The Lancet Neurology October 15, 2016

Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial

Serge Bracard, Xavier Ducrocq, Jean-Louis Mas, Marc Soudant, Catherine Oppenheim, Thierry Moulin, Francis Guillemin, et al.

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Bottom Line

Mechanical thrombectomy combined with intravenous thrombolysis significantly improved functional independence at 3 months compared to intravenous thrombolysis alone in patients with acute ischemic stroke due to proximal cerebral artery occlusion.

Key Findings

1. The primary outcome of functional independence at 3 months (modified Rankin Scale score 0–2) was achieved in 53% (106/200) of patients in the thrombectomy plus IV thrombolysis (IVTMT) group compared with 42% (85/202) in the IV thrombolysis alone group (OR 1.55, 95% CI 1.05–2.30; p=0.028) [4.2.3].

2. Mortality rates at 3 months were similar between the IVTMT group (13%) and the IVT alone group (12%) (p=0.70).

3. Safety outcomes were highly comparable, with rates of symptomatic intracranial hemorrhage at 24 hours being 2% in both groups.

Study Design

Design

RCT

Open-Label

Sample

414

Patients

Duration

3 mo

Median

Setting

Multicenter, France

Population Patients aged 18-80 years presenting with acute ischemic stroke and confirmed proximal cerebral artery occlusion, eligible to receive intravenous thrombolysis within 4 hours and mechanical thrombectomy within 5 hours of symptom onset.

Intervention Intravenous thrombolysis (alteplase 0.9 mg/kg) plus mechanical thrombectomy (IVTMT).

Comparator Intravenous thrombolysis (alteplase 0.9 mg/kg) alone (IVT).

Outcome Proportion of patients achieving functional independence at 3 months, defined as a modified Rankin Scale (mRS) score of 0 to 2.

Study Limitations

• The trial was terminated early after an unplanned interim analysis, which carries the risk of overestimating the treatment effect magnitude.

• The open-label design inherently risks bias, although the assessors of the primary clinical outcome at 3 months were blinded.

• Patients older than 80 years were excluded, limiting the trial's generalizability to the elderly stroke population.

• A small number of randomized patients (12 total) were excluded from the modified intention-to-treat analysis due to loss to follow-up or missing data.

Clinical Significance

The THRACE trial bolstered the massive paradigm shift in acute ischemic stroke management. Unlike several other landmark thrombectomy trials that utilized highly restrictive advanced perfusion imaging criteria, THRACE employed pragmatic, broad inclusion criteria based merely on confirmed large-vessel occlusion. By demonstrating a significant 11% absolute increase in functional independence without an increase in symptomatic hemorrhage, it confirmed the profound real-world benefit and safety of modern stent retrievers used alongside standard IV alteplase in routine clinical practice.

Historical Context

Following a series of negative endovascular stroke trials published in 2013 (such as IMS III and MR RESCUE), the landscape of acute stroke care was revolutionized in 2015 by the publication of five landmark trials (MR CLEAN, ESCAPE, REVASCAT, EXTEND-IA, SWIFT PRIME). These trials definitively proved the superiority of newer-generation stent retrievers for large vessel occlusions. THRACE, conducted contemporaneously in France, provided crucial, large-scale corroborative evidence in 2016, further solidifying endovascular thrombectomy as the irrefutable standard of care.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of intravenous alteplase, and why might it fail to recanalize large vessel occlusions (LVOs) like the proximal middle cerebral artery (MCA), necessitating mechanical thrombectomy?

Key Response

Alteplase is a tissue plasminogen activator (tPA) that converts plasminogen to plasmin, degrading fibrin clots. However, it is often insufficient for LVOs because these clots are large, have a high red blood cell and platelet burden, and expose limited surface area to circulating tPA, leading to low recanalization rates without mechanical extraction.

Resident

A patient presents with a proximal M1 MCA occlusion within 3 hours of symptom onset. Based on trials like THRACE, what is the standard management regarding the administration of IV alteplase before mechanical thrombectomy (bridging therapy), and what are the specific clinical risks of this approach?

Key Response

Standard management for eligible patients presenting within the IVT window is to administer IV alteplase followed rapidly by mechanical thrombectomy, rather than skipping IVT. The main clinical risks of bridging therapy include delayed door-to-puncture times and a potentially increased risk of symptomatic intracranial hemorrhage or systemic bleeding.

