Antithrombotic Treatment of Acute Stroke Due to Large Artery Atherosclerosis

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Early Recurrence Rates in Large Artery Disease Stroke due to LAA has been associated with a higher risk of early recurrence compared to cardioembolic, undetermined, and lacunar subtypes. A meta-analysis of population studies found a 4.5% recurrent stroke risk associated with LAA at 7 days and 9.4% recurrence at 1 month, a threefold increase in adjusted risk as compared to other subtypes.52 Patients with strokes caused by LAA appear to be at the greatest risk of worsening and recurrence in the early poststroke period. In the National Institute of Neurological Disorders and Stroke (NINDS) stroke database, patients with LAA had a 30% risk of worsening during acute hospitalization and a 7.9% risk of stroke recurrence within 30 days.

Clinical trials and meta-analyses have demonstrated that early carotid endarter-ectomy (CEA) is the preferred treatment for most patients with severe symptomatic internal carotid artery (ICA) stenosis and selected patients with moderate disease.53 However, CEA is often delayed in clinical practice, or may not be appropriate in some patients due to an unfavorable risk-benefit profile. In these settings, it is reasonable to consider acute antithrombotic treatment to prevent early recurrent stroke.

The relationship between LAA and early recurrence is likely to be largely mediated by arterial embolism from atherosclerotic plaque, although recurrent low-flow stroke may also occur due to severe vessel stenosis or occlusion. In recently symptomatic individuals with moderate-or-severe ICA stenosis, platelet-fibrin embolic signals (ES) are commonly detected in the MCA using transcranial Doppler (TCD) ultrasound and have been reported to independently predict a fivefold increase in 90-day recurrence.54

Antiplatelet Agents in LAA Disease No large randomized trials comparing acute antiplatelet agents with placebo in patients with LAA have been performed. The CARESS trial compared dual antiplatelet therapy (clopidogrel 300 mg loading dose followed by 75 mg daily, plus aspirin 75 mg daily) with aspirin monotherapy in 107 recently symptomatic patients with >50% ICA stenosis, using TCD ES detection as a surrogate marker of efficacy.55 A 40% reduction (95% CI 13.8-58, p = 0.005) in the proportion of ES-positive patients was detected at 7 days with reduced ES frequency per hour in the dual therapy group (p = 0.001). Although not powered for clinical endpoints, four recurrent strokes and seven TIAs occurred in the monotherapy group compared to no strokes and four TIAs in the combination therapy group.

Junghans and Siebler56 reported a series of 24 patients with recent stroke or TIA due to LAA and detected ES on TCD who were treated acutely with intravenous tirofiban, a GP IIb/IIIa receptor antagonist. Median ES rate at baseline was 38 signals per hour. ES were abolished by tirofiban in all patients, and returned following cessation of infusion. Although preliminary, these data support the rationale for trials of acute GP IIb/IIIa receptor blockade in patients with recently symptomatic LAA awaiting CEA.

Subgroup analyses of the MATCH data suggested a 12% risk reduction in recurrent vascular events at 18 months in patients with large vessel disease who were given combination aspirin and clopidogrel compared with clopidogrel alone.

Finally, a Cochrane review of antiplatelet therapy following CEA found no evidence of a difference in mortality when antiplatelets were compared with placebo. However, treatment with antiplatelet agents following CEA decreased the risk of postoperative stroke (OR 0.58, 95% CI 0.34-0.98).57

Anticoagulation in Stroke Due to LAA Disease Few clinical trials have been performed in this population. In the TOAST trial, a secondary analysis in patients with stroke due to LAA found favorable outcomes at 7 days in 54% of danaparoid-treated patients, compared to 38% of the placebo-treated group (p = 0.02). At 3 months, 68% of patients in the danaparoid group compared to 53% of those in the placebo group had favorable outcomes (p = 0.02).

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