THRACE
Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial
Clinical Question
In acute ischaemic stroke with proximal anterior-circulation large-vessel occlusion, does IV alteplase plus mechanical thrombectomy (bridging therapy) improve 90-day functional independence versus IV alteplase alone?
Bottom Line
Adding mechanical thrombectomy (mostly with stent retrievers) to IV alteplase within 5 h of onset in patients aged 18-80 with NIHSS 10-25 and proximal anterior-circulation occlusion increased 90-day functional independence (mRS 0-2) from 42% to 53% (OR 1.55, 95% CI 1.05-2.30; p=0.028; NNT=9), without increasing mortality (12% vs 13%) or symptomatic ICH (2% vs 2%). The trial supports bridging therapy as standard of care for anterior-circulation LVO across age, sex, severity, and occlusion site.
Major Points
- Randomised, open-label, multicentre, blinded-endpoint-imaging trial in 26 French centres; 414 patients enrolled Jun 2010-Feb 2015; stopped early after second interim analysis showed superiority.
- Population: age 18-80, NIHSS 10-25, intracranial ICA/M1 (or superior third basilar) occlusion on CT/MR angiography; IVT within 4 h and thrombectomy within 5 h of onset; no imaging-based penumbral or ASPECTS selection.
- Median time from IVT to randomisation was only 18 min (IQR 6-32), so fast responders to alteplase were not preferentially excluded; 29% of IVTMT-assigned patients did not ultimately undergo thrombectomy (35 for clinical improvement, 18 for early recanalisation, 6 for exclusion violations).
- Primary: mRS 0-2 at 3 months 106/200 (53%) IVTMT vs 85/202 (42%) IVT; OR 1.55, 95% CI 1.05-2.30; p=0.028; NNT=9. Ordinal mRS shift OR 1.39, 95% CI 0.99-1.97; p=0.05.
- Secondary benefits: lower NIHSS at 24 h (9 vs 12; p=0.04), at day 7 (4 vs 8; p=0.001), at 3 months (2 vs 4; p=0.01); more Barthel 95-100 at 3 months (61% vs 49%; OR 1.59, 1.02-2.49; p=0.04). EQ-5D similar (p=0.38).
- Safety: 3-month mortality 12% vs 13% (p=0.70); symptomatic ICH at 24 h 2% vs 2% (p=0.71); parenchymal haematoma type 2 7% vs 4%.
- Procedural outcomes in IVTMT arm: mTICI 2b-3 reperfusion 69% (95/138); stent retriever first-line in 83%, aspiration in 16%; complications were vasospasm 23%, new-territory embolisation 6%, dissection 3%, arterial perforation 1%, groin haematoma 2%.
- Prespecified subgroup analyses showed no significant effect modification by age, sex, NIHSS, ASPECTS, occlusion site (ICA vs M1), diabetes, hypertension, hypercholesterolaemia, or time to randomisation.
- Per-protocol analysis was underpowered (only 336 patients) and did not reach significance (OR 1.33, 95% CI 0.86-2.06; p=0.198), reflecting the large proportion of IVTMT-assigned patients who improved before angiography.
- Trial featured a longer randomisation-to-groin-puncture time (~82 min) than 2015 US/EU trials, which may explain the somewhat smaller absolute benefit (11%) than MR CLEAN/ESCAPE/SWIFT-PRIME.
Design
Study Type: Randomised, open-label, multicentre, blinded-endpoint-imaging phase 3 trial (PROBE-like)
Randomization: 1
Blinding: Open-label to patients, investigators, and clinical outcome assessors (vascular neurologists) — not feasible to blind. Imaging (CT/MRI and pre/post angiography) reviewed by independent masked committees.
Enrollment Period: Jun 1, 2010 - Feb 22, 2015 (stopped early Mar 3, 2015 after second interim analysis showed superiority)
Follow-up Duration: 3 months primary; safety at 24 h and 3 months
Centers: 26
Countries: France
Sample Size: 414
Power Calculation: Assumed 15% absolute increase in mRS 0-2 (40% vs 25%), power 90%, alpha 0.05, two-sided → 220 patients/arm; with 10% loss to follow-up, target N=240/arm (480 total). Planned interim analysis at 220 patients using O'Brien-Fleming; second unplanned interim at 385 patients after MR CLEAN results, using adjusted alpha.
Analysis: Unadjusted logistic regression for primary outcome in modified ITT (excluding lost-to-follow-up and missing-data patients); ordinal logistic regression for mRS shift; Poisson regression with robust SE for RR; per-protocol used for safety; SAS 9.3.
