Rapido: Results from a UK-Wide Audit of 2477 Patients Who Received a Reversal Agent for a Direct Oral Anticoagulant

Introduction

Major bleeding in patients treated with direct oral anticoagulants (DOACs) is associated with high morbidity and mortality. Although a specific reversal agent for dabigatran, idarucizumab, was approved for use in the UK in 2016, the predominant option for patients taking apixaban, edoxaban, and rivaroxaban has until recently been off-licence prothrombin complex concentrate (PCC). In early 2020, the Scottish Medicines Consortium agreed reimbursement for andexanet alfa for all sites of major bleeding in patients on apixaban and rivaroxaban. Later in 2020, the National Institute of Health and Clinical Excellence (NICE) recommended andexanet alfa for patients on apixaban and rivaroxaban only as an option for the management of major gastrointestinal (GI) hemorrhage, a recommendation that covers England, Wales, and Northern Ireland. Given the poor outcomes in patients who bleed on DOACs, the uncertain benefits of treatment with reversal agents, and the geographical differences in approvals across the UK, we set out to audit UK-wide use of reversal agents for DOACs.

Methods

This was a retrospective, observational audit that included patients who received andexanet alfa, PCC (Beriplex, or Octaplex), or idarucizumab for reversal of a DOAC between October 1, 2020 and June 30, 2023. The primary outcome was proportion of patients who received a reversal agent who had major bleeding as defined by International Society of Thrombosis and Haemostasis (ISTH) criteria. Key secondary outcomes were death within 90 days and thrombosis within 30 days. Data were entered into a secure, online REDCap database and data collection was conducted by members of HaemSTAR, a UK-wide network of trainee hematology doctors, along with healthcare students and other healthcare professionals.

Results

Demographics and medical history
We collected data on 2,477 patients who were treated with a reversal agent. Median age was 80 years (IQR 73-86), 1,447 patients (58.4%) were male, 1,982 (80.0%) had atrial fibrillation, and 512 (20.7%) had a history of venous thromboembolism.

Bleeding events
1,010 (40.8%) had intracranial hemorrhage (ICH), 880 (35.5%) GI hemorrhage, 393 (15.9%) bleeding at other sites, and 194 (7.8%) received a reversal agent prior to surgery or an invasive procedure. 1,320 (53.3%) patients were taking apixaban, 710 (28.7%) rivaroxaban, 319 (12.9%) edoxaban, and 128 (5.2%) dabigatran. Amongst patients with bleeding, 2080 (91.1%) fulfilled the criteria for major hemorrhage. For those with a drug level available retrospectively (n=232; 9.4%), median level was 108.5 ng/mL (IQR 57.5-211.5) and 50 (21.5%) had a level <50 ng/mL.

Reversal agent use and dosing
323 patients (13.0%) received andexanet alfa, 698 (28.2%) Beriplex, 1,339 (54.1%) Octaplex, and 117 (4.7%) idarucizumab. As reimbursement for andexanet alfa is restricted to GI hemorrhage in most of the UK, 266 (82.4%) uses of andexanet alfa were for this indication. 268 (83.0%) patients received a low dose andexanet alfa bolus (400 mg). The median dose of Beriplex was 3,000 IU (IQR 2,000-3,750) and the median dose of Octaplex was 2,000 IU (IQR 1,500-3,000). Of patients who received idarucizumab, 114 (97.4%) received 5 g and 3 (2.6%) received a second dose. Median times to administration of a reversal agent were: 16.1 h (IQR 9.8-24.5) from last dose of anticoagulation (where known), 6.8 h (IQR 3.8-12.6) from bleed onset (where known), and 4.3 h (IQR 2.2-8.3) from arrival at hospital (where bleeds occurred in outpatients)

Patient outcomes
At 90 days, 463 (45.8%) patients had died after ICH, 326 (37.0%) following GI hemorrhage, and 120 (30.5%) after bleeds at other sites. 73 (3.0%) patients had a thrombotic event within 30 days at a median of 10 days (IQR 4-16) post-reversal agent administration. 35 (1.4%) had a venous event and 41 (1.6%) had an arterial event.

Conclusion

In this audit, the majority of patients fulfilled the ISTH definition of major bleeding. Furthermore, the high mortality rates demonstrate that the cohort is enriched for severe presentations of bleeding. Importantly, the data highlight delays in identification and treatment of bleeds. Further, detailed analysis of this rich dataset is on-going, and a propensity score-matched analysis of patients with GI hemorrhage will be performed to compare outcomes in patients treated with andexanet alfa, Beriplex and Octaplex.

Funding

This project was conducted with support from AstraZeneca UK Limited.