Aortic Arch Related Cerebral Hazard Trial (ARCH)

• Recurrent brain infarction [ Time Frame: during the trial ] [ Designated as safety issue: Yes ]
  Recurrent brain infarction
• brain infarction and transient ischemic attack (TIA) [ Time Frame: during the studing ] [ Designated as safety issue: Yes ]
  brain infarction and transient ischemic attack (TIA)
• new vascular events and revascularization procedure [ Time Frame: during the trial ] [ Designated as safety issue: Yes ]
  new vascular events and revascularization procedure
• vascular death [ Time Frame: during the trial ] [ Designated as safety issue: No ]
  vascular death
• death from all causes [ Time Frame: during the trial ] [ Designated as safety issue: No ]
  death from all causes
• combination of primary end-point and TIA [ Time Frame: during the trial ] [ Designated as safety issue: Yes ]
  combination of primary end-point and TIA
• revascularization procedures [ Time Frame: during the trial ] [ Designated as safety issue: Yes ]
  revascularization procedures
• urgent rehospitalization for ischemic [ Time Frame: during the trial ] [ Designated as safety issue: Yes ]
  urgent rehospitalization for ischemic

The ARCH is a controlled trial with a sequential design and with a prospective, randomized, open-label, blinded-endpoint (PROBE) methodology. The objective is to compare the efficacy and tolerance (net benefit) of two antithrombotic strategies in patients with atherothrombosis of the aortic arch and a recent (less than 6 months) cerebral or peripheral embolic event.

Hypothesis:

The association of clopidogrel 75 mg/d plus aspirin 75 mg/d is 25% more effective than an oral anticoagulant (target International Normalized Ratio [INR] 2 to 3) in preventing brain infarction, brain hemorrhage, myocardial infarction, peripheral embolism, and vascular death.

Patients with Transient Ischemic attack or brain infarction of unknown cause (no ipsilateral internal carotid artery origin stenosis greater than 70%, no ipsilateral severe intracranial stenosis of an artery supplying the infarcted area, no definite cardiac source of embolism) in the preceding 6 months and atherosclerotic plaques.

≥ 4 mm in the aortic arch, or patients with a peripheral event (e.g. renal infarct) in the preceding 6 months and plaque ≥ 4 mm in the thoracic aorta above the origin of the embolized artery.

• Brain Infarction
• Transient Ischemic Attack
• Embolism

• Drug: Warfarin
  Warfarin
  Other Name: Warfarin
• Drug: Clopidogrel-aspirin
  Clopidogrel-aspirin
  Other Name: Clopidogrel-aspirin

• Experimental: Clopidogrel-aspirin
  Clopidogrel-aspirin
  Intervention: Drug: Clopidogrel-aspirin
• Active Comparator: Warfarin
  Warfarin
  Intervention: Drug: Warfarin

Inclusion Criteria:

Patients of both sexes aged ≥ 18 years with the following 4 inclusion criteria:

• One of the 3 following ischemic events in the preceding 6 months:

  • Transient ischemic attack (TIA)

  • Non-disabling brain infarcts:

    • Inclusion within 6 months after onset
    • Duration of symptoms and signs greater than 24 hours
    • Neurological signs at the time of randomization with a Rankin Scale grade 3 or less
    • With normal computed tomography (CT) scan or CT scan showing a brain infarct (even hemorrhagic infarct)
  • Peripheral embolism
• Atherosclerotic plaque in the thoracic aorta is defined as wall thickness ≥ 4 mm where the protruding material is the largest, measured at transesophageal echocardiography with multiplane transducer or a plaque less than 4 mm but with mobile component.
• Informed consent signed
• Life expectancy > 3 years

Exclusion Criteria:

• Other causes of embolism:

  • Cardiac: endocarditis, atrial fibrillation, intra-cardiac thrombus, valvular prosthesis, rheumatic valvulopathy, left ventricular aneurysm, or ejection fraction less than 25%
  • Atherosclerotic stenosis ipsilateral to the embolic territory: internal carotid artery stenosis greater than 70%, or severe (judgment of the investigator) intracranial stenosis, or scheduled carotid endarterectomy (in that case inclusion is possible 30 days after the procedure)
  • Uncommon causes: dissection, vasculitis, procoagulant state, or sickle cell disease

• Other exclusion criteria:

  • Intercurrent illness with life expectancy less than 36 months
  • Pregnancy and non-menopausal women
  • Unwillingness to participate
  • Poor medication compliance expected
  • Toxicomania
  • Absolute indication for anticoagulant therapy (e.g. atrial fibrillation, intracardiac thrombus, prosthetic valve)
  • Scheduled for carotid endarterectomy (randomization is possible 30 days after endarterectomy)
• CT scan with an intracranial lesion other than brain infarction (space occupying mass, intracranial hemorrhage)
• Transesophageal echocardiography (TEE) with plaque ≥ 4 mm in thickness distal to the supposed embolized artery (judgement of the investigator).
• Contraindication to clopidogrel, aspirin, and oral anticoagulants

• National Health and Medical Research Council, Australia
• Sanofi
• Bristol-Myers Squibb