Background:
Smoking cessation is crucial to reduce the health risks associated with tobacco use. Varenicline and Nicotine Replacement Therapy (NRT) are commonly used pharmacotherapies, each with distinct mechanisms of action. This systematic review compares the effectiveness of Varenicline versus NRT in achieving long-term smoking cessation.

Methods:
A comprehensive literature search was conducted across PubMed, Cochrane Library, Scopus, and Web of Science, covering studies from 2014 to 2024. The review included randomized controlled trials (RCTs) and cohort studies comparing Varenicline with NRT in adult smokers. The quality of studies was assessed using the Cochrane risk of bias tool and the Newcastle-Ottawa Scale (NOS).

Results:
Ten studies were included, comprising nine RCTs and one cohort study. The pooled analysis revealed that Varenicline was significantly more effective than NRT in promoting smoking cessation, with a pooled risk ratio of 2.09 (95% CI: 1.52, 2.67). This superiority was consistent across various populations, including younger and older smokers and those with chronic obstructive pulmonary disease (COPD). The effectiveness of Varenicline was observed in achieving continuous abstinence at various intervals, including six months, 12 weeks, and 24 weeks. The combination of Varenicline with NRT also showed a synergistic effect, resulting in even higher cessation rates compared to either therapy alone. Additionally, the analysis indicated moderate heterogeneity among the studies, potentially attributable to differences in study design, population characteristics, and intervention protocols.

Conclusions:
Varenicline is a more effective option than NRT for smoking cessation, particularly when combined with NRT. Healthcare providers should consider these findings in treatment planning, especially in populations that may benefit most from Varenicline’s efficacy. Further research is recommended to optimize treatment protocols and address accessibility issues.