Caution: Reperfusion Therapy in Mild Stroke Due to Large Vessel Occlusion Needs Randomized Controlled Trials

Michael D. Hill, MD, MSc; Shelagh B. Coutts, MD


Stroke. 2019;50(8):1952-1953. 

Some patients with mild or even fully resolved stroke symptoms have an underlying large vessel occlusion. What to do clinically with such patients when they present acutely or subacutely for emergency or urgent assessment remains a conundrum. Many patients will actually fair well with conservative management.[1] Yet others will deteriorate and go on to suffer progressive ischemic stroke and chronic disability.[2]

Among patients presenting with mild stroke symptoms, a demonstrable arterial occlusion is a strong poor prognostic factor. Approximately, 10% to 15% of mild stroke and transient ischemic attack patients with motor or speech symptomatology and presenting acutely will have an intracranial or cervical extracranial arterial occlusion or severe stenosis.[3] If such patients are treated conservatively, some will deteriorate over the first night in hospital and have progression of their initial small infarction. At 90 days, they will have moderate disability and a poorer quality of life, and 1% to 2% will be deceased at 90 days from complications of their stroke.[2]

Aggressive treatment with thrombolysis or endovascular thrombectomy (EVT) can be offered. Milder stroke patients (although not many) were included in the NINDS tPA Stroke trial (National Institutes of Health tPA Stroke Trial). It is likely that the effect size for treatment is much smaller. The trouble is that it is not yet clear how to identify which patients should be treated with reperfusion therapies and which patients can be managed conservatively with antithrombotic therapy. Recognition of large vessel occlusion is now straightforward with use of noninvasive neurovascular imaging using computed tomography angiography. A simple clinical, bedside approach is to sit the patient up and observe if they deteriorate when gravity reduces cerebral perfusion pressure. But the sensitivity of this technique is probably low, even as the specificity is high. The TEMPO-1 trial (TNK-tPA Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) was a pilot study examining thrombolysis of milder stroke patients with intracranial occlusion using tenecteplase.[4] PRISMS (A Study of the Efficacy and Safety of Alteplase in Participants With Mild Stroke) examined a more general minor stroke population of minor stroke patients but was stopped early because of slow recruitment.[5] TEMPO-2 is the follow-on larger randomized trial enrolling patients with minor stroke and proven occlusion. Treatment is with tenecteplase versus antiplatelet control, and the study is ongoing globally.

EVT is a powerful, effective, and generally safe therapy. It has a low complication rate, but adverse effects of treatment do occur, including catastrophic intracranial hemorrhage. In major stroke trials, the rates of intracranial vessel perforation, subarachnoid hemorrhage, or major intracerebral hemorrhage were very low (≤2%). Most trials excluded patients with National Institutes of Health Stroke Scale score ≤5. There were only 14 patients included in the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stent Retriever Trials) dataset with a National Institutes of Health Stroke Scale score ≤5.[6] There are not enough data to convincingly state that EVT should be offered in this low–National Institutes of Health Stroke Scale patient subgroup. No guidelines recommend the use of EVT for this patient population. But guidelines have not stopped the use of this therapy in routine clinical practice.

In this issue of the Journal, Asdaghi et al[7] describe the breadth of EVT use among patients with mild stroke. Using data from a large Florida-Puerto Rico registry, a total sample of 4110 (of 69 714 presenting with 24 hours of symptoms onset) underwent EVT. Among these, 446 (11%) had mild symptoms, National Institutes of Health Stroke Scale score ≤5, at baseline assessment. This population was younger, more often male sex, more likely to be current smokers, and less likely to have atrial fibrillation compared with those with more severe stroke. Consistent with prior literature, the milder strokes arrived at the hospital with more delay from onset, were less likely to receive intravenous alteplase, and if they did receive intravenous alteplase, then door-to-needle times were slower, compared with patients with more severe stroke. Interestingly, the rate of treatment of the milder subgroup gradually rose over the course of the study from 2010 to 2018, likely consistent with the growing use of EVT more generally after 2015.

The report is limited by the nature of the registry. With such a large and distributed study, there are much missing data at both baseline and outcome time points. However, the study is important in demonstrating how far EVT therapy has penetrated in the clinically mild patient subgroup without supporting evidence. What is remarkable is that the rate of complications in the EVT group, even without accompanying thrombolysis, is not negligible. The rate of symptomatic intracerebral hemorrhage was 4%, and in-hospital mortality was 5%. Nearly 75% of patients were discharged home. At this high rate of favorable hospital discharge outcome, most physicians will not personally see enough cases in a year to appreciate that 4% symptomatic intracerebral hemorrhage and 5% mortality is very high for this patient group. In a population of patients where many do well, this complication rate may be high enough to obviate any benefit from EVT. This real-world evidence provides very important data that convincingly show that randomized trials are needed in this population.

Randomized trials are about to begin in this area. Endovascular studies are planned that will examine this population of patients using a novel stent retriever. The TEMPO-2 trial ( Unique identifier: NCT02398656) will continue and provide an assessment of how to manage both large vessel occlusion with minor stroke.

Many questions remain to be sorted out with minor stroke and arterial occlusion. In many places in the world, few minor stroke patients get urgent neurovascular imaging and are simply never identified as possible treatment candidates. The first step is to perform acute neurovascular imaging on all minor stroke patients in the Emergency Department; this is recommended in the Canadian guidelines.[8] What imaging paradigm might help us understand who is most at risk of deteriorating and, therefore, deserves aggressive therapy, including EVT? Are there patients that can be safely managed with antiplatelet therapy while the work-up for stroke mechanism is completed? When will medical treatment with alteplase or perhaps tenecteplase be enough, and when should EVT be used? It is likely, in our view, that EVT is being overused in the Florida-Puerto Rico region, but by how much we do not know. The treatment is well remunerated; there is boundless enthusiasm because it is relatively new, and there is a sense of urgency to act when confronted with these patients. We will need more information to be able to assess the appropriateness of aggressive therapy in this patient population. Where possible, randomize appropriate patients into ongoing trials.