Following the publication of PACIFIC-AF,1 a Hot Line session yesterday saw the presentation of results from two further trials in the PACIFIC clinical programme investigating the safety and efficacy of the factor XIa inhibitor, asundexian.
Presenter of the first trial, Professor John Alexander (Duke University Medical Center - Durham, USA), explains, “Asundexian, and other factor XIa inhibitors, may be promising new therapies to potentially reduce ischaemic events without significantly increasing bleeding for patients following a myocardial infarction (MI) and in other clinical settings where vascular thrombosis or thromboembolism play a role.” By working upstream in the contact activation pathway, factor XIa inhibitors may prevent pathologic thrombosis, but not adversely impact haemostasis, and thus not cause bleeding.2
The PACIFIC-AMI trial investigated asundexian versus placebo in 1,601 patients who had experienced an acute MI. Patients aged ≥45 years were randomised within 5 days of MI to once-daily asundexian (10 mg, 20 mg or 50 mg) or placebo, in addition to aspirin plus a P2Y12 inhibitor, and were treated for 6–12 months. Similar numbers of participants had STEMI (51%) and non-STEMI (49%); 99% underwent percutaneous coronary intervention.
After median follow up of around 1 year, the primary efficacy outcome of CV death, MI, stroke or stent thrombosis occurred in 6.8%, 6.0% and 5.5% of patients in the 10 mg, 20 mg and 50 mg asundexian groups, respectively, compared with 5.5% of patients in the placebo group.
For the main safety outcome, BARC 2, 3 or 5 bleeding occurred in 7.6%, 8.1% and 10.5% of patients in the asundexian 10 mg, 20 mg and 50 mg groups, respectively, and in 9.0% of patients in the placebo group. Asundexian was associated with dose-related inhibition of factor XIa, reaching >90% inhibition with 50 mg.
Prof. Alexander says: “In this phase 2 study, there was no significant observed increase in bleeding with asundexian at any dose or compared with placebo. There was also no significant reduction in ischaemic events with asundexian, although the trial was not designed to be large enough to detect a clinically meaningful reduction in these events.” According to Prof. Alexander, plans are underway for larger phase 3 trials to test asundexian in patients with acute MI and other thrombosis-related conditions.
Doctor Ashkan Shoamanesh (Population Health Research Institute - Hamilton, Canada) presented results from the PACIFIC-STROKE trial, which investigated asundexian in patients who had experienced an acute non-cardioembolic ischaemic stroke. In total, 1,808 participants were randomised within 48 hours of stroke to receive once-daily asundexian (10 mg, 20 mg or 50 mg) or placebo, in addition to usual antiplatelet therapy. The primary efficacy outcome was the dose-response effect on the composite of symptomatic ischaemic stroke or covert brain infarcts detected by magnetic resonance imaging (MRI) at 6 months.
The primary endpoint was not met. MRI-detected covert brain infarcts or recurrent symptomatic ischaemic stroke occurred in 18.9%, 22% and 20.1% of patients in the 10 mg, 20 mg and 50 mg asundexian groups, respectively, compared with 19.1% on placebo, with no dose-dependent reduction (t-statistic −0.68; p=0.80) at 6 months.
Over the total follow-up period (median 10.6 months), recurrent symptomatic ischaemic strokes or transient ischaemic attacks (TIA) occurred in 7.7%, 6.2% and 5.4% of patients in the 10 mg, 20 mg and 50 mg asundexian groups, respectively, and 8.3% in the placebo group. In a secondary exploratory analysis, the risk of recurrent ischaemic stroke or TIA was lower with asundexian 50 mg compared with placebo (hazard ratio [HR] 0.64; 90% CI 0.41 to 0.98), particularly in patients with extracranial or intracranial atherosclerotic plaque (HR 0.39; 90% CI 0.18 to 0.85). For the primary safety outcome, there was no significant difference in major or clinically relevant non-major bleeding at 12 months between asundexian (3.9%) and placebo (2.4%) (HR 1.57; 90% CI 0.91 to 2.71). Dr. Shoamanesh concludes, “The results of PACIFIC-STROKE indicate that the potential of asundexian to prevent stroke in selected patients should be investigated further.”