Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial.

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; P>0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.

The effect of acute medication with cilostazol, an anti-platelet drug, on the outcome of small vessel brain infarction.

Our objective was to investigate the effect of cilostazol in acute therapy for small vessel stroke patients. The neurologic deficits in some patients of small vessel brain infarction will progress even if a patient takes immediate medical treatments including aspirin or other antiplatelet drugs. In Japan, cilostazol, presenting not only the antiplatelet effect but also the arteriole dilation, is used for treatment of ischemic stroke. In this study, acute stroke patients with small vessel occlusion were treated with cilostazol instead of aspirin in the conventional medication after 2010. Therefore, patients between April 2007 and March 2009 were classified into the conventional group (group-con, n=220), and patients between April 2010 and March 2012 were classified into the cilostazol group (group-cilo, n=230). Enrolled patients were classified into lacunar infarction (LI) and branch atheromatous disease. Progressing stroke was defined as the increase of National Institutes of Health Stroke Scale score of 2 or more within 48 hours. The clinical outcome was assessed by the modified Rankin Scale (mRS) score at 1 month. As the result, the significant reduction in progressing stroke was dominant in the LI of brainstem (P=.01). The length of hospital stay was significantly shorter in the group-cilo compared with the group-con (18.6 and 21.2 days, P=.03). Moreover, mRS score at 1 month was significantly lower in the group-cilo than the group-con (1.9 and 2.3, P=.03). In conclusion, cilostazol reduced the risk of early neurologic deterioration of patients with small vessel brain infarction. It is eagerly desired to conduct a large randomized control trial.

Cerebral microbleeds development after stroke thrombolysis: A secondary analysis of the THAWS randomized clinical trial.

BACKGROUND AND AIM: We determined to investigate the incidence and clinical impact of new cerebral microbleeds after intravenous thrombolysis in patients with acute stroke. METHODS: The THAWS was a multicenter, randomized trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with wake-up stroke or unknown onset stroke. Prescheduled T2*-weighted imaging assessed cerebral microbleeds at three time points: baseline, 22-36 h, and 7-14 days. Outcomes included new cerebral microbleeds development, modified Rankin Scale (mRS) ≥3 at 90 days, and change in the National Institutes of Health Stroke Scale (NIHSS) score from 24 h to 7 days. RESULTS: Of all 131 patients randomized in the THAWS trial, 113 patients (mean 74.3 ± 12.6 years, 50 female, 62 allocated to intravenous thrombolysis) were available for analysis. Overall, 46 (41%) had baseline cerebral microbleeds (15 strictly lobar cerebral microbleeds, 14 mixed cerebral microbleeds, and 17 deep cerebral microbleeds). New cerebral microbleeds only emerged in the intravenous thrombolysis group (seven patients, 11%) within a median of 28.3 h, and did not additionally increase within a median of 7.35 days. In adjusted models, number of cerebral microbleeds (relative risk (RR) 1.30, 95% confidence interval (CI): 1.17-1.44), mixed distribution (RR 19.2, 95% CI: 3.94-93.7), and cerebral microbleeds burden ≥5 (RR 44.9, 95% CI: 5.78-349.8) were associated with new cerebral microbleeds. New cerebral microbleeds were associated with an increase in NIHSS score (p = 0.023). Treatment with alteplase in patients with baseline ≥5 cerebral microbleeds resulted in a numerical shift toward worse outcomes on ordinal mRS (median [IQR]; 4 [3-4] vs. 0 [0-3]), compared with those with <5 cerebral microbleeds (common odds ratio 17.1, 95% CI: 0.76-382.8). The association of baseline ≥5 cerebral microbleeds with ordinal mRS score differed according to the treatment group (p interaction = 0.042). CONCLUSION: New cerebral microbleeds developed within 36 h in 11% of the patients after intravenous thrombolysis, and they were significantly associated with mixed-distribution and ≥5 cerebral microbleeds. New cerebral microbleeds development might impede neurological improvement. Furthermore, cerebral microbleeds burden might affect the effect of alteplase.