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PACIFIC-Stroke

Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial

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Year of Publication: 2022

Authors: Ashkan Shoamanesh MD, Hardi Mundl MD, Prof Eric E Smith MD, ..., Prof Robert G Hart

Journal: The Lancet

Citation: Lancet, Volume 400, Issue 10357, 24–30 September 2022, Pages 997-1007

Link: https://doi.org/10.1016/S0140-6736(22)01588-4

Clinical Question

Does Factor XIa inhibition with asundexian reduce recurrent stroke and covert brain infarcts when added to antiplatelet therapy in patients with acute non-cardioembolic ischemic stroke?

Bottom Line

Asundexian did not reduce the primary composite outcome of recurrent stroke and covert brain infarcts, but post-hoc analyses suggest potential benefit in patients with atherosclerotic disease without increased bleeding risk.

        Major Points
        Phase 2b dose-finding trial of asundexian (10mg, 20mg, 50mg) vs placebo in 1808 patients with acute non-cardioembolic stroke
Primary outcome was composite of symptomatic recurrent ischemic stroke and incident covert brain infarcts at 26 weeks
No significant difference in primary outcome: 19% placebo vs 19%, 22%, 20% for ascending doses
75% of primary outcome events were covert brain infarcts, mostly small subcortical lesions
Post-hoc analysis showed reduction in stroke/TIA with 50mg dose, particularly in atherosclerotic patients
No significant increase in major or clinically relevant bleeding
43% of patients received dual antiplatelet therapy for mean 70 days

      

Design

Study Type: Randomized, double-blind, placebo-controlled, phase 2b dose-finding trial

Randomization: 1

Blinding: Participants, investigators, and outcome assessors were masked to treatment assignment

Enrollment Period: June 15, 2020 to July 22, 2021

Follow-up Duration: 26-52 weeks (median 46.1 weeks)

Centers: 196

Countries: Multiple countries - 23 total including Western Europe, Australia, Eastern Europe, Asia, North America

Sample Size: 1808

Analysis: Intention-to-treat principle for efficacy, multiple comparison procedures with modelling techniques for dose-response, Cox proportional hazard models, logistic regression, SAS software

Inclusion Criteria

Adults aged 45 years or older
Non-cardioembolic ischemic stroke with persistent signs/symptoms lasting ≥24 hours or acute brain infarction on imaging
Within 48 hours of symptom onset or last known normal
Intended treatment with antiplatelet therapy
Brain imaging (CT or MRI) excluding hemorrhagic stroke
Able to undergo baseline MRI within 72 hours of randomization
NIHSS score ≤7 (Part A) or ≤15 (Part B)
Willing to adhere to study procedures

Exclusion Criteria

Previous ischemic stroke within 30 days of index event
History of atrial fibrillation or suspicion of cardioembolic stroke
Active bleeding or history of major bleeding
Uncontrolled hypertension
eGFR <30 mL/min per 1.73 m²
Clinically significant liver disease
Major surgery within 30 days or planned during study
Strong CYP3A4 inducer/inhibitor within 14 days
Indication for full-dose anticoagulation
Thrombolysis or thrombectomy (Part A only)

Arms

Field	Control	Asundexian 10mg	Asundexian 20mg	Asundexian 50mg
Intervention	Matched placebo tablets once daily plus standard antiplatelet therapy	Asundexian 10mg once daily plus standard antiplatelet therapy	Asundexian 20mg once daily plus standard antiplatelet therapy	Asundexian 50mg once daily plus standard antiplatelet therapy
Duration	26-52 weeks	26-52 weeks	26-52 weeks	26-52 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischemic stroke at or before 26 weeks after randomization	Primary	87/456 (19%)	86/455 (19%) for 10mg, 99/450 (22%) for 20mg, 90/447 (20%) for 50mg	0.18%	0.80 (dose-response test)
Incident covert brain infarcts on MRI	Secondary	64/456 (14%)	63/455 (14%) for 10mg, 74/450 (16%) for 20mg, 74/447 (17%) for 50mg
Recurrent symptomatic ischemic stroke	Secondary	28/456 (6%)	26/455 (6%) for 10mg, 26/450 (6%) for 20mg, 22/447 (5%) for 50mg	HR 0.80 (90% CI 0.50-1.27) for 50mg
All-cause mortality	Secondary	10/456 (2%)	10/455 (2%) for 10mg, 6/450 (1%) for 20mg, 17/447 (4%) for 50mg
Major or clinically relevant non-major bleeding	Adverse	11/452 (2%)	52/1334 (4%) pooled	HR 1.57 (90% CI 0.91-2.71)
Major bleeding	Adverse	4/452 (1%)	14/1334 (1%) pooled	HR 1.17 (90% CI 0.46-2.96)
Intracerebral hemorrhage	Adverse	1/452 (<1%)	3/1334 (<1%) pooled	HR 1.00 (90% CI 0.15-6.70)

