Direct oral anticoagulants versus phenprocoumon: Mortality, thromboembolism and major hemorrhage. A systematic review and meta-analysis of routine data studies

BACKGROUND: In the randomized controlled trials (RCTs) of the non-vitamin K dependent oral anticoagulants (NOACs) that led to their approval, the vitamin K antagonist (VKA) warfarin was used as a comparator drug. The efficacy and safety of NOACs compared to phenprocoumon, the VKA predominantly used in Germany, are unknown, as it has not been studied in RCTs. METHODS: For this systematic review and meta-analysis (registration: CRD42024619047), we systematically searched 3 databases for studies based on routine data that yielded matched or adjusted results for overall mortality, thromboembolism, and major hemorrhage in anticoagulant-naïve patients who were treated with either phenprocoumon or a NOAC. RESULTS: Seven studies based on German routine data were identified, covering a total of 1 842 015 anticoagulant-naïve patients. In a pooled analysis of all NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban), these were associated with a notably higher risk of mortality (hazard ratio [HR] 1.14, 95% confidence interval [1.00; 1.30]), a higher risk of thromboembolic events (HR 1.08, [1.01; 1.15]), and a lower risk of major hemorrhages (HR 0.80, [0.72; 0.90]) than phenprocoumon. Among individual NOACs, rivaroxaban was associated with a notably higher risk of mortality than phenprocoumon; the other NOACs also displayed a higher risk of mortality than phenprocoumon, but the differences were not statistically significant. CONCLUSION: In this meta-analysis of NOACs versus phenprocoumon, the former were found in a pooled analysis to be associated with a higher overall risk of mortality and a higher risk of thromboembolic events on the one hand, but a lower risk of major hemorrhages on the other hand. Warfarin was the comparator drug in all of the clinical trials that led to the approval of NOAC. The findings of this meta-analysis cast doubt on the benefit of the preferential use of NOACs in countries where phenprocoumon is the standard VKA.