Alteplase Also Shows Its Mettle for Late Strokes in HOPE Trial

LOS ANGELES — The HOPE trial made another case for extending the therapeutic window for IV thrombolysis in acute ischemic stroke, potentially widening the pool of people eligible for therapy.

Among patients with stroke clots in large and medium vessels not planned for endovascular therapy (EVT), those who got alteplase at 4.5-24 hours after stroke onset were disproportionately more likely to achieve excellent functional outcomes at 90 days than controls (modified Rankin Scale [mRS] scores 0-1: 40.3% vs 26.3%, adjusted RR 1.52, 95% CI 1.14-2.02).

The IV alteplase group also showed a significantly better distribution of mRS scores as whole, reported Min Lou, MD, PhD, of the Second Affiliated Hospital of Zhejiang University in China, at the International Stroke Conference (ISC).

The caveat: the alteplase tested did confer excess symptomatic intracranial hemorrhages within 36 hours (3.8% vs 0.5%, adjusted RR 7.34, 95% CI 1.54-34.84). Meanwhile, a trend for more parenchymal hematomas with the approach did not reach statistical significance (7.6% vs 3.3%, adjusted RR 2.14, 95% CI 0.87-5.26).

In any case, there was no mortality signal associated with alteplase administered up to 24 hours after a stroke in HOPE. Alteplase and usual care groups had the same 10.8% incidence of 90-day mortality (adjusted RR 0.91, 95% CI 0.52-1.62).

Lou concluded that the study’s results support extending the therapeutic window for IV thrombolysis in stroke patients for whom thrombectomy is not available or indicated.

Indeed, HOPE builds on a growing evidence base for the concept of going as far out as 24 hours.

Previously, the TRACE-III found that late administration of another thrombolytic, tenecteplase, was of clinical benefit in the 4.5-24 hour window after a stroke in situations where thrombectomy was not available immediately. The TRACE-III patients were those with ischemic stroke due to large vessel occlusion (LVO) and proof of salvageable brain tissue identified on CT perfusion or perfusion-diffusion MRI using iStroke software.

That trial marked a comeback for late lytics after the TIMELESS trial failed to prove tenecteplase’s benefit in LVO patients with evidence of salvageable tissue on perfusion imaging at 4.5-24 hours. Given that TIMELESS had 77.3% of people also receiving endovascular thrombectomy due to the participation of comprehensive stroke centers, however, it was deemed not applicable to non-EVT patients.

At ISC, Lou pointed out that with the inclusion of medium-distal vessel occlusion strokes, HOPE had less restrictive criteria than either TRACE-III and TIMELESS. Also, the study had no mandate for any specific software for CT perfusion and was therefore more representative of real-world clinical practice.

HOPE had screened for suitable candidates, namely those who showed salvageable tissue. Salvageable tissue was defined as ischemic core volumes 70 mL or lower, penumbra at least 10 mL, and mismatch of at least 20% based on CT perfusion imaging.

The open-label trial was conducted at 26 sites across China. Patients were eligible if they presented 4.5-24 hours after stroke onset with a NIH Stroke Scale score 4-26. Both LVO and medium-distal vessel occlusion strokes were included in the trial.

Investigators had 372 patients randomly assigned alteplase (0.9 mg/kg) or standard treatment. Across the cohort, the median age was 72-73 and over half were men. Over 15% of participants had had a previous ischemic stroke. The baseline NIH Stroke Scale score was 10 in both alteplase and control groups. Median ischemic cores were 12.4 mL and 13.9 mL, respectively, and perfusion lesions were 48.8 mL and 51.9 mL.

On subgroup analysis, the benefit of alteplase seemed to hinge on whether the patient had an occlusion at the M2 segment of the middle cerebral artery as opposed to one in M1 or the internal carotid artery. Additionally, strokes related to intracranial atherosclerosis responded disproportionately better to alteplase.

These analyses were underpowered and hypothesis-generating, Lou warned ISC attendees. Additionally, the trial results as a whole may have limited generalizability to non-Chinese populations.

Finally, Lou emphasized that HOPE was not a study applicable to LVO patients presenting directly to thrombectomy-capable stroke centers.

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