Aortic Arch Related Cerebral Hazard Trial (ARCH) (ARCH)

Prevention of New Vascular Events in Patients With Brain Infarction or Peripheral Embolism and Thoracic Aortic Plaques ≥ 4 mm in Thickness in the Aortic Arch or Descending Aortic Upstream to the Embolized Artery

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.

Study Overview

• Status: Completed
• Conditions: Embolism; Transient Ischemic Attack; Brain Infarction
• Intervention / Treatment: Drug: Warfarin; Drug: Clopidogrel-aspirin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 350
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Heidelberg Heights, Australia, Vic 3081
    • National Stroke Research Institute-Austin Health
• France
  • Paris, France, 75018
    • Bichat Hospital Head of Neurology Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clopidogrel-aspirin	Drug: Clopidogrel-aspirin; Clopidogrel-aspirin
Active Comparator: Warfarin	Drug: Warfarin; Warfarin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
New vascular events assessed every 4 months including stroke, myocardial infarction (MI), peripheral events, and vascular death	New vascular events assessed every 4 months including stroke, myocardial infarction (MI), peripheral events, and vascular death	every 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrent brain infarction	Recurrent brain infarction	during the trial
brain infarction and transient ischemic attack (TIA)	brain infarction and transient ischemic attack (TIA)	during the studing
new vascular events and revascularization procedure	new vascular events and revascularization procedure	during the trial
vascular death	vascular death	during the trial
death from all causes	death from all causes	during the trial
combination of primary end-point and TIA	combination of primary end-point and TIA	during the trial
revascularization procedures	revascularization procedures	during the trial
urgent rehospitalization for ischemic	urgent rehospitalization for ischemic	during the trial

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: National Health and Medical Research Council, Australia; Bristol-Myers Squibb; Sanofi
• Investigators: Principal Investigator: Pierre Amarenco, Pr, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Amarenco P, Davis S, Jones EF, Cohen AA, Heiss WD, Kaste M, Laouenan C, Young D, Macleod M, Donnan GA; Aortic Arch Related Cerebral Hazard Trial Investigators. Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques. Stroke. 2014 May;45(5):1248-57. doi: 10.1161/STROKEAHA.113.004251. Epub 2014 Apr 3.

Study record dates

Study Major Dates

• Study Start: February 1, 2002
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: October 6, 2005
• First Submitted That Met QC Criteria: October 6, 2005
• First Posted (Estimate): October 10, 2005

Study Record Updates

• Last Update Posted (Estimate): July 10, 2012
• Last Update Submitted That Met QC Criteria: July 6, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: TIA/Brain infarct; and plaque>4mm in the aortic arch; Or peripheral embolism; and plaque>4 mm in the thoracic aorta
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Embolism and Thrombosis; Brain Ischemia; Stroke; Infarction; Embolism; Ischemic Attack, Transient; Brain Infarction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Anticoagulants; Aspirin; Clopidogrel; Warfarin
• Other Study ID Numbers: P991205