CLOTBUST-ER
Combined Lysis of Thrombus With Ultrasound and Systemic tPA for Emergent Revascularization in Acute Ischemic Stroke–Enhanced Regimen
Clinical Question
Does adding 2 hours of transcranial ultrasound to IV tPA improve functional outcomes in acute ischemic stroke compared to tPA alone?
Bottom Line
In this prematurely terminated trial, ultrasound plus tPA did not significantly improve 90-day functional independence versus tPA alone, but was safe without increasing sICH.
Major Points
- Planned 830 patient enrollment; stopped after 126 due to slow recruitment
- Randomized 1:1 to tPA + ultrasound vs tPA + sham
- Primary endpoint: mRS 0–1 at 90 days (33% vs 29%, OR 1.14, p=0.70)
- Symptomatic ICH: 3% in each arm
- Mortality: 8% (ultrasound) vs 10% (sham)
- NIHSS median 16; median onset-to-tPA time ~150 minutes
Design
Study Type: Multicenter, randomized, blinded-endpoint, sham-controlled trial
Randomization: 1
Blinding: Outcome assessors blinded; patients and treating teams not blinded to ultrasound
Enrollment Period: 2013–2015
Follow-up Duration: 90 days
Centers: 10
Countries: USA, Europe
Sample Size: 126
Analysis: Intention-to-treat; logistic regression adjusted for baseline NIHSS and age
Inclusion Criteria
- Age ≥18 years
- Acute ischemic stroke within 3 hours of onset
- NIHSS ≥10
- Eligible for standard IV tPA
Exclusion Criteria
- Contraindications to tPA
- Large established infarct on imaging
- Inability to insonate temporal bone window
- Prior intracranial hemorrhage
Arms
| Field | tPA + Ultrasound | Control |
|---|---|---|
| Intervention | Standard IV alteplase plus 2-hour continuous 2-MHz transcranial Doppler insonation of occluded artery | Standard IV alteplase plus sham insonation |
| Duration | Single acute treatment | Single acute treatment |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| mRS 0–1 at 90 days | Primary | 29% | 33% | 0.70 | |
| Symptomatic ICH | Secondary | 3% | 3% | 1.00 | |
| Mortality | Secondary | 10% | 8% | 0.75 | |
| Symptomatic ICH | Adverse | 3% | 3% | ||
| Any ICH | Adverse | 8% | 10% |
Subgroup Analysis
No significant treatment interaction by occlusion site, baseline NIHSS, or time to treatment
Criticisms
- Terminated early with only 15% of planned enrollment, underpowered
- No blinding of treating clinicians
- High rate of technical exclusions due to poor bone window
- Findings not generalizable to patients without adequate insonation window
Funding
National Institute of Neurological Disorders and Stroke
Based on: CLOTBUST-ER (Stroke, 2019)
Authors: Andrei V. Alexandrov, Georgios Tsivgoulis, Haralampos Milionis, et al.
Citation: Stroke. 2019;50:351-354. doi:10.1161/STROKEAHA.118.023687
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