Impact of Clinical Complexity Features on the Risk of Major Bleeding and Subsequent Outcomes in Atrial Fibrillation Patients: A Multistate Model analysis from Two Large Observational Registries

Background Clinical complexity features, such as multimorbidity, polypharmacy and frailty, emerged as significant determinants of clinical course in patients with atrial fibrillation (AF). Evidence suggests that clinical complexity affects major bleeding (MB) risk. Purpose We aimed to investigate the impact of clinical complexity features on the risk of MB events and the subsequent impact on adverse outcomes using a multistate model analysis. Methods We analysed AF patients from two large prospective observational registries, one conducted in Europe and one in Asia. Using multistate models, we examined transitions from baseline to MB events and, ultimately, to a composite outcome of all-cause death and major adverse cardiovascular events (MACEs). We examined the effects of multimorbidity, frailty and polypharmacy on transition rates using Cox proportional hazards regression models. We then evaluated the impact of the transition to MB events on the risk of adverse outcomes, adjusted according to the presence of the clinical complexity features. Results 12,360 patients with AF (mean age 68.9, SD 11.6 years; 38.7% female) were included in the analysis. Over a median follow-up of 696 days (IQR 365–735), 204 patients (1.6%, incident rate [IR] 1.1 per 100 person-years [pys]) had MB events, of whom 36 (17.6%, IR 17.4 per 100 pys) later experienced the composite outcome. An additional 1,151 patients (9.3%, IR 5.9 per 100 pys) transitioned directly from baseline to the composite outcome. Prevalence of multimorbidity (p<0.001), polypharmacy (p<0.001) and frailty (p=0.004) were higher in those patients experiencing MB. After adjustments, being pre-frail or frail was associated with a 2-fold higher risk of experiencing a MB event [Figure 1]. In contrast, all three clinical complexity features were independently associated with transitioning directly to a composite outcome event [Figure 1]. After adjusting for the presence of multimorbidity, polypharmacy and frailty, patients who experienced MB showed a trend in higher risk of the composite outcome than those who did not (HR 5.02, 95% CI 0.87–28.97, Figure 2). Conclusions In AF patients, the presence of frailty significantly increased the risk of MB. After adjusting for clinical complexity features, patients reporting a MB event showed a trend in higher risk for the composite outcome, compared to those who did not. Integrated care strategies are needed to control for the risk of MB and subsequent adverse outcomes.