The new anticoagulant Asundexian has a better outlook in patients after myocardial infarction or stroke, and the RESULTS of the PACIFIC study were published esc 2022

At that time, on August 27, the results of two asundexian-related trials (PACIFIC-AMI and PACIFICIC-Stroke trials) were released at the HOT LINE 5 session of the ESC 2022 annual meeting, suggesting that the new oral anticoagulant asundexian may have a good prospect

PACIFIC-AMI trial: asundexian in post-myocardial infarction or has a good outlook

Patients with acute myocardial infarction are at higher

Asundexia is a novel oral anticoagulant that inhibits factor XIa to prevent pathological thrombosis and thus the recurrence

Introduction to the study

The pharmacodynamics, safety and efficacy

Research results

A total of 1600 patients within 5 days of myocardial infarction from 157 regions in 14 countries were included and randomly assigned to the ascendexian 10 mg, 20 mg, 50 mg or placebo group
in a 1:1:1 ratio.

Patients aged ≥ 45 years (median 68 years), 23% were female, about 51% had ST-segment elevation myocardial infarction (STEMI), and 49% had non-ST-STEMI
.

99% of patients received percutaneous coronary intervention (PCI) to treat myocardial infarction
.

Patients were treated for 6-12 months
.

From the first dose, the median follow-up was 368 days
.

The primary efficacy outcomes studied were cardiovascular death, myocardial infarction, stroke, or end-of-event
combination events of thrombosis within a stent.

The primary safety outcome was a compound event outcome
for BARC grade 2, grade 3, or grade 5 bleeding.

Studies have shown that asundexian significantly inhibits factor XIa and has a dose-dependent relationship, and asundexia in the 50 mg dose group can inhibit factor XIa by more than 90%.


In terms of bleeding events, asundexian does not significantly increase the risk of bleeding events, but it does not reduce the risk
of ischemic events.

The researchers say

Professor John Alexander from Duke University School of Medicine said that in post-myocardial infarction and other patients at risk of thromboembolism, asundexian and other factor XIa inhibitors could become a promising treatment that reduces the risk of ischemic events while significantly increasing the risk
of bleeding.

This study is the first randomised controlled trial
to explore the efficacy and safety of adding a factor XIa inhibitor (asundexian) to a dual antiplatelet drug in patients with acute myocardial infarction.

50 mg asundexian inhibited factor XIa by more than 90% without increasing the risk of bleeding, but was not significantly reduced in ischemic events and the incidence of events was not high
in patients in the asundexian group.

In response, Professor Alexander said the trial was small or not large enough to obtain a clinically significant reduction in
events.

Therefore, there is reason for a larger Phase 3 trial to further explore whether the XIa inhibitor asundexan can be a potentially safer anticoagulant in patients with acute post-myocardial infarction
.

PACIFIC-Stroke trial: asundexian in the 50 mg group reduces the risk of recurrent ischemic stroke and TIA

The PACIFIC-Stroke Phase 2 trial aims to explore the safety, efficacy and optimal dose
of asundexian for secondary prevention of stroke in patients with acute non-cardiogenic ischemic stroke.

The study included a total of 1808 patients (with an average age of 67 years and 34% female)
in 196 districts in 23 countries.

Patients were randomized within 48 hours (average 36 hours) of non-cardiogenic ischemic stroke and treated with ascendexian (10 mg/day, 20 mg/day, and 50 mg/day) or placebo on the basis of conventional antiplatelet therapy
.

Patients underwent magnetic resonance imaging (MRI) of the brain at the beginning of the trial and 6 months
later.

Follow-up for 6-12 months
.

The primary outcome was a complex of occult cerebral infarction or recurrent symptomatic ischemic stroke detected by MRI at 6 months
.

The primary safety outcome was a primary or clinically relevant non-primary bleeding event at 12 months
.

Secondary exploratory outcomes included ischemic stroke and compound event endpoints
for ischemic stroke and transient ischemic attack (TIA).

Research results

At 6 months, asundexian did not reduce the combined event endpoint of occult cerebral infarction or recurrent symptomatic ischemic stroke compared with placebo, and there was no dose-dependent primary
efficacy outcome.

Median follow-up of 10.
6 months showed recurrent symptomatic ischemic stroke or TIAs
in the placebo group, 10 mg group, 20 mg group, and 50 mg group, respectively, 35 cases (7.
7%), 28 cases (6.
2%), and 24 cases (5.
4%).

Secondary analyses showed a significant reduction in the risk of recurrent symptomatic ischemic stroke and TIA in the 50 mg group compared with placebo, and the decrease was greatest
in patients with intracranial or extracranial atherosclerotic plaque.

At 12 months, the primary safety endpoint for patients in the asundexian group did not increase
significantly compared with the placebo group.

The researchers say

Dr.
Ashkan Shoamanesh from the Population Health Institute of Canada (PHRI) said this is the first complete randomized controlled trial
to explore secondary prevention with factor XIa inhibitors (based on antiplatelet therapy) in patients with non-cardiogenic ischemic stroke.

The PACIFIC-Stroke trial failed to reach its primary endpoint, but exploratory analysis found that asundexian reduced the risk of recurrent ischemic stroke and TIA without increasing the risk
of bleeding events.

Dr Shoamanesh said the results of the PACIFIC-Stroke trial suggest that asundexian may have some promise in preventing stroke; However, a robust Phase 3 trial is still needed to explore the potential
of asundexian for stroke prevention in selected patients.

Source:

[1] New oral anticoagulant shows promise in post-myocardial infarction patients.
Presented at: ESC 2022.
28 Aug 2022.

[2] Efficacy and Safety of the Oral Factor XIa Inhibitor, Asundexian, Added to Dual Antiplatelet Therapy After an Acute Myocardial Infarction-Main Results of PACIFIC-AMI.
Presented at: ESC 2022.
28 Aug 2022.

[3] New anticoagulant may prevent recurrent ischaemic stroke.
Presented at: ESC 2022.
28 Aug 2022.

[4] Phase 2 Program of AntiCoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334 – Non-Cardioembolic Stroke Study- Main Results of the PACIFIC-Stroke Trial.
Presented at: ESC 2022.
28 Aug 2022.