Thirty‐day mortality with andexanet alfa compared with prothrombin complex concentrate therapy for life‐threatening direct oral anticoagulant‐related bleeding

Abstract

Objective Compare 30‐day mortality among patients receiving the specific reversal agent andexanet alfa versus replacement prothrombin complex concentrate (PCC) in the management of direct‐acting oral anticoagulant (DOAC)–related bleeds. Methods Two patient‐level datasets were used: ANNEXA‐4, a prospective, single‐arm trial of patients taking apixaban or rivaroxaban who received andexanet alfa and ORANGE, a prospective, observational study of anticoagulated patients in UK hospitals, some of whom received PCC. Patients were propensity score matched based on demographic and clinical characteristics. Subgroup analyses were performed by bleed type (intracranial hemorrhage [ICH], gastrointestinal [GI], other). Relative risk (RR) of all‐cause 30‐day mortality was calculated. Results 322 ANNEXA‐4 patients treated with andexanet alfa (mean age = 77.7 years; 64.9% ICH) were matched with 88 ORANGE patients treated with PCC (mean age = 74.9 years, 67.1% ICH). Adjusted 30‐day mortality for patients treated with andexanet alfa (14.6%) was lower than patients treated with PCC (34.1%; RR, 0.43; 95% CI, 0.29–0.63). In the ICH subgroup, patients treated with andexanet alfa had lower mortality (15.3%) than patients treated with PCC (48.9%; RR, 0.31; 95% CI, 0.20–0.48). Mortality risk was lowest for patients in the GI subgroup but did not differ significantly by treatment (12.2% for andexanet alfa vs 25.0% for PCC; RR, 0.49; 95% CI, 0.21–1.16). Conclusions In this propensity score–matched comparison across 2 independent datasets, adjusted 30‐day mortality rates were lower for patients treated with andexanet alfa than in matched patients receiving PCC. This indirect comparison was limited in that it could not account for several highly predictive variables including GCS score, hematoma volume, and expected survival. Further research is warranted to confirm the mortality differences between reversal/replacement agents for DOAC‐related bleeding.

Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis

“…The results of our analysis are generally consistent with prior, considerably smaller, comparative case series [23][24][25]. Barra and colleagues [26] reported a case series of apixaban-or rivaroxaban-associated intracranial hemorrhage patients managed with andexanet alfa (n = 18) or 4F-PCC (n = 11).…”

“…The results of this analysis also align with other indirect comparison studies for andexanet alfa versus usual care-treated patients with FXa inhibitor bleeding in the UK and Germany. Cohen and colleagues compared propensity score (model based on age, bleed location, history of atrial fibrillation, venous thromboembolism, stroke, renal dysfunction, and cancer)-adjusted cohorts of andexanet alfa-and PCC-managed FXa inhibitor major bleeding patients [24]. As in our study, the andexanet alfa cohort was derived from ANNEXA-4, while a synthetic control arm of PCC patients was drawn from the prospective, observational ORANGE study (which assessed the presentation and clinical outcomes of major bleeding episodes associated with oral anticoagulant use in the UK between October 2013 and August 2016) [25].…”

“…It is noteworthy that the present study is the largest comparison to date to assess the comparative effectiveness of andexanet alfa and 4F-PCC in the management of apixaban-or rivaroxaban-associated intracranial hemorrhage. Prior studies have compared andexanet alfa to any prothrombin complex concentrate [24] or usual care [27], whereas all patients in our study received 4F-PCC. The substantially overlapping time frame between the two arms in our study likely attenuated selection and chronologic biases present in earlier comparative studies.…”

Intrakranielle Blutungen unter oraler Antikoagulation

“…Bislang wurden indirekte Kohortenanalysen publiziert, welche die ANNEXA-4-Patienten mit nationalen Registern (RETRACE II, ORANGE) vergleichen, in denen Patienten mit PCC/4 F-PCC behandelt wurden. Sie gelangen zu sehr heterogenen Ergebnissen hinsichtlich klinischer Outcome-Parameter und Komplikationsraten [13,14]. Dies gilt ebenso für unterschiedliche Dosierungsstrategien für PCC/4F-PCC.…”

Management of severe peri-operative bleeding

“…A recent propensity score-matched analysis showed that the adjusted 30day mortality rates were lower for patients treated with andexanet alfa than in matched patients receiving PCC. 20 Further studies comparing these two drugs on different outcomes are necessary to reach a final conclusion. The recommendation regarding the use of idarucizumab for dabigatran reversal in an ongoing haemorrhage is surprisingly restrained.…”