In December 2021, University Hospital Basel (Basel, Switzerland) enrolled the world’s first patient in the DISTAL study, a multicenter randomized controlled trial evaluating the clinical effectiveness of endovascular therapy (EVT) in patients with stroke. acute ischemic stroke with isolated middle vessel occlusion (MeVO )*. Specifically, its main objective will be to determine whether these patients show superior long-term functional outcomes, measured via the Modified Rankin Scale (mRS) at 90 days, when treated with EVT plus Best Medical Therapy (BMT ) compared to BMT alone. According to DISTAL’s core team, this international, pragmatic, randomized 1:1 trial with blinded evaluation of the endpoints aims to provide conclusive and concrete information on the efficacy and safety of EVT in patients MeVO stroke victims. Here the team – consisting of lead researchers Marios Psychogios and Urs Fischer, project leader Luzia Balmer and lead scientist Alex Brehm (all from University Hospital Basel) – discusses the finer details and ambitions larger parts of the study.
Have EVT results for other indications, such as stroke with great vessel occlusion (LVO), been the subject of more clinical research than MeVO so far, and why?
Absolutely, but it could also be seen as the natural evolution of establishing evidence for the endovascular treatment approach. In 2010, we were all convinced that EVT was a game-changer for stroke patients with OVG, but the so-called “unhappy triad” was published in 2013: three randomized controlled trials (RCTs) showing no no beneficial effect of EVT on results.
This put us back to square one. It was necessary to draw lessons from these trials and refine the techniques as well as the target population. The largest effect sizes were seen in patients with LVO stroke, who were then selected as the target population for further pivotal trials. Therefore, trials have proven an overwhelming treatment effect of EVT on the clinical outcomes of these selected patients. Now, for patients with MeVO, we are in the same situation we found ourselves in ten years ago – we suspect that it might be beneficial to treat these patients endovascularly, but the randomized evidence makes default. Therefore, we started the DISTAL trial.
What is the current unmet need for MeVO stroke, and as such, why is shedding light on VTE outcomes in these patients particularly important?
Currently, the only evidence-based treatment for MeVO stroke patients is intravenous thrombolysis. However, we all know that intravenous thrombolysis has a rather narrow time window and rapidly decreasing efficacy, along with relevant contraindications, leaving many MeVO stroke patients without an effective treatment option. The outcome of a MeVO stroke can be devastating and lead to lifelong disability or death. It is therefore of utmost importance to establish an effective treatment option for these patients.
Why was mRS selected as the primary endpoint in the DISTAL trial? And what are the key secondary endpoints of the study?
Despite its limitations, the mRS is currently the most established outcome parameter in stroke trials and its use is also supported by stroke patients. We consulted the largest patient organization for stroke survivors in Switzerland (Fragile Suisse) and they agreed that achieving a good functional outcome, measured with the mRS, is of very high importance for patients under MeVO. However, we are aware that the mRS does not capture minor clinical deficits, which can have a major impact on the quality of life of individual patients. The change in clinical deficit from baseline to follow-up, measured with the National Institute of Health Scale (NIHSS) score, might have been more sensitive in capturing stroke-related deficits, but the NIHSS is not a patient-centered outcome.
However, secondary endpoints include NIHSS change from baseline to follow-up, quality of life, cognitive function, all-cause mortality, percent brain saved on imaging, and place of residence. one year after the stroke. The latter was a suggestion from Fragile Suisse, as they stressed that returning home – and staying home – is of the utmost importance for patients. Cognitive function, on the other hand, was chosen as a secondary criterion because it is very sensitive to subtle differences.
We will use percent brain saved as the primary imaging outcome since this is a direct image-based measure of treatment effect. We chose not to use the final infarct volume as an imaging outcome parameter due to the heterogeneity of the sizes of the territories provided by different MeVOs. Since the percentage of brain saved is derived from the final infarct volume, it is reasonable to assume that, as the final infarct volume, it can be used as a proxy for the functional outcome. Several studies have shown a strong correlation between final infarct volume and functional outcome. And, in patients with posterior cerebral artery occlusions in particular, this result will be of great value, as clinical assessment tools such as mRS and NIHSS are known to underestimate the clinically relevant sequelae of these obstructions.
