Key Points:
- Previous studies have investigated the use of direct oral anticoagulants (DOACs) instead of warfarin for reduction of stroke risk in AF, but the risk of clinically significant bleeding remains.
- Abelacimab is a novel Factor XI inhibitor that may be useful in reducing thromboembolic events while also being less likely to cause major bleeding.
- Patients were assigned to rivaroxaban 20 mg/ day or two different doses of abelacimab, 150mg SC monthly and 90mg SC monthly. The primary endpoint was major or clinically relevant non-major bleeding.
- The trial was stopped premature due to significant reduction in bleeding with 74% reduction in major bleeding and 93% reduction in GI bleeding on abelacimab 150mg SC versus rivaroxaban.
Multiple previous randomized controlled trials (RCTs) have been conducted to compare warfarin and DOACs, finding decreased risk of death, hemorrhagic stroke, and major bleeding. However, DOACs are still associated with risk of increased risk of GI bleeding, for which this medicine may be stopped in the community or not prescribed again by another provider. Abelacimab is a highly selective, fully human monoclonal antibody against Factor XI, which has been shown to be associated with lower amounts of bleeding rather than pro-thrombosis. In this trial, the investigators compare abelacimab to rivaroxaban to compare the risk of stroke for patients with AF with moderate-to-high ischemic stroke risk.
A total of 1287 patients with AF were randomized 1:1:1 to one of three arms: abelacimab 150mg SC monthly, abelacimab 90mg SC monthly, or rivaroxaban 20mg daily (or 15mg daily if CrCl < 50). Primary outcome in this trial was major or clinically relevant non-major bleeding. Included patients were at least 55 years old with either CHA2DS2-Vasc ≥ 4 or CHA2DS2-Vasc ≥ 3 with associated use of antiplatelets or CrCl ≤ 60. Mean age of included patients was 74, and 44% of included patients were female. Of note, abelacimab showed successful inhibition of Factor XI during the trial: from baseline to three months into the trial, there was 97% reduction in free Factor XI for abelacimab 90mg SC and 99% reduction in free Factor XI for abelacimab 150mg SC. This was consistent with >95% inhibitor of Factor XI for the duration of the trial. This trial was ended prematurely because of the substantially greater than anticipated reduction in major and clinically relevant non-major bleeds in the abelacimab arms compared to rivaroxaban and a benefit:risk ratio favoring abelacimab.
Both abelacimab doses achieved more than 95% inhibition of factor XI. For abelacimab 150mg SC monthly, the HR for major or CRNM bleeding was 0.33 (95% CI: 0.19-0.55; p<0.001). For abelacimab 90mg SC monthly, the HR for major or CRNM bleeding was 0.23 (95% CI: 0.13-0.42; p<0.001). Across specific endpoints, incidence rate of major or CRNM bleeding with rivaroxaban was 8.1, compared to 2.7 with abelacimab 150mg, and 1.9 for abelacimab 90mg. Major bleeding, comprised of GI bleeding and intracranial hemorrhage (ICH), also showed statistically significant reduction with HR 0.26 (95% CI: 0.11-0.61; p=0.002) for abelacimab 150mg as well as HR 0.19 (95% CI: 0.07-0.50; p<0.001). Furthermore, GI bleeding itself was significantly lower with abelacimab, with HR 0.07 (95% CI: 0.01-0.50; p=0.008) for 150mg and HR 0.07 (0.01-0.51; p=0.009) for 90mg. Notably, rates of ICH were not significantly difference between each arm: for abelacimab 150mg, HR 0.50 (95% CI: 0.09-2.72; p=0.42), and for abelacimab 90mg, HR 1.03 (95% CI: 0.26-4.10; p=0.97).
In summary, this novel therapy abelacimab showed more than 95% successful inhibition of Factor XI over the dosing interval and had substantial reduction in major and CRNM bleeding compared to daily rivaroxaban. Compared to rivaroxaban, abelacimab 150mg SC monthly showed a 67% reduction in CRNM bleeding, 74% reduction in major bleeding, and 93% reduction in major bleeding.