Fellow

The THRACE trial supported bridging therapy, but recent non-inferiority trials (e.g., DIRECT-MT, DEVT) have investigated direct mechanical thrombectomy without prior IVT. How do the pathophysiological benefits of pre-thrombectomy IV alteplase balance against its potential to complicate endovascular procedures?

Key Response

Pre-MT IV alteplase can soften the primary clot, increasing first-pass effect rates, and may dissolve distal micro-emboli. However, it carries risks such as clot fragmentation leading to distal embolization in inaccessible territories, increased bleeding risk during catheterization, and potential delays in groin puncture.

Attending

As stroke systems of care evolve post-THRACE, how should regional transfer protocols (e.g., drip-and-ship vs mothership models) be optimized to maximize functional outcomes for LVO stroke patients?

Key Response

The robust benefit of mechanical thrombectomy underscores that time to reperfusion is critical. Systems must be tailored locally: bypassing primary stroke centers for comprehensive centers (mothership) may lead to faster puncture times but delays IVT administration. Optimizing requires pre-hospital screening tools to route likely LVOs directly to MT-capable centers while initiating IVT en route or at the nearest center.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

THRACE utilized a PROBE (Prospective, Randomized, Open-label, Blinded-Endpoint) design. How does this design impact the internal validity of trials evaluating interventional stroke therapies, and what specific biases might arise in the acute treatment phase versus the follow-up phase?

Key Response

The PROBE design allows for pragmatic acute intervention where blinding providers to surgery is impossible. While blinded assessment of the primary endpoint (mRS at 90 days) mitigates detection bias, the open-label acute phase risks performance bias, where post-procedure care or rehabilitation referral might differ between arms due to provider expectations.

Journal Editor

In reviewing trials comparing bridging therapy to IVT alone, the choice of the primary outcome (dichotomized modified Rankin Scale 0-2) is standard but statistically limits power. How might a shift analysis (ordinal logistic regression over the entire mRS) have altered the interpretation or statistical power of the THRACE trial findings?

Key Response

Dichotomizing mRS throws away granular data regarding transitions between severe disability and moderate disability. A shift analysis retains the full spectrum of the scale, increasing statistical power to detect treatment effects and capturing meaningful clinical improvements across all levels of disability, an expected secondary analysis in modern high-impact stroke trials.

Guideline Committee

Based on the findings from THRACE and concurrent trials, how should current AHA/ASA and ESO guidelines classify the strength of recommendation and level of evidence for mechanical thrombectomy in anterior circulation LVOs, and what specific patient selection criteria are mandated?

Key Response

These landmark trials elevated mechanical thrombectomy to a Class 1, Level of Evidence A recommendation in both AHA/ASA and ESO guidelines for patients with acute ischemic stroke due to a causative occlusion of the ICA or proximal MCA. Guidelines mandate specific criteria: baseline NIHSS greater than or equal to 6, pre-stroke mRS 0-1, presentation within 6 hours of onset, and concurrent treatment with IV alteplase if eligible.

Clinical Landscape

Noteworthy Related Trials

2015

MR CLEAN Trial

n = 500 · NEJM

Tested

Intraarterial treatment (mechanical thrombectomy) plus usual care

Population

Acute ischemic stroke patients with proximal intracranial arterial occlusion

Comparator

Usual care alone (including IV alteplase)

Endpoint

Modified Rankin Scale (mRS) score at 90 days

Key result: Intraarterial treatment significantly shifted the distribution of mRS scores in favor of functional independence with an absolute difference of 13.5 percentage points.

2015

ESCAPE Trial

n = 316 · NEJM

Tested

Rapid endovascular treatment (mechanical thrombectomy)

Population

Acute ischemic stroke patients with proximal anterior circulation occlusion and small infarct core

Comparator

Standard care (including IV alteplase)

Endpoint

Modified Rankin Scale (mRS) score at 90 days

Key result: Endovascular treatment significantly improved functional independence and reduced mortality from 19 percent to 10.4 percent.

2015

EXTEND-IA Trial

n = 70 · NEJM

Tested

Endovascular therapy (stent retriever) after IV alteplase

Population

Acute ischemic stroke patients with anterior circulation occlusion and salvageable tissue on perfusion imaging

Comparator

IV alteplase alone

Endpoint

Reperfusion at 24 hours and early neurologic improvement

Key result: Endovascular therapy resulted in a significantly higher rate of early neurologic improvement and 90-day functional independence compared to alteplase alone.

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