Table 3.
Studies Reporting on MACE and MACE+
| Treatment | Contrave®/Naltrexone-Bupropion ER | Bupropion | ||||
|---|---|---|---|---|---|---|
| Author | Nissen78 | Benowitz54 | Eberg61 | Eisenberg62 | Kittle69 | |
| 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.