Efficacy of combined varenicline and nicotine replacement therapy compared with varenicline or nicotine replacement therapy alone for smoking cessation: A systematic review and meta‐analysis

AIMS: To assess whether combining nicotine replacement therapy (NRT) with varenicline improves long-term smoking cessation rates compared with varenicline or NRT alone. METHOD: Systematic review and meta-analysis of randomized controlled trials (RCTs) or quasi-RCTs, conducted according to PRISMA guidelines. A comprehensive literature search of PubMed, MEDLINE, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials was conducted through June 2025. The primary outcome was smoking abstinence at the longest follow-up (≥6 months). Secondary outcomes included adverse events (AEs) and serious adverse events (SAEs). Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects meta-analyses. The certainty of evidence was assessed using the GRADE approach. Risk of bias was assessed using the Cochrane RoB 2.0 tool. The protocol was pre-registered in the PROSPERO (registration number CRD42024600510). A sensitivity analysis including trials with ≥3 months of follow-up yielded similar results (RR = 1.31, 95% CI = 1.06-1.62; 6 studies). However, when excluding the trial at high risk of bias, the result was not statistically significant (RR = 1.26, 95% CI = 0.94-1.68). Compared with NRT alone, only one RCT was included, and the effect of combination therapy on abstinence was not statistically significant (RR = 0.94, 95% CI = 0.51-1.72). AEs were more common with combination therapy compared with varenicline alone (RR = 1.11, 95% CI = 1.02-1.20). Specifically, skin reactions were significantly increased with NRT patch plus varenicline (RR = 1.67; 95% CI = 1.29-2.16). Compared with NRT alone, combination therapy was associated with increased AEs (RR = 1.23; 95% CI = 1.07-1.41). SAEs were infrequent and generally unrelated to treatment. CONCLUSIONS: Low-certainty evidence indicates that combining varenicline with nicotine replacement therapy may improve long-term smoking cessation rates compared with varenicline alone and is generally well tolerated.