Vitamin-K-antagonist phenprocoumon versus low-dose direct oral anticoagulants (DOACs) in patients with atrial fibrillation: a real-world analysis of German claims data

Abstract

Background For stroke prevention in patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been increasingly prescribed instead of vitamin-K-antagonists (VKA). For some patients a lower dosage of DOACs (ld-DOACs) is recommended. Ld-DOAC prescribing seems to be common, although previous studies did not show clear superiority of ld-DOACs over warfarin. In Germany, phenprocoumon is used almost exclusively as VKA. Randomized controlled trials comparing DOACs and phenprocoumon in the general population of patients with AF do not exist. Therefore, we aimed to compare ld-DOACs and phenprocoumon in a real-world setting in Germany. Methods In a retrospective observational cohort study, claims data from a group of small to medium-sized health insurance companies were analysed. Risks for the outcomes thromboembolism, death and major bleeding were estimated by Cox regression. Out of 93,685 patients with atrial fibrillation and a first prescription of an oral anticoagulant, 20,179 receiving VKA and 21,724 ld-DOACs (29.6% of all DOAC patients) were included. For the sensitivity analysis phenprocoumon was compared to the five ld-DOAC groups (ld-apixaban, ld-dabigatran, ld-edoxaban, ld-rivaroxaban, and the composite of all ld-DOACs) after propensity-score matching. Results Phenprocoumon was associated with statistically significant fewer thromboembolic events (HR = 1.29, 95% CI [1.13, 1.48], p < .001) and deaths (HR = 1.52, 95% CI [1.41, 1.63], p < .001) and a non-significant higher bleeding risk (HR = 0.89, 95% CI [0.79, 1.00], p = .051) than composite ld-DOAC. Regarding the subgroups, only patients with ld-apixaban had a statistically significant higher risk for thromboembolic events (HR = 1.42, 95% CI [1.21, 1.65], p < .001) and a lower bleeding risk (HR = 0.75, 95% CI [0.65, 0.86], p < .001). Ld-apixaban, ld-edoxaban, and ld-rivaroxaban were associated with a higher risk of death. The sensitivity analysis confirmed these associations. Conclusion Phenprocoumon seems to be superior to ld-DOACs for patients with AF. As a hypothesis phenprocoumon might turn out to be the wiser choice for high-risk patients with AF as compared to ld-DOACs, especially regarding thromboembolic events and death. Therefore, RCTs comparing ld-DOACs with phenprocoumon are needed.

Vitamin-K-antagonist phenprocoumon versus direct oral anticoagulants in patients with atrial fibrillation: a real-world analysis of German claims data

“…16–19 Patients with a lower dose, for example, due to renal impairment were excluded and analysed separately. 13 Dose assignment for DOACs was operated by the Pharmacy-Central-Number (identification number for pharmaceutical products in Germany) ( online supplemental table S1 ).…”

“…Standard dose was defined according to the standard dose suggested for stroke prevention in patients with AF by the respective Summaries of Product Information of the DOACs 16–19. Patients with a lower dose, for example, due to renal impairment were excluded and analysed separately 13. Dose assignment for DOACs was operated by the Pharmacy-Central-Number (identification number for pharmaceutical products in Germany) (online supplemental table S1).…”

“…A recent analysis comparing phenprocoumon to low-dose DOACs revealed that phenprocoumon was associated with fewer thromboembolic events and deaths and a non-significant higher bleeding risk than low-dose DOACs. 13 Low-dose therapy is mainly used for patients with certain pre-existing medical conditions or risks. RCTs comparing DOACs with phenprocoumon being largely absent, real-world studies form an even more important complement to the evidence.…”

“…However, with slightly different study designs (ie, differences in statistical analyses, outcome definition and/or data source) the results of these real-world studies were also ambiguous. A recent analysis comparing phenprocoumon to low-dose DOACs revealed that phenprocoumon was associated with fewer thromboembolic events and deaths and a non-significant higher bleeding risk than low-dose DOACs 13. Low-dose therapy is mainly used for patients with certain pre-existing medical conditions or risks.…”

Syntheses, reactivity, and biological applications of coumarins

“…Several coumarin derivatives have been approved by FDA for clinical usage. These include anticoagulant drugs such as warfarin ( Ansell et al, 2004 ), acenocoumarol ( Cesar et al, 2004 ), dicoumarol ( Duxbury and Poller, 2001 ) and phenprocoumon ( Warkentin et al, 2022 ), trioxsalen ( Sehgal, 1974 ) which is employed for the treatment of vitiligo, and esculin ( Smith and Moodie, 1988 ) which is used in combination against hemorrhoids.…”