Intracranial bleeding under vitamin K antagonists or direct oral anticoagulants: results of the RADOA registry

Abstract

Background and purpose: The use of direct oral anticoagulants (DOAC) has increased sharply and DOAC are the oral anticoagulant therapy (OAT) of choice for the majority of patients with newly-diagnosed atrial fibrillation. Intracranial hemorrhage is the most severe adverse event of OAT. Systematic data on the course of intracranial hemorrhage under DOAC compared to vitamin K antagonists (VKA) are warranted to enable shared decision making in AF patients needing OAT.

Methods: This is a secondary analysis of the patients with intracranial bleedings from the prospective multicenter emergency department-based RADOA registry, which collected data on patients admitted with major bleeding while taking VKA or DOAC. The primary endpoint was in-hospital mortality until day 30. We evaluated hematoma volume and short-term clinical outcomes in relation to the extent of active OAT according to coagulation parameters and OAT plasma levels measured by UPLC-MS/MS.

Results: Of 193 patients with major bleeding, 109 (56.5%) had intracranial hemorrhage [52.3% intracerebral (ICH), 33.9% subdural (SDH), 11.0% subarachnoidal (SAH)]. 64 (58.7%) were on VKA and 45 (41.2%) were on DOAC. On admission, we could confirm active anticoagulation in 97.7% of VKA-treated patients based on either INR > 1.3 or phenprocoumon levels and in 75.8% of DOAC-treated patients based on DOAC levels. Patients suffering an intracranial hemorrhage under VKA showed significantly larger hematoma volumes and a higher in-hospital mortality. Especially in intracerebral hemorrhage, we observed a higher initial severity and numerically greater proportion of early changes towards palliative therapy under VKA, which coincided with a numerically higher case fatality.

Conclusions: We show significantly smaller hematoma volumes for ICH and SDH under DOAC in comparison to VKA and a significantly lower 30-day in-hospital mortality rate of DOAC-ICH, even before the introduction of specific antidotes. These data strongly support the use of DOAC whenever possible in patients requiring OAT.

Trial registration: http://www.

Clinicaltrials: gov ; Unique identifier: NCT01722786.

Conflict of interest statement

Waltraud Pfeilschifter has received lecture honoraria and advisory fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Alexion, and institutional research support from Boehringer Ingelheim. Edelgard Lindhoff-Last has received lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Portola, CSL Behring, Alexion and Aspen and institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo and CSL-Behring. Ali Alhashim: none declared. Ingvild Birschmann has received speaker’s honoraria from Bristol-Myers Squibb/Pfizer, Siemens Healthcare, LFB biomedicaments and CSL Behring and reimbursement for congress travelling and accommodation from Aspen and Bristol-Myers Squibb. She has performed contract research for Siemens Healthcare and is a member of the advisory board of LFB biomedicaments and of the expert groups of CSL Behring GmbH and Siemens Healthcare Diagnostics Products GmbH. Simone Lindau: none declared. Stavros Konstantinides has received lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, MSD, Actelion, and Daiichi-Sankyo; and institutional research support from Bayer AG, Boehringer Ingelheim, MSD, Actelion, and Daiichi-Sankyo. Oliver Grottke has received research funding from Alveron, Bayer Healthcare, Boehringer Ingelheim, Biotest, CSL Behring, Octapharma, Novo Nordisk, Nycomed and Portola. He has also received honoraria for lectures and consultancy support from Bayer Healthcare, Boehringer Ingelheim, CSL Behring, Octapharma, Sanofi, Shire, Pfizer and Portola. Ulrike Nowak-Goettl has received lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Octapharma and LFB. Barbara Zydek: none declared. Christian von Heymann has received honoraria for lectures and consultancy work potentially related to this topic, as well as travel reimbursements from Bayer GmbH, Biotest GmbH, Pfizer GmbH, Daiichi Sankyo, CSL Behring, NovoNordisk GmbH, and HICC GbR. Jan Beyer-Westendorf has received personal honoraria (lectures, advisory boards) and travel support from Bayer, Daiichi Sankyo, Janssen, Portola and institutional research support from Bayer, Daiichi Sankyo, Janssen, LEO, Pfizer, and Portola. Patrick Meybohm has received grants from B. Braun Melsungen, CSL Behring, Fresenius Kabi, and Vifor Pharma for the implementation of Frankfurt’s Patient Blood Management program and honoraria for scientific lectures from B. Braun Melsungen, Vifor Pharma, Fearing, CSL Behring, and Pharmacosmos. Andreas Greinacher has received lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer and Daiichi-Sankyo, ASPEN. Eva Herrmann: none declared.

© 2022. The Author(s).

Figures

Fig. 1

Panel A and B: 30-day in-hospital mortality and hematoma volume of VKA- and DOAC-associated ICH and SDH. Kaplan Meier curves and p-values from log-rank test for 30 day in-hospital mortality in patients with intracerebral (A) and subdural (B) hemorrhage. Compared are patients treated with vitamin K antagonists and direct oral anticoagulants at hospital admission. Panel (C) Boxplots comparing hematoma volume in patients with intracerebral and subdural hemorrhage treated with vitamin K antagonist (VKA) and direct oral anticoagulants (DOAC) at hospital admission. As usual, horizontal lines represent the median of the corresponding subgroups. P-values are from a two-sided nonparametric Wilcoxon–Mann–Whitney U-test