.1
	Patients	0	325,708	78

Notes: Patients is the sum of study participants from each distinct study population. For studies that conducted analyses on the same patient population, only the study reporting the full patient population is counted here to avoid duplication of patients.

Abbreviations: N, number (of); N-B, naltrexone-bupropion.

Table 3 Studies Reporting on MACE and MACE+

Treatment	Contrave^®/Naltrexone-Bupropion ER	Bupropion
Author	Nissen^Citation78	Benowitz^Citation54	Eberg^Citation61	Eisenberg^Citation62	Kittle^Citation69
Year	2016	2018	2019	2013	2017
Study design	RCT	RCT	Observational cohort	RCT	RCT
Study indication	Weight loss	Smoking cessation	Smoking cessation	Smoking cessation	Smoking cessation
Reported length of follow-up	Median 121 weeks, interquartile range 114–128 weeks	52 weeks	1 year	12 months	>6 weeks
No. Patients	8,905	8,058	233,738	392	7224	1616
Adverse event frequency, treatment group	Naltrexone-bupropion: MACE 119/4455 (2.7%) at end of study 90/4455 (2.0%) at 50% interim 35/4455 (0.8%) at 25% interim MACE30* 47/4455 (1.1%) at end of study 43/4455 (1.0%) at 50% interim 23/4455 (0.5%) at 25% interim MACE+^† 164/4455 (3.7%) at end of study 133/4455 (3.0%) at 50% interim 63/4455 (1.4%) at 25% interim MACE30+^‡ 226/4455 (5.1%) at end of study 188/4455 (4.2%) at 50% interim 91/4455 (2.0%) at 25% interim	Bupropion: MACE 9/2006 (0.4%) MACE+^§ 15/2006 (0.7%)	MACE+^‖ 13/9931 (0.1%)	MACE Bupropion: 25/192 (13.0%)	Bupropion vs placebo (primary comparison) MACE 3/4,297 (0.070%; 95% CI: 0.014–0.204%) MACE+^¶ 6/4297 (0.140%; 95% CI: 0.051–0.304%)	Bupropion vs active control group (secondary comparison): MACE 1/598 (0.2%) MACE+^¶ NR
Adverse event frequency, comparator group	Placebo: MACE 124/4450 (2.8%) at end of study 102/4450 (2.3%) at 50% interim 59/4450 (1.3%) at 25% interim MACE30* 39/4450 (0.9%) at end of study 37/4450 (0.8%) at 50% interim 30/4450 (0.7%) at 25% interim MACE+^† 171/4450 (3.8%) at end of study 142/4450 (3.2%) at 50% interim 79/4450 (1.8%) at 25% interim MACE30+^‡ 244/4450 (5.5%) at end of study 205/4450 (4.6%) at 50% interim 105/4450 (2.4%) at 25% interim	MACE Varenicline: 3/2016 (0.1%) NRT: 6/2022 (0.3%) Placebo: 8/2014 (0.4%) MACE+^§ Varenicline: 10/2016 (0.5%) NRT: 10/2022 (0.5%) Placebo: 12/2014 (0.6%)	MACE+^‖ Varenicline: 90/68,468 (0.1%) NRT: 513/155,339 (0.3%)	MACE Placebo: 22/200 (11.0%)	Placebo: MACE 4/2927 (0.137%; 95% CI: 0.037–0.349%) MACE+^¶ 7/2927 (0.239%; 95% CI: 0.096–0.492%)	Active comparator: MACE 0/1018 (0%) MACE+^¶ NR
Effect measure	HR (99.7% CI): MACE 0.95 (0.65–1.38) at end of study 0.88 (0.57–1.34) at 50% interim 0.59 (0.39–0.90) at 25% interim MACE30* 0.99 (0.52–1.87) at end of study 0.97 (0.50–1.88) at 50% interim 0.71 (0.41–1.22) at 25% interim MACE+^† 0.95 (0.69–1.31) at end of study 0.93 (0.66–1.33) at 50% interim 0.80 (0.57–1.11) at 25% interim MACE30+^‡ 0.92 (0.70–1.20) at end of study 0.91 (0.68–1.23) at 50% interim 0.87 (0.65–1.15) at 25% interim	MACE Varenicline: RD (95% CI) = −0.91 (−4.78 to 2.96) HR (95% CI) = 0.37 (0.12–1.13) NRT: RD (95% CI) =0.22 (−2.48 to 2.93) HR (95% CI) = 1.46 (0.53–4.02) Placebo: RD (95% CI) = −0.08 (−2.63 to 2.48) HR (95% CI) =1.09 (0.42–2.83) MACE+^§ Varenicline: RD (95% CI) = −0.59 (−2.84 to 1.67) HR (95% CI) = 0.67 (0.30–1.46) NRT: RD (95% CI) = 0.27 (−1.95 to 2.49) HR (95% CI) = 1.46 (0.67–3.21) Placebo: RD (95% CI) = 0.11 (−2.04 to 2.25) HR (95% CI) = 1.21 (0.57–2.58)	MACE+^‖ Adjusted HR (95% CI): Varenicline/Bupropion: 1.08 (0.57–2.04)/1.00 (ref) Bupropion/NRT: 0.76 (0.43–1.33)/1.00 (ref)	MACE Fisher’s exact p = 0.64 (calculated)	Difference in proportions: MACE p = 0.4517 MACE+^¶ p=0.3998	MACE Fisher’s exact p = 0.37 (calculated)

