Trials of GP IIbIIIa Antagonists in Acute Ischemic Stroke

The abciximab in Acute Ischemic Stroke trial was a randomized, placebo-controlled dose-escalation study to examine the safety of abciximab in acute stroke.23 It randomized 74 patients within 24 hours of stroke onset to receive one of four doses of abciximab (by bolus with or without additional infusion, 54 patients) or placebo (20 patients). The median baseline National Institute of Health Stroke Scale (NIHSS) score was 15. The rates of asymptomatic ICH were 19% in the intervention group compared to 5% in the placebo group (p = 0.07). Most (9 of 11) of the asymptomatic ICH patients had more severe stroke (NIHSS >14). No cases of symptomatic ICH or major systemic bleeding occurred. There was a trend toward a lower rate of stroke recurrence (2% vs. 5%) and a higher rate of functional recovery at 3 months in the group treated with abciximab than with placebo.

Based on these findings, the Abciximab Emergent Stroke Treatment Trial (AbESTT) randomized 400 patients with stroke within 6 hours of onset to receive abciximab or placebo.24 The abciximab dose chosen was the highest of the four strata studied in the previous dose-escalation study (i.e., 0.25 mg/kg intravenous bolus followed by 0.125 mg/kg/min infusion for 12 hours). No difference in the primary safety outcome of symptomatic ICH within 5 days was detected, but a trend toward a higher rate was detected in the intervention arm (3.6% vs. 1%, p = 0.09). Eighty-eight percent (seven of eight) of abciximab-treated patients with sICH had severe strokes (NIHSS > 14). Although this phase 2 trial was not powered to detect efficacy, a nonsignificant shift in favorable outcomes on mRS score at 3 months was observed (p = 0.33).

Following this trial, AbESTT-II was initiated as a phase 3 randomized trial, which aimed to recruit 1800 patients, 1200 within 4.5 hours of onset, and a further 600 later than 4.5 hours or within 2.5 hours of waking with stroke symptoms.25 Due to an excess of hemorrhages in the abciximab group, AbESTT-II was discontinued in 2005 upon the recommendation of the Safety and Efficacy Monitoring Committee, initially for patients waking with stroke, and later for all patients. Eight hundred and eight patients had been recruited at this point.

The Safety of Tirofiban in Acute Ischemic Stroke (SaTIS) trial examined 250 patients 6-22 hours after stroke onset treated with tirofiban infusion or placebo for 48 hours.26 No increase in ICH was reported in the active group. Although no benefit in early functional recovery was observed, 5-6-month mortality was lower in the tirofiban-treated group (relative risk reduction (RRR) 27%, 95% CI 0.080.95, p = 0.03).

Combination GP IIb/IIIa and rt-PA Therapy for Acute Stroke The combination of antiplatelet and thrombolytic drugs has proven efficacy in the setting of myocardial ischemia where an additive effect is seen. In acute stroke thrombolysis with a very narrow time window and less than 50% optimal reperfusion rates,27 adjunctive therapy with antiplatelets may be a promising approach. However, MAST-I concluded that the group of patients receiving streptokinase plus aspirin had a marked increase in 10-day mortality.

Early studies indicate that combined GP IIb/IIIa inhibition with rt-PA thrombolysis may improve clinical and MRI outcomes after acute ischemic stroke, with an acceptable safety profile. The dual targeting of platelets and fibrin by combination therapy may provide synergistic benefits, including increased arterial reca-nalization, reduced microvascular thrombosis, reduced arterial reocclusion, and less rt-PA-mediated blood-brain barrier injury and secondary activation of the coagulation system.

In 2004, the abciximab and rt-PA in Acute Ischemic Stroke Treatment trial treated five patients with abciximab and half dose of rt-PA within 3 hours of symptom onset.28 The primary aim was to examine the frequency of SICH at 24 hours. This occurred in one of the five patients. The median NIHSS improvement was 6.

In another study of 19 patients with complete or near-complete (TIMI grade 0 or 1) middle cerebral artery (MCA) occlusion, combination therapy with reduced-dose rt-PA and tirofiban infusion was associated with recanalization in 68% of patients, significant reductions of MRI ischemic lesion volumes, and substantial clinical improvement (median NIHSS change from 17 at baseline to 2 after treatment, p = 0.002).29 No cases of sICH occurred.

The same investigators found significant improvements in clinical outcomes and reduction in ischemic lesion volumes on MRI in 13 patients treated with tirofiban and reduced-dose rt-PA compared to 16 patients treated with standard rt-PA

therapy.30

Further carefully designed trials incorporating a range of clinical and surrogate measures are required to further examine the potential of GP IIb/IIIa antagonist monotherapy for selected (e.g., large artery disease) and unselected patients with acute stroke. Equally, further trials of combination therapy with GP IIb/IIIa antagonists and fibrinolytic agents are needed. Ongoing trials, such as the Reopro Retavase Reperfusion of Stroke Safety Study-Imaging Evaluation (ROSIE)31 and ROSIE-232 are designed to determine the optimal dose of abciximab (combined with rt-PA reteplase 3-24 hours after onset) and epifibatide (combined with ASA/LMWH/rt-PA within 3 hours).

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