New anticoagulant safe and maybe effective: PACIFIC-AMI and PACIFIC-Stroke outcomes

In back-to-back late-breaking presentations of the phase 2 PACIFIC-AMI and PACIFIC-Stroke trials, adding the oral factor XIa inhibitor asundexian on top of dual antiplatelet therapy (DAPT) successfully reduced factor XIa activity after acute myocardial infarction (MI) and stroke reassuring safety. Although there was no clear signal for efficacy after MI, there appeared to be a signal in stroke patients with atherosclerosis for symptomatic stroke prevention.

Results from PACIFIC-AMI

Prof. John Alexander (Duke University, NC, USA) presented the results from the phase 2 PACIFIC-AMI trial (NCT04304534), which were simultaneously published in Circulation [1,2]. By means of explaining the rationale of the study, Prof. Alexander said: “Following an acute MI, patients remain at increased risk for recurrent events despite the excellent therapies we have today. Antiplatelet therapy with aspirin and P2Y12 inhibitors is a benefit and considered standard-of-care but is limited because of the risk of bleeding. Oral anticoagulation, that is, vitamin K antagonists and the factor X inhibitor rivaroxaban, have also been shown to be beneficial post-MI, but their use is also limited by bleeding and are, thus, rarely used.”

PACIFIC-AMI aimed to test the efficacy and safety of 3 different doses of asundexian after acute MI, when added to standard of care DAPT. Participants (n=1,600, 51% had an ST-segment elevation MI) were randomised to 10 mg, 20 mg, 50 mg asundexian, or placebo once daily for 6–12 months.

The primary efficacy endpoint was a composite of cardiovascular death, MI, stroke, or stent thrombosis. The primary safety endpoints were Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding and any bleeding in the 2 weeks after study drug discontinuation.

As evidence of on-target activity, participants exhibited >70%, 80%, and 90% reduction in factor XIa activity when given asundexian 10 mg, 20 mg, and 50 mg once daily, compared with placebo (see Figure). With a median follow-up of 368 days, there were no trends for reductions in the composite primary outcome among patients assigned to any dose of asundexian compared with placebo. Notably, Prof. Alexander pointed out, there were only few total events, and therefore the conclusion is still uncertain. The primary safety endpoint, however, was met: there was no increase in bleeding among patients assigned to asundexian compared with placebo.

Figure: Factor XIa inhibition at 4 weeks in PACIFIC-AMI [1]



Vertical bars indicate the % residual Factor XIa activity compared with baseline

Prof. Alexander concluded: “These results, together with existing genetic and preclinical evidence, support the further study of the factor XIa inhibitor asundexian, in adequately sized phase 3 trials as a potentially safer anticoagulant for patients following an acute MI.”

Results from PACIFIC-Stroke

Associate Prof. Ashkan Shoamanesh (McMaster University, Canada) presented the results of the PACIFIC-Stroke trial (NCT04304508), which assessed the same doses of asundexian compared with placebo [3]. PACIFIC-Stroke randomised patients (n=1,808, mean age 67 years, 34% women) within 48 hours of non-cardioembolic stroke symptom onset (mean interval 36 hours), with a primary efficacy endpoint of ischaemic stroke or brain infarct at 6 months.

With a median follow-up of 10.6 months, recurrent symptomatic ischaemic stroke or transient ischaemic attack (TIA) occurred in 8.3% of the placebo arm compared with 7.7% of the asundexian 10 mg arm, 6.2% in the 20 mg arm, and 5.4% in the 50 mg arm. Although there were numeric differences, statistical significance was not reached in the risk of events in patients given asundexian compared with placebo (P=0.8). However, after a post-hoc exploratory analysis that replaced the initial primary endpoint component of covert brain infarct with TIA, researchers observed a lower risk with 50 mg asundexian compared with placebo (5.4% vs 8.3%; HR 0.64; 95% CI 0.41–0.98), especially in the subgroup of patients with atherosclerotic plaques (3.1% vs 8.1%; HR 0.39; 95% CI 0.18–0.85).

At 12 months follow-up, the rates of bleeding were not significantly different between asundexian and placebo (3.9% vs 2.4%; HR 1.57; 90% CI 0.91–2.71).

“Asundexian did not reduce the composite endpoint of intracranial infarction or ischaemic stroke in a dose-dependent manner,” explained Associate Prof. Shoamanesh. “However, treatment with asundexian 50 mg daily did reduce recurrent symptomatic ischaemic strokes and TIAs in this population with acute non-cardioembolic ischaemic stroke, particularly among those with atherosclerosis, without a statistically significant increase in major bleeding.” He concluded: “The promising results from this phase 2 trial require validation in an adequately powered phase 3 randomised trial”.

1. Alexander J, et al. PACIFIC-AMI - Efficacy and safety of factor XIa inhibitor asundexian on top of dual antiplatelet therapy after acute myocardial infarction. Hot Line Session 5, ESC Congress 2022, Barcelona, Spain, 26–29 August.
2. Rao SV, et al. Circulation. 2022 Aug 27. doi: 10.1161/CIRCULATIONAHA.122.061612. Epub ahead of print.
3. Shoamanesh A, et al. PACIFIC-STROKE - Phase 2 Program of AntiCoagulation via Inhibition of FXIa by the oral Compound BAY 2433334 – non-cardioembolic STROKE study. Hot Line Session 5, ESC Congress 2022, Barcelona, Spain, 26–29 August.

 

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Posted on 27 October 202222 February 2024