Notes: *MACE within 30 days of last treatment. ^†MACE + hospitalization for unstable angina. ^‡MACE + hospitalization for unstable angina within 30 days of last treatment. ^§Any MACE or a new-onset or worsening peripheral vascular disease requiring intervention, a need for coronary revascularization, or hospitalization for unstable angina. ^‖Composite of myocardial infarction, coronary revascularization, stroke, and all-cause mortality. ^¶MACE + new diagnosis of peripheral vascular disease + hospitalization for unstable angina or coronary revascularization.

Table 4 Studies Reporting on Cardiovascular Death

	Author	Year	Study Design	Study Indication	Reported Length of Follow-Up	No. Patients	Outcome	Adverse Event Frequency, Treatment Group	Adverse Event Frequency, Comparator Group	Effect Measure
Contrave^®	Nissen^Citation78	2016	RCT	Weight loss	Median 121 weeks, interquartile range 114–128 weeks	8,905	Cardiovascular death	Naltrexone-bupropion:	Placebo:	HR (99.7% CI)
								26/4455 (0.6%) at end of study	42/4450 (0.9%) at end of study	0.61 (0.30–1.27) at end of study
								17/4455 (0.4%) at 50% interim	34/4450 (0.8%) at 50% interim	0.50 (0.21, 1.19) at 50% interim
								5/4455 (0.1%) at 25% interim	19/4450 (0.4%) at 25% interim	0.26 (0.10–0.70) at 25% interim
							Cardiovascular death within 30 days of last treatment	Naltrexone-bupropion:	Placebo:	HR (99.7% CI)
								9/4455 (0.2%) at end of study	11/4450 (0.2%) at end of study	0.67 (0.18–2.54) at end of study
								8/4455 (0.2%) at 50% interim	10/4450 (0.2%) at 50% interim	0.67 (0.17–2.72) at 50% interim
								4/4455 (0.1%) at 25% interim	7/4450 (0.2%) at 25% interim	0.57 (0.16–1.94) at 25% interim
Bupropion	Anthenelli^Citation52	2016	RCT	Smoking cessation	24 weeks	8,058	CV death within 30 days of last dose	Non-psychiatric bupropion: 0/989 (0.0%) (0 cardiovascular deaths > 30 days after last dose)	Non-psychiatric nicotine patch: 0/1006 (0.0%) (0 cardiovascular deaths > 30 days after last dose)	Fisher’s exact p = 1.00 (calculated)
									Non-psychiatric placebo: 0/999 (0.0%) (1 death (0.1%) from myocardial infarction > 30 days after last dose)	Fisher’s exact p = 1.00 (calculated)
								Psychiatric bupropion: 1/1017 (0.1%) death from cardiovascular event (0 cardiovascular deaths > 30 days after last dose)	Psychiatric varenicline: 0/1026 (0.0%) (0 cardiovascular deaths > 30 days after last dose)	Fisher’s exact p = 1.00 (calculated)
									Psychiatric nicotine patch: 0/1016 (0.0%) (0 cardiovascular deaths > 30 days after last dose)	Fisher’s exact p = 0.50 (calculated)
									Psychiatric placebo: 1/1015 (0.1%) death from pulmonary embolism (0 cardiovascular deaths > 30 days after last dose)	Fisher’s exact p = 1.00 (calculated)
