Our study did not confirm our primary hypothesis that penumbral imaging would identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke within 8 hours after symptom onset. Moreover, among all enrolled patients regardless of penumbral-imaging pattern on study entry, no significant differences were noted in clinical and imaging outcomes for patients undergoing embolectomy, as compared with those receiving standard medical care.
These results raise important questions. There are several possible explanations for the neutral results independent of the validity of the imaging-selection hypothesis. One is the relatively low rate of substantial revascularization in the embolectomy group, which was perhaps associated with the use of first-generation embolectomy devices. In randomized trials, newer-generation stent retrievers have had higher revascularization rates and better clinical outcomes than has the Merci Retriever.7,8
It is possible that these newer-generation devices would show a treatment benefit (and a benefit in patients with a favorable penumbral pattern) because of both higher recanalization rates and lower complication rates.7,8
Other potential factors contributing to the neutral results include the extended time from imaging to embolectomy, the use of intravenous t-PA in some patients in the standard-care group, and heterogeneity of imaging approaches that were tested (both MRI and CT). Patients who were evaluated on CT tended to have larger predicted core volumes than those evaluated on MRI, which suggests that the two imaging approaches and predictive models may differ in some respects.
An alternative consideration is that the imaging-selection hypothesis is flawed as currently conceived. In our study, there was no difference in outcomes among patients with a favorable penumbral pattern who were treated with embolectomy, as compared with those treated with standard medical care.19
Moreover, data analysis with the use of a receiver-operating-characteristic curve did not show any threshold of predicted core volume that would have yielded a positive treatment effect in patients with a favorable penumbral pattern.
It is possible that patients with a favorable penumbral pattern, particularly in late time windows (i.e., ≥3 hours), may have a good functional outcome regardless of which recanalization treatment they undergo.20
In our study, patients with a favorable penumbral pattern had improved outcomes, smaller infarct volumes, and attenuated infarct growth, as compared with patients with a nonpenumbral pattern, regardless of treatment assignment. In early time windows (<3 hours), recanalization may be particularly beneficial in patients with large-vessel occlusions and poor collateral vessels. However, in later time windows, a favorable penumbral pattern may be a biomarker for a good outcome because of the presence of more vigorous collateral vessels and therefore greater tolerance of occlusion, increased likelihood of eventual spontaneous recanalization, and good final outcome.17,21
In patients with a favorable penumbral pattern without early recanalization, collateral flow may support penumbral tissue until spontaneous recanalization occurs.
Among patients with 7-day follow-up imaging, there were greater rates of good functional outcome as well as smaller infarct volumes in patients who had undergone reperfusion, recanalization, or both. Although the timing of follow-up imaging differed, these findings are similar to those of the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE 2) trial and previous studies showing that reperfusion was associated with a better clinical outcome.13,19
However, unlike patients in the DEFUSE 2 trial, patients in our trial who had a nonpenumbral pattern showed a benefit in clinical outcome from late (but not early) reperfusion, albeit less pronounced. It is notable that if we had not included the control group in our study, we would not have been able to show that the benefit from reperfusion was not an effect of acute embolectomy. Unlike the DEFUSE 2 investigators, among patients who underwent embolectomy, we did not see a differential benefit in patients with a favorable penumbral pattern, as compared with those with a nonpenumbral pattern. However, our study differed from the DEFUSE 2 trial in that our patients had a longer time until treatment and larger predicted infarct cores, and we used varying approaches to predicting penumbral patterns, including a larger threshold for the predicted ischemic-lesion volume in the group with a favorable penumbral pattern.
Our study was also designed to explore outcomes in patients who were treated with embolectomy, as compared with standard medical care, regardless of imaging pattern. The trial found no evidence of benefit from embolectomy on clinical outcome, possibly because of the overall low rates of recanalization. This finding is unlikely to be explained by increased rates of procedural complications, since there were no significant between-group differences in the rates of death and symptomatic hemorrhage.
There are several limitations to this study. The trial was completed over an 8-year period, during which time there were advances in techniques and clinical practices. Study enrollment was also completed before the introduction of the new stent retrievers.7,8
Baseline-imaging prediction maps came from a single time point, and therefore the neuroimaging pattern may have changed by the time of recanalization in patients undergoing embolectomy. In addition, the time to groin puncture was more than 6 hours after the onset of symptoms, which is longer than in many previous trials of endovascular surgery.5,7,8,10,22
In our study, we used automated image-analysis software, allowing for the onsite identification of penumbral-pattern status in real time, which allowed the patients to be stratified according to pattern. However, real-time analysis was only modestly successful. An additional limitation, inherent to all studies of acute stroke, is that follow-up imaging was not available for all patients.
There are several important aspects of our study that may help guide the design of future trials. Despite FDA clearance of embolectomy devices and the relative lack of equipoise in the stroke community regarding the putative benefits on clinical outcomes of embolectomy versus standard medical care, we were able to complete a randomized clinical trial of embolectomy versus standard medical care, showing that true controlled trials of embolectomy are achievable (though arduous) for acute ischemic stroke. Our study also showed the feasibility and importance of performing trials that directly test the full spectrum of the imaging-selection hypothesis by enrolling patients with both favorable penumbral patterns and nonpenumbral patterns, rather than excluding patients with nonpenumbral patterns a priori.
In conclusion, our study did not show a treatment benefit in patients with a favorable penumbral pattern or an overall benefit from mechanical embolectomy versus standard medical care. Further randomized clinical trials that use new-generation devices are needed to test both the imaging-selection hypothesis and the clinical efficacy of mechanical embolectomy for the treatment of acute ischemic stroke. Our findings do not support the efficacy of using CT or MRI to select patients for acute stroke treatment or the efficacy of mechanical embolectomy with first-generation devices.