An Evaluation of Andexanet Alfa v. Standard of Care for Reversal of Doac-Induced Intracranial Hemorrhage – a Systematic Review and Meta-Analysis

Background

Direct oral anticoagulants (DOACs) are reversible factor X inhibitors used to treat and prevent thrombotic complications such as venous thromboembolism and stroke in patients with atrial fibrillation. While offering benefits over traditional anticoagulants, they continue to present the risk of bleeding events, including intracranial hemorrhage (ICH). A recombinant form of factor Xa, Andexanet alfa, is available in some jurisdictions to reverse DOAC effects in patients with life-threatening or uncontrolled bleeding. Previous studies, including a recently published randomised controlled trial (RCT) have observed improvements in hemostatic efficacy and reductions in anti-factor Xa activity compared with “standard of care”. However, pooled efficacy, thrombotic events, and the impact on 30-day mortality reduction is unclear.

Objective

We performed a systematic review and meta-analysis to determine hemostatic efficacy, thrombotic complications, and mortality in ICH patients receiving Andexanet alfa compared to standard of care.

Methods

We searched Ovid Medline, EMBASE, CINAHL, and the reference lists of eligible publications for relevant studies published until June 7^th, 2024 using a librarian-approved search strategy. Studies were included if they were a prospective or retrospective cohort study or randomized controlled trial (RCT) enrolling more than 15 patients that directly compared Andexanet alfa to standard of care options, as defined by the study, in the context of DOAC-induced ICH. The primary efficacy outcome was hemostatic efficacy, as defined by individual studies. Primary safety outcomes included rates of thrombotic complications, both venous and arterial, and mortality. Secondary outcomes included subgroup analyses of different standard-of-care options. The Review Manager (RevMan) tool, version 7.14.1, was used to pool outcome rates and calculate Mantel-Haenszel (M-H) risk ratios using a random effects model.

Results

A total of 2423 records were screened, with a total of 22 studies (n = 4330 patients) included in this analysis. Twenty (90.9%) studies were retrospective cohort studies, one (4.5%) was a randomized controlled trial, and one (4.5%) was an analysis of two prospective cohort studies. Eighteen (81.8%) studies predominately or exclusively used 4-factor prothrombin complex concentrate (4F-PCC) as the standard of care, 4 (18.2%) studies used 3-factor and activated PCC, one examined fresh frozen plasma (FFP), and one examined tranexamic acid. The two most commonly documented DOACs were apixaban (n = 1072) and rivaroxaban (n = 716). The most common indication for DOAC use was atrial fibrillation (n = 1874), followed by VTE (n = 239). Of the studies examining hemostatic efficacy, the majority (n = 9, 64.3%) used the ANNEXA-4 criteria for hemostasis, followed by ISTH criteria (n = 3, 21.4%).

Fourteen studies reported hemostatic efficacy, with a pooled risk ratio of 1.1 (95% CI 1.03-1.20, p = 0.005, I² = 18%) favouring Andexanet alfa. Thirteen studies reported thrombotic events, with a pooled risk ratio of 1.22 (95% CI 0.86-1.74, p = 0.26, I² = 0%). Finally, 13 studies examined mortality, with a pooled risk ratio of 0.81 (95% CI 0.63-1.05, p = 0.26, I² = 42%). Subgroup analyses comparing Andexanet alfa to 4F-PCC found similar results across hemostatic efficacy and thrombotic complications but noted a significant mortality risk reduction in favour of Andexanet alfa (RR 0.76, 95% CI: 0.58-0.99, p=0.04, I² = 38%). Heterogeneity was low for both hemostatic efficacy and thrombotic complications and moderate for mortality.

Conclusions

Our meta-analysis found improved hemostatic efficacy with Andexanet alfa compared to standard-of-care, with no effect on thrombotic complications and mortality rates. This suggests that Andexanet alfa is a favourable treatment option for hemostasis in patients experiencing life-threatening ICH.