New Trial Expands Window For Stroke Thrombectomy With Simpler Imaging

01 Mar 2024

The recent thrombectomy study from Brazil in low income population from public hospitals showed benefit for individuals with large vessel occlusion stroke presenting in the late time window (8-24 hours) and identified as suitable for treatment without requiring expensive imaging techniques. The study was coordinated by Hospital de Clínicas de Porto Alegre and sponsored by the Ministry of Health of Brazil.

The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window conducted outside first-world countries, and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment as MRI and CT perfusion.

The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT and angioCT, potentially altering current guidelines. “We need to show that MT can be extended to the 80% of the global population in middle- and low-income countries that do not have access to advanced imaging,” said Sheila Martins, MD, PhD, professor of neurology at the Universidade Federal do Rio Grande do Sul, and president of the World Stroke Organization.

However, there were some caveats that need to be considered, in particular a lack of benefit with thrombectomy in older patients (over 68 years of age) which can reflect the particular population enrolled in this study. The study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Raul Nogueira, who is professor of neurology and neurosurgery at the University of Pittsburgh, US, and Sheila Martins, who is a professor of neurology at Hospital de Clinicas Porto Alegre, Brazil and President of the World Stroke Organization, co- principal investigators of the study, presented the RESILIENT-Extend results at the International Stroke Conference 2024, being held in Phoenix, Arizona.

The lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window especially in lower income countries and the main objective of study was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 hours) for thrombectomy. In this way our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.

The RESILIENT-Extend trial was conducted in the public health service of Brazil, coordinated by Hospital de Clínicas de Porto Alegre, and involved a different population of people than have been included in other thrombectomy trials which have mostly been conducted in first world countries. The public health system in Brazil is not well resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first world recruited into most other thrombectomy trials.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the NIHSS score and the stroke burden on imaging as measured by the ASPECTS scores. They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale, created by Raul, that adjusted for age to avoid enrolling elderly patients with large strokes. These patients were identified exclusively using non contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years, slightly younger than seen in other thrombectomy trials because in lower middle income countries strokes occur at a younger age and have a higher case fatality rate.

The median baseline NIHSS score was 16 and the median ASPECTS score was 7-8. The median time to treatment was 12.5 hours which is similar to other late window thrombectomy trials.

Conflicting Results On Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bi-directional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS 0-3) but there was also a non-significant increased risk of a bad outcome (mRS 5-6).

“This bi-directional result prevents a common odds ratio from being calculated so the primary endpoint is not applicable, “Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These show that the numbers of patients achieving a good outcome (mRS 0-2) was significantly increased with thrombectomy (25% versus 14%, adjusted odds ratio 2.56; P=.012).

The number of patients achieving an excellent outcome (mRS 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk of severe disability or death (mRS 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6 the odds ratio was 0.58. Both these results were non-significant.

No Benefit In Older Patients

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in patients over 68 years of age. In general trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that is related to the patient population included. In the Brazilian public heath service, older patents are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process.

Frailty: A Ceiling Effect For Thrombectomy Benefit?

These results from the two RESILIENT trials give a word of caution to the thrombectomy field.

“This procedure was initially thought suitable only for patients with small core strokes but we now have a series of trials showing benefit of thrombectomy in large core strokes as well. We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world. But our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account,” Nogueira commented.

Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients (68-70 years of age) in the public health service in Brazil. In this population, a patient aged 70 can be quite different to a patient of the same age in a first world country. I think in our population an age of over 68-70 is a surrogate for frailty, which will not be the case in first world countries. We speculated that the bidirectional effect on the mRS shift analysis may also have been caused by frailty of some of the patients.

What the results may be showing is that for most of the population there is a benefit of thrombectomy but for some patients (possibly the most frail) then the procedure can be too overwhelming for them. But the suggestion of harm was not significant so this observation could have also just been the play of chance.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Ohio, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in a resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect, warranted further investigation.

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