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

Alexander T Cohen, Megan Lewis, Augusta Connor, Stuart J Connolly, Patrick Yue, John Curnutte, Raza Alikhan, Peter MacCallum, Joachim Tan, Laura Green, Alexander T Cohen, Megan Lewis, Augusta Connor, Stuart J Connolly, Patrick Yue, John Curnutte, Raza Alikhan, Peter MacCallum, Joachim Tan, Laura Green

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.

Conflict of interest statement

ATC has received fees for serving on an adjudication committee from Boehringer Ingelheim and AbbVie; grant support and fees for serving on committees from Bristol Myers Squibb, Daiichi Sankyo and Pfizer; consulting fees from Janssen, Portola Pharmaceuticals and Ono Pharmaceuticals; fees for serving on a steering committee and consulting fees from Bayer, and travel support to present this work at the American College of Cardiology annual meeting. ML and AC are employed by FIECON, which performed this analysis at Portola's request and received payment for their contributions to the statistical analysis and drafting the manuscript. SJC has received grant support and consulting fees from Portola Pharmaceuticals, Bristol Myers Squibb, Bayer, and Daiichi Sankyo. PY and JC were employed by and held stock options in Portola Pharmaceuticals at the time of this work. RA has received grant support and consulting fees from Portola Pharmaceuticals, Bristol Myers Squibb, Bayer, Daiichi Sankyo, and Pfizer. PMC has received fees for serving on a committee from Portola Pharmaceuticals. JT and LG report no conflicts of interest.

© 2022 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.

Figures

FIGURE 1
FIGURE 1
Patient numbers used in PSM analysis for ANNEXA‐4 and ORANGE. Individual data were extracted from the ANNEXA‐4 study for the andexanet alfa–treated group and from the ORANGE study for the PCC‐treated group. PCC, prothrombin complex concentrate; PSM, propensity score matching
FIGURE 2
FIGURE 2
Forest plot showing RR of all‐cause 30‐day mortality. RR of all‐cause 30‐day mortality and 95% CI were calculated after PSM for the 2 treatment groups in the whole cohort and in the subgroups. Individual data were extracted from the ANNEXA‐4 study for the andexanet alfa–treated group and from the ORANGE study for the PCC‐treated group. Because of the low number of matches for the other major bleeds subgroup, the CI was large (RR, 1.29; 95% CI, 0.17‐9.55) and was not included in the forest plot. CI, confidence interval; GI, gastrointestinal; ICH, intracranial hemorrhage; PCC, prothrombin complex concentrate; PSM, propensity score matching; RR, relative risk

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