6.1 Three Strikes & Striking Out on a New Path

In 2013, three major randomized controlled trials (RCTs) comparing the effectiveness of endovascular approaches to intravenous (IV) tissue plasminogen activator (tPA) for acute stroke were published—the Interventional Management of Stroke (IMS) III, Local Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS), and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE)—all of which showed negative results. However, the neurointerventional community has reason strongly to feel that these RCTs were not representative of the contemporary mechanical thrombectomy landscape. Common criticisms included marked heterogeneity in use of modern stent retrievers, delays in treatment time, and lack of baseline imaging. As such, new trials were conceived which pitted contemporary stent retrievers against medical standard care, this time with a focus of reducing door-to-puncture times and ensuring baseline computed tomography angiography (CTA) was performed.

Learning from the lessons of the three major strikes against stroke intervention (i.e., IMS III, SYNTHESIS and MR RESCUE), a new era debuted with MR CLEAN, ESCAPE, EXTEND IA, SWIFT PRIME and REVASCAT, THRACE and THERAPY. Excepting THERAPY, which was underpowered at the time of its termination, these trials would come to be known as heralds of the new epoch of positive evidence of mechanical therapy.

The first of these trials was directed in the Netherlands and was called MR CLEAN. The trail enrolled 233 participants presenting with emergent large vessel occlusion (ELVO) of the anterior circulation (intracranial internal carotid artery [ICA] and promixal middle cerebral artery [MCA]) who were randomized to endovascular treatments with usual care, while another 267 were randomized to standard of care. Ultimately, 196 underwent endovascular treatment, and 190 were treated with modern stent retrievers. Occlusion was always confirmed via CTA, and patients were treated within 6 hours of ictus with an NIHSS of ≥ 2. As is now famous, there were significant differences between patients who achieved a good functional outcome (Modified Ranking Scale [mRS] ≤ 2) in the endovascular arm (32.6%) and the standard of care arm (19.1%), with an adjusted odds ratio of 1.67 (95% CI 1.21 to 2.30). There were no significant differences in mortality, rate of symptomatic intracerebral hemorrhage (sICH), or other serious adverse events. It is now accepted that the remarkable result of MR CLEAN relative to the three negative trials is owed to a standard of baseline imaging and modern stent retrievers. Importantly, most patients were included after they had failed to respond to 1 hour of IV tPA. Thus it was known in these patients that standard of care was approaching futility. At the time of the study, the Dutch health system only permitted endovascular therapy in the context of the trial, reducing selection bias in favor of easier patients. MR CLEAN possessed the longest onset to puncture (~260 minutes) of any of the modern trials.

The culmination of MR CLEAN caused pandemonium within the endovascular community, and spurred investigators across the world to urgently perform interim analysis of their data. The ESCAPE trial was the first of these to do so and discovered a result in favor of mechanical thrombectomy which mandated cessation of the trial on safety grounds. This international trial randomized 165 patients to the endovascular plus standard care arm and 150 to the standard care arm, albeit with a timeline extended to 12 hours post ictus. Furthermore, small infarct cores were one of the explicit inclusion criteria, as well as the presence of moderate-to-good collateral circulation as identified on computed tomography perfusion (CTP) and CTA. Within the endovascular group, the incidence of functional independence (mRS ≤ 2) at 90 days (53.0% vs. 29.3%) was significantly greater, with a common odds ration (OR) of 2.6. Moreover, the number needed to treat (NNT) was onlyfour, which was stunning, as it had already dwarfed the efficacy of primary percutaneous coronary intervention. There was also an overall reduction in mortality (10.4% vs. 19%) in favor of intervention, with no difference in sICH. While MR CLEAN and ESCAPE are certainly akin, the differences are felt to be attributable to a mean time from ictus to puncture of 185 minutes and the exclusion of large infarct cores as well as poor collaterals. General anesthesia was also less commonly employed.

Table 6‑1

6.2 The Solitary Armamentarium

Following the heartening results emanating from Rotterdam and Calgary, EXTEND IA, SWIFTPRIME, and REVASCAT sought specifically to compare the Solitaire stent retriever (Medtronic), rather than the comparatively heterogeneous trials which permitted also the use of Trevo (Stryker) devices among others. Conducted in Australia and New Zealand, EXTEND IA randomized patients receiving IV tPA within 4.5 hours of ictus to additional Solitaire thombectomy. Seeking to further optimize imaging selection in patients, RAPID CTP software was employed identify ischemic penumbra in a standardized fashion. Whilst the study planned to enroll 100 patients with occlusions of the ICA or MCA, the results were so overwhelmingly positive at 35 patients that the trial was ceased. In addition, coprimary outcomes of 24-hour MRI reperfusion and 3-day NIHSS both overwhelmingly supported mechanical thrombectomy, with 100% reperfusion of the ischemic territory with Solitaire (37% with IV thrombolysis). Furthermore, a ≥ 8-point reduction on the NIHSS, or a score of 0 or 1, was achieved in 80% of thrombectomy patients (again 36% with thrombolysis). Good functional outcome at 90 days was 71% vs. 40%, with no significant difference in rates of sICH or mortality. Here, ictus to puncture averaged 210 minutes, and rates of vascularization (86%) were the highest ever.

Conducted in the United States, Canada, and Europe, SWIFT PRIME limited its inclusion to 6 hours post ictus and the Solitaire device. Devised to randomize 477 patients between standard treatment and Solitaire with intracranial ICA, M1 or carotid terminus occlusions and absence of large ischemic core lesions on CTA or MRA, it was halted due to efficacy at ad hoc analysis of 196 patients. Using the usual good outcome measures of mRS ≤ 2 and disability at 90 days, the endovascular NNT was 2.6, functional independence was achieved in 60% (vs. 35%) with no differences in mortality and sICH rates. Here, ictus-to-puncture time averaged 224 minutes. Taking stock of the functional independences achieved at the time, the neurointerventional community noted that this was higher than MR CLEAN and emphasized efficiency and speed of workflow. In ascending order of functional independence, the trials stood at: MR CLEAN, 33%; ESCAPE, 53%; SWIFT PRIME, 60%; and EXTEND IA, 71%.( Table 6‑2 ).