Abciximab for Prevention of Stroke Recurrence Before Endarterectomy in Symptomatic Carotid Stenosis
Abciximab for Prevention of Stroke Recurrence Before Endarterectomy in Symptomatic Carotid Stenosis
The purpose of the present prospective, randomized, double-blind, double dummy controlled
 multicenter pilot study is to investigate whether abciximab, compared with aspirin, is able
 to reduce the rate of recurrent ischemic strokes before and during carotid endarterectomy
 [CEA] (primary endpoints); and the degree of carotid stenosis, number of microembolic signal
 (MES) counts, number of ischemic infarcts at diffusion weighted imaging (DWI) and amount of
 intraluminal thrombus at pathological examination (secondary endpoints) in patients with
 ischemic stroke due to a >50% carotid stenosis who will undergo CEA.
Prospective randomized trials have shown that carotid endarterectomy (CEA) is beneficial for
 stroke prevention in symptomatic severe or moderate stenoses of the carotid artery. Medical
 treatment and timing of CEA after a recent stroke due to carotid narrowing, however, remain
 controversial. Prospective, placebo-controlled acute stroke trials did either not screen for
 or excluded carotid stenoses. The early experience with CEA resulted in a generally accepted
 policy to delay surgery for 4 to 6 weeks for fear of clinical deterioration associated with
 conversion of a bland to a hemorrhagic infarction. Subsequent studies suggest that
 endarterectomy need not necessarily be postponed in patients with nondisabling strokes, which
 was not confirmed by Giordano. Furthermore, not all patients recover fast enough to allow
 early carotid surgery for a nondisabling stroke. The risk of a recurrent stroke while waiting
 4 to 6 weeks for CEA was 9.5% in 74 prospectively studied patients and 21% in a retrospective
 series of 19 patients. Similarly, 4.9% of the 103 medically treated patients with stroke and
 severe carotid stenosis had recurrent ipsilateral strokes within 30 days after entry in the
 NASCET trial. Analogous to coronary artery disease, carotid stenoses are assumed to become
 symptomatic from plaque fissure leading to exposure of its contents to the blood, platelet
 activation and thrombosis that may cause cerebral or ocular emboli and further narrows the
 vessel lumen. Therefore, the administration of a drug, which reduces the amount of carotid
 thrombosis and thus stabilizes the plaque would be expected to reduce the risk of recurrent
 stroke and progression of carotid stenosis to occlusion, and allow to postpone CEA.
 Furthermore, also intraoperative ischemic strokes due to cerebral emboli arising from a
 friable plaque during dissection and cross-clamping of the carotid artery may decrease.

 Prospective percutaneous coronary revascularization trials using balloon angioplasty,
 stenting and atherectomy in patients with ischemic heart disease have shown that the addition
 of abciximab, a blocker of platelet glycoprotein (GP) IIb/IIIa receptors, during intervention
 reduced the rates of thrombotic complications, particularly myocardial infarction, and death
 within 30 days. Symptomatic intracranial hemorrhage (ICH) occurred in 0.0-0.1% of 2535
 patients treated with abciximab, medium-dose aspirin, low-dose heparin and endovascular
 procedures. Endovascular coronary interventions disrupt or dissect the arterial wall, which
 leads to exposure of plaque contents and components of the vascular wall to the blood,
 resulting in platelet activation and thrombosis. Interestingly, also abciximab given 18 to 24
 hours prior to intervention reduced the rate of thrombotic events suggesting some
 stabilization of the coronary plaque.

 A recent prospective, placebo-controlled safety and pilot efficacy trial of abciximab in 74
 patients with acute ischemic stroke treated within 24 hours from symptoms onset found that
 abciximab caused no symptomatic ICH and showed a trend toward a higher rate of patients with
 minimal residual disability. Thus, abciximab may be an attractive therapy option to prevent
 stroke recurrence in patients with embolic carotid territory stroke due to carotid stenosis.

