Adding Bupropion or Varenicline to NRT After ACS Linked to Lower Mortality

Photo by Alexas_Fotos / Unsplash

medRxiv Published April 24, 2026 Medically reviewed April 24, 2026 Study authors: Qadeer, A.; Gohar, N.; Maniyar, P.; Shafi, N.; Juarez, L. M.; Mortada, I.; Pack, Q. R.; Jneid, H.; G… DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider adding bupropion or varenicline to NRT in post-ACS patients, but interpret results cautiously as this is an observational study.

This retrospective cohort study using the TriNetX US Collaborative Network (67 healthcare organizations) analyzed adults hospitalized with acute coronary syndrome (ACS) who received nicotine replacement therapy (NRT) within one month. After propensity matching, 8,574 pairs were compared for combined pharmacotherapy (bupropion or varenicline added to NRT) versus NRT alone. Separate analyses included 4,654 pairs for bupropion and 2,126 pairs for varenicline.

At 1 year follow-up, addition of pharmacotherapy was associated with lower all-cause mortality (HR 1.26, 95% CI 1.16-1.37, p < 0.001), MACE (HR 1.16, 95% CI 1.12-1.21, p < 0.001), heart failure exacerbations (HR 1.16, 95% CI 1.08-1.25, p < 0.001), and major bleeding (HR 1.18, 95% CI 1.08-1.28, p < 0.001). Cardiac rehabilitation utilization was also greater (HR 0.82, 95% CI 0.74-0.92, p < 0.001). No significant difference was seen for TIA/stroke.

Safety analysis revealed higher rates of new-onset depression in the pharmacotherapy group, driven predominantly by bupropion recipients. Serious adverse events, discontinuations, and tolerability were not reported.

Key limitations include the retrospective design, potential unmeasured confounders despite propensity matching, and misclassification of smoking status using NRT as a proxy. As an observational study, causality cannot be inferred.

These findings support broader integration of prescription smoking cessation pharmacotherapy into post-ACS care, but results should be interpreted with caution given the associative nature of the evidence.

Study Details

Study typeCohort

EvidenceLevel 3

PublishedApr 2026

View Original Abstract ↓

Introduction: Smoking cessation after acute coronary syndrome (ACS) is a Class I recommendation, yet prescription pharmacotherapy use remains low and its real-world cardiovascular effectiveness when added to nicotine replacement therapy (NRT) is poorly characterized. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network (67 healthcare organizations). Adults hospitalized with ACS who received NRT within one month, serving as a proxy for active smoking status, were identified. Two co-primary propensity-matched (1:1, 50 covariates, caliper 0.10 SD) comparisons evaluated bupropion + NRT and varenicline + NRT individually versus NRT alone; a supportive analysis evaluated combined pharmacotherapy versus NRT alone. All-cause mortality was the primary endpoint. Secondary outcomes included MACE, heart failure exacerbations, major bleeding, TIA/stroke, emergency rehospitalizations, and cardiac rehabilitation utilization, assessed at 6 months and 1 year via Kaplan-Meier analysis. Hazard ratios (HRs) greater than 1.0 indicate higher hazard in the NRT-only group. Results: After matching, the combined analysis comprised 8,574 pairs, the bupropion analysis 4,654 pairs, and the varenicline analysis 2,126 pairs. At 1 year, the combined pharmacotherapy group had significantly lower all-cause mortality (HR 1.26, 95% CI 1.16-1.37), MACE (HR 1.16, 95% CI 1.12-1.21), heart failure exacerbations (HR 1.16, 95% CI 1.08-1.25), major bleeding (HR 1.18, 95% CI 1.08-1.28), and greater cardiac rehabilitation utilization (HR 0.82, 95% CI 0.74-0.92; all p < 0.001). TIA/stroke did not differ significantly. Six-month results were consistent. Both varenicline and bupropion individually showed lower mortality and MACE. A urinary tract infection falsification endpoint showed no between-group differences, supporting matching validity. The pharmacotherapy group had higher rates of new-onset depression, driven predominantly by bupropion recipients. Conclusions: In this propensity-matched real-world analysis, adding prescription smoking cessation pharmacotherapy to NRT after ACS was associated with lower mortality and fewer adverse cardiovascular events, supporting broader integration into post-ACS care pathways.