Forecast of Functional Outcome and Impact of Anti Factor Xa-levels in Patients With Intracerebral Haemorrhage Related to Direct Factor Xa Inhibitors - a Multi-center Cohort Study

The utilization of direct oral anticoagulants (DOACs), such as factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) and the thrombin inhibitor dabigatran, has emerged as a pivotal strategy for preventing stroke in patients with atrial fibrillation and thromboembolic diseases. While the risk of intracranial bleeding is notably lower (by about 50%) with DOACs in comparison to Vitamin K antagonists, a fraction of patients (0.2-1.0% annually) still experiences intracranial hemorrhages, primarily intracerebral. Notably, based on data from the Swiss Stroke Registry spanning 2014 to 2019, 9.1% of patients admitted to stroke units or centers for intracerebral hemorrhage (ICH) had prior DOAC therapy. This incidence continues to rise, with 95% of DOAC-associated intracerebral hemorrhages occurring during factor Xa inhibitor therapy.

Treatment strategies for factor Xa inhibitor-associated intracerebral hemorrhage encompass prothrombin complex concentrate (PCC) and the specific reversal agent andexanet alfa. However, the available evidence relies on observational cohort studies and independent patient samples, lacking direct comparative trials. The ongoing randomized controlled trial, ANNEXA-I, aims to assess the efficacy of andexanet alfa compared to standard care. The primary outcome includes hemostatic efficacy measured by imaging within a 12-hour window and functional outcomes evaluated at 30 days. While ANNEXA-I anticipates providing valuable insights into factor Xa-associated intracerebral hemorrhage treatment, significant aspects concerning the role of anticoagulant activity, particularly in patients presenting late after their last dosage intake, and long-term outcomes will remain unanswered.

Assessing anticoagulant activity through anti-FXa levels remains integral yet inconclusive regarding its correlation with hematoma expansion risk. Despite streamlined anti-FXa level measurements at the investigators' institution, heterogeneity in these levels persists, including elevated levels (>100ng/ml) observed even beyond 12 hours post-intake. Notably, the inclusion criteria for ANNEXA-I predominantly consider the time since the last intake (≤15 hours) of factor Xa inhibitors, often omitting anti-FXa level measurements. This oversight might exclude a subgroup of patients who could potentially benefit from andexanet alfa treatment beyond the current strict time window.

Early hematoma expansion significantly impacts outcomes; however, challenges such as recurrent events and rehabilitation intensity may dilute the benefits of preventing hematoma expansion. ANNEXA-I primarily focuses on short-term outcomes, necessitating additional data to comprehend long-term prognoses post intracerebral hemorrhage.

This research aims to establish associations between hematoma expansion and anti-FXa levels, identify risks in late-presenting patients, and predict favorable outcomes at 3, 6, and 12 months. Primary endpoints include functional outcomes, while secondary endpoints involve expansion rates, anticoagulant activity, and various events at the 12-month mark. The comprehensive analysis seeks to bridge gaps in understanding intracerebral hemorrhages associated with DOACs, guiding clinical decisions for both immediate and extended prognoses.