	Benowitz^Citation54	2018	RCT	Smoking cessation	52 weeks	8,058	CV death	Bupropion: 2/2006 (0.1%)	Varenicline: 1/2016 (<0.1%)	Varenicline: Fisher’s exact p = 0.62 (calculated) NRT: Fisher’s exact p = 0.25 (calculated) Placebo: Fisher’s exact p = 1.00 (calculated)
									NRT: 0/2022 (0.0%)
									Placebo: 2/2014 (0.1%)
	Eisenberg^Citation62	2013	RCT	Smoking cessation	12 months; 9 weeks for primary analysis	392	Cardiac death	Bupropion: 9/192 (4.7%) 4 cardiac deaths occurred during the 9-week treatment period: - 2 days post-randomization due to coronary dissection - 5 days post-randomization due to cardiac arrest - 9 days post-randomization due to multisystem organ failure post-coronary artery bypass graft - 4 weeks post-randomization due to myocardial infarction leading to cardiac arrest	Placebo: 6/200 (3.0%) 2 cardiac deaths occurred during the 9-week treatment period: - 9 weeks post-randomization due to complications related to duodenal perforation and recurrent septic shock - 9 weeks post-randomization due to ischemic event in bowel or spinal cord, possible embolic event could not be ruled out	Fisher’s exact p = 0.44 (calculated)
	Kittle^Citation69	2017	RCT	Smoking cessation	≥ 6 weeks	7,224	CV death	Bupropion vs placebo: 0/4297 (0%)	Placebo comparator: 0/2927 (0%)	Fisher’s exact p = 1.00 (calculated)
	Svanström^Citation82	2012	Observational cohort	Smoking cessation	6 months (primary analyses)	35,852	CV death	Bupropion: 6 events per 8425 person-years. Incidence rate per 1000 person-years: 0.7	Varenicline: 3 per 8281 person-years. Incidence rate per 1000 person-years: 0.4	HR (95% CI) 1.96 (0.50–7.69)
Naltrexone	Bisaga^Citation55	2018	RCT	Substance use	NR	378	CV death	Naltrexone/placebo/buprenorphine: 0/126 (0.0%)	Naltrexone/placebo: 0/126 (0.0%) Placebo: 0/126 (0.0%)	Fisher’s exact p = 1.00 (calculated)
	Kelty^Citation68	2019	Observational cohort	Substance use	Mean ± SD from start of treatment to start of new treatment, death, or end of follow-up (31 December 2012): Naltrexone implant: 4.9 ± 3.3 years Methadone: 5.5 ± 3.3 years Buprenorphine: 4.5 ± 3.4 years	8,226	CV death	Naltrexone implant (1461 users): 0.6 per 1000 patient-years (95% confidence interval: 0.2–1.5)	Methadone (3515 users): 0.9 per 1000 patient-years (95% confidence interval: 0.5–1.4)	NR
									Buprenorphine (3250 users): 0.8 per 1000 patient-years (95% confidence interval: 0.4–1.4)
	Krupitsky^Citation72	2013	RCT	Substance use	18 months from baseline	114	CV death	Continued on naltrexone: 0/67 (0%)	Switched from placebo to naltrexone: 0/47 (0%)	Fisher’s exact p = 1.00 (calculated)
	Krupitsky^Citation73	2019	RCT	Substance use	48 weeks	200	Death from heart disease	Oral naltrexone: 0/100 (0%) Naltrexone implant: 2/100 (2.0%)	NA	Fisher’s exact p = 0.50 (calculated)

