Intravenous Tirofiban After Tenecteplase in Acute Ischemic Stroke

Key Takeaways

• Tirofiban was associated with more patients reaching mRS 0 to 1 at 90 days than placebo.
• Symptomatic intracranial hemorrhage and 90-day mortality were uncommon in both groups.
• mRS shift and EQ-5D-5L favored tirofiban, while subgroup analyses were descriptive and sensitivity analyses were mixed, limiting broader inferences.

Adjunctive intravenous tirofiban was associated with more excellent 90-day outcomes than placebo in adults with acute ischemic stroke who had limited response to tenecteplase. In the INSTANT randomized clinical trial published in JAMA, modified Rankin Scale scores of 0 to 1 at 90 days occurred in 63.8% with tirofiban and 52.2% with placebo. The cohort excluded large or medium vessel occlusion and confirmed or suspected cardioembolic stroke based on imaging and clinical criteria. It therefore represented a selected post-thrombolysis population without an endovascular target or suspected cardioembolic source.

INSTANT was an investigator-initiated, randomized, double-blind, placebo-controlled trial at 37 hospitals in China that randomized 359 patients, including 177 to tirofiban and 182 to matching placebo. Eligible participants were at least 18 years old, had NIHSS scores of 4 or higher, lacked large or medium vessel occlusion, and had no confirmed or suspected cardioembolic stroke.

In acute ischemic stroke patients treated with intravenous tenecteplase, insufficient response meant no significant change from baseline NIHSS score (increase or decrease of 0 or 1 point), neurological deterioration (worsening by ≥2 points), or neurological fluctuation (a ≥4-point increase followed by a ≥4-point decrease, or vice versa) on serial assessment within 4 to 24 hours. After a minimum 4-hour interval, study drug began 4 to 24 hours after tenecteplase as a 0.3-μg/kg/min bolus over 30 minutes followed by 0.075 μg/kg/min infusion for up to 47.5 hours. Under the double-dummy protocol, active oral antiplatelet therapy started 24 hours after thrombolysis in the placebo group and 44 hours after thrombolysis in the tirofiban group.

The primary outcome was modified Rankin Scale score 0 to 1 at 90 days. The unadjusted effect estimate was a risk ratio of 1.22, with a 95% CI of 1.02 to 1.46 and P=.03. The prespecified adjusted analysis gave a risk ratio of 1.17, with a 95% CI of 0.98 to 1.41 and P=.08. Researchers also reported a number needed to treat of 8.7 for one additional excellent outcome. One patient in the placebo group was lost to 90-day follow-up, and the overall pattern favored tirofiban, although the prespecified adjusted analysis was not statistically significant and significance was not maintained across all sensitivity analyses.

Secondary outcomes included mRS shift, mRS 0 to 2, mRS 0 to 3, early neurological improvement, and EQ-5D-5L at 90 days. The 90-day mRS shift favored tirofiban with a generalized odds ratio of 1.38, and EQ-5D-5L favored tirofiban with a win ratio of 1.42. For other measures, mRS 0 to 2 occurred in 78.5% versus 72.0%, mRS 0 to 3 in 93.2% versus 89.6%, and early improvement in 54.2% versus 50.0%. Prespecified subgroup analyses appeared in Figure 2, and sensitivity analyses of the primary outcome included complete-case, worst-case, and best-case scenarios. Confidence intervals were not adjusted for multiple comparisons, so these secondary findings remained supportive and exploratory.

Symptomatic intracranial hemorrhage within 48 hours occurred in 1 patient with tirofiban and 0 patients with placebo. Any radiologic intracranial hemorrhage within 48 hours occurred in 2 patients with tirofiban and 0 patients with placebo. Ninety-day mortality was 0.6% with tirofiban and 1.6% with placebo, although event counts were very small. Generalizability was limited by enrollment at hospitals in China and by exclusion of patients with large or medium vessel occlusion, suspected cardioembolic stroke, or NIHSS below 4. The 90-day functional findings came from a highly selected post-tenecteplase cohort.