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. 2025 Jul 1;160(7):804-813.
doi: 10.1001/jamasurg.2025.1503.

Drug-Gene Interactions and Clinical Outcomes After Vascular Surgery in the Million Veteran Program

Sony Tuteja  1   2 , William J O'Brien  3   4 , Jeffrey P Ferraro  4   5 , Scott M Damrauer  1   2 , Kamal M F Itani  3   6   7   8 , Benjamin F Voight  1   2 , Craig C Teerlink  4 , Julie A Lynch  4   5 , Scott L DuVall  4   5 , Timothy Strebel  9   10 , Michael J Kim  11   12 , Mark A Wilson  13 , Thomas W Barrett  14   15 ; Million Veteran Program
Collaborators, Affiliations

Drug-Gene Interactions and Clinical Outcomes After Vascular Surgery in the Million Veteran Program

Sony Tuteja et al. JAMA Surg. .

Abstract

Importance: Pharmacogenetics can improve medication-related outcomes by optimizing efficacy and minimizing adverse effects. It is unknown whether the presence of drug-gene interactions (DGIs) at the time of surgery results in adverse outcomes in the postoperative setting.

Objective: To determine the association of active DGIs on postsurgical outcomes following vascular surgery procedures.

Design, setting, and participants: This was a retrospective cohort study of Veterans Affairs (VA) hospital patients participating in the Million Veteran Program who had a vascular procedure documented in the VA Surgical Quality Improvement Program (VASQIP) from January 1, 2011, to December 31, 2022. Data analysis was performed from June 1, 2023, to October 31, 2024.

Exposure: Receipt of drugs impacted by pharmacogenetic variants 30 days prior to and up to 7 days following the vascular surgery procedure.

Main outcomes and measures: Clinical outcomes collected as part of VASQIP, including length of stay (LOS), 30-day readmission, composite of myocardial infarction, stroke, and myocardial injury after noncardiac surgery, and 30-day postoperative death.

Results: Among 10 098 patients (mean [SD] age, 68.8 [8.3] years; 1581 [15.7%] Black [self-reported]; 9884 [97.9%] male), 5020 (49.7%) had a DGI. The most common DGIs included proton pump inhibitors with CYP2C19, statins with SLCO1B1, and clopidogrel with CYP2C19. Compared with 0 DGIs, the presence of 1, 2, or 3 or more DGIs was associated with a longer median (IQR) LOS: with 0 DGIs, 3 (1-6) days vs 1 DGI, 3 (1-7) days (adjusted incidence rate ratio [IRR], 1.12; 95% CI, 1.10-1.14; P < .001); 2 DGIs, 3 (1-7) days (adjusted IRR, 1.22; 95% CI, 1.19-1.25; P < .001); and 3 or more DGIs, 4 (2-8) days (adjusted IRR, 1.40; 95% CI, 1.35-1.44; P < .001). The 30-day readmission rate, which was 17.4% among those with 0 DGIs, was not significantly different in those with 1 DGI (17.6%; adjusted odds ratio [aOR], 1.01; 95% CI, 0.90-1.14; P = .84) but was significantly higher in those with 2 DGIs (21.2%; aOR, 1.26; 95% CI, 1.08-1.47; P = .004) and 3 or more DGIs (25.1%; aOR, 1.61; 95% CI, 1.30-1.99; P < .001). The risk of the composite outcome, which was 3.5% in those with 0 DGIs, was not significantly different in those with 1 DGI (4.1%; aOR, 1.15; 95% CI, 0.91-1.45; P = .24) but was significantly higher in those with 2 DGIs (5.7%; aOR, 1.62; 95% CI, 1.22-2.15; P = .001) and those with 3 or more DGIs (5.5%; aOR, 1.60; 95% CI, 1.04-2.36; P = .02).

Conclusions and relevance: The findings suggest that patients with DGIs at the time of vascular surgery have increased risk of cardiovascular morbidity, increased readmission, and longer LOS. Further work is needed to determine which DGIs contribute to these outcomes and whether preoperative pharmacogenetic testing has the potential to mitigate these risks.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Tuteja reported grants from the Department of Veterans Affairs during the conduct of the study; and patent for OI 2025-05884 pending outside the submitted work. Dr Damrauer reported personal fees from Tourmaline Bio and nonfinancial support from Novo Nordisk outside the submitted work. Dr Teerlink reported grants from Alnylam, Astellas, AstraZeneca, Biodesix, Celgene, Cerner Enviza, GSK, IQVIA, Janssen, Novartis, and Parexel through the University of Utah or Western Institute for Veterans Research outside the submitted work. Dr Lynch reported grants from the Department of Veterans Affairs during the conduct of the study; and grants from Alnylam, Astellas, AstraZeneca, Biodesix, Celgene, Cerner Enviza, GSK, IQVIA, Janssen, Novartis, and Parexel through the University of Utah or Western Institute for Veterans Research outside the submitted work. Dr DuVall reported grants from Alnylam, Astellas, AstraZeneca, Biodesix, Celgene, Cerner Enviza, GSK, IQVIA, Janssen, Novartis, and Parexel through the University of Utah or Western Institute for Veterans Research and grants from Boehringer Ingelheim, Eli Lilly and Co, Genentech, Gilead, Innocrin, MDx Health, Merck and Co, and Myriad Genetic Laboratories outside the submitted work. Dr Barrett reported grants from the Veterans Health Administration, Health Systems Research during the conduct of the study. No other disclosures were reported.

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