Intra-arterial (IA) alteplase was associated with superior 90-day functional outcomes than standard therapy alone in Chinese patients with large-vessel occlusion (LVO) stroke who had achieved successful endovascular reperfusion, new research showed.

In a large randomized clinical trial, investigators found the incidence of all-cause mortality and any intracranial hemorrhage was higher in those who received IA alteplase, but the differences weren’t statistically significant.

Investigators, led by Raul G. Nogueira, MD, director of the University of Pittsburgh Medical Center Stroke Institute, Pittsburgh, noted that these findings may be particularly relevant for Asian patients because large-artery atherosclerosis is a more common cause of stroke in this population compared with Western patients. Differences in stroke subtype and vascular pathology could influence response to adjunctive thrombolysis, highlighting the need for confirmation in more diverse cohorts.

The results should spur changes to clinical practice for Asian patients, although further research will be needed to move the needle in that direction for Western patients, study investigator Nogueira, who is also professor of neurology and neurosurgery at the University of Pittsburgh School of Medicine, told Medscape Medical News.

The research is in a “transition phase,” Nogueira said, adding that he hopes further studies will help post-thrombectomy IA thrombolysis become gradually incorporated into clinical practice.

The findings were published online on October 13 in JAMA.

Low Rate of Functional Independence

Mechanical thrombectomy restores blood flow and preserves ischemic penumbra, resulting in improved neurologic recovery. However, fewer than half of patients with stroke undergoing this procedure achieve functional independence at 90 days.

Residual thrombi within the microcirculation could help explain incomplete neurologic recovery. IA recombinant human tissue plasminogen activator may enhance neurologic recovery by dissolving these smaller downstream clots.

This study is the latest in a series of trials exploring IA thrombolysis strategies after successful thrombectomy.

For example, the phase 2 CHOICE trial, published in 2022, showed that IA alteplase reduced 90-day disability in Spanish patients with LVO stroke. The trial, however, was terminated early due to a shortage of placebo, after only 121 of the planned 200 patients had been enrolled.

Published in 2025, the phase 3 TN trial reported that administering IA tenecteplase (TNK) resulted in better 90-day functional outcomes than standard medical management in Chinese patients with LVO stroke.

Both the POST-UK trial, which tested intravenous (IV) urokinase, and the POST-TNK trial, which evaluated IA TNK in Chinese patients, reported neutral results. Even so, a meta-analysis indicated a trend toward better functional outcomes.

Multi-center Trial

The new Intra-arterial Alteplase for Acute Ischemic Stroke After Mechanical Thrombectomy (PEARL) trial enrolled adults with anterior-circulation LVO stroke at 28 hospitals across China, all of whom had successful mechanical thrombectomy within 24 hours of stroke onset.

Successful reperfusion was defined as an expanded Thrombolysis in Cerebral Infarction score between 2b50 (indicating reperfusion of 50%-66% of the affected territory) and 3 (representing complete reperfusion).

Participants had a mean age of 68 years, and 30.6% were female. The median National Institutes of Health Stroke Scale (NIHSS) score was 15, and the median Alberta Stroke Program Early CT Score (ASPECTS) was nine.

Researchers randomly assigned 164 participants to receive IA alteplase in addition to standard care (intervention group) and 160 to standard care alone (control group). Randomization occurred after the neurointerventionalist confirmed successful reperfusion.

Complete reperfusion at the time of randomization was observed in nine patients in the IA alteplase group and 20 in the standard treatment group.

Participants in the intervention group received an IA alteplase infusion (0.225 mg/kg; maximum 20 mg) over 15 minutes, regardless of whether they had previously received IV thrombolysis.

The study’s primary endpoint was the proportion of patients with a Modified Rankin Scale (mRS) score of 0 or 1 at 90 days — an indicator of excellent recovery — assessed by blinded personnel. The mRS ranges from 0 (no symptoms) to 5 (severe disability) and 6 (death).

Underpowered for Secondary Outcomes

Excellent outcomes were achieved in 44.8% of patients in the IA alteplase group vs 30.2% in the standard treatment group (adjusted risk difference [RD], 14.99; 95% CI, 3.71-26.27; adjusted risk ratio [RR], 1.45; 95% CI, 1.08-1.96; P = .01).

The robustness of the primary findings was confirmed by sensitivity analyses across multiple statistical models. Subgroup analyses revealed no evidence of treatment effect modification by sex, age, IV thrombolysis use, occlusion site, stroke severity, or other factors.

There were no statistically significant between-group differences for secondary outcomes, including functional independence (mRS 0-2: 55.2% in the intervention group vs 48.4% in the control group; RR, 1.13; 95% CI, 0.92-1.39; P = .25), lower overall disability (mRS shift: odds ratio, 1.23; 95% CI, 0.92-1.54; P = .10), or being ambulatory and capable of self-care (mRS 0-3: 65.6% vs 62.3%; RR, 1.04; 95% CI, 0.93-1.17; P = .50).

There were also no significant between-group differences in infarct growth or in neurologic improvement at 48 hours, defined as an NIHSS score of 0 or 1 or a reduction of ≥ 10 points. 

Secondary outcomes were not adjusted for multiple comparisons and should be interpreted as exploratory, the authors noted.

