Effect of primary prevention on major adverse cardiac event in breast cancer patients on cytotoxic chemotherapy

Abstract

Advances in cancer detection and treatment have improved 5-year survival rates, creating a growing population of cancer survivors. However, multi-modal therapies carry cardiotoxic risks, and cardiovascular events during treatment can interrupt curative care and increase morbidity, healthcare costs, and mortality. We evaluated the real-world effectiveness of primary prevention with cardioprotective pharmacological therapy on major adverse cardiovascular events (MACE) among adults with breast cancer receiving cytotoxic chemotherapy. We conducted a retrospective cohort study within a large integrated healthcare delivery system. Adult members (≥18 years) diagnosed with primary breast cancer between January 2007 and December 2022 were identified through the cancer registry. Eligible patients maintained continuous health plan enrollment prior to diagnosis and received cytotoxic chemotherapy. Covariates, exposure, and outcome data were extracted from electronic medical records. MACE was defined as a composite of myocardial infarction, stroke, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, and all-cause mortality. Primary prevention exposure was based on prescription fills for cardioprotective pharmacological therapy during the 12 months preceding chemotherapy initiation. Parametric survival models were adjusted for demographics, lifestyle factors, tumor characteristics, insurance type, primary breast cancer surgery, and comorbidities. To address non-randomized treatment assignment, we applied the potential outcomes framework using a control function derived from a first-stage treatment selection model with two instrumental variables: (1) the number of cardiologists at the patient’s treatment center and (2) lagged prescribing preferences for cardioprotective medications among prior breast cancer patients at the same center. Statistical inference used 1,000 bootstrap replications with bias-corrected confidence intervals. Patients were followed until MACE, disenrollment, or end of follow-up (December 2025). Among 12,203 patients, median follow-up after chemotherapy initiation was 6.6 years (mean 7.5; maximum 19). Over 91,636 person-years, 2,434 patients experienced a MACE (26.6 per 1,000 person-years). Primary prevention with cardioprotective pharmacological therapy was associated with a 95% longer time to MACE versus no therapy (Time Ratio = 1.95; 95% CI: 1.15–4.21). Among breast cancer patients receiving cytotoxic chemotherapy, primary prevention with cardioprotective pharmacological therapy was significantly associated with prolonged time to major adverse cardiovascular events. These findings support proactive cardioprotective strategies to mitigate treatment-related cardiovascular risk and reinforce the value of integrating preventive cardiology into cardio-oncology care pathways.