Letters to the Editor Increased Risk of Bleeding in Elderly Patients Treated With Oral Anticoagulants and Angiotensin- Converting Enzyme Inhibitors To the Editor: Information about bleeding events (BEs) in patients on non- vitamin K antagonist oral anticoagulants (NOACs) is derived from clinical trials, in which participants do not share the characteristics of real-life older populations. Also, knowledge about adverse reactions to NOACs is restricted to few in- teractions with medicationsdmostly infrequently used in older populationsdthat share common metabolic pathways. 1 We assessed the correlates of BEs in a cohort of 101 patients aged 65þ with nonvalvular atrial fibrillation who were pre- scribed NOACs at the geriatric service of the Catholic Uni- versity, Rome, from February 2017, to January 2018, and followed for a median of 11 months (Table 1). The percent population attributable risk (PAR) was calculated as 100*(Px*[odds ratio (OR)-1])/(1þ (Px*[OR-1]). Forty-nine participants took apixaban, 29 dabigatran, 15 rivaroxaban, and 8 edoxaban. BEs occurred in 12 participants; 2 required transfusions, and 1 died from gastrointestinal bleeding. Use of angiotensin-converting enzyme inhibitors (ACEIs) was recorded in 26 subjects: 15 ramipril, 7 enalapril, 2 peri- ndopril, 1 captopril, and 1 zofenopril. No differences were found in incident BEs when comparing single NOACs (all P > 0.700). ACEIs were taken by 7 of 12 (58%) participants with incident BEs and by 19 of 89 (21%) patients without BEs (P ¼ 0.011). In logistic regression, use of ACEIs was associ- ated with BEs in crude model (OR ¼ 5.16; 95% CI, 1.47- 18.09; P ¼ 0.010); adjusting for age and sex (OR ¼ 5.65; 95% CI, 1.56-20.51; P ¼ 0.008); and adjusting for age, sex, serum creatinine, and HAS-BLED score (OR ¼ 5.73; 95% CI, 1.54-21.32; P ¼ 0.009). KaplaneMeier analysis indicated that the risk of bleeding was significantly increased among participants on ACEIs. Increasing ACEIs dosages were associated with increasing risk of bleeding (c2 ¼ 8.94; log-rank P ¼ 0.030). The effect of single agents could not be analyzed because of insufficient statistical power. The PAR of bleeding for treatment with ACEIs was 21%. Our results indicate that, in older patients on NOACs, use of ACEIs is associated with increased risk of bleeding in a dose-dependent manner. This finding is of interest, as ACEIs are frequently prescribed for older patients with atrial fibril- lation. In this study, the PAR indicated that switching patients treated with ACEIs to alternative drugs would reduce the occurrence of bleeding by 21%. ACEIs might increase the risk of bleeding associated with NOACs by interfering with CES-1 metabolism 2 or through their anticoagulant and antiplatelet effects. 3 More simply, NOACs kinetics might be altered by ACEIs because these agents frequently induce subclinical impairment of renal function in older populations. 4 The interaction of ACEIs with NOACs deserves further investi- gation by large, dedicated databases. Alice Laudisio, MD lavoralice@gmail.com Michele Ciaburri, MD Domenico Gabrielli, MD Daniele Sticchi, MD Silvia Giovannini, PhD Roberto Bernabei, MD Giuseppe Zuccalà, MD Disclosures The authors have no conflicts of interest to disclose. References 1. Chang S-H, Chou I-J, Yeh Y-H, et al. Association between use of non- vitamin k oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA 2017;318:1250-9. 2. Kristensen KE, Zhu H-J, Wang X, et al. Clopidogrel bioactivation and risk of bleeding in patients cotreated with angiotensin-converting enzyme inhibitors after myocardial infarction: a proof-of-concept study. Clin Pharmacol Ther 2014;96:713-22. 3. Brecher AS, Murrey SJ, Gray KD, Poulimenos JN. Anticoagulant activity of captopril. J Cardiovasc Pharmacol 2008;51:99-105. 4. Zuccalà G, Onder G, Pedone C, et al. Use of calcium antagonists and worsening renal function in patients receiving angiotensin-converting- enzyme inhibitors. Eur J Clin Pharmacol 2003;58:695-9. https://doi.org/10.1016/j.cjca.2019.02.001 0828-282X/Ó 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. Canadian Journal of Cardiology 35 (2019) 545.e3e545.e4 www.onlinecjc.ca