Stroke Alert: A Review of Current Clinical Stroke Literature
By Matthew E. Fink, MD, Professor and Chairman, Department of Neurology, Weill Cornell Medical College, and Neurologist-in-Chief, New York Presbyterian Hospital. This article originally appeared in the March 2013 issue of Neurology Alert. It was peer reviewed by M. Flint Beal, MD. Dr. Beal is Anne Parrish Titzel Professor, Department of Neurology and Neuroscience, Weill Cornell Medical Center. Dr. Fink is a retained consultant for MAQUET and Dr. Beal reports no financial relationships relevant to this field of study.
Synopsis: Special Report from the International Stroke Conference: Current Endovascular Interventions for Acute Ischemic Stroke Do Not Result in Better Clinical Outcomes than Intravenous Thrombolysis
Attendees of the international stroke meeting in Hawaii in February 2013 were astonished by three reports of long-awaited trials comparing endovascular therapies with intravenous thrombolysis — IMS III,1 SYNTHESIS,2 and MR RESCUE.3 In all three studies, the clinical outcomes were not statistically different between the intra-arterial interventional groups and the intravenous-medical groups.
In IMS III, the study was stopped, for futility, after 656 patients with moderate-to-severe ischemic stroke were randomized to either intravenous tPA alone or endovascular therapy after IV tPA. The primary outcome measure, a modified Rankin score of 2 or less at 90 days, did not differ significantly between the two groups (40.8% for endovascular and 38.7% with intravenous tPA), and there were no subgroups based on clinical severity that showed any differences in outcome. Mortality was similar between the groups (19.1% vs 21.6%) as was symptomatic intracerebral hemorrhage (6.2% vs 5.9%). The trial showed similar safety profiles and outcomes. Of note, there was variability in the devices used for endovascular therapy at the discretion of the operators — Merci retreiver, Penumbra system, Solitaire device, or intra-arterial tPA. Angiography had to begin within 5 hours of symptom onset and be completed within 7 hours.
In the SYNTHESIS trial, 362 patients with acute ischemic stroke were randomly assigned, within 4.5 hours of symptom onset, to intravenous thrombolysis with tPA or intra-arterial endovascular therapy using a combination of thrombolysis or clot retrieval, or both. The median time from stroke onset to start of treatment was 3.75 hours for endovascular therapy and 2.75 hours for intravenous tPA. The primary outcome was survival free of disability (Rankin score of 0 or 1) at 3 months, and there was no significant difference between the groups (30.4% for endovascular and 34.8% for intravenous). Odds ratios were adjusted for age, sex, stroke severity, and atrial fibrillation at baseline. Symptomatic intracranial hemorrhage occurred in 6% of each group and there were no significant differences in other serious adverse events or death rates.
The MR RESCUE trial used imaging in an attempt to select patients for treatment and predict outcome based on CT or MR measurements of potentially reversible ischemic penumbra. The study randomly assigned 118 eligible patients within 8 hours after onset of large-vessel, anterior-circulation ischemic strokes to undergo mechanical embolectomy with Merci retriever or Penumbra system, or receive standard care, which might include intravenous tPA. All patients underwent CT or MRI studies to determine infarct core and penumbra, and were stratified to favorable penumbra group or a non-penumbra pattern. For all patients, the mean time to enrollment was 5.5 hours, and 58% had a favorable penumbra pattern. Revascularization was successful in 67% of the embolectomy group. Mortality at 90 days was 21%, and the rate of symptomatic hemorrhage was 4%, without any significant differences between the two groups. Mean scores in the modified Rankin score did not differ between the groups, and there were no differences between the favorable penumbra pattern or the nonpenumbral pattern group. A favorable penumbra pattern did not predict a better outcome, and there was no difference between embolectomy vs standard care.
We congratulate the investigators of all three of these studies for their herculean efforts to complete this work, but we are disappointed by the results. How can we explain the findings, and what should be our next steps?
First, the methodology for clot extraction in all three studies used a first generation of devices, and the newer devices that are becoming available are technically superior at performing clot extraction. So, it is expected that use of these newer devices will result in better outcomes. But second and more importantly, the time windows allowed for these studies had a negative impact on the results. The IMS III study allowed angiography to begin as long as 5 hours after onset of symptoms and was completed by 7 hours. In the SYNTHESIS trial, the intravenous tPA group was treated on average 1 hour faster than the endovascular intervention group. In MR RESCUE, mean time to enrollment was 5.5 hours and extended up to 8 hours.
We know from experimental studies in animals as well as humans that speed and time to revascularization has a profound impact on outcome. We constantly state that “time is brain” and urge our physicians to institute thrombolysis as fast as possible. Yet, these studies all had delays in the institution of treatment, often due to the extensive diagnostic studies that were part of the protocols. In this situation “perfect is the enemy of good.” The future studies must have protocols that limit the diagnostic studies to only what is absolutely necessary to make a triage decision — intravenous thrombolysis or intra-arterial clot extraction. Then we will need to repeat these studies using the newest devices in the shortest time window possible. Imaging studies will have to follow treatment and not delay it. Time is still the enemy, and remains the single most important variable that influences the results of therapies. Although it is certainly important and intellectually interesting to evaluate the penumbra and the collaterals, we cannot allow those studies to slow us down in our attempts to treat patients. New trials must reflect real-world practice issues, or we will not make the progress we are seeking. I would propose a simple clinical scale and rapid CT or MRI as we are currently performing it, and then an immediate decision to go to the angiography suite for interventional clot retrieval or standard therapy. Any further delays will result in worse outcomes. I am optimistic that future studies, if properly designed, will show that new interventional techniques will improve the clinical outcomes for patients with acute ischemic stroke.
1. Broderick JP, et al, for the IMS III Investigators. Endovascular therapy after intravenous versus tPA alone for stroke. N Engl J Med 2013; [Epub ahead of print] DOI: 10.1056/NEJMoa1214300.
2. Ciccine A, et al, for the SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; DOI: 10.1056/NEJMoa1213701.
3. Kidwell CS, et al, for the MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; [Epub ahead of print] DOI: 10.1056/NEJMoa1212793.
4. Chimowitz M. Endovascular treatment for acute ischemic stroke — Still unproven. N Engl J Med 2013; [Epub ahead of print].