Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack - PACIFIC-AMI

Aug 28, 2022
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Bayer AG
Date Presented:
08/28/2022
Date Published:
08/28/2022
Original Posted Date:
08/28/2022
References

Contribution To Literature:

Asundexian in addition to DAPT among patients undergoing PCI for AMI did not increase bleeding with any of the doses studied compared with placebo.

Description:

The goal of the trial was to assess the safety and efficacy of 3 doses of asundexian compared with placebo in patients with acute myocardial infarction (AMI) treated with dual antiplatelet therapy (DAPT).

Study Design

This was a phase II trial. Patients were randomized in a double-blind 1:1:1:1 fashion to either asundexian 50 mg daily (n= 402), asundexian 20 mg daily (n = 401), asundexian 10 mg daily (n = 397), or matching placebo (n = 401). All patients were on aspirin 81 mg and a P2Y12 inhibitor.

  • Total screened: 1,664
  • Total number of enrollees: 1,601
  • Duration of follow-up: 6 months
  • Mean patient age: 68 years
  • Percentage female: 22%

Inclusion criteria:

  • AMI admission that did not occur in the context of revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery)
  • Planned to be treated with DAPT after hospital discharge
  • Age ≥45 years

Exclusion criteria:

  • Hemodynamic instability at the time of randomization
  • Active bleeding or bleeding diathesis
  • Severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m2)
  • Planned use of full-dose anticoagulation

Other salient features/characteristics:

  • White: 85%
  • Type 2 diabetes: 40%
  • Prior stroke: 6%
  • ST-segment elevation MI as qualifying MI: 52%
  • PCI for index MI: 99.5%
  • Use of prasugrel or ticagrelor as P2Y12 inhibitor: 80%

Principal Findings:

The primary safety outcome, Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 6 months for asundexian 50 mg daily vs. asundexian 20 mg daily vs. asundexian 10 mg daily vs. placebo, was: 10.5% vs. 8.1% vs. 7.6% vs. 9.0% (all asundexian vs. placebo p > 0.05). Two patients with asundexian 50 mg and one patient with placebo had intracerebral hemorrhage (ICH).

  • Primary efficacy outcome, cardiovascular death, MI, stroke, stent thrombosis: 5.5% vs. 6.0% vs. 6.8% vs. 5.5% (all asundexian vs. placebo p > 0.05).

Secondary outcomes:

  • Cardiovascular death: 1.2% vs. 1.0% vs. 1.8% vs. 0.5% (p > 0.05)
  • Stroke: 0% vs. 0.8% vs. 1.0% vs. 0.5% (p > 0.05)
  • All-cause mortality: 2.5% vs. 1.8% vs. 2.5% vs. 1.8% (p > 0.05)

Interpretation:

The results of this phase II trial indicate that asundexian in addition to DAPT among patients undergoing PCI for AMI did not increase bleeding with any of the doses studied compared with placebo, although there appeared to be stepwise increase with higher doses. Ischemic events were infrequent but also no different between asundexian and placebo. Measured factor XIa levels were also reduced in a dose-related fashion with >90% reduction compared with baseline with asundexian 50 mg daily.

Asundexian is a novel oral factor XIa inhibitor that is being evaluated across a variety of indications. Based on this trial, asundexian 50 mg daily will be tested in a cardiovascular outcomes trial among patients with AMI. In the APPRAISE-2 trial, apixaban 5 mg BID resulted in unacceptably high bleeding among patients with acute coronary syndrome who were already on DAPT. Interestingly, asundexian 50 mg daily had lower bleeding compared with apixaban 5 mg BID in the PACIFIC AF study (a population with atrial fibrillation as indication for anticoagulation).

References:

Rao SV, Kirsch B, Bhatt DL, et al., on behalf of the PACIFIC-AMI Investigators. A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes Following Acute Myocardial Infarction. Circulation 2022;Aug 28:[Epub ahead of print].

Editorial: Gue YX, Gorog DA, Lip GY. Factor XIa Inhibition – A Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients? Circulation 2022;Aug 28:[Epub ahead of print].

Presented by Dr. John Alexander at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 28, 2022.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Anticoagulation Management and ACS, Aortic Surgery, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Novel Agents, Interventions and ACS

Keywords: Acute Coronary Syndrome, Aspirin, Cerebral Hemorrhage, Coronary Artery Bypass, ESC22, ESC Congress, Factor XIa, Hemorrhage, Myocardial Infarction, Patient Discharge, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors, Secondary Prevention, Stents, Stroke, Thrombosis


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