 The number of microembolic signals (MES) detected in the middle cerebral artery (MCA)
 downstream to a symptomatic carotid stenosis by transcranial Doppler sonography (TCD) has
 been shown to predict the stroke risk, and is dramatically reduced in patients with acute
 ischemic stroke not caused by carotid artery disease during the administration of the GP
 IIb/IIIa inhibitor tirofiban. These data suggest that the monitoring of MES in the MCA distal
 to a symptomatic carotid stenosis before and after the administration of abciximab may be a
 useful surrogate marker to assess the efficacy of this drug to prevent MES and stroke in
 patients with symptomatic carotid stenosis. Diffusion-weighted MR imaging (DWI) has a high
 sensitivity for detecting acute brain ischemia, and recent DWI studies have assessed the
 incidence of asymptomatic ischemic brain lesions in patients who underwent CEA.

 The purpose of the present prospective, randomized, double-blind, double dummy controlled
 multicenter pilot study is to investigate whether abciximab compared with aspirin is able to
 reduce the rate of recurrent ischemic strokes before and during CEA (primary endpoints), and
 the degree of carotid stenosis, number of MES counts, number of ischemic infarcts at DWI and
 amount of intraluminal thrombus at pathological examination (secondary endpoints) in patients
 with ischemic stroke due to a >50% carotid stenosis who will undergo CEA.
Inclusion Criteria:

 -  Age at least 18 years.

 -  Presence of symptoms of an ischemic stroke with a baseline National Institutes of
 Health Stroke Scale (NIHSS) scale of one up to 20 or due to an ipsilateral
 atherosclerotic >50% stenosis of the extracranial internal carotid artery (ICA) as
 shown by ultrasonography.

 -  Latency between the onset of stroke symptoms and intended administration of the study
 drugs is not more than 24 hours.

 -  Latency between the intended administration of the study drugs and intended carotid
 endarterectomy is at least three days.

 Exclusion Criteria:

 -  Documented peptic ulcer disease within the preceding 30 days.

 -  Septicemia or severe localized infection.

 -  Severe illness (active cancer or significant liver or renal disease) or disability.

 -  Alcohol or illicit drug abuse.

 -  Pregnancy.

 -  Need for chronic anticoagulant therapy (e.g. atrial fibrillation, deep venous
 thrombosis).

 -  Need for long-term daily nonsteroidal antiinflammatory drugs.

 -  Contraindications for platelet therapy such as severe bleeding disorder within the
 past three months prior to randomization (coagulopathy, platelet disorder including
 history of heparin-induced thrombopenia, hemorrhage) or significant retinopathy with
 hemorrhages and exudates.

 -  Hypersensitivity to abciximab, murine monoclonal antibodies or aspirin.

 -  Any preexisting intracranial neurological disease such as tumor or multiple sclerosis.

 -  Intracranial or intraspinal operation or trauma or lumbar puncture within the last 2
 months.

 -  Cardiac lesions likely to cause cardioembolism.

 -  Suspicion of or established non-atherosclerotic carotid artery disease such as
 dissection or vasculitis (Takayasu disease, giant cell arteritis, significant collagen
 vascular disease, systemic necrotizing vasculitis, granulomatous angiitis of the
 nervous system).

 -  Participation in another acute stroke trial investigating drugs other than abciximab.

 -  Treatment for the present stroke with tissue plasminogen activator, urokinase or
 ancrod.

 -  ICH, aneurysm, vascular malformation or arteriovenous fistula or sinovenous thrombosis
 of the brain.

 -  Brain infarct involving the whole territory of the middle cerebral artery (MCA).

 -  Stupor or coma.

 -  Uncontrolled hypertension (systolic pressure >200 mmHg and/or diastolic pressure >110
 mmHg).

 -  No informed consent.

 -  Contraindication to undergo magnetic resonance (MR) imaging (eg pacemaker).