Inclusion Criteria
- Age 18-80 years
- Acute ischaemic stroke with NIHSS 10-25
- Occlusion of intracranial internal carotid artery, M1 segment of middle cerebral artery, or superior third of basilar artery, confirmed by CT or MR angiography
- IV thrombolysis able to be started within 4 h of symptom onset (originally 3 h; extended to 4 h after enrolment of 80 patients)
- Mechanical thrombectomy able to be initiated within 5 h of symptom onset
- Written informed consent from patient or legal representative
Exclusion Criteria
- Cervical internal carotid artery occlusion
- Subocclusive cervical carotid stenosis
- History of prior surgery precluding femoral catheterisation
- Standard IV alteplase contraindications (per label)
- (Full inclusion/exclusion list in the trial appendix)
Arms
| Field | IVT + mechanical thrombectomy (IVTMT) | Control |
|---|---|---|
| Intervention | IV alteplase 0.9 mg/kg (max 90 mg; 10% bolus then 60-min infusion) within 4 h + mechanical thrombectomy within 5 h of onset, using stent retriever (83% first-line) or aspiration (16%); complementary IA alteplase up to 0.3 mg/kg allowed for persistent distal occlusion | IV alteplase 0.9 mg/kg (max 90 mg; 10% bolus then 60-min infusion) within 4 h of onset (standard care) |
| N | 204 | 208 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Proportion of patients with modified Rankin scale score 0-2 (functional independence) at 3 months, modified ITT | Primary | 85/202 (42%) | 106/200 (53%) | 1.55 | 0.028 |
| NIHSS at 24 h, median (IQR) | Secondary | 12 (6-19) | 9 (4-18) | 0.04 | |
| NIHSS at discharge/day 7, median (IQR) | Secondary | 8 (2-16) | 4 (1-14) | 0.001 | |
| NIHSS at 3 months, median (IQR) | Secondary | 4 (0-10) | 2 (0-8) | 0.01 | |
| Barthel index at 3 months, mean (SD) | Secondary | 73.0 (32.2) | 80.4 (30.5) | not reported | |
| Barthel index 95-100 at 3 months | Secondary | 79/161 (49%) | 92/152 (61%) | 1.59 | 0.04 |
| EQ-5D at 3 months, median (IQR) | Secondary | 0.616 (0.3-0.8) | 0.642 (0.3-0.8) | 0.38 | |
| mRS at 3 months as ordinal shift (7-category) | Secondary | - | - | 1.39 | 0.05 |
| mTICI 2b-3 reperfusion (IVTMT only) | Secondary | NA | 95/138 (69%) | - | |
| Mortality at 3 months | Safety | 27/206 (13%) | 24/202 (12%) | 0.81 | 0.70 |
| Symptomatic intracranial haemorrhage at 24 h (NIHSS worsening ≥4) | Safety | 3/192 (2%) | 4/185 (2%) | 1.39 | 0.71 |
| Haemorrhagic infarction type 1 at 24 h | Safety | 24/201 (12%) | 21/195 (10%) | 0.53 (composite) | |
| Haemorrhagic infarction type 2 at 24 h | Safety | 23/201 (11%) | 27/195 (13%) | ||
| Parenchymal haematoma type 1 at 24 h | Safety | 11/201 (5%) | 13/195 (6%) | ||
| Parenchymal haematoma type 2 at 24 h | Safety | 8/201 (4%) | 14/195 (7%) | ||
| Subarachnoid haemorrhage at 24 h | Safety | 2/201 (1%) | 8/195 (4%) | ||
| Intraventricular haemorrhage at 24 h | Safety | 5/201 (2%) | 8/195 (4%) | ||
| Vasospasm (thrombectomy-related) | Safety | NA | 33/145 (23%) | ||
| Embolisation in new territory | Safety | NA | 9/141 (6%) | ||
| Dissection (procedural) | Safety | NA | 5/145 (3%) | ||
| Arterial perforation (procedural) | Safety | NA | 1/145 (1%) | ||
| Groin haematoma | Safety | NA | 3/145 (2%) | ||
| Renal failure | Safety | 13 (6%) | 21 (10%) | 0.12 | |
| Any adverse events at 3 months | Safety | 65/208 (31%) | 55/204 (27%) | 0.33 |
Subgroup Analysis
No significant treatment-effect modification across prespecified subgroups (sex, age, NIHSS, ASPECTS, occlusion site [ICA vs M1], diabetes, hypertension, hypercholesterolaemia, time to randomisation). Among 57 patients with baseline ASPECTS 0-4 (large core), 17 (30%) achieved mRS 0-2 at 3 months (26% IVT vs 36% IVTMT). No difference in mRS 0-2 between general anaesthesia and conscious sedation/local anaesthesia subgroups (52% vs 49%, p=0.67).
Criticisms
- Open-label with unblinded clinical outcome assessment (vascular neurologists assessed mRS knowing arm assignment) — risk of assessor bias on primary endpoint.
- Trial stopped early (after 414 of planned 480 patients) following an unplanned second interim analysis triggered by MR CLEAN publication — early-stopping trials can inflate treatment-effect estimates.
- Two protocol amendments mid-trial: IVT window extended from 3 h to 4 h after 80 patients enrolled; clinical assessment moved from post-IVT to before end of infusion after Oct 2012 — introduces heterogeneity.
- Only 141/204 (69%) of IVTMT-assigned patients actually received thrombectomy; the mITT effect size therefore dilutes the true procedural effect, while the per-protocol analysis was underpowered (OR 1.33, p=0.198).
- Long randomisation-to-groin-puncture time (~82 min) exceeded contemporary US/EU trials and may partly explain the smaller absolute benefit (11%) than MR CLEAN (14%), ESCAPE (24%), or EXTEND-IA (31%).
- Ordinal mRS shift OR (1.39, 95% CI 0.99-1.97; p=0.05) did not reach significance, in contrast to the dichotomised primary outcome.
- Basilar occlusions were pre-specified but effectively excluded (only 4 patients enrolled), so results apply only to anterior-circulation LVO.
- Baseline imbalance in vascular risk factors (more HTN, DM, HLD in IVT arm) despite minimisation — unadjusted analysis was used for primary outcome.
- Older-generation devices used early in trial and evolving thrombectomy technique over 4 years may have kept the reperfusion rate (69% mTICI 2b-3) below what modern practice achieves.
Funding
French Ministry for Health (2009 STIC programme, grant number 2009 A00753-54). The funder had no role in study design, data collection, analysis, interpretation, or writing.
Based on: THRACE (Lancet Neurology, 2016)
Authors: Bracard S, Ducrocq X, Mas JL, et al; THRACE investigators
Citation: Lancet Neurol 2016;15(11):1138-1147. DOI: 10.1016/S1474-4422(16)30177-6
Content summarized and formatted by NeuroTrials.ai.