Transcranial Ultrasound Used As an Adjunct to tPA Fails To Improve Functionality in Ischemic Stroke Patients Sonothrombolysis with ultrasound delivered transcranially via a headframe shows no clinical benefit in ischemic stroke

A randomized, mutilcenter, placebo-controlled, phase 3 clinical trial which enrolled 676 patients (aged 18-80 years) presenting to the ER with acute ischemic stroke assessed  the efficacy and safety of transcranial ultrasound (US) as an adjunctive therapy to intravenous tissue plasminogen activator (IV-tPA, administered over 60 minutes) treatment (CLOTBUST-ER trial). The results from the trial, which was stopped due to futility show that although the use of sonothrombolysis was feasible and most likely safe, no clinical benefit was seen at 90 days. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score (mRSC) at 90 days in the intervention group was 1.05 (95% CI 0.77–1.45; p=0.74). Andrei Alexandrov, MD (University of Tennessee Health Science Center, Memphis), and colleagues reported in the April 2019 issue of the Lancet Neurology.

The current standard of care of patients presenting within 3 hours of ischemic stroke is intravenous administration of recombinant tissue plasminogen activator (rtPA, alteplase), to allow clot lysis and restore blood flow to the ischemic area of the brain. It has been shown by prior randomized clinical trials that ultrasound aimed at the residual flow and thrombus interface can at least double the chance of early recanalization when compared with IV tPA alone. Based on this background, the investigators of the CLOTBUST-ER trial tested the use of an operator-independent novel device that delivers low-power high-frequency (2 MHz pulsed-wave) ultrasound waves transcranially via an external headframe for 120 minutes. Investigators obtained NIH Stroke Scale (NIHSS) scores (0 being normal functioning and 4 being completely impaired) before treatment, 2 h and 24 h after treatment, on either day 7 or at discharge from an acute facility to home (if the patient was discharged before day 7), and at day 90. Modified Rankin Scale scores (lowest score 0= The patient has no residual symptoms and highest score 7= Unable to contact patient/caregiver) were recorded on either day 7 or at discharge and at day 90. The primary efficacy outcome was a functional improvement (defined as a 1-point decrease across all scale scores [shift analysis]) in modified Rankin Scale score at 3 months (range of days 80–100). The primary safety endpoint was the proportion of subjects in the Target vs Control group experiencing symptomatic intracranial hemorrhage (sICH) within 24 hours of treatment (defined as a reduction in NIHSS score of 4 points or more compared with best previous examination) and assessment of overall adverse events. Patients in the intervention and control groups enrolled within 3 h of symptom onset did not differ in terms of modified Rankin Scale scores at 90 days (adjusted cOR 1·05, 95% CI=0·77–1·45; p=0·74). The difference remained non-significant after adjusting for age, NIHSS score at baseline, time from stroke onset to alteplase bolus, and baseline serum glucose, across the different pre-specified subgroups. In terms of safety, symptomatic intracranial bleeding rates did not differ between the intervention and control groups at 24 h (eight [3%] of 317 patients vs six [2%] of 329 patients; unadjusted OR 1·39, 95% CI 0·48–5·06; p=0·60) or at 36 h (nine [3%] of 317 patients vs seven [2%] of 329 patients; 1·34, 0·49–3·65; p=0·62), implying that the device was safe. However, the rate of asymptomatic intracranial hemorrhage at 24h was found to be significantly increased in the intervention group compared to the control group (34 [11%] of 317 patients vs 20 [6%] of 329 patients; unadjusted OR 1·86, 95% CI 1·04–3·30; p=0·046). The only adverse event that differed between intervention and control groups was atrial fibrillation (28 [9%] of 317 patients vs 14 [4%] of 329 patients; unadjusted OR 2·18, 95% CI 1·12–4·22; p=0·025) but the difference was found to non-significant after excluding patients with baseline atrial fibrillation.

The investigators discussed that the failure in functional improvement at 90 days compared to prior studies was due to lack of adequate targeted ultrasound delivery in the treatment group because of unavailability of imaging documentation of the site of thrombus; whereas prior trials employed the use of imaging documentation of proximal intracranial occlusions and sonographic waves targeted to those sites, the COLTBUST-ER relied on stroke severity as a surrogate marker of large vessel occlusion. This may have led to less direct thrombus exposure to ultrasound.

 

In terms of limitations, the CLOTBUST-ER trial had non-significant difference in time from symptom onset to treatment in favor of the intervention group (117 min vs 126 min in the control group) and the delivery of sonothrombolysis relied on the investigator’s ability to properly mount the device and gel pads without any further onsite validation being done. A phase 3, randomized, placebo-controlled, double-blind study of the Aureva Transcranial Ultrasound Device With Tissue Plasminogen Activator in Patients With Acute Ischemic Stroke (TRUST) is the successor randomized clinical trial for the CLOTBUST-ER, which will enroll 596 patients and test the use an optimized sonothrombolysis device design for a more adequate ultrasound delivery to the clot to improve clinical outcomes.