Effects of oral anticoagulant adherence on stroke, death, and major bleeding in patients with atrial fibrillation: A long-term retrospective cohort study

Background Patients with atrial fibrillation (AF) are frequently nonadherent to oral anticoagulants (OACs) prescribed for prevention of stroke and systemic embolism (SSE). The effects of OAC adherence on clinical outcomes are uncertain because previous studies used short time periods, treated adherence as binary, and/or excluded VKA users. Our objectives were to quantify the relationship between adherence to OACs as a continuous variable and AF-related clinical outcomes, and to compare the consequences of nonadherence between OAC classes and individual OACs. Methods This retrospective, observational cohort study included incident cases of AF from population-based administrative data of 5 million British Columbians from 1996 to 2020. The exposure of interest was proportion of days covered (PDC) for incident OAC prescriptions during 90 days before a clinical event or end of follow-up. Multivariable Cox proportional hazard models were used to evaluate time to first composite outcome of SSE, transient ischemic attack (TIA), or death and SSE and several secondary outcomes. Models were also stratified by the OAC patients were receiving within 90 days of the outcome event. Results The study cohort included 34,946 patients (mean age 70.1, 45% female) with median follow-up of 6.7 years. Each 10% absolute decrease in PDC was associated with a 4.3% (95%CI 2.9-5.6) and 10.3% (95%CI 7.5-13.0) increase in hazard of SSE, TIA, or death for VKA and direct OAC (DOAC) users, respectively. For SSE, hazard increases per 10% PDC reduction were 22.5% (95%CI 19.6-25.4) and 34.2% (95%CI 28.2-40.6) for VKA and DOAC, respectively. Similar significant effects were seen for all secondary efficacy outcomes. Differences between VKA and DOAC were statistically significant for all outcomes (p<0.001 all contrast tests) except major bleeding. Conclusions Even small reductions in OAC adherence in patients with AF are associated with significant increases in risk of SSE and death, and these effects are significantly greater with DOAC nonadherence than with VKA nonadherence. These results suggest that DOAC recipients are more vulnerable than VKA recipients to increased risk of stroke and death even with small reductions in adherence. The worsening efficacy outcomes associated with decreasing adherence occur without any benefit in terms of major bleeding reduction. KEY POINTS ### Competing Interest Statement Dr. Andrade has received honoraria from Bayer, Biosense-Webster, BMS Pfizer, Medtronic, and Servier, as well as Grants from Medtronic. Dr. Deyell has received honoraria from Pfizer, Servier, and Bayer. Other authors have no conflicts of interest to disclose. ### Clinical Trial Not a clinical trial. ### Funding Statement This research was supported by Canadian Institutes of Health Research grant (FRN 168896). Dr. Loewen?s research is also partially supported by the UBC David H MacDonald Professorship in Clinical Pharmacy (Vancouver, Canada). Dr. Salmasi?s research was supported by a Canadian Institutes of Health Research Postdoctoral Fellowship award. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UBC Clinical Research Ethics Board (H17-02420 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. Not Applicable 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). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable Access to data provided by the Data Steward(s) is subject to approval, but can be requested for research projects through the Data Steward(s) or their designated service providers. All inferences, opinions, and conclusions drawn in this publication are those of the author(s), and do not reflect the opinions or policies of the Data Steward(s).