Shashank Shekhar, MD, MS

Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. New England Journal of Medicine. 2018

The last few months have been very exciting in the stroke world. DEFUSE 3, a multicentral, randomized, open-label clinical trial, showed the successful outcome after mechanical thrombectomy in ischemic stroke 6-16 hours and shared the same success of the DAWN trial, which supports mechanical thrombectomy 6-24h. Over 300 U.S. hospitals and 38 centers participated in the trial and were funded by NIH through StrokeNet. The trial compared medical therapy (MT) against endovascular therapy plus standard medical therapy (ET+MT). Patient were randomized in a 1:1 ratio to both treatment groups after matching for the baseline characteristics.

Inclusion criteria were initial ischemic volume <70 ml, ratio of the volume of ischemic/initial infarct volume > 1.8, the absolute penumbra of 15ml or more, the presence of occlusion of the cervical or intracranial internal carotid artery or proximal, middle cerebral artery confirmed on CT/MR angiography. Similar to DAWN, a CT perfusion or MRI perfusion or diffusion scan was calculated using the RAPID software. Any FDA-approved thrombectomy device was allowed for mechanical thrombectomy at the discretion of the neurointerventionalist. The protocol required groin puncture to occur within 90 minutes after qualifying image.

The primary outcome was modified ranking scale at the 90 days. The secondary outcome was functional independence defined as the score on the modified ranking scale of 0 to 2 and 90 days. The primary safety outcome was death at 90 days and the presence of symptomatic intracranial hemorrhage within 36 hours, defined as an increase of at least 4 points on the NIHSS. Imaging outcome was infarct volume measured at 24 hours. For statistical analysis, the study used adaptive enrichment design.

The primary efficacy outcome showed significantly better efficacy with ET+MT than MT (OR 2.77 and 95% CI 1.6-4.7, P <0.001), and the secondary outcome of functional independence was significantly better in the ET+MT vs. MT group (OR 2.67, 95% CI 1.6-4.48, P <0.001). The below figure compares the disability scores for the DEFUSE 3 and DAWN trials. Mortality was significantly less in the ET+MT group vs. MT (14% vs. 26%, p=0.05), while the rate of symptomatic intracranial hemorrhage was similar. Parenchymal hematoma type 2 (PH-2) occurred more in the ET+MT vs. MT group (9% vs. 3%, P=0.21), thus resulted in higher mortality in this subgroup (5 vs. 2) respectively. Regarding imaging outcome, median infarct volume and growth were non-significant between groups. However, as expected, treatment arm had significantly higher reperfusion, complete recanalization, and higher TICI scores. In the subgroup analysis considering less power to the pool, showed no significant difference between the known time of onset vs. unknown time of onset except those <9 hours of onset.

Composite disability scores from the DEFUSE 3 and DAWN trials on the modified rankin scale at 90 days.

Figure: Composite disability scores from the DEFUSE 3 and DAWN trials on the modified rankin scale at 90 days. Blocks within dashed line are more disabled. Data derived from the DEFUSE 3 trial (reference above) and the DAWN trial (Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. New England Journal of Medicine. 2018).

DEFUSE 3, in line with the DAWN trial, suggests mechanical thrombectomy with standard medical therapy is recommended when performed between 6-16 hours and could result in significant outcome in terms of functional recovery and disability at three months. The new 2018 AHA/ASA guidelines for acute ischemic stroke now reflect it as Class 1 A evidence.

First, let’s highlight key differences between the DAWN and DEFUSE 3 trials and their implications. In DAWN, patients were selected based on a mismatch between clinical deficit and infarct volume, a somewhat tedious and unconventional approach for the recruitment, considering not all centers are currently trained to do so. Moreover, the primary outcome in DAWN measured utility based modified ranking scale, again not a widely used tool in day-to-day stroke management. The DEFUSE 3 trial did not have any such requirements. DAWN utilized the Trevo device (Stryker Neurovascular), whereas DEFUSE 3 allowed all types of FDA-approved devices, which is good news for the patients and equally to physicians since both having multiple devices to choose from and still maintaining a lower price with good competition amongst manufacturers.

That said, both of these trials are going to increase the number of stoke activations and admissions in coming months and year. Around 1/3 of all stroke admissions have the unknown onset of stroke and amongst them wake up strokes account for almost 15-25 % patients. Most of the endovascular equipped primary centers and some comprehensive stroke centers are not yet prepared for the patients’ influx. There will be an urgent need for more acute rehab facilities to accommodate the efflux of patients from the hospitals and help to maintain flow. Also, the hospital would require increasing the number of stroke/ICU beds and maintaining a higher ratio of the physicians, residents to patients ratio to prevent the burnouts since they will be required 24/7. Increasing the reimbursement for the stroke/endovascular physicians would keep the next generation of physicians greatly interested in choosing the elite career of vascular neurology and eventually making the world a better place!