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Intra-arterial thrombolysis after reestablishing flow with mechanical thrombectomy improved outcomes in acute ischemic stroke, according to a small randomized trial, although its premature termination may mandate another for confirmation.

The combination strategy increased the chances of an excellent 90-day outcome, as indicated by a modified Rankin Scale score of 0-1, by an adjusted absolute 18.4% compared with thrombectomy with intra-arterial placebo (59.0% vs 40.3%, P=0.047).

Safety outcomes were at least as good with intra-arterial alteplase use in the trial, Angel Chamorro, MD, PhD, of the Hospital Clinic of Barcelona, Spain, reported at the American Stroke Association's International Stroke Conference (ISC), held virtually and in person in New Orleans, and simultaneously online in .

These "remarkable" findings may add stock to a provocative theory that micro-occlusions that persist in the capillaries after gross revascularization cause damage through edema, vasoconstriction, and inflammation, noted Pooja Khatri, MD, MSc, of the University of Cincinnati in Ohio, in an accompanying .

At the late-breaking clinical trial session, Chamorro pointed to mechanistic support from the trial's finding of benefits in neurologic outcomes despite no significant impact on angiographic flow improvements (9% expanded TICI score improvement in the intra-arterial alteplase group versus 8% in the placebo group, five vs four patients).

"The clinical versus angiographic mismatch stresses the limitations of cerebral angiography to predict stroke outcomes and highlights the relevance of the microcirculation to improve the clinical efficacy of mechanical thrombectomy," Chamorro concluded.

"However, because of study limitations, these findings should be interpreted as preliminary and require replication," the researchers cautioned.

The trial reached only 60% of the enrollment it had been planned and powered for before their placebo reached its shelf-life expiration. The supplier informed the researchers in March 2020 when the COVID pandemic began that the placebo could not be restocked.

Khatri pointed to the wide 95% confidence intervals in the primary endpoint and the small sample size of the trial that had provided power to detect a 21% effect size, "which is larger than that observed in pivotal trials of intravenous thrombolysis," Khatri noted.

The researchers also acknowledged that trials with early termination risk overestimating the treatment effect.

Their initial Chemical Optimization of Cerebral Embolectomy () trial randomized 121 patients with large vessel occlusion with complete or near-complete recanalization of a proximal vessel occlusion and successful brain reperfusion on cerebral angiogram (mTICI score of 2b or 2b/3) after mechanical thrombectomy. Patients were treated within 24 hours of symptom onset and had an ASPECTS score of 6 or higher.

The intra-arterial alteplase group got a 15- or 30-minute infusion at 0.225 mg/kg of drug directed distal to the exit of the lenticulostriates.

Notably, interventionalists were allowed to administer alteplase prior to thrombectomy when indicated based on standard care and to stop that 60-minute infusion early at their discretion. Thus, 57% of patients got at least half a dose of pre-thrombectomy lytic and 10% got a lesser dose.

This part of the protocol "limits the external validity of this study," Khatri wrote, because "intra-arterial alteplase may, in whole or in part, simply be replacing the withheld intravenous alteplase."

Another concern was an imbalance in the groups, as the intra-arterial alteplase group had 40-minute faster onset to study drug initiation, which Khatri wrote "could be an especially important confounder, given the well-established, strong time dependence of the benefit of angiographic reperfusion on clinical outcome; this difference could contribute to a 5% to 10% higher rate of excellent outcome."

But for a phase IIb trial, the signal of efficacy was there and -- more importantly -- the safety.

No symptomatic intracerebral hemorrhage occurred within 24 hours in the intervention group compared with two cases in the placebo group (3.8%). Mortality at 90-days also favored intra-arterial alteplase (five vs eight cases, 8% vs 15%), although this was likewise non-significant.

The infarct expansion ratio did not differ between treatment groups, although the non-significant, numerically lower ratio with alteplase supported the approach's safety as well.