Impact of preoperative varenicline on postoperative outcomes in cardiac surgery: comparison with nicotine replacement therapy and active smoking

Abstract Background Nicotine dependence increases the risk of adverse outcomes after cardiac surgery, but there are no current established studies directly comparing different smoking cessation medications’ effect on postoperative outcomes. We studied the association of varenicline, nicotine replacement therapy (NRT) use and postoperative outcomes. Methods We performed a retrospective cohort study using the TriNetX Research Network, including adults with documented nicotine dependence who underwent cardiac surgery between November 1, 2005, and November 1, 2025. We included two independent comparative studies which compared preoperative varenicline use vs. preoperative NRT use and preoperative varenicline use vs. active smokers who did not receive pharmacologic cessation therapy. Patients with concurrent preoperative use of both varenicline and NRT were excluded to avoid confounding. For each analysis, we used an independent 1:1 propensity score matching to create matched cohorts. Primary outcome was major adverse cardiovascular events. Secondary outcomes included all-cause mortality, ED visit, myocardial infarction (MI), arrhythmias, pneumonia, acute respiratory failure or ARDS, mechanical ventilation, postoperative infection, and antipsychotic use. All outcomes are measured at 3,6 and 12 months postoperatively. Results At 3, 6, and 12 months postoperatively, varenicline use was associated with a significantly lower risk of the primary outcome, MACE, when compared to both NRT (at 12 months: 19.9% vs. 37.3%; RR 0.53, 95% CI 0.41–0.70; p < 0.01) and active smokers (at 12 months: 19.8% vs. 30.3%; RR 0.65, 95% CI 0.50–0.86; p < 0.01). Among secondary outcomes, varenicline demonstrated significantly lower rates of MI across all three time points compared to NRT (at 12 months: 13.6% vs. 28.2%; RR 0.48, 95% CI 0.35–0.67; p < 0.01) and active smokers (at 12 months: 13.6% vs. 24.5%; RR 0.56, 95% CI 0.40–0.78; p < 0.01). Additionally, when compared to NRT, the varenicline cohort had consistently lower rates of ED visits at 3, 6, and 12 months (at 12 months: 18.0% vs. 25.6%; RR 0.70, 95% CI 0.52–0.95; p = 0.02) and postoperative infection at 6 months (4.8% vs. 9.2%; p = 0.03). There were no significant differences observed in all-cause mortality or other secondary outcomes across the comparison groups. Conclusions Varenicline use was associated with significantly lower risks of MACE, MI, postoperative infection, and ED admission compared to NRT. Pre-operative use of varenicline was also associated with reduced risks of MI and MACE when compared to active smokers. Clinical trial number Not applicable.