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Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques
Pierre Amarenco1, Stephen Davis, Elizabeth F Jones
1From the Department of Neurology, Stroke Centre, DHU FIRE, INSERM U 1148, Paris Diderot-Sorbonne University, Hôpital Bichat (P.A.), Department of Cardiology, Saint-Antoine Hospital and Medical School, Univeristé Pierre et Marie Curie (A.A.C.), and Department of Biostatistics, Paris-Diderot-Sorbonne University, Hôpital Bichat (C.L.), Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Neurology, Royal Melbourne Hospital (S.D.) and Florey Institute of Neuroscience and Mental Health (D.Y., M.M., G.A.D.), University of Melbourne, Melbourne, Australia; Department of Cardiology, Austin Health, Heidelberg, Victoria, Australia (E.F.J.); Max Planck Institute for Neurological Research, Cologne, Germany (W.-D.H.); Department of Neurology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland (M.K.); Stroke and Ageing Research Centre, Monash University, Melbourne, Australia (D.Y.); and Division of Clinical Neurosciences, University of Edinburgh (SC005336), Scotland, United Kingdom (M.M.).
Insights
Aspirin plus clopidogrel did not prove superior to warfarin for preventing vascular events in severe aortic arch atherosclerosis. However, the trial was underpowered, suggesting further research is needed.
Area of Science:
- Cardiovascular Medicine
- Neurology
- Vascular Surgery
Background:
- Severe aortic arch atherosclerosis poses a high risk for recurrent vascular events.
- Optimal antithrombotic strategies for this condition remain uncertain.
- Aortic plaque is a significant source of embolism.
Purpose of the Study:
- To compare the efficacy of aspirin plus clopidogrel versus warfarin in preventing vascular events in patients with severe aortic arch atherosclerosis.
- To evaluate the safety and effectiveness of dual antiplatelet therapy against anticoagulation in this high-risk population.
Main Methods:
- A prospective, randomized, open-label trial (PROBE design) was conducted.
- Patients with ischemic stroke, TIA, or peripheral embolism and aortic plaque were randomized to aspirin plus clopidogrel (A+C) or warfarin (INR 2-3).
- The primary endpoint included composite vascular events and intracranial hemorrhage, with follow-up for up to 3.4 years.
Main Results:
- The trial was stopped early with 349 patients randomized.
- The primary endpoint occurred in 7.6% of the A+C group and 11.3% of the warfarin group (P=0.2), indicating no significant difference.
- Vascular deaths were lower in the A+C group (0%) compared to warfarin (3.4%, P=0.013), though major hemorrhages were similar.
Conclusions:
- The trial lacked sufficient statistical power to draw definitive conclusions.
- Results suggest a potential benefit of aspirin plus clopidogrel regarding vascular death, but this is hypothesis-generating.
- Further large-scale studies are warranted to clarify the optimal antithrombotic strategy.
Background And Purpose:
Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear.
Methods:
This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2-3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta>4 mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage. Follow-up visits occurred at 1 month and then every 4 months post randomization.
Results:
The trial was stopped after 349 patients were randomized during a period of 8 years and 3 months. After a median follow-up of 3.4 years, the primary end point occurred in 7.6% (13/172) and 11.3% (20/177) of patients on A+C and on warfarin, respectively (log-rank, P=0.2). The adjusted hazard ratio was 0.76 (95% confidence interval, 0.36-1.61; P=0.5). Major hemorrhages including intracranial hemorrhages occurred in 4 and 6 patients in the A+C and warfarin groups, respectively. Vascular deaths occurred in 0 patients in A+C arm compared with 6 (3.4%) patients in the warfarin arm (log-rank, P=0.013). Time in therapeutic range (67% of the time for international normalized ratio 2-3) analysis by tertiles showed no significant differences across groups.
Conclusions:
Because of lack of power, this trial was inconclusive and results should be taken as hypothesis generating.
Clinical Trial Registration Url:
http://www.clinicaltrials.gov. Unique identifier: NCT00235248.
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