Clinical Trials of Aspirin in Acute Ischemic Stroke

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Three large randomized trials have examined the efficacy of aspirin treatment within 48 hours of stroke onset. IST compared 300 mg aspirin to no aspirin and also compared two doses of UFH to no heparin in a 3X2 factorial design.18 IST found no significant difference in death and dependency at 6 months in patients treated with aspirin, heparin, or neither of these drugs. There was, however, a nonsignificant trend at 6 months toward a smaller percentage of the aspirin group being dead or dependent (62.2% vs. 63.5%, 2p = 0.07). Secondary analysis revealed fewer recurrent ischemic strokes at 2 weeks among the aspirin-treated group (2.8% vs. 3.9%, 2p < 0.001), which was not offset by any significant excess of hemorrhagic strokes (0.9% vs. 0.8%).

The Chinese Acute Stroke Trial (CAST) compared 160 mg aspirin to placebo given for 4 weeks to 21,106 patients with acute ischemic stroke19 treated within 48 hours. Eighty-seven percent of patients had a brain computed tomography (CT) scan. The mortality rate after 1 month in the aspirin group was lower than in the placebo group (3.3% vs. 3.9%, 2p = 0.04) with areduction in the rate of recurrent ischemic stroke at 1 month(1.6% vs.2.1%, p = 0.01). A small (nonsignificant) increase in hemorrhagic stroke in the aspirin-treated group was observed (0.21%, p > 0.1).

The reasons for the observed differences in mortality between aspirin-treated patients in 1ST and CAST are unclear. The findings may relate to baseline differences between the treated groups. CAST had a younger age profile (72% under 70 compared to 38% in 1ST), excluded some patients with severe stroke, and likely included more subjects with lacunar stroke, an etiology associated with lower mortality and less disability.

In the Multicenter Acute Stroke Trial Italy (MAST-I) study, 622 patients were randomized in a 2 x 2 factorial design to receive either a 1-hour infusion of 1.5 IU streptokinase or 300 mg aspirin or both, or neither.20 Streptokinase (alone or with aspirin) was associated with a greater number of fatalities at 10 days (OR 2.7,95% CI 1.7-4.3). In MAST-I, neither aspirin monotherapy nor combination therapy reduced the primary outcome of combined 6-month fatality and severe disability.

When the CAST collaborative group performed a meta-analysis of IST, CAST, and MAST-I, the trend seen in CAST and IST toward a beneficial effect of aspirin on the rate of death or dependency reached the threshold for statistical significance. Early aspirin therapy (160-300 mg/day) conferred an absolute reduction in the rate of recurrent ischemic stroke by 0.7% (7 per 1000 patients treated) (p < 0.001) and reduced the rate of death or dependency by 1.3% (13 per 1000 patients treated) (2p = 0.007). Aspirin caused about 2 hemorrhagic strokes among every 1000 patients treated, but prevented about 11 other strokes or deaths in hospital.

In addition, the approximately 1-2% risk of peristroke myocardial infarction was slightly reduced,21 which increased the net clinical benefit of 9 per 1000 to about 10 favorable outcomes per 1000 treated.

Despite the low overall risk of the CAST population, the trial was large and included substantial numbers of patients at high risk of early death (e.g., 2600 of patients were drowsy or comotase at entry, of whom 16.2% randomized to aspirin died or suffered nonfatal recurrent stroke compared to 18.5% of placebo). It is reasonable to conclude that the results of CAST and IST can therefore be applied to both low- and high-risk patients following acute stroke.

In IST and CAST not all patients underwent brain imaging with CT before randomization. It was estimated that about 800 of the 40,000 included subjects in fact had ICH on subsequent imaging. The investigators found no indication in either trial that aspirin treatment led to a deterioration in clinical condition, leading the CAST group to suggest that the hazard of aspirin use in these patients cannot be large (Fig. 7.3).

Clinical Approach Ischemic Stroke
FIGURE 7.3 CAST, IST and MAST—overview of overall effects of early aspirin treatment in acute ischemic stroke on clinical events during scheduled treatment periods. (From reference 19, with permission.)

GLYCOPROTEIN IIb/IIIa ANTAGONISTS Mechanism

Inhibition of platelet function is an important strategy in the prevention and treatment of ischemic stroke. Platelet function is regulated by three categories of substances. The first group are agents generated outside the platelet that interact with platelet membrane receptors, for example, catecholamines, collagen, thrombin, and prostacyclin. The second group are agents generated within the platelet that interact with the membrane receptors, for example, adenosine diphosphate (ADP), prostaglandin D2, prostaglandin E2, and serotonin. The third group contains agents generated within the platelet that act within the platelet, for example, prostaglandin endoperoxides and thromboxane A2, cAMP, and cGMP.22 Glycoprotein IIb/IIIa (GP IIb/IIIa) antagonists fall into the third group targeting the platelet IIb/IIIa receptor complex.

Platelets adhere to damaged foci on the vascular endothelium and become activated. They undergo a conformational change, exposing phospholipids and GP IIb/ IIIa receptors and express mediators such as thromboxane A2 (TXA2) and ADP, which further stimulate platelet aggregation by promoting the binding of fibrinogen to GP IIb/IIIa receptors. GP IIb/IIIa antagonists have the advantage of inhibiting platelet adhesion via this nonselective ''final common pathway.''

GP IIb/IIIa antagonists may be broadly classified as monoclonal antibodies or cyclic peptides. Earlier drugs were intravenously administered hybrid murine/ human monoclonal antibody Fab fragments directed against the GP IIb/IIIa receptor, including abciximab, eptifibatide, and tirofiban. More recently, cyclic peptides based on the Arg-Gly-Asp sequence common to many GP IIb/IIIa receptor ligands have been developed (e.g., lotrafiban, xemilofiban, sibrafiban). These agents are orally administered as a prodrug, which is converted by plasma and liver esterases to a peptidomimetic on the Arg-Gly-Asp amino acid sequence.

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