By Aimee Aysenne, MD, MPH, and Kyle Hobbs, MD
Recently, two landmark studies supporting an extended time window for the treatment of large vessel occlusion (LVO) have been published. DAWN, published in November, investigated thrombectomy between six and 24 hours from last known well time (LKW) and used clinical severity to imaging mismatch for the selection of patients. In January, DEFUSE3 was published and found benefit of thrombectomy for patients in the six to 16 hour window using infarcted core to ischemic penumbra mismatch on imaging alone. Both trials used RAPID software for automated volumetric calculations. These studies led to a change in the American Heart Association 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke.
DAWN NEJM Nov 2017
Summary: DAWN is a multinational, prospective, randomized, open-label trial with a Bayesian adaptive-enrichment design for the use of mechanical thrombectomy with TREVO device in patients with LVO between six and 24 hours of last well-known (LWK) time. Patients who were > 18 years with occlusion of intracranial ICA, the proximal MCA or both on CTA or MRA, +/- IV tPA, baseline mRS 0-1, no infarct > 1/3 of MCA on baseline imaging and a target mismatch were randomized to thrombectomy plus standard medical care or standard medical care alone. Patients were classified into three groups based on mismatch criteria: Group A: ³ 80 years, NIHSS ³ 10, infarct < 21 ml; Group B: < 80 years, NIHSS ³ 10, infarct < 31 ml; Group C: < 80 years, NIHSS ³ 20, infarct 31- <51 ml. Baseline infarct volume was assessed with DWI or CT perfusion (rCBF < 30 percent indicating core) using automated RAPID software. Randomization was 1:1, with block minimization and stratification based on mismatch group, time from LWK (6-12 or > 12-24 hours) and site of occlusion. Rescue interventions and stenting were not allowed, but carotid angioplasty was.
Two-hundred six patients (107 in thrombectomy) with median NIHSS 17 were enrolled. Median infarct was 7.6 ml in thrombectomy group versus 8.9 ml in control and randomization from LWK was 12.2 hours versus 13.3 hours in control. Thrombectomy was done in 105/107 (3/105 had alternate rescue therapies). Eighty-four percent had immediate reperfusion, with median time from LWK to reperfusion of 13.6 hours. At 24 hours, recanalization was 77 percent in thrombectomy versus 36 percent in control. The mean score for disability on utility-weighted mRS (uwMRS weights between zero, death to 10, no symptoms) was 5.5 in thrombectomy compared to 3.4 in control. Similarly, for the traditional mRS, 49 percent versus 13 percent achieved mRS 0-2 at 90 days. No evidence of heterogeneity was present for any of the pre-specified subgroups. Neurologic deterioration was lower in thrombectomy (14 percent versus 26 percent, p=0.04).
Comments: Patients with acute ischemic stroke between six to 24 hours from LKW time due to an intracranial ICA or M1 occlusion, who had clinical-imaging mismatch had significantly better outcomes for disability and functional independence at 90 days with thrombectomy using TREVO when compared to standard medical care alone. The rate of functional independence (mRS 0-2) was similar to pooled outcomes from prior endovascular trials < 6 hours. Number needed to treat for benefit was 2.8 thrombectomy patients. The number needed to save one life with return to normal function was 4.9. Earlier treatment (6-12 hours) did have better outcomes (54 percent versus 44 percent), but this was not statistically significant.
DEFUSE3 NEJM Jan 2018
Summary: DEFUSE3 is a multicenter, prospective, randomized, open-label trial for the use of mechanical thrombectomy in patients with LVO between six and 16 hours of LKW time. Patients who were > 18 years old with occlusion of the ICA or proximal MCA on CTA or MRA and a core infarct volume of less than 70 ml with a ratio of ischemic tissue to initial infarct core volume of 1.8 or more with a potentially reversible penumbra of at least 15 ml. Candidates were randomized 1:1 to mechanical thrombectomy plus medical management or medical management alone. Any FDA approved thrombectomy device was allowed as well as carotid angioplasty and stenting. Femoral puncture must occur within 90 minutes of qualifying imaging. Intraarterial tPA was not allowed. All medical care was based on the American Heart Association guidelines, including administration of IV tPA in 10 (11 percent) of patients in the endovascular group and 8 (9 percent) of the medical group.
The trial was stopped after early analysis, requested by the sponsor (NIH) after the publication of DAWN. A total of 182 patients were randomized (92 endovascular plus medical treatment and 90 medical treatment alone). The groups were similar in baseline demographics. Patients who underwent endovascular thrombectomy had better mRS at 90 days than the medically treated group (unadjusted common OR, 2.77). After adjustment for stratification factors, the odds ratio was 3.36. For 90 day dichotomized functional outcome (mRS= 0-2 vs 3-6), 45 percent of the endovascular group compared to 17 percent in the medical group had good outcomes (RR, 2.67). Mortality at 90 days was 14 percent in the endovascular group and 26 percent in the medical group (p=0.05). The rate of symptomatic hemorrhage was the same in the two groups. Serious adverse reactions were reported in 43 percent of the endovascular group and 53 percent of the medically treated group.
The median time from LKW time to endovascular therapy was 10 hours and 29 minutes. The median time from randomization to groin puncture was 28 minutes. Final angiography showed TICI 0 in 10 (11 percent) of patients, TICI 2a 12 (13 percent), TICI 2b 52 (57 percent), and TICI 3 17 (19 percent) of patients. The median growth of infarct size between baseline and 24 hour imaging was 23 ml in the endovascular group and 33 ml in the medically treated group (p=0.08), reperfusion of penumbra was more common in the endovascular group (79 percent versus 18 percent, p<0.001), and recanalization of the vessel was more common in the endovascular group (78 percent versus 18 percent, p<0.001). Subgroup analyses were underpowered for statistical significant analysis.
Comments: DEFUSE3 has demonstrated significant improvement in functional outcome with mechanical thrombectomy within the six to 16 hour extended window with use of automated volumetric software for patient selection. The number needed to treat to prevent disability is two. Patients in this trial did better clinically than those in trials for thrombectomy within six hours. This is likely because patients with mismatch have favorable collateral flow and slower progression of stroke. #NEWSReview #LiteratureWatch #AimeeAysenne #KyleHobbs