Major bleeding increases the risk of subsequent cardiovascular events in patients with atrial fibrillation: Insights from the SAKURA AF registry and RAFFINE registry

Background Bleeding events are one of the major concerns in patients using oral anticoagulants (OACs). We aimed to evaluate the association between major bleeding and long-term clinical outcomes in atrial fibrillation (AF) patients taking OACs. Methods We analyzed a database comprising two large-scale prospective registries of patients with documented AF: the RAFFINE and SAKURA registries. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of all-cause death, ischemic stroke, and myocardial infarction. Major bleeding was defined in accordance with the criteria of the International Society on Thrombosis and Haemostasis. Cox multivariate analysis was used to determine the impact of major bleeding on the incidence of MACCE. Results The median follow-up period was 39.7 months. Among 6,633 patients with AF who were taking OAC, 298 (4.5%) had major bleeding and 737 (11.1%) had MACCE. The incidence of MACCE was higher in patients with bleeding than in those without (18.33 and 3.22, respectively, per 100 patient-years; log-rank p <0.0001). Multivariate logistic regression analysis revealed older age, vitamin K antagonist use, and antiplatelet drug use as independent predictors of major bleeding. Multivariate Cox hazard regression analysis showed that the risk of MACCE was significantly higher in patients with major bleeding compared to those without (hazard risk, 4.64; 95% confidence interval, 3.62–5.94; p <0.0001). Conclusions Major bleeding was associated with long-term adverse cardiovascular events among AF patients taking OAC. Therefore, reducing the risk of bleeding is important for improving clinical outcomes in patients with AF. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by scholarship funds received from the following (in alphabetical order): Abbott Japan, Astellas Pharma, AstraZeneca, Bayer Healthcare, Boehringer-Ingelheim, Boston Scientific Japan, Bristol-Meyers Squibb, Crosswill Medical, Daiichi-Sankyo, Eisai, Fukuda Denshi, FUJIFILM RI Pharma, Japan Lifeline, Kowa Pharmaceutical, Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma, Medical Hearts, Medtronic Japan, Mochida, MSD, Nippon Shinyaku, Otsuka Pharmaceutical, Pfizer, Philips Respironics, Roche Diagnostics, Sanwa Kagaku Kenkyusho, Sanofi, Shionogi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and Nihon Medi-Physics. This study was conducted as investigator-initiated research based on a contract with, and financially supported by, Bayer Yakuhin Ltd. The funding sources had no roles in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: approval numbers: M11-0799 [11 November 2014] for RAFFINE RK-130111-2 [1 February 2013] for SAKURA I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data referenced in the manuscript is available.