Intra-arterial tPA boosts benefit of stroke thrombectomy

Adjunct thrombolysis with intra-arterial alteplase (tPA) following a successful thrombectomy in patients with acute ischaemic stroke due to large vessel occlusion (LVO) significantly improves neurologic outcomes at 90 days, according to the CHOICE* study presented at ISC 2022.

“The study results support the safety of adjunct intra-arterial tPA in patients with successful reperfusion at the end of thrombectomy,” said principal investigator Dr Ángel Chamorro from Hospital Clinic of Barcelona in Barcelona, Spain, which she noted was consistent with current guidelines suggesting that all eligible patients receive intravenous tPA before thrombectomy.

The rationale behind the study stems from previous observation that despite the high rate of successful reperfusion with mechanical thrombectomy, only about 27 percent of the patients are disability-free (mRS** 0 to 1) at 3 months, Chamorro explained.

“[It could be that] there is an impaired reperfusion of the microcirculation despite complete recanalization of the occluded vessel,” she suggested.

To test if this can be resolved by intra-arterial tPA after thrombectomy such that the drug can more readily access smaller, downstream clots, the investigators conducted the phase IIb, double-blind CHOICE trial. Participants were 121 patients (mean age 70.6 years, 47 percent women) with LVO acute ischaemic stroke who had undergone thrombectomy within 24 hours of stroke onset. They were randomized to intra-arterial tPA (0.225 mg/kg) infused over 15–30 minutes (n=61) or placebo (n=52). [ISC 2022, abstract LB6; JAMA 2022;doi:10.1001/jama.2022.1645]

Significantly more patients treated with intra-arterial tPA than those on placebo achieved excellent neurologic outcome at 90 days, as defined by mRS score of 0 or 1 (59.0 percent vs 40.3 percent; adjusted risk difference, 18.4 percent; p=0.047).

The clinical benefit could not be attributed to angiographic improvements, as differences in angiographic scores between the two groups were minor.

“This suggests that the improved functional outcome may be explained by an amelioration in the microcirculatory reperfusion,” the researchers hypothesized. “These findings stress the relevance of adequate perfusion of the microcirculation to improve the clinical efficacy of thrombectomy.”

Furthermore, there was no increase in symptomatic intracranial haemorrhage (ICH) within 24 hours with adjunct tPA vs placebo (0 percent vs 3.8 percent; risk difference, -3.8 percent, 95 percent confidence interval [CI], −13.2 to 2.5) — which Chamorro said was “reassuring … supporting that pharmacological thrombolysis did not increase the risk of haemorrhagic complications after thrombectomy.”

The two groups also did not differ in terms of 90-day mortality (8 percent vs 15 percent; risk difference, -7.2 percent, 95 percent CI, −19.2 to 4.8).

Exciting results

Calling the results as “very exciting”, session chair Professor Louise McCullough from the University of Texas Health Science, Texas, Houston said “The CHOICE trial is going to be a highlight of the meeting because it could change care now.”

Describing intra-arterial tPA as akin to “a cleanup” of residual clots after thrombectomy, she explained that this might help prevent the remaining clot fragments from traveling to the distal end which could block reperfusion in the more peripheral vessels.

“The 18 percent treatment effect observed in this 113-patient trial is remarkable,” concurred Professor Pooja Khatri from University of Cincinnati, Cincinnati, Ohio, in a linked editorial. [JAMA 2022;doi:10.1001/jama.2021.25014]

“This approach runs counter to the recent movement to consider bypass of intravenous tPA altogether in thrombectomy-eligible patients, and suggests that additional or perhaps more targeted thrombolysis will be the most beneficial approach,” she wrote.

“However, because of study limitations, these findings should be interpreted as preliminary and require replication,” cautioned Chamorro, who pointed out that the trial was stopped prematurely due to inadequate supply of placebo during COVID-19 when only 60 percent of the intended sample size had been enrolled.

 

*CHOICE: Chemical Optimization of Cerebral Embolectomy

**mRS: modified Rankin Scale