What are the safety endpoints of the study and how will you minimize the potential risks and complications associated with VTE?
The main safety criterion will be the occurrence of symptomatic intracranial haemorrhage after randomisation. Retrospective studies have shown similar rates of symptomatic intracranial hemorrhage in patients treated with either VTE or GMO alone. In our experience, the use of dedicated materials and techniques significantly reduces the risk of complications and inconvenience of EVT. As with the SAVE (Stent retriever-assisted vacuum-locked extraction) technique for LVO before, we are now in the process of publishing refined techniques as video cases, in peer-reviewed journals, and on our One Stop In Stroke YouTube channel. Additionally, discussions of materials and techniques are an important part of our site selection and initiation visits as we strive to achieve the highest technical standards within the trial.
What revascularization devices will be used in the DISTAL study?
DISTAL is a pragmatic trial and does not restrict the use of devices. Commercially available CE certified stent retrievers, suction catheters, balloon catheters and other devices are therefore freely chosen by the treating physician based on their clinical judgment and expertise, as the trial evaluates the procedure and not a medical device.
Regarding the margin of superiority of the trial, how much better will EVT plus BMT have to be than BMT alone to be considered a success?
The primary mRS outcome at 90 days will be assessed using lag analysis. We based our sample size calculation on recently published data regarding the outcomes of MeVO patients treated with BMT alone, which estimated that 67% had regained functional independence by day 90. Although other published data and our own analysis from the Swiss Stroke Registry suggests lower rates of functional independence (55% in the Swiss Stroke Registry), we used this result as a conservative estimate. Based on this functional independence rate in MeVO patients, the margin in the trial is 14%, which means that 81% of patients in the EVT group are expected to be functionally independent at 90 days. However, in the event that the control group performs less well, lower margins would lead to the trial being considered a success. This approach was chosen based on the results observed in previous basilar artery occlusion trials.
Having recently initiated the DISTAL study, what are your future objectives in terms of deadlines?
At the time of writing, 14 patients have been randomized into the trial. Our primary goal is to launch as many sites as possible in the coming months, and we expect to enroll a total of 526 patients across ≥ 40 global sites over a 36 month period. In Switzerland, we already have five recruitment sites and we have obtained ethical approval to expand into Germany this year. Ethical approval in Belgium, Spain, Finland, Israel and Portugal is also in progress. Our goal is to complete registrations at the end of 2024 and present our results in mid-2025.
What impact could the results of this trial have in the field of stroke care?
If the trial shows the superiority of EVT, this could impact future guidelines and clinical practice. As with the 2015 LVO trials, several MeVO trials are starting now, so we can expect good evidence in the next few years. EVT could eventually become the standard of care for MeVO patients, improving their quality of life and reducing the burden of stroke in these patients.
In addition, meta-analyses of individual patient data will be performed with other similar trials evaluating the efficacy of VTE in MeVO patients, for example, the DISCOUNT trial in France and the ESCAPE-MeVO trial in Canada. We intend to perform meta-analyses of individual patient data from all published trials, and believe that combining our results with such studies, which also use mRS as the primary endpoint, will help corroborate the evidence for EVT in MeVO patients. It would also allow us to perform subgroup analyzes for different patient cohorts, i.e. type and site of vascular occlusions, different time windows, and other important background factors. In addition, the effect of different technical approaches and the safety of the devices used can be evaluated with this pooled data set.
*Defined as an isolated occlusion of the co- or non-dominant segment M2, M3 or M4 of the middle cerebral artery, segment A1, A2 or A3 of the anterior cerebral artery, segment P1 or P2 of the posterior cerebral artery .