September 06, 2022
3 min read
Alexander JH, et al. Hot Line 5. Presented at: European Society of Cardiology Congress; Aug. 26-29, 2022; Barcelona, Spain (hybrid meeting).
The PACIFIC-AMI and PACIFIC-STROKE trials were funded by Bayer AG. Alexander reports receiving research contracts from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring, FDA, Humacyte, the NIH and XaTek and having other financial ties with AbbVie, Akros, Artivion/CryoLife, AtriCure, Bristol Myers Squibb, Ferring, GlaxoSmithKline, Janssen, Pfizer, Portola and Quantum Genomics. Shoamanesh reports receiving financial ties with Bayer AG.
Asundexian on top of dual antiplatelet therapy successfully reduced factor XIa activity after acute MI and stroke with no excess bleeding risk, two speakers reported.
However, the oral factor Xia inhibitor asundexian (Bayer) did not reduce risk for thrombotic events after acute MI; nor did it reduce risk for ischemic stroke or covert brain infarcts after noncardioembolic ischemic stroke. But asundexian 50 mg compared with placebo did confer reduced risk for ischemic stroke and transient ischemic attack in patients with atherosclerosis who had a prior noncardioembolic ischemic stroke.
These data come from the results of the phase 2 PACIFIC-AMI and PACIFIC-Stroke trials presented at the European Society of Cardiology Congress.
In February, asundexian for secondary stroke prevention had previously received fast track designation from the FDA.
As Healio previously reported, the results of the phase 2 PACIFIC-AF trial indicated that patients with atrial fibrillation requiring stroke prevention experienced less bleeding compared with apixaban (Eliquis, Bristol Myers Squibb/Pfizer).
Results of PACIFIC-AMI
“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,” John H. Alexander, MD, MHS, cardiologist and professor of medicine at Duke University School of Medicine and member in the Duke Clinical Research Institute, said during a press conference. “Oral anticoagulation, that is, vitamin K antagonists and the factor X inhibitor rivaroxaban (Xarelto, Janssen/Bayer), have also been shown to be beneficial post-MI … but their use is also limited by bleeding and [they] are, thus, rarely used.”
The PACIFIC-AMI phase 2 trial was designed to assess the efficacy and safety of three different doses of asundexian, on top of DAPT after acute MI. Researchers enrolled 1,600 patients who were randomly assigned to asundexian 10 mg, 20 mg, 50 mg or placebo once daily for 6 to 12 months.
The primary efficacy outcome was a composite of CV death, MI, stroke or stent thrombosis and the primary safety outcomes were Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding and any bleeding in the 2 weeks after study drug discontinuation. The results were simultaneously published in Circulation.
Among patients assigned to asundexian 10 mg, 20 mg and 50 mg once daily, researchers observed a more than 70%, 80% and 90% reduction in factor XIa activity, respectively, compared with placebo.
Alexander and colleagues observed no reductions in the composite primary outcome among patients assigned to any dose of asundexian compared with placebo. However, there were few total events, and the efficacy of asundexian remains uncertain, Alexander said.
In addition, there was no increase in bleeding among patients assigned to asundexian compared with placebo.
“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 myocardial infarction,” Alexander said during the press conference.
Results of PACIFIC-Stroke
The PACIFIC-Stroke trial had a similar design to PACIFIC-AMI, assessing the same doses of asundexian compared with placebo, but enrolled 1,808 patients within 48 hours of noncardioembolic stroke symptom onset.
The primary efficacy outcome was ischemic stroke or covert brain infarct at 6 months, when researchers observed no reduction or dose response with asundexian compared with placebo (Emax2 model t statistic, –0.68; P = .8).
However, after a post hoc exploratory analysis that replaced the initial primary outcome component of covert brain infarct with TIA, researchers observed a lower risk with asundexian 50 mg compared with placebo (5.4% vs. 8.3%; HR = 0.64; 95% CI, 0.41-0.98).
The findings of the post hoc analysis were strongest in the subgroup of patients with atherosclerosis (3.1% vs. 8.1%; HR = 0.39; 95% CI, 0.18-0.85).
Moreover, there was no increased risk for any bleeding in patients assigned to asundexian compared with placebo.
“Asundexian did not reduce the composite endpoint of intracranial infarction or ischemic stroke in a dose-dependent manner,” Ashkan Shoamanesh, MD, FRCPC, associate professor of medicine (neurology) at McMaster University in Hamilton, Ontario, Canada, said during the presentation. “However, treatment with asundexian 50 mg daily did reduce recurrent symptomatic ischemic strokes and TIAs in this population with acute noncardioembolic ischemic stroke, particularly among those with atherosclerosis, without significantly increasing major bleeding.
“The promising results from this phase 2 trial require validation in an adequately powered phase 3 randomized trial,” Shoamanesh said.