From tPA augmentation and stroke systems of care through to the rise of neuroprotective investigations, Santiago Ortega-Gutiérrez, University of Iowa (Iowa City, USA) kick started the Society of NeuroInterventional Surgery (SNIS) annual meeting (22–25 July, Miami, USA) by outlining an array of ongoing stroke trials. “Everybody here in this room has witnessed an amazing 10 years of building something together that has made a huge difference. However, the more we progress, the more we realise we have many more things to do.”
Alluding to the studies that address tPA augmentation, Ortega-Gutierrez first detailed the MOST (Multi-arm optimisation of stroke thrombolysis) trial, which he said is the only National Institutes of Health (NIH) sponsored trial he included. “It is a phase 3, large vessel occlusion (LVO) and non-LVO stroke trial with a complex design that includes five arms. The control arm will be IV recombinant tPA [rtPA] only. With the other four arms, the synergistic effect of Argatroban or Eptifibatide in both low and high does in addition to IV rtPA will be assessed.” The primary outcome consists of a utility function modified Rankin Scale (mRS) at 90 days, with the sample size set to be 1,500. Enrolment is due to begin in the next few months, Ortego-Gutiérrez added.
The second tPA augmentation trial he outlined was the TRUST (Aureva transcranial ultrasound device with tPA in patients with acute ischaemic stroke) trial. Patients with LVO ischaemic stroke, receiving IV tPA, as well as being transferred to an endovascular therapy centre are going to be randomised to the intervention group: tPA plus ultrasound frame (placed in the patient for 90–120 minutes), versus tPA with sham ultrasound frame. He commented, “In this case, the primary outcome is complete recanalisation by modified Arterial Occlusive Lesion [mAOL] on the first catheter angiogram. The planned sample size is around 556 patients, and the principal investigators are Andrei Alexandrov and Andrew Barreto.”
Moving on to the development of the best systems of care for endovascular therapy in LVO, he said, “We are having a huge debate over what is the best approach. Our current systems are developed for IV tPA delivery, but not for LVO treatment. And, because of this, the trial results coming up are very important.”
The RACECAT (Direct transfer to an endovascular centre compared to transfer to the closest stroke centre in acute stroke patients with suspected LVO) trial is a prospective cluster randomised controlled trial currently underway in Barcelona. Patients are being selected by emergency medical services in the field based on the RACE scale. If it is more than 4, and once they identify the patients as potential LVO, they will be randomised to direct transfer to a comprehensive stroke centre, or to the closest local stroke centre. The outcome is 90 day mRS and the sample size is 1,754 patients. “I was speaking with [the lead principal investigator] Marc [Ribo] this morning, and I can tell you that they have enrolled well over 1,000 patients,” confirmed Ortega-Gutiérrez.
Addressing another important issue, he asks the SNIS audience: “Do we really need tPA in these patients with LVO?”. The SWIFT DIRECT (Bridging thrombolysis versus direct mechanical thrombectomy in acute ischaemic stroke) trial is aiming to answer that very question, Ortega-Gutiérrez said. Patients with anterior circulation of LVO stroke that are IV tPA eligible within four hours and 15 minutes are going to be randomised to treatment with Solitaire (Medtronic) stent-retriever thrombectomy versus Solitaire with IV tPA. Again, the primary outcome of this non-inferiority study will be mRS at 90 days. The target sample size is 404 patients.
“In terms of imaging selection, we all know that imaging allows us to, especially in the late window, have a better selection of patients, everything adds time. And, if we look outside Europe and the USA, this technology is not available everywhere. There is a group from The Netherlands that is applying the same inclusion criteria, but now to the late window, 6–24 hours,” said Ortega-Gutiérrez. The corresponding study, MR CLEAN-LATE (Multicentre randomised clinical trial of endovascular treatment of acute ischaemic stroke in The Netherlands for late arrivals), randomises patients to endovascular therapy plus medical management, or the latter alone (the control). The sample size is set to reach 400 subjects, with the primary outcome as improvement in ordinal mRS at 90 days.
