Prevalence of atrial fibrillation (AF) increases with age, along with comorbidities and, thus, polypharmacy. Non-adherence is associated with polypharmacy. This study aimed to identify patients at risk for cardiovascular events according to their pharmacological treatment intensity and adherence. Patients (n = 18,113) with a mean age of 71.5 ± 8.7 years, at high cardiovascular risk were followed between December 2005 until December 2007 for a median time of 2 years. The association between polypharmacy and adherence and their impact on cardiovascular and bleeding events were explored. Adherence was defined as a study drug intake of ≥80%. Patients with more co-medications had a higher body mass index, higher prevalence of hypertension, coronary heart disease, heart failure, and diabetes mellitus (all p < 0.0001) compared to ≤4 or 5-8 co-medications, but no differences in history of stroke (p = 0.68) or transient ischemic attack (p = 0.065). Across all treatments, the adjusted hazard ratios (HRs) increased in patients with more co-medications (≥9 vs ≤4) for all-cause death (HR 1.30; 1.06–1.59), major bleeding (HR 1.65; 1.33–2.05), and all bleeding events (HR 1.44; 1.31–1.59). Yearly event rates were higher in non-adherent than adherent patients for stroke and systemic embolism (SSE) (3.14 vs 1.00), all-cause death (7.76 vs 2.66), major bleeding (6.21 vs 2.65), and all bleeding (28.71 vs 19.05; all p < 0.0001). After an event the patients were more likely to become non-adherent (adherence after SSE 30.3%, after major bleeding 33.4%, after all bleeding 66.7%; all p < 0.0001). The treatment effects were consistent to the overall group in the different polypharmacy groups. In conclusion, polypharmacy and non-adherence are risk indicators for increased adverse cardiovascular and bleeding events. Dabigatran is safe to use across the full spectrum of AF patients, independent of the number of co-medications and adherence. Patients with co-medications and comorbidities require special attention and encouragement to adhere to oral anticoagulation.

Schematic representation of the relationship between polypharmacy with comorbidity (green) and medication adherence (blue), as well as the associated risk (red). Patients with polypharmacy show an increased risk with the increasing number of medications for both cardiovascular outcome events, such as all-cause death as well as for bleeding events, like major bleeding. Polypharmacy is associated with an increased risk for non-adherence, which leads to an increased cardiovascular risk as well. Thus, the cardiovascular risk increases with non-adherence and co-medication load.