Tirofiban After Lytic Helps Select Acute Ischemic Stroke Patients

An adjunctive infusion of tirofiban (Aggrastat) after inadequate response to thrombolytics in acute ischemic stroke without large or medium vessel occlusion or a cardioembolic source improved the likelihood of an excellent outcome in the INSTANT randomized trial from China.

The rapid-acting glycoprotein IIb/IIIa inhibitor boosted the proportion of patients with a modified Rankin Scale score of 0-1, indicating full independence in activities of daily living, at 90 days by a relative 22% compared with placebo (63.8% vs 52.2%, risk ratio 1.22, 95% CI 1.02-1.46, P=0.03), Guoyong Zeng, MD, of the Affiliated Ganzhou Hospital of Nanchang University in China, and colleagues reported in JAMA.

Safety profiles were deemed comparable between the tirofiban and placebo groups, “with similarly low rates” of mortality at 90 days (0.6% vs 1.6%) and symptomatic intracranial hemorrhage within 48 hours (0.9% vs 0.0%).

The findings were also presented at the European Stroke Organisation conference in Maastricht, the Netherlands.

Patient selection is likely critical, as with most stroke treatments.

Along with negative findings with tirofiban for stroke patients undergoing endovascular therapy in the Chinese RESCUE BT trial, there was a significant increase in symptomatic intracranial hemorrhage among patients with cardioembolic stroke. Following positive findings among those not eligible for thrombolysis or endovascular therapy in the RESCUE BT2 and TREND trials, the researchers selected a “pathophysiologically relevant subgroup” without large or medium vessel occlusion or a cardioembolic source — “a population in whom underlying mechanisms such as microcirculatory impairment might be most responsive to adjunctive antiplatelet therapy with tirofiban.”

Zeng and colleagues suggested that the beneficial treatment effects they found in INSTANT might be through targeting platelet-mediated thrombosis during the vulnerable period following thrombolysis.

“Intravenous thrombolysis, while promoting clot dissolution, can paradoxically trigger platelet activation … by reexposing the underlying atherosclerotic plaque during thrombus breakdown, and second, by releasing thrombin and highly activated platelets from the dissolving clot into the circulation” which might “contribute to early vessel reocclusion and early neurological deterioration,” they wrote.

Their trial enrolled 359 patients (mean age 66 years, 39.3% females) at 37 hospitals in China who had acute ischemic stroke without large or medium vessel occlusion or cardioembolic etiology and who had no significant change from baseline, neurological deterioration, or neurological fluctuation based on serial assessment of the National Institutes of Health Stroke Scale (NIHSS) score within 4-24 hours after tenecteplase (TNKase) infusion.

Participants were randomly assigned to double-blind treatment with IV tirofiban (0.3-μg/kg/min bolus over 30 minutes, followed by a continuous infusion of 0.075 μg/kg/min for up to 47.5 hours) or matching placebo. Both were started within 4 to 24 hours after IV tenecteplase.

The double-dummy design extended to oral antiplatelet therapy (aspirin and/or clopidogrel). Active oral therapy started 24 hours after thrombolysis in the placebo group but 44 hours after thrombolysis in the tirofiban group “to avoid confounding during the investigational infusion period. This design allows the comparison to attribute any early benefit specifically to tirofiban,” the researchers wrote. Oral antiplatelet therapy continued through 90-day follow-up.

Participants had predominantly mild to moderate neurological deficits (median NIHSS score of 6) with small infarct volumes (median Alberta Stroke Program Early Computed Tomography Score of 10), which the researchers noted “inherently carries a lower risk of hemorrhagic transformation,” as does the fact that the patients enrolled had already gotten tenecteplase without incident.

Other notable safety measures were the minimum 4-hour interval (median about 7.5 hours) between tenecteplase completion and tirofiban initiation to reduce risk of synergistic bleeding complications. Neurological deterioration or fluctuation after tenecteplase prompted urgent noncontrast CT imaging before randomization, which kept 21 patients with post-thrombolysis hemorrhage from enrollment.

Significance was not maintained across all sensitivity analyses, which Zeng and colleagues wrote “implies that although the point estimate suggests a clinically meaningful effect, the results still require confirmation through future larger-scale trials to validate their robustness and generalizability.”

At least two trials are ongoing in China testing similar therapeutic approaches, “which may provide additional insights into optimal patient selection and treatment protocols,” although “exclusive enrollment of Chinese patients may restrict the applicability of the results in other populations known to differ in the frequency of intracranial atherosclerosis and other mechanisms,” they added.

Meta-analysis with trial data from INSTANT, a prior pilot trial, RESCUE BT2, and these ongoing studies may help clarify optimal timing of tirofiban initiation relative to thrombolysis as well as optimal dosing, and patient subgroups most likely to benefit from this therapeutic approach, Zeng and colleagues suggested.