Table 5 Studies Reporting on Myocardial Infarction

	Author	Year	Study Design	Study Indication	Reported Length of Follow-Up	No. Patients	Outcome	Adverse Event Frequency, Treatment Group	Adverse Event Frequency, Comparator Group	Effect Measure
Contrave^®	Apovian^Citation53	2013	RCT	Weight loss	56 weeks; 28 weeks for primary efficacy analyses	1,484	Myocardial infarction	Naltrexone-bupropion: 1/992 (0.1%) Naltrexone-bupropion treated participant had active coronary artery disease, angina pectoris, hyperlipidemia, and hypertension.	Placebo: 0/492 (0.0%)	Fisher’s exact p = 1.00 (calculated)
	Nissen^Citation78	2016	RCT	Weight loss	Median 121 weeks, interquartile range 114–128 weeks	8,905	Nonfatal myocardial infarction	Naltrexone-bupropion:	Placebo:	HR (99.7% CI)
								68/4455 (1.5%) at end of study	67/4450 (1.5%) at end of study	1.01 (0.61–1.66) at end of study
								54/4455 (1.2%) at 50% interim	54/4450 (1.2%) at 50% interim	1.00 (0.57–1.75) at 50% interim
								23/4455 (0.5%) at 25% interim	33/4450 (0.7%) at 25% interim	0.70 (0.41–1.18) at 25% interim
							Fatal or nonfatal myocardial infarction	Naltrexone-bupropion:	Placebo:	HR (99.7% CI)
								69/4455 (1.5%) at end of study	71/4450 (1.6%) at end of study	0.96 (0.59–1.58) at end of study
								55/4455 (1.2%) at 50% interim	57/4450 (1.3%) at 50% interim	0.96 (0.55–1.67) at 50% interim
								24/4455 (0.5%) at 25% interim	34/4450 (0.8%) at 25% interim	0.70 (0.42–1.19) at 25% interim
							Nonfatal myocardial infarction within 30 days of last treatment	Naltrexone-bupropion:	Placebo:	HR (99.7% CI)
								26/4455 (0.6%) at end of study	22/4450 (0.5%) at end of study	0.98 (0.42–2.30) at end of study
								24/4455 (0.5%) at 50% interim	21/4450 (0.5%) at 50% interim	0.96 (0.40–2.3) at 50% interim
								13/4455 (0.3%) at 25% interim	16/4450 (0.4%) at 25% interim	0.77 (0.37–1.60) at 25% interim
Bupropion	Benowitz^Citation54	2018	RCT	Smoking cessation	52 weeks	8,058	Nonfatal MI	Bupropion: 4/2006 (0.2%)	Varenicline: 2/2016 (0.1%)	Varenicline: Fisher’s exact p = 0.45 (calculated) NRT: Fisher’s exact p = 0.73 (calculated) Placebo: Fisher’s exact p = 1.00 (calculated)
									NRT: 3/2022 (0.1%)
									Placebo: 5/2014 (0.2%)
	Chen^Citation58	2021	Observational cohort	Psychiatric	Maximum 1999–2013	500,990	Myocardial infarction	NR	NR	HR (95% CI) Bupropion ≥ 180 days vs 0 or < 180 days: adjusted 1.25 (0.78–2.03) Bupropion < 180 cumulative defined daily doses vs 0: adjusted 1.024 (0.664–1.580) Bupropion ≥ 180 cumulative defined daily doses vs 0: adjusted: 0.528 (0.075–3.733)
	Eisenberg^Citation62	2013	RCT	Smoking cessation	12 months; 9 weeks for primary analysis	392	Myocardial infarction	Bupropion: 5/192 (2.6%)	Placebo: 5/200 (2.5%)	Fisher’s exact p = 1.00 (calculated)
	Graham^Citation64	2014	Observational cohort	Smoking cessation	6 months	88,957	Acute myocardial infarction	Bupropion: 31/14,133 (0.2%)	Varenicline: 133/74,824 (0.2%)	Adjusted HR (95% CI) 0.79 (0.5–1.24)
	Kittle^Citation69	2017	RCT	Smoking cessation	≥ 6 weeks	7,224	Nonfatal myocardial infarction	Bupropion vs placebo: 2/4297 (Proportion: 0.047%; 95% CI, 0.006–0.168%)	Placebo comparator: 3/2927 (Proportion: 0.102%; 95% CI, 0.021–0.299%)	Fisher’s exact p = 0.40 (calculated)
	Monárrez-Espino^Citation77	2018	Other observational	Smoking cessation	12 weeks	325,708	Myocardial infarction	Bupropion: 1–14 days before event: 16 discordant pairs during case period, 14 during control period 15–28 days before event: 14 discordant pairs during case period, 19 during control period 29–84 days before event: 47 discordant pairs during case period, 60 during control period 1–84 days before event: 73 discordant pairs during case period, 86 during control period	Varenicline: 1–14 days before event: 46 discordant pairs during case period, 43 during control period 15–28 days before event: 40 discordant pairs during case period, 43 during control period 29–84 days before event: 107 discordant pairs during case period, 140 during control period 1–84 days before event: 171 discordant pairs during case period, 173 during control period	OR (95% CI) Bupropion vs none: 1–14 days before event: 1.14 (0.55–2.34) 15–28 days before event: 0.73 (0.36–1.46) 29–84 days before event: 0.78 (0.53–1.14) 1–84 days before event: 0.84 (0.62–1.15)
Naltrexone	Garbutt^Citation63	2016	RCT	Substance use	12 weeks	80	Myocardial infarction	Naltrexone: 1/40 (2.5%) ”One serious adverse event, a myocardial infarction, was not attributed to naltrexone treatment”	Placebo: 0/40 (0.0%)	Fisher’s exact p = 1.00 (calculated)

