Asundexian + DAPT a treatment alternative for acute MI?

Adding the oral factor XIa (FXIa) inhibitor asundexian to dual antiplatelet therapy (DAPT) may be a safe and effective oral anticoagulation (OAC) alternative for acute MI patients, findings from the PACIFIC-AMI study suggest.

DAPT (aspirin + P2Y12 inhibitor) is considered standard of care following an acute MI. OAC with a VKA* or a NOAC* has also shown potential in preventing recurrent ischaemic events in patients post-MI and with chronic vascular disease. [N Engl J Med 2012;366:9-19; N Engl J Med 2017;377:1319-1330]

However, both DAPT and OAC post-MI is limited by bleeding risk, stressed Dr John Alexander from Duke University Medical Center, Durham, North Carolina, US, at ESC 2022. “FXIa inhibition poses a promising therapeutic target,” he continued, citing evidence supporting its potential as an alternative for OAC. [N Engl J Med 2015;372:232-240; Thromb Res 2016;141:S8-S11; Blood 2019;133:1507-1516; J Thromb Haemost 2022;20:1400-1411]

“FXIa inhibitors … have the theoretical potential to uncouple haemostasis and vascular thrombosis. Thrombin amplification is inhibited, which prevents pathologic thrombi, and the tissue factor pathway still produces thrombin, which allows beneficial blood clots to form to stop bleeding,” added Alexander.

Within 5 days of MI onset, 1,600 patients with acute MI (median age 68 years, 78 percent male, 13 percent Asian, 54 percent with NSTEMI**) were randomized 1:1:1:1 to either asundexian 10, 20, or 50 mg or placebo QD, on top of aspirin and a P2Y12 inhibitor***. They were followed for 2 weeks after study drug discontinuation. [ESC 2022, Hot Line Session 5]

At week 4, asundexian 10 mg generated ~70 percent inhibition of baseline FXIa activity, with a greater effect at peak^# than trough^# (mean ratio to baseline, 0.23 vs 0.35). The 20-mg asundexian dose yielded about 80 percent inhibition, also with a greater effect at peak vs trough (mean ratio to baseline, 0.14 vs 0.21). The 50-mg dose produced >90 percent inhibition with similar effects at peak and trough (mean ratio to baseline, 0.07 vs 0.09).

There were similar rates of significant (BARC^## 2, 3, or 5) bleeding events across arms (7.6, 8.1, 10.5, and 9.0 percent for asundexian 10, 20, and 50 mg, and placebo, respectively). A comparison between placebo and all asundexian doses yielded a hazard ratio (HR) of 0.98. Between asundexian 50 mg and placebo, the HR was 1.20.

In terms of any bleeding, the placebo arm had the numerically highest rate (21 percent), followed by asundexian 50 mg (20 percent). The rates of any bleeding events with the two lower asundexian doses were 18 percent (10 mg) and 19 percent (20 mg).

Efficacy outcome event^### rates were also similar across arms (6.8, 6.0, 5.5, and 5.5 percent for asundexian 10, 20, and 50 mg, and placebo, respectively). The HRs were similar when comparing placebo against asundexian 20 and 50 mg (HR, 1.05) and against asundexian 50 mg only (HR, 1.01).

“[Our findings show that] asundexian 50 mg daily on top of DAPT resulted in near-complete inhibition of FXIa activity … [There was] no increase in significant or any bleeding with any dose of asundexian vs placebo,” said Alexander.

PACIFIC-AMI is the first randomized placebo-controlled trial evaluating a small-molecule FXIa inhibitor in this patient setting, he continued. Apart from producing dose-dependent FXIa inhibition, asundexian does not interact with clopidogrel to influence bleeding time, has no differences in pharmacokinetics/dynamics across age or sex, does not inhibit or induce CYP3A4, is not impacted by food or pH-modulating drugs, and has a consistent and predictable pharmacologic profile, he added.

“[T]ogether with existing genetic and preclinical evidence, [our findings] support further investigation of asundexian as a potentially safer anticoagulant in an adequately powered phase III clinical trial of patients following an acute MI,” concluded Alexander.

PACIFIC-AMI is one of three clinical trials in a phase II programme evaluating asundexian at different doses. The other two – PACIFIC-AF and PACIFIC-STROKE – assessed the efficacy and safety of asundexian for patients with atrial fibrillation and non-cardioembolic ischaemic stroke, respectively. [Lancet 2022;399:1383-1390]