THRACE
(2016)Objective
Determine whether mechanical thrombectomy added to intravenous alteplase improves functional independence at 3 months in patients with acute ischaemic stroke and proximal anterior-circulation large-vessel occlusion.
Study Summary
• NIHSS at 24 h was lower with thrombectomy (median 9 vs 12; p=0.04) and Barthel 95-100 at 3 months more frequent (61% vs 49%; OR 1.59, 1.02-2.49; p=0.04).
• Mortality at 3 months 12% vs 13% (p=0.70) and symptomatic ICH at 24 h 2% vs 2% (p=0.71) did not differ.
Intervention
IV alteplase 0.9 mg/kg (max 90 mg) plus mechanical thrombectomy (stent retriever ≈83%, aspiration ≈16%) within 5 h of onset vs IV alteplase alone
Inclusion Criteria
Age 18-80; NIHSS 10-25; proximal occlusion of intracranial ICA, M1 middle cerebral artery, or superior third of basilar artery on CT/MR angiography; IV thrombolysis within 4 h and thrombectomy within 5 h of symptom onset
Study Design
Arms: IV alteplase + thrombectomy (IVTMT, n=204) vs IV alteplase alone (IVT, n=208)
Patients per Arm: 204 vs 208 (N=414 randomised; 402 in modified ITT primary analysis)
Outcome
• Secondaries: NIHSS 24 h median 9 vs 12 (p=0.04); NIHSS day 7 4 vs 8 (p=0.001); NIHSS 3 mo 2 vs 4 (p=0.01); Barthel 95-100 at 3 mo 61% vs 49%, OR 1.59 (1.02-2.49), p=0.04; ordinal mRS OR 1.39 (0.99-1.97), p=0.05; EQ-5D no difference (p=0.38)
• Safety: 3-mo mortality 24/202 (12%) IVTMT vs 27/206 (13%) IVT, OR 0.81 (0.53-1.24), p=0.70; symptomatic ICH at 24 h 4/185 (2%) vs 3/192 (2%), p=0.71
• Procedural (IVTMT): mTICI 2b-3 reperfusion 95/138 (69%); vasospasm 33/145 (23%); embolisation in new territory 9/141 (6%); dissection 5 (3%); arterial perforation 1 (1%)
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.
Study Design
- Study Type
- Randomised, open-label, multicentre, blinded-endpoint-imaging phase 3 trial (PROBE-like)
- Randomization
- Yes
- 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.
- Sample Size
- 414
- Follow-up
- 3 months primary; safety at 24 h and 3 months
- Centers
- 26
- Countries
- France
Primary Outcome
Definition: Proportion of patients with modified Rankin scale score 0-2 (functional independence) at 3 months, modified ITT
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 85/202 (42%) | 106/200 (53%) | 1.55 (1.05-2.30) | 0.028 |
Limitations & 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.
Citation
Lancet Neurol 2016;15(11):1138-1147. DOI: 10.1016/S1474-4422(16)30177-6