PDF: TO-ACT
(2020)Objective
Endovascular treatment plus medical care versus medical treatment alone in patients with severe cerebral venous thrombosis.
Study Summary
Intervention
Endovascular treatment (mechanical thrombectomy and/or local thrombolysis with alteplase or urokinase) plus medical therapy vs. standard medical therapy alone. EVT initiated within 24 hours of randomization.
Inclusion Criteria
Adults with radiologically confirmed CVT and at least one poor prognostic factor (mental status disorder, coma, ICH, or deep venous system thrombosis), enrolled within 10 days of diagnosis.
Study Design
Arms: Endovascular + Medical Therapy vs. Medical Therapy Alone
Patients per Arm: EVT: 33, Medical Therapy: 34
Outcome
Bottom Line
The TO-ACT trial, while underpowered and prematurely terminated due to futility, found no significant improvement in functional outcome (mRS score of 0-1 at 12 months) in patients with severe CVT treated with EVT plus standard medical care compared to standard medical care alone. Mortality and symptomatic ICH rates were not statistically different between groups.
Major Points
- The trial was halted after the first interim analysis (55 patients completed 12-month follow-up) for reasons of futility (conditional power of 11%).
- 67 patients were enrolled and randomized (33 to EVT + standard care, 34 to standard care only).
- At 12 months, 67% (22/33) of EVT patients had an mRS score of 0-1 compared with 68% (23/34) of control patients (relative risk ratio, 0.99; 95% CI, 0.71-1.38).
- Mortality was not statistically significantly higher in the EVT group (12% [n=4] vs 3% [n=1]; P=.20).
- The frequency of symptomatic intracerebral hemorrhage was not statistically significantly lower in the intervention group (3% [n=1] vs 9% [n=3]; P=.61).
- Complete recanalization of the superior sagittal sinus was more frequent among patients who underwent EVT (79% [22/28]) than those who received standard care alone (52% [15/29]; relative risk ratio, 1.52; 95% CI, 1.02-2.27).
- Seizures after randomization occurred less often in patients randomized to undergo EVT (3% [n=1]) than those in the control group (30% [n=10]; P=.006).
Study Design
- Study Type
- Multicenter, open-label, blinded end point, randomized clinical trial (PROBE design)
- Randomization
- Yes
- Blinding
- Assessors of functional outcome (mRS score at 6 and 12 months) and radiologists scoring recanalization rate were blinded to treatment randomization.
- Sample Size
- 67
- Follow-up
- 12 months
- Centers
- 8
- Countries
- Netherlands, China, Portugal
Primary Outcome
Definition: Proportion of patients with a good outcome (recovered without a disability; modified Rankin Scale [mRS] score of 0-1) at 12 months.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 23 (68%) | 22 (67%) | 0.99 (0.71-1.38) | - |
Limitations & Criticisms
- The trial was prematurely terminated due to futility, resulting in a small sample size (67 patients) and being underpowered to detect a small difference between the two treatment groups (calculated sample size was 164 patients).
- Early recanalization rate immediately after EVT was not assessed, which would have been useful for identifying the technical success rate of EVT.
- A log of patients screened for eligibility but not included in the trial was not kept prospectively, though a retrospective screening log was established.
- Due to the small sample size and limited number of outcome events, the primary analysis could not be adjusted for prognostic variables.
- The open-label design could have influenced physician choices regarding medical management after the acute phase, although this was deemed unlikely given similar oral anticoagulation use.
- The high rate of good outcomes with medical management in the control group (68% at 12 months) made it difficult to show an additional benefit of EVT.
- The heterogeneity of the cerebral venous system and methods to identify appropriate target occlusions for EVT should be considered in future studies.
- The observation of perforations of the cerebral venous system, while rare in literature, occurred in 3 of 33 procedures in this study, highlighting a potential complication not always reported.
Citation
JAMA Neurol. 2020:77(8):966-973. doi:10.1001/jamaneurol.2020.1022