He pointed to another study outside of the USA, the BEST (Acute basilar artery occlusion: Endovascular interventions versus standard medical treatment) trial, a randomised trial for basilar occlusion within eight hours. “With a projected sample size of 344, these results were presented at the Society of Vascular and Interventional Neurology (SVIN) last year in October, but unfortunately this trial was stopped ahead of time because there was a lot of crossover from the medical management group to the treatment group, meaning the analysis was not valid.
“However, we [now] have an ongoing basilar artery occlusion Chinese endovascular trial.” Lead by Tudor Jovin and Xunming Ji, the investigators are randomising patients with basilar occlusion or bilateral vertebral artery occlusion at 6–24 hours. In terms of selection, MR or CT based posterior circulation ASPECTS (Alberta Stroke Program Early CT Score) is being used. The sample size is 318 with the primary outcome 90 day mRS (0–4).
“But what about anaesthesia? […] Lately, we have some single centre European studies that have shown no inferiority of conscious sedation compared to general anaesthesia when the blood pressure was controlled,” noted Ortega-Gutiérrez. The SEGA (Sedation versus general anaesthesia for endovascular therapy in acute ischaemic stroke) is a USA based multicentre trial aiming to randomise patients with symptom onset at 0–16 hours to conscious sedation (the control), with very strictly controlled blood pressure, versus general anaesthesia. The primary outcome is mRS at 90 days, with the target sample size at 216 patients. “At this moment, about 40 patients have been enrolled in this study,” he added.
“There is also a lot of emphasis on how much we can push thrombectomy,” remarked Ortega-Gutiérrez. “And, we treat patients with large core, and we treat patients with very low NIHSS. For this, there are several studies coming up. One of them is in Europe, called the TENSION trial.”
The TENSION (Efficacy and safety of thrombectomy in stroke with extended lesion and extended time window) trial will include LVO acute ischaemic stroke patients with ASPECTS 3–5, from zero to 12 hours from last known well or an unknown time onset. Randomised to either mechanical thrombectomy plus medical management or medical therapy alone, the primary outcome for these patients is again an mRS shift analysis at 90 days. Ortega-Gutiérrez added, “The sample size is going to be 714 patients, stratified on time from symptom onset (early or late window) and stroke severity (NIHSS ≤18, or NIHSS ≥18).
Moreover, in the USA, the TESLA (Thrombectomy for emergent salvage of large anterior circulation ischaemic stroke) trial will commence next month, said Ortega-Gutiérrez. Patients with ASPECTS 2–5 within 24 hours are to be selected and randomised to endovascular therapy plus medical management, or the latter alone. With the sample size estimated at 300 patients, the primary outcome is 90-day utility-weighted mRS.
“We also have a slightly more complex large core study; SELECT 2. In addition to selecting patients using CT, CT perfusion will also be applied. Patients will be divided into six different groups […] to assess whether patients may benefit from thrombectomy when they have large core, they [the investigators] will assess the prospective concordance of CT perfusion and CT to measure large core infarct.” The primary aim of SELECT 2 is to investigate whether endovascular therapy is superior to medical management alone.
The penultimate trial he points to is the ENDOLOW trial. “This is a prospective phase 2 trial, which can be converted to phase 3. Patients will have NIHSS 0–5, with an ASPECTS of more than six. They will be randomised to medical therapy versus endovascular therapy using the Embotrap device.”
Finally, Ortega-Gutiérrez said, “We will see a lot of neuroprotective studies coming up, but it is worth mentioning the one that has almost finished enrolment: ESCAPE-NA1 [Safety and efficacy of NA-1 in subjects undergoing endovascular thrombectomy for stroke].” Designed as an RCT, patients with large vessel occlusion, small core and good collaterals are being randomised to an IV dose of NA-1 (2.6mg/kg) 10±1 minutes in addition to thrombectomy, or a placebo dose, with the outcome set as the proportion of favourable outcome 0–2 mRS at three months. “I am sure we will hear about these results very soon,” he concluded.