Ultrasound-Enhanced Thrombolysis No Help in Stroke: CLOTBUST-ER

Using ultrasound to boost the effectiveness of IV thrombolysis—an approach called sonothrombolysis—is feasible but does not improve functional outcomes in patients with acute ischemic stroke, results of the prematurely halted CLOTBUST-ER trial show.

At 90 days, the likelihood of having an improved modified Rankin Scale (mRS) score was not greater in patients who had ultrasound applied versus those who received IV thrombolysis alone (adjusted common OR 1.05; 95% CI 0.77-1.45), researchers led by Andrei Alexandrov, MD (University of Tennessee Health Science Center, Memphis), report in the April 2019 issue of the Lancet Neurology.

But, Alexandrov told TCTMD, there’s still room for an approach like sonothrombolysis in the treatment of acute stroke even at a time when the dominant position of mechanical thrombectomy makes it difficult to test other strategies for improving early reperfusion.

“Using a noninvasive way of trying to amplify tPA remains an important goal in the overall development of effective systems of stroke care,” he said, noting that most patients with acute ischemic stroke do not go directly to comprehensive stroke centers equipped to deliver mechanical thrombectomy. Thus, he said, there remains a need to both administer IV thrombolytics as early as possible and to augment their effectiveness, particularly in patients who need to be transferred to a comprehensive center in a “drip-and-ship” scenario.

If proven effective in future trials, sonothrombolysis could fill that role, Alexandrov said. “Sonothrombolysis is an adjunct to amplify tPA, particularly among those unfortunate patients that can only come to the closest emergency room because they live in a rural area or because of traffic congestion or whatever reasons,” he said. These patients would have to be transferred for mechanical thrombectomy, he added, “and then if the delay for thrombectomy is over 100 minutes, it can negate the beneficial effect, so these are the patients in whom sonothrombolysis to break up the large proximal occlusion systemically and noninvasively would be the only option to reverse their stroke effectively.”

Commenting for TCTMD, Jürgen Eggers, MD, PhD (Sana Hospital Lübeck, Germany), said bridging patients being transferred between centers is one potential area sonothrombolysis could be helpful. Another is in parts of the world where access to mechanical thrombectomy is limited.

Though CLOTBUST-ER did not demonstrate a benefit for this approach, he added, it is worth pursuing in additional trials because of limitations of the current one. The major problem—one also acknowledged by the researchers—was that brain imaging was not used for inclusion, which means that there was no confirmation of large-vessel occlusions or clot location.

Other issues, Eggers said, included the lack of an assessment of adequate bone windows—areas that allow for sufficient penetration of ultrasound—and the possibility that the ultrasound probes were not optimal for this use.

Together, all of that means that CLOTBUST-ER “was false-negative probably,” he said.

Potential Safety Concerns

Prior research had suggested that ultrasound might be able to safely enhance the effectiveness of IV thrombolysis and improve the chances of early revascularization, which in turn might have a beneficial impact on functional outcomes. One obstacle to that approach, however, was that application of ultrasound was dependent on the operator, the authors say.

The phase III CLOTBUST-ER trial evaluated use of an operator-independent, head-mounted device (Cerevast Therapeutics) that delivers low-power, high-frequency ultrasound to the intracranial vessels. At 76 centers in 14 countries, investigators enrolled patients with acute ischemic stroke and a National Institutes of Health Stroke Scale score of at least 10 who received IV thrombolysis within either 3 hours of symptom onset (in North America) or 4.5 hours (in other parts of the world). Patients were randomized to receive active 2 MHz pulsed-wave ultrasound or sham ultrasound for 2 hours.

The trial was stopped early for futility after the second interim analysis, at which point 676 patients had been enrolled; the final results confirm that sonothrombolysis did not lead to greater functional improvements in the first 90 days over the sham procedure. Results were consistent across various subgroups defined by age, sex, baseline stroke severity, and time from stroke onset to thrombolysis.

None of the secondary outcomes differed between groups.

The procedure appeared to be safe, with similar rates of mortality (16% with sonothrombolysis vs 13% with sham; P = 0.48) and serious adverse events (26% vs 24%; P = 0.69) in the two arms.

Alexandrov et al point to numerically higher numbers of cerebral edema, brain herniation, and asymptomatic intracranial hemorrhage in the sonothrombolysis-treated patients as a potential safety concern, however.

“These adverse events were recorded based on radiology reports by local investigators, without undergoing central adjudication,” they note, adding that the between-group differences were not significant after adjustment for confounders. “Nevertheless, the potential relation between 2 MHz sonothrombolysis and cerebral edema deserves further investigation in future randomized controlled trials with central adjudication of brain herniation.”

Eggers said, “I think there is no safety concern.”

Not Dead Yet

And additional trials are warranted, Alexandrov and colleagues indicate, because there were issues with CLOTBUST-ER that could have affected the result. For one, vascular imaging was not mandated as an inclusion criterion, and it is possible that some patients did not have a proximal occlusion within area targeted by the ultrasound device, they say. In addition, the operator-independent device may have resulted in less direct thrombus exposure to ultrasound compared with handheld devices used in prior studies.

The authors note, too, that there was a high proportion of patients (9%) for whom information on 90-day functional outcomes were not available and that it is possible some centers were less likely to enroll patients with large-vessel occlusions into the trial, instead sending them for endovascular treatments.

“In view of the positive results of recent thrombectomy trials (highlighting CT angiography as part of standard-of-care treatment), we have redesigned the operator-independent ultrasound device to target CT angiography-located large-vessel occlusions with only one set of transducers that will be placed either over the right or left temporal window or suboccipitally dependent on occlusion location seen on CT angiography. The redesigned device will also use novel coupling gel pads to achieve improved headframe fixation during insonation,” they explain, noting that the new device will be evaluated in the TRUST trial, which is set to begin this summer.

In an accompanying editorial, Maxime Gauberti, PhD (Université de Caen Normandie, Caen, France), says the CLOTBUST-ER trial is probably not the end of the line for sonothrombolysis in acute stroke, citing some of the same issues with the trial highlighted by the investigators.

“Future trials of sonothrombolysis will have to consider the new landscape of acute ischemic stroke diagnosis and treatment,” he says. “Patients’ selection should rely on emergent imaging to identify individuals with large-vessel occlusion. Moreover, the largest benefit of ultrasound-induced reperfusion is expected for patients who need to be transferred from primary care to a thrombectomy-capable comprehensive stroke center, in which delays between imaging and reperfusion are extensive.”

Gauberti notes that TRUST is enrolling patients with large-vessel occlusions who are being transferred to a stroke center, uses an optimized device, and has a primary endpoint of recanalization before thrombectomy.

“As supported by the results of a similarly designed trial of tenecteplase versus alteplase, achieving a higher incidence of reperfusion before thrombectomy can translate into better functional outcome,” Gauberti writes. “In addition to new thrombolytic, antiplatelet, or anticoagulant agents, sonothrombolysis remains a promising method to achieve this goal.”

To TCTMD, Alexandrov said he’s concerned that the success of mechanical thrombectomy will lead to a decline in use of IV thrombolytics. “I’m hoping that a successful sonothrombolysis trial will boost the confidence in tPA, and in the future if and when we’re going to be using tenecteplase (TNK), we can repeat the same study with TNK and show that we can perhaps bust even more clots in the drip-and-ship scenario using sonothrombolysis.”