Comparisons of high-dose and combination nicotine replacement therapy, varenicline, and bupropion for smoking cessation: A systematic review and multiple treatment meta-analysis

Figures & data

Figure 1. Flow diagram of included studies by pharmacotherapy.

Table I. Pairwise meta-analysis results for smoking abstinence.

Number of studies	References*	Time point	Response rate, responders/total randomized	Relative risk (95% confidence interval)	I^2	P value
NRT patch standard-dose (≤ 22 mg) versus controls
45 RCTs	(1–37)	4 weeks	3100/7374 vs. 1732/5980	1.51 (1.38–1.65)	67%	< 0.001
46 RCTs	(2,3,5–8,10,11,13–15,17, 20–24,26–28,31–34,37–51,113)	3 months	2605/8528 vs. 1368/7143	1.63 (1.42–1.88)	80%	< 0.001
42 RCTs	(3–5,7–9,11–23,30,34–38, 40,41,43–45,47,49–55)	6 months	2437/10833 vs. 1210/9096	1.59 (1.41–1.80)	63%	< 0.001
32 RCTs	(5,7,8,12,14–16,20–23,25,27–29,33, 37,38,40,41,45–48,53,55,56)	12 months	1431/8174 vs. 863/7343	1.53 (1.35–1.73)	41%	< 0.001
NRT patch high-dose (> 22 mg) versus placebo
6 RCTs	(12,53,57–60)	4 weeks	1041/2703 vs. 458/1990	1.63 (1.46–1.83)	15%	0.001
3 RCTs	(53,58,59)	3 months	421/1909 vs. 150/1195	1.88 (1.15–3.08)	62%	0.01
5 RCTs	(12,53,58–60)	6 months	186/1242 vs. 120/1245	1.82 (1.20–2.75)	60%	0.005
3 RCTs	(12,53,60)	12 months	105/763 vs. 81/764	1.47 (0.94–2.30)	37%	0.08
NRT patch high-dose (> 22 mg) versus NRT patch standard-dose (≤ 22 mg) therapy
4 RCTs	(12,40,52,53)	4 weeks	765/1586 vs. 653/1611	1.22 (1.11–1.34)	17%	< 0.001
3 RCTs	(40,53,61)	3 months	511/1743 vs. 427/1723	1.09 (0.84–1.43)	74%	0.49
5 RCTs	(12,40,52,53,61)	6 months	356/1792 vs. 317/1813	1.16 (0.99–1.37)	19%	0.054
4 RCTs	(12,40,53,61)	12 months	265/1741 vs. 225/1758	1.23 (1.05–1.46)	1%	0.01
Combination NRT (patch + acute formulation) versus placebo/control
2 RCTs	(35,62)	4 weeks	193/403 vs. 85/298	1.67 (1.35–2.05)	0%	< 0.001
1 RCT	(62)	3 months	35/136 vs. 22/109	1.27 (0.79–2.04)	NA	0.31
4 RCTs	(35,47,54,62)	6 months	184/817 vs. 90/1031	1.67 (1.32–2.11)	0%	< 0.001
3 RCTs	(47,62,63)	12 months	138/769 vs. 90/687	1.37 (1.07–1.75)	0%	0.012
Combination NRT (patch + acute formulation) versus NRT patch
4 RCTs	(56,71,83,84)	4 weeks	390/1044 vs. 311/1053	1.19 (1.00–1.43)	47%	0.045
4 RCTs	(22,64–66)	3 months	204/822 vs. 173/842	1.15 (0.96–1.38)	1%	0.11
4 RCTs	(22,35,64,65)	6 months	105/822 vs. 91/842	1.16 (0.82–1.64)	10%	0.38
3 RCTs	(22,64,66)	12 months	42/360 vs. 24/383	1.41 (0.51–3.88)	29%	0.66
Bupropion versus placebo/control
31 RCTs	(20,29,34,67–94)	4 weeks	2897/6442 vs. 1256/4676	1.65 (1.46–1.85)	75%	< 0.001
40 RCTs	(20,34,67–90,92–102,104,114)	6 months	2557/6545 vs. 1299/5004	1.52 (1.39–1.68)	56%	< 0.0001
41 RCTs	(20,34,67–90,92–102)	3 months	1973/7189 vs. 941/5378	1.50 (1.36–1.66)	39%	< 0.0001
27 RCTs	(20,29,67–71,74–76,79,80, 85–88,93–95,100,103,104)	12 months	1352/5249 vs. 704/3908	1.39 (1.19–1.61)	62%	< 0.001
Varenicline versus bupropion
3 RCTs	(74–76)	4 weeks	224/797 vs. 382/1073	1.40 (1.17–1.66)	33%	< 0.001
3 RCTs	(74–76)	3 months	245/797 vs. 426/1073	1.41 (1.13–1.77)	63%	< 0.001
3 RCTs	(74–76)	6 months	150/797 vs. 256/1073	1.43 (1.20–1.71)	0%	< 0.001
3 RCTs	(74–76)	12 months	121/797 vs. 239/1073	1.49 (1.19–1.86)	88%	< 0.001
Varenicline versus placebo
7 RCTs	(74–76,105–108)	4 weeks	785/1564 vs. 328/1549	2.33 (1.82–2.99)	80%	< 0.001
9 RCTs	(74–76,105–110)	3 months	951/2104 vs. 353/1968	2.26 (1.69–3.02)	86%	< 0.001
8 RCTs	(74–76,105,106,108–110)	6 months	567/2363 vs. 249/1968	2.24 (1.75–2.88)	69%	< 0.001
7 RCTs	(74–76,105,107,108,110)	12 months	389/1813 vs. 145/1676	2.48 (1.92–3.21)	45%	< 0.001
Varenicline versus standard-dose NRT
1 RCT	(111)	3 months	210/376 vs. 160/370	1.29 (1.11–1.49)	NA	< 0.001
1 RCT	(111)	6 months	122/370 vs. 101/370	1.18 (0.95–1.48)	NA	0.07
1 RCT	(111)	12 months	98/376 vs. 75/370	1.28 (0.98–1.67)	NA	0.06
Varenicline versus high-dose NRT
1 RCT	(112)	3 months	11/16 vs. 13/16	0.92 (0.60–1.38)	NA	0.28
1 RCT	(112)	6 months	10/16 vs. /16	0.83 (0.49–1.36)	NA	0.33