Nogueira said the PEARL trial lacked sufficient power to demonstrate efficacy across secondary outcomes, which would require a much larger sample size.

All-cause mortality at 90 days was numerically higher in the IA alteplase group (17.1%) than in the standard treatment group (11.3%), but the difference was not statistically significant (adjusted hazard ratio, 1.60; 95% CI, 0.88-2.89; P = .12).

Nogueira suggested the higher mortality rate may have been a random finding. The authors added that the complexity of administering IA alteplase could have prolonged procedure time and compromised marginally perfused brain tissue, potentially contributing to the increased mortality.

The incidence of any intracranial hemorrhage within 36 hours was higher in the IA alteplase group but was not statistically significant (32.9% vs 26.9%; RR, 1.22; 95% CI, 0.92-1.63; P = .17). Nogueira noted that the higher rate may have been related to the use of IV thrombolysis.

There was also no difference in the rate of symptomatic intracranial hemorrhage (4.3% vs 5.0%), which Nogueira described as a “more critical safety endpoint.”

Efficacy Underestimated?

One important question remains, said Yamei Tang, MD, PhD, of Sun Yat-sen University in Guangzhou, China, and an investigator in the PEARL trial. Tang said the next step is to determine which patients benefit most from post-thrombectomy IA thrombolysis — those with partial or complete reperfusion.

Both the ANGEL-TNK and PEARL trials demonstrated improved 90-day functional outcomes, but they used different IA thrombolytic agents. It remains unclear whether alteplase or TNK is superior, Nogueira noted.

Another key difference between the ANGEL-TNK and PEARL studies was that PEARL allowed the use of IV thrombolytics, whereas ANGEL-TNK did not. This may, to some extent, explain the differing outcomes — 90-day mortality, for instance, was similar between groups in ANGEL-TNK.

Enrolling thousands of patients is routine in cardiac research but far more difficult in stroke thrombectomy studies. Nogueira said pooled patient-level meta-analyses combining smaller trials will be needed to determine the most effective post-thrombectomy interventions.

China continues to lead post-thrombectomy research, aided by strong infrastructure, lower costs, and a large patient population — a trend Nogueira said could soon influence regional stroke treatment guidelines. Trials in Western populations, including CHOICE2 and TECNO (evaluating IA TNK), aim to expand the global evidence base.

Limitations of the PEARL trial included its open-label design, lack of placebo control, limited female and ethnic representation, and exclusion of patients with large infarcts (ASPECTS < 6).

The antiplatelet agent tirofiban was also used more frequently in the control group (34.3% vs 26.2%). Because some evidence suggests tirofiban may improve outcomes after mechanical thrombectomy, this imbalance could have led to an underestimation of IA alteplase’s efficacy.

Experts Weigh In

Commenting for Medscape Medical News, Brandon Giglio, MD, director of vascular neurology at NYU Langone Hospital-Brooklyn, New York City, said that because findings to date have been a “mixed bag,” further studies in more diverse populations are needed to confirm the results.

He noted that determining the optimal thrombolytic agent remains an open question, as many institutions in the US and worldwide are shifting to TNK.

Giglio added that while the current approach without IA thrombolysis is “proven to be safe and effective,” adoption of IA thrombolysis should proceed gradually until its safety is better established.

In an accompanying editorial, Alison Seitz, MD, and Thabele M. Leslie-Mazwi, MD, of the University of Washington, Seattle, described the PEARL trial as “an important part” of ongoing efforts to improve outcomes after endovascular treatment.

“Patients with large-vessel occlusion urgently need more solutions, and the results from the PEARL trial are an energizing lead,” they wrote.

Still, they urged caution in interpreting the findings, citing the mortality signal and inconsistencies in statistical significance across outcomes. While the primary endpoint reached significance, secondary outcomes did not, they noted.

Seitz and Leslie-Mazwi suggested that patients with complete reperfusion might not benefit from additional IA thrombolysis and that it may be more appropriate for those with impaired distal perfusion. They also raised the possibility that IA thrombolysis alone could eventually prove safer than device-based approaches for smaller cerebral vessel occlusions.

For now, they concluded, the evidence remains insufficient to support widespread use of IA thrombolysis after thrombectomy.

The study received support from China’s Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, the Guangdong Science and Technology Program, the Science and Technology Program of Guangzhou, the Sun Yatsen Memorial Hospital Clinical Research 5010 Program, and Johnson & Johnson MedTech and Genesis MedTech.

Nogueira reported receiving consulting fees for advisory roles with Anaconda, Biogen, Boehringer Ingelheim, Cerenovus, Genentech, Philips, Hybernia, Hyperfine, Imperative Care, Medtronic, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, Synchron, and Takeda Pharmaceuticals. He also reported receiving stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, CrestecBio, Euphrates Vascular, Vesalio, Viz.ai, RapidPulse, Sensome, and Perfuze. In addition, he reported being an investor in Viz.ai, Perfuze, Cerebrotech, Reist/Q’Apel Medical, Truvic, Tulavi Therapeutics, Vastrax, Piraeus Medical, Brain4Care, Quantanosis.ai, Unity Medical, and Viseon.Tang, Giglio, Seitz, and Leslie-Mazwi reported having no relevant conflicts of interest.