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Abstract
Objective To assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs.
Methods We conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted.
Results A total of 73 989 patients were eligible for analysis. Notably, 52.8%–81.9% of patients received reduced doses of NOACs. After applying s-IPTW, patient characteristics were well balanced across warfarin/NOAC cohorts. The mean within-cohort age, CHADS2 score and CHA2DS2-VASc score were 76 years, 2.2–2.3 and 3.8, respectively. In all age categories, the majority of the HRs for major bleeding, any bleeding and stroke/SE were equal to or below 1 for all NOACs versus warfarin. Apixaban was the only NOAC associated with a significantly lower risk of any bleeding. There was a trend towards increased risk reduction with NOACs versus warfarin in patients with body weight ≥60 kg. In patients with renal disease, the HRs for apixaban versus warfarin were below 1 for major bleeding, any bleeding and stroke/SE, with statistical significance observed for the risk reduction in stroke/SE versus warfarin. In the sensitivity analysis, there were no large differences in HRs between the two observational periods.
Conclusions In patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.
- warfarin
- direct oral anticoagulant
- NVAF
- stroke
- bleeding
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Footnotes
Contributors SK and YT were involved in designing the study, defining each disease and comorbid condition according to 10th Revision of the International Classification of Diseases codes, interpreting the obtained results and critically reviewing the drafted manuscript. KS was involved in designing the study, managing the project and interpreting the obtained results. JK was involved in designing the study, managing the project, interpreting the obtained results and drafting the manuscript. AJ contributed to planning the study protocol and statistical analysis, managing the project throughout the study, interpreting the results and reviewing the manuscript critically. JM and BL, who are statisticians, carried out the statistical analysis and contributed to the interpretation of results. All authors provided final approval for this version to be published and agreed to be accountable for all aspects of the work.
Funding This study was funded and conducted by Bristol-Myers Squibb Co and Pfizer Inc. Both companies had significant roles in the study design, data collection/analysis, manuscript preparation and decision to publish.
Competing interests KS is a full-time employee of Bristol-Myers Squibb Co. JK, AJ and BL are full-time employees of Pfizer Inc. JM was a full-time employee of Pfizer Inc until January 2020 and currently serves as a Teaching Professor at Rutgers University, New Jersey, USA. SK reports investigator-initiated grant funding from Bayer and Daiichi Sankyo, and personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb Co, Daiichi Sankyo, Pfizer Inc, Teikoku Seiyaku and Boehringer Ingelheim, outside the submitted work. YT has served as a consultant for Bristol-Myers Squibb Co and Pfizer Inc.
Patient consent for publication Not required.
Ethics approval The study was conducted in accordance with the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects and was approved by the independent institutional review board (IRB) of Takahashi Clinic as a central IRB (approval date: July 17, 2018).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data may be obtained from a third party and are not publicly available. Raw data used for this analysis are not available owing to the terms of the contract between Pfizer Japan Inc and Medical Data Vision Co Ltd. If access to the raw data is necessary, please make direct contact with Medical Data Vision Co Ltd. The authors declare that all other supporting data, including the definitions of the diseases, are available within the article and its online supplementary files.