Cardiovascular Risks of Aromatase Inhibitors versus Tamoxifen in Postmenopausal Breast Cancer: A Multinational Cohort Study

Shu-Chen Hu,1 Charles E Gaber,2 Chiao Lo,3 Hsuanyun Neo Su,2 Chi-Chuan Wang,1,4,5 Chih-Fan Yeh,6 Lubna Hassan,2 A Simon Pickard,2,7 Todd A Lee,2,7 Fang-Ju Lin1,4,5 1Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; 2Department of Pharmacy Systems, Outcomes and Policy, Retzky College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA; 3Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan; 4School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; 5Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan; 6Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan; 7Center for Pharmacoepidemiology and Pharmacoeconomics, Retzky College of Pharmacy, University of Illinois Chicago, Chicago, IL, USACorrespondence: Fang-Ju Lin, Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, No. 33, Linsen S. Road, Zhongzheng Dist, Taipei City, 100025, Taiwan, Tel +886-2-33668809, Fax +886-2-33668780, Email fjilin@ntu.edu.twBackground: Aromatase inhibitors (AIs) are the preferred treatment for postmenopausal women with hormone receptor-positive (HR+) breast cancer, but their cardiovascular safety remains uncertain. This study compared cardiovascular risks associated with AIs versus tamoxifen in two distinct populations.Patients and methods: This retrospective cohort study used data from the US SEER-Medicare database (2007– 2020) and Taiwan’s National Health Insurance claims database and cancer registry (2010– 2021). Postmenopausal women with HR+ stage I–III breast cancer were categorized by their initial endocrine therapy. Study outcomes included major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and heart failure (HF). Covariate balance was achieved through inverse probability of treatment weighting, and cause-specific hazard models were used for risk assessment in each cohort.Results: The study included 36,950 US patients (89% AI users) and 22,676 Taiwan patients (71% AI users). In the US, AIs were associated with an HR of 1.13 (95% CI 0.83– 1.52) for MACE and 1.17 (95% CI 0.93– 1.48) for HF, compared to tamoxifen. In Taiwan, the HRs were 1.23 (95% CI 0.87– 1.73) for MACE and 0.93 (95% CI 0.73– 1.21) for HF. AI use was linked to a lower VTE risk in the US (HR: 0.35, 95% CI 0.27– 0.45), while the Taiwan cohort showed a non-significant trend (HR: 0.72, 95% CI 0.42– 1.25).Conclusion: AIs were not associated with a definitive increase in MACE or HF risk compared with tamoxifen, although confidence intervals suggest some uncertainty in the estimates. The observed differences in VTE risk across cohorts highlight the need for population-specific considerations when selecting endocrine therapy.Keywords: aromatase inhibitors, tamoxifen, cardiotoxicity, major adverse cardiovascular events, venous thromboembolism, heart failure