Subgroup Analysis

Post-hoc analysis showed large effect in patients with large-artery atherosclerosis (HR 0.53, 90% CI 0.24-1.17 for recurrent stroke with 50mg) and those with any extracranial/intracranial atherosclerosis (HR 0.39, 90% CI 0.18-0.85 for stroke/TIA composite with 50mg)

Criticisms

Primary endpoint negative, limiting conclusions about efficacy
Substantial proportion (21%) did not undergo serial study MRIs, requiring imputation
Post-hoc and exploratory analyses require cautious interpretation
Relatively low mean NIHSS score (2.8), limiting generalizability to more severe strokes
Women comprised only 34% of participants
Covert brain infarcts as surrogate endpoint not validated for stroke therapies
Phase 2 study with limited power for secondary outcomes and subgroup analyses

Funding

Bayer AG

Based on: PACIFIC-Stroke (The Lancet, 2022)

Authors: Ashkan Shoamanesh MD, Hardi Mundl MD, Prof Eric E Smith MD, ..., Prof Robert G Hart

Citation: Lancet, Volume 400, Issue 10357, 24–30 September 2022, Pages 997-1007

Content summarized and formatted by NeuroTrials.ai.

PACIFIC-Stroke

(2022)

Objective

To assess the safety and potential efficacy of the Factor XIa inhibitor asundexian for prevention of recurrent stroke and covert brain infarcts in patients with acute non-cardioembolic ischemic stroke

Study Summary

• Asundexian (10mg, 20mg, or 50mg daily) did not reduce the primary composite outcome of symptomatic recurrent ischemic stroke and incident covert brain infarcts compared to placebo
• Post-hoc analysis showed asundexian 50mg reduced recurrent ischemic stroke and transient ischemic attack, particularly in patients with atherosclerosis (HR 0.64, 90% CI 0.41-0.98)
• No significant increase in major or clinically relevant non-major bleeding with asundexian versus placebo

Intervention

Asundexian (oral Factor XIa inhibitor) at doses of 10mg, 20mg, or 50mg once daily, added to standard antiplatelet therapy

Inclusion Criteria

Adults ≥45 years with acute non-cardioembolic ischemic stroke within 48 hours, intended for antiplatelet therapy, able to undergo baseline MRI

Study Design

Arms: Four arms: Placebo (n=456), Asundexian 10mg (n=455), Asundexian 20mg (n=450), Asundexian 50mg (n=447)

Patients per Arm: Approximately 450 patients per arm

Outcome

• Primary outcome (stroke/covert infarcts at 26 weeks): 19% placebo vs 19% (10mg), 22% (20mg), 20% (50mg); no significant difference
• Major/clinically relevant bleeding: 2% placebo vs 4% pooled asundexian (HR 1.57, 90% CI 0.91-2.71)
• Post-hoc analysis showed benefit in atherosclerotic subgroup

Bottom Line

Major Points

Phase 2b dose-finding trial of asundexian (10mg, 20mg, 50mg) vs placebo in 1808 patients with acute non-cardioembolic stroke
Primary outcome was composite of symptomatic recurrent ischemic stroke and incident covert brain infarcts at 26 weeks
No significant difference in primary outcome: 19% placebo vs 19%, 22%, 20% for ascending doses
75% of primary outcome events were covert brain infarcts, mostly small subcortical lesions
Post-hoc analysis showed reduction in stroke/TIA with 50mg dose, particularly in atherosclerotic patients
No significant increase in major or clinically relevant bleeding
43% of patients received dual antiplatelet therapy for mean 70 days

Study Design

Study Type: Randomized, double-blind, placebo-controlled, phase 2b dose-finding trial
Randomization: Yes
Blinding: Participants, investigators, and outcome assessors were masked to treatment assignment
Sample Size: 1808
Follow-up: 26-52 weeks (median 46.1 weeks)
Centers: 196
Countries: Multiple countries - 23 total including Western Europe, Australia, Eastern Europe, Asia, North America

Primary Outcome

Definition: Composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischemic stroke at or before 26 weeks after randomization

Control	Intervention	HR/OR	P-value
87/456 (19%)	86/455 (19%) for 10mg, 99/450 (22%) for 20mg, 90/447 (20%) for 50mg	- (90% CI: 0.79-1.24 for 10mg, 0.93-1.43 for 20mg, 0.85-1.32 for 50mg)	0.80 (dose-response test)

Limitations & Criticisms

Primary endpoint negative, limiting conclusions about efficacy
Substantial proportion (21%) did not undergo serial study MRIs, requiring imputation
Post-hoc and exploratory analyses require cautious interpretation
Relatively low mean NIHSS score (2.8), limiting generalizability to more severe strokes
Women comprised only 34% of participants
Covert brain infarcts as surrogate endpoint not validated for stroke therapies
Phase 2 study with limited power for secondary outcomes and subgroup analyses

Citation

Lancet, Volume 400, Issue 10357, 24–30 September 2022, Pages 997-1007

View Original Publication →

PACIFIC-Stroke

Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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