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The Number of Concomitant Drugs and the Safety of Direct Oral Anticoagulants in Routine Care Patients with Atrial FibrillationFunding None.
Background The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice.
Study Design Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0–5, 6–8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA).
Results A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87–1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68–0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88–0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use (p-value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed (p-value for interaction <0.01).
Conclusion In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.
Keywordsatrial fibrillation - anticoagulation - polypharmacy - major bleeding - effect modification
C.J.D., S.D., G.-J.G., P.S., and H.A.H. wrote the ISAC study protocol. P.S. and R.P. prepared the dataset. C.J.D., R.P., and S.D. performed the analyses. K.G.M.M., G.-J.G. and A.W.H. advised in interpreting the results. C.J.D. wrote the first version of the manuscript. All authors participated in revising the manuscript. H.A.H. is the guarantor.
The study was conducted according to the principles of the Declaration of Helsinki (latest version as adopted by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013). Separate ethical approval from an NHS Research Ethics Committee was not required.
The CPRD license agreement does not permit data sharing; however, R scripts are available upon request.
Received: 16 April 2020
Accepted: 22 October 2020
Article published online:
23 December 2020
© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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