Table 6 Studies Reporting on Stroke

	Author	Year	Study Design	Study Indication	Reported Length of Follow-Up	No. Patients	Outcome	Adverse Event Frequency, Treatment Group	Adverse Event Frequency, Comparator Group	Effect Measure
Contrave^®	Nissen^Citation78	2016	RCT	Weight loss	Median 121 weeks, interquartile range 114–128 weeks	8,905	Nonfatal stroke	Naltrexone-bupropion:	Placebo:	HR (99.7% CI)
								28/4455 (0.6%) at end of study	21/4450 (0.5%) at end of study	1.32 (0.57–3.08) at end of study
								21/4455 (0.5%) at 50% interim	19/4450 (0.4%) at 50% interim	1.10 (0.44, 2.78) at 50% interim
								7/4455 (0.2%) at 25% interim	10/4450 (0.2%) at 25% interim	0.70 (0.27–1.83) at 25% interim
							Fatal or nonfatal stroke	Naltrexone-bupropion:	Placebo:	HR (99.7% CI)
								31/4455 (0.7%) at end of study	23/4450 (0.5%) at end of study	1.34 (0.60–2.99) at end of study
								22/4455 (0.5%) at 50% interim	21/4450 (0.5%) at 50% interim	1.04 (0.43–2.55) at 50% interim
								7/4455 (0.2%) at 25% interim	11/4450 (0.2%) at 25% interim	0.63 (0.25–1.64) at 25% interim
							Nonfatal stroke within 30 days of last treatment	Naltrexone-bupropion:	Placebo:	HR (99.7% CI)
								12/4455 (0.3%) at end of study	7/4450 (0.2%) at end of study	1.35 (0.33–5.47) at end of study
								11/4455 (0.2%) at 50% interim	7/4450 (0.2%) at 50% interim	1.25 (0.30–5.18) at 50% interim
								6/4455 (0.1%) at 25% interim	7/4450 (0.2%) at 25% interim	0.72 (0.24–2.16) at 25% interim
Bupropion	Benowitz^Citation54	2018	RCT	Smoking cessation	52 weeks	8,058	Nonfatal stroke	Bupropion: 4/2006 (0.2%)	Varenicline: 0/2016 (0.0%)	Varenicline: Fisher’s exact p = 0.06 (calculated) NRT: Fisher’s exact p = 0.73 (calculated) Placebo: Fisher’s exact p = 0.22 (calculated)
									Nicotine replacement therapy: 3/2022 (0.1%)
									Placebo: 1/2014 (<0.1%)
	Carney^Citation56	2020	Observational cohort	Smoking cessation	12 months or patient therapy duration plus 30 days	618,497	Cerebral infarction (primary analyses)	Bupropion: 290/131,562 (0.2%)	Nicotine replacement therapy: 192/32,237 (0.6%)	RR (95% CI)Adjusted: 0.78 (0.64–0.96)
									Varenicline: 1052/454,698 (0.2%)	Fisher’s exact p = 0.49 (calculated)
							Cerebral infarction (time-to-event sensitivity analyses)	Bupropion: 138/131,562 (0.1%), patient years: 52,680, Incidence rate per 1000 patient-years: 2.6	NRT: 57/32,237 (0.2%), patient years: 5878, Incidence rate per 1000 patient-years: 9.7	HR (95% CI) Adjusted: 0.77 (0.54–1.10)
									Varenicline: 288/454,698 (0.1%), patient years: 95,893, Incidence rate per 1000 patient-years: 3.0	Fisher’s exact p = <0.00001 (calculated)
	Carney^Citation57	2021	Observational cohort	Smoking cessation	Primary analysis 1 year	116,442	Cerebral infarction	Bupropion: 9/5838 (0.2%)	NRT: 186/71,510 (0.3%)	RR (95% CI)Adjusted: 0.73 (0.37–1.45)