*References correspond to Appendix XIII.

Figure 2. Geometric distribution of included studies in MTC analysis. Nodes represent the study drugs. Links between nodes represent direct comparisons from RCTs. The numbers beside the links represent the number of RCTs for each comparison.

Table II. Estimated relative risk (RR) and 95% credibility intervals (CrI) produced by the random-effects multiple treatment comparison (MTC) analysis.

	RR (95% CrI)
	Short term	3 months	6 months	12 months
Control versus
Standard-dose nicotine patch therapy (≤ 22 mg)	1.52 (1.43–1.61)	1.65 (1.50–1.81)	1.60 (1.45–1.77)	1.48 (1.30–1.69)
High-dose nicotine patch therapy (> 22 mg) NRT	1.73 (1.62–1.84)	1.79 (1.44–2.16)	2.10 (1.77–2.47)	1.69 (1.32–2.11)
Combination NRT	1.68 (1.30–2.08)	1.29 (0.73–2.07)	1.66 (1.26–2.19)	1.34 (0.96–1.84)
Bupropion	1.71 (1.58–1.83)	1.59 (1.47–1.72)	1.59 (1.45–1.74)	1.40 (1.22–1.60)
Varenicline	2.19 (1.94–2.44)	2.37 (2.04–2.71)	2.19 (1.86–2.56)	2.39 (1.96–2.88)
Standard-dose nicotine patch therapy (≤ 22 mg) versus
High-dose nicotine patch therapy (> 22 mg) NRT	1.14 (1.07–1.21)	1.09 (0.87–1.33)	1.32 (1.11–1.57)	1.15 (0.91–1.43)
Combination NRT	1.10 (0.85–1.37)	0.77 (0.42–1.29)	1.05 (0.76–1.41)	0.91 (0.62–1.29)
Bupropion	1.12 (1.02–1.22)	0.96 (0.84–1.10)	0.99 (0.86–1.14)	0.94 (0.77–1.15)
Varenicline	1.43 (1.26–1.60)	1.48 (1.23–1.75)	1.38 (1.15–1.64)	1.65 (1.29–2.07)
High-dose nicotine patch therapy (> 22 mg) versus
Combination NRT	0.97 (0.73–1.23)	0.68 (0.34–1.25)	0.77 (0.52–1.11)	0.78 (0.50–1.20)
Bupropion	0.98 (0.88–1.09)	0.87 (0.66–1.13)	0.73 (0.58–0.91)	0.81 (0.60–1.09)
Varenicline	1.29 (1.12–1.46)	1.40 (1.05–1.80)	1.05 (0.80–1.36)	1.47 (1.06–2.01)
Combination NRT versus
Bupropion	1.01 (0.79–1.25)	1.24 (0.71–1.92)	0.95 (0.69–1.26)	1.04 (0.72–1.45)
Varenicline	1.28 (1.02–1.53)	1.85 (1.15–2.65)	1.31 (0.95–1.75)	1.78 (1.25–2.41)
Bupropion versus
Varenicline	1.29 (1.12–1.45)	1.43 (1.24–1.63)	1.34 (1.13–1.57)	1.61 (1.32–1.93)

For efficacy, RRs higher than 1 favor the row-defining treatment.

Table III. Probability of each treatment being best, derived on the basis of the random-effects multiple treatment comparison (MTC) model for smoking cessation.

Treatment	Short term	3 months	6 months	12 months
Control	0.0000	0.0000	0.0000	0.0000
Standard-dose NRT	0.0000	0.0000	0.0000	0.0000
High-dose NRT	0.0005	0.0112	0.3572	0.0099
Combination NRT	0.0181	0.0075	0.0287	0.0005
Bupropion	0.0005	0.0000	0.0000	0.0000
Varenicline	0.9809	0.9813	0.6141	0.9896