HOPE Supports IV Alteplase in Late Window After Acute Ischemic Stroke

Intravenous alteplase is beneficial for patients who present with an acute ischemic stroke and salvageable brain tissue on imaging—with or without a large-vessel occlusion (LVO)—up to 24 hours after symptom onset, the HOPE trial indicates.

The proportion of patients who were functionally independent at 90 days was 40.3% among those treated with alteplase and 26.3% among those who received standard care, researchers led by Ying Zhou, PhD (Second Affiliated Hospital of Zhejiang University, Hangzhou, China), report in a paper published online last week in JAMA.

That boost in outcomes with IV thrombolysis came at the cost of a higher up-front rate of symptomatic intracranial hemorrhage (3.8% vs 0.5%), with no difference in 90-day mortality.

“These findings support extending the therapeutic window for IV thrombolysis in appropriately selected patients when endovascular thrombectomy is not initially planned or indicated,” the researchers conclude.

Commenting for TCTMD, Eva Mistry, MD (University of Cincinnati College of Medicine, OH), said the results are mostly applicable to places where thrombectomy isn’t readily available. In the US and Europe, for instance, nearly all patients with large-vessel occlusions who are eligible for thrombectomy will undergo that procedure. Of note, roughly 60% of patients in HOPE had an LVO.

“That still concerns me in terms of generalizability of the results outside of resource-poor settings where thrombectomy isn’t available,” Mistry said. In low-to-middle-income countries with insufficient resources, long transfer times, and/or no thrombectomy services, on the other hand, it is encouraging “that now, patients may be considered for a reperfusion therapy based on advanced imaging selection in the extended time window.”

The HOPE Trial

IV thrombolysis is indicated for treatment of acute ischemic stroke for patients presenting within 4.5 hours of symptom onset, but most patients don’t get to the hospital that fast. Several trials have examined the impact of treatment beyond that early window, both with alteplase and its molecular cousin tenecteplase. For instance, the EXTEND trial, and a later meta-analysis, showed the benefit of IV alteplase when administered 4.5 to 9 hours after stroke onset in patients who had a perfusion mismatch seen on imaging.

“Evidence suggests that in patients with robust collateral circulation, salvageable ischemic tissue may persist beyond 24 hours, highlighting the potential to extend the therapeutic window even further,” Zhou et al write.

That concept was tested in the TIMELESS and TRACE-III trials with IV tenecteplase, which demonstrated the safety of administering IV thrombolysis up to 24 hours after stroke onset in patients with LVOs, but with mixed efficacy results. That was possibly related to the proportion of patients undergoing thrombectomy (77% in TIMELESS and less than 2% in TRACE-III).

The HOPE trial similarly examined IV thrombolysis administered 4.5 to 24 hours after stroke onset, but without restricting the study population to those with LVOs. The open-label trial, conducted at 26 stroke centers in China, included 372 patients (median age 72 years; 43% women) who had an acute ischemic stroke, salvageable brain tissue on CT perfusion imaging, and no initial plan for endovascular thrombectomy. At baseline, median NIHSS score was 10 and median ASPECTS was 9.

The patients were randomized to IV alteplase 0.9 mg/kg (maximum dose 90 mg) or standard medical treatment, which included antiplatelet therapy and other types of supportive care. Though thrombectomy wasn’t initially planned, it was ultimately performed as bailout in three patients in the alteplase arm and seven in the control arm.

The primary efficacy outcome was functional independence, defined by a modified Rankin Scale (mRS) score of 0-1, at 90 days. Patients treated with alteplase were significantly more likely to meet that goal (adjusted risk ratio 1.52; 95% CI 1.14-2.02). The ordinal distribution of mRS scores also favored alteplase (common odds ratio 1.51; 95% CI 1.04-2.18), indicating greater odds of achieving a better functional outcome.

In addition, IV thrombolysis in this extended window resulted in a higher rate of major neurologic improvement at 24 hours (21.0% vs 12.9%; adjusted risk ratio 1.66; 95% CI 1.03-2.66).

The risk of symptomatic intracranial hemorrhage within the first 36 hours was higher with alteplase (adjusted risk ratio 7.34; 95% CI 1.54-34.84), although that didn’t translate into a difference in 90-day all-cause mortality (10.8% in both groups; adjusted risk ratio 0.91; 95% CI 0.52-1.62).

Global Relevance

“This trial contributes to the evidence base that supports the applicability of IV thrombolysis beyond the 9-hour window established by the EXTEND trial that included patients with both large and distal medium-vessel occlusions,” Zhou et al write, noting that it specifically indicates that alteplase may be effective up to 24 hours in patients without proximal LVOs (37% of the HOPE population).

HOPE also expands on the findings of TIMELESS and TRACE-III by using less restrictive imaging criteria for inclusion and not mandating use of any one commercial software.

“This approach facilitates exploration of real-world clinical practices, alleviates the financial burden associated with certain commercial software packages, and helps navigate the practical challenges of standardizing imaging protocols across diverse clinical centers,” the authors say, highlighting the findings’ applicability for settings that have fewer resources or are geographically isolated.

“By demonstrating benefit across a heterogeneous cohort using widely applicable methods, this trial may help inform stroke care across low- and middle-income health systems,” they write.

Mistry noted that regions that have spotty access to thrombectomy also will likely have issues with access to the CT perfusion (CTP) scans needed to identify patients eligible for IV thrombolysis in the extended time window.

But despite those limitations, she indicated that this trial would influence her thoughts on using alteplase beyond 4.5 hours in the right situation and setting.

“It would probably make me more comfortable offering thrombolysis as a treatment option to extended-window patients with CTP if I know that they are in an extremely rural setting and it is going to take several hours for them to come to a center that can perform thrombectomy,” Mistry said. “It’s probably the only situation I would apply these results to in my clinical practice or . . . generally in the US or Europe.”