									Varenicline: 83/39,094 (0.2%)	Fisher’s exact p = 0.44 (calculated)
	Graham^Citation64	2014	Observational cohort	Smoking cessation	6 months	88,957	Stroke	Bupropion: 13/14,133 (0.1%)	Varenicline: 83/74,824 (0.1%)	HR (95% CI) Adjusted: 1.27 (0.63–2.55)
	Kittle^Citation69	2017	RCT	Smoking cessation	≥ 6 weeks	7,224	Nonfatal stroke	Bupropion vs placebo: 1/4297 (0.023%; 0.001–0.130%)	Placebo comparator: 1/2927 (0.034%; 0.001–0.190%)	Fisher’s exact p = 1.00 (calculated)
	Kotz^Citation70	2015	Observational cohort	Smoking cessation	6 months	164,766	Cerebral infarction	Bupropion: 18/6557 (0.3%)	Nicotine replacement therapy: 871/106,759 (0.8%)	HR (95% CI) Adjusted: 0.55 (0.35–0.89) Propensity score matched: 0.46 (0.24–0.89)
									Varenicline: 164/51,450 (0.3%)	Fisher’s exact p = 0.64 (calculated)
	Kotz^Citation71	2017	Observational cohort	Smoking cessation	6 months	16,679	Stroke	Bupropion: 3/350 (0.9%)	Nicotine replacement therapy: 155/10,426 (1.5%)	HR (95% CI) Adjusted: 0.62 (0.20–1.96) Propensity score matched: 0.49 (0.12–1.95)
									Varenicline: 34/3574 (1.0%)	Fisher’s exact p = 1.00 (calculated)
	Monárrez-Espino^Citation77	2018	Other observational	Smoking cessation	12 weeks	249,430	Ischemic stroke	Bupropion: 1–14 days before event: 7 discordant pairs during case period, 6 during control period 15–28 days before event: 7 discordant pairs during case period, 5 during control period 29–84 days before event: 29 discordant pairs during case period, 31 during control period 1–84 days before event: 41 discordant pairs during case period, 38 during control period	Varenicline: 1–14 days before event: 29 discordant pairs during case period, 23 during control period 15–28 days before event: 25 discordant pairs during case period, 28 during control period 29–84 days before event: 62 discordant pairs during case period, 73 during control period 1–84 days before event: 99 discordant pairs during case period, 93 during control period (p. 611)	OR (95% CI): Bupropion vs none: 1–14 days before event: 1.16 (0.39–3.47) 15–28 days before event: 1.40 (0.44–4.41) 29–84 days before event: 0.93 (0.56–1.55) 1–84 days before event: 1.07 (0.69–1.67) Varenicline vs none: 1–14 days before event: 1.26 (0.72–2.17) 15–28 days before event: 0.89 (0.52–1.53) 29–84 days before event: 0.84 (0.60–1.19) 1–84 days before event: 1.06 (0.80–1.41)
	Svanström^Citation82	2012	Observational cohort	Smoking cessation	6 months (primary analyses)	35,852	Ischaemic stroke	Bupropion: 21 events per 8419 person-years. Incidence rate per 1000 person-years: 2.5	Varenicline: 16 events per 8278 person-years. Incidence rate per 1s000 person-years: 1.9	HR (95% CI): 1.30 (0.68–2.50)

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