THERAPY
The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke (THERAPY)
Clinical Question
Does aspiration thrombectomy after intravenous alteplase (IAT) administration improve clinical outcomes compared with intravenous alteplase alone in patients with large vessel ischemic stroke due to a thrombus length of ≥8 mm?
Bottom Line
The THERAPY trial, while underpowered due to early termination, showed consistent trends towards benefit for aspiration thrombectomy after intravenous alteplase (IAT) across all prespecified outcomes, including functional independence and mortality, without an increase in symptomatic intracranial hemorrhage rates. Further study is indicated to definitively determine the benefit of primary aspiration in selected large vessel occlusion patients.
Major Points
- Enrollment was halted early after 108 patients (of 692 planned) due to external evidence of the added benefit of endovascular therapy.
- Functional independence (mRS 0-2 at 90 days) was achieved in 38% in the IAT group and 30% in the intravenous group (P=0.52).
- Intention-to-treat ordinal modified Rankin Scale odds ratio was 1.76 (95% CI, 0.86-3.59; P=0.12) in favor of IAT.
- Secondary efficacy analyses consistently showed a direction of effect toward benefit of IAT.
- No significant differences were observed in symptomatic intracranial hemorrhage rates (9.3% IAT vs 9.7% intravenous, P=1.0) or 90-day mortality (12% IAT vs 23.9% intravenous, P=0.18).
- Successful reperfusion (mTICI 2b/3) was achieved in 70% of patients treated with only the Penumbra system after aspiration thrombectomy alone.
Design
Study Type: International, multicenter, prospective, randomized (1:1), open label, blinded end point evaluation, concurrent controlled clinical trial
Randomization: 1
Blinding: Blinded end point evaluation by independent adjudicators and neuroradiologists, and NIHSS-certified assessors.
Enrollment Period: March 2012 and October 2014
Follow-up Duration: 90 days
Centers: 36
Countries: United States, Germany
Sample Size: 108
Analysis: Intention-to-treat (ITT) analysis for primary efficacy endpoint (mRS 0-2 at 90 days); as-treated analysis for primary safety endpoint (SAEs by 90 days). Secondary efficacy analyses included mRS shift, NIHSS improvement, and infarct volume. Comparisons used 2-sided χ² test for primary endpoint.
Inclusion Criteria
- Patients aged 18-85 years old
- Intracranial internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion on CT angiography
- National Institute of Health Stroke Scale (NIHSS) score of >8
- Received intravenous alteplase based on standard eligibility criteria
- Nonenhanced thin-section (≤2.5 mm) CT scan demonstrating ≥8 mm clot length.
Exclusion Criteria
- >1/3 of the affected middle cerebral artery territory with established infarction
- Cervical ICA stenosis/occlusion requiring treatment before thrombectomy
- Prestroke disability (modified Rankin Scale [mRS] score >1)
Arms
| Field | Intravenous Alteplase + Thrombectomy (IAT) | Control |
|---|---|---|
| Intervention | Intravenous alteplase plus aspiration thrombectomy (Penumbra System, including 3D Separator and ACE aspiration catheter). | Intravenous alteplase alone. |
| Duration | Acute procedure | Acute procedure |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Proportion of patients achieving functional independence (modified Rankin Scale score, 0-2) by 90 days. | Primary | 30% (14/46) | 38% (19/50) | 7.57% | 0.44 |
| Ordinal mRS at 90 days (ITT) | Secondary | median 4 (IQR 2-5) | median 3 (IQR 1-4) | 1.76 | 0.12 |
| Ordinal mRS at 90 days (PP) | Secondary | median 4 (IQR 2-5) | median 3 (IQR 2-4) | 2.2 | 0.047 |
| 30-day good outcome (mRS 0-2) (ITT) | Secondary | 32% (17/53) | 45% (24/53) | 2 | 0.03 |
| 30-day good outcome (mRS 0-2) (PP) | Secondary | 34% (16/47) | 51% (20/39) | 2.5 | 0.02 |
| ASPECTS improvement at 24 hours (ITT) | Secondary | 5 (IQR 2-7) | 6 (IQR 4-8) | 1.9 | 0.01 |
| ASPECTS improvement at 24 hours (PP) | Secondary | 5 (IQR 3-7) | 7 (IQR 4-8) | 2.5 | 0.02 |
| 90-day mortality (ITT) | Secondary | 23.9% | 12% | 2.3 | 0.18 |
| 90-day mortality (PP) | Secondary | 24% | 7.3% | 4.1 | |
| Severe Adverse Events (SAEs) by 90 days (as treated) | Adverse | 48% (30/62) | 42% (18/43) | 1.3 | 0.55 |
| Symptomatic intracranial hemorrhage (sICH) (as treated) | Adverse | 9.7% (6/62) | 9.3% (4/43) | 1 | 1.0 |
Criticisms
- The trial was halted early due to external evidence of the benefit of endovascular therapy, resulting in an underpowered sample size (108 patients enrolled out of 692 planned).
- The small sample size led to imbalances in baseline characteristics (sex, history of atrial fibrillation, smoking status, and clot location) between the two treatment arms, despite randomization.
- Generalizability is limited as the study focused on a highly selected patient population (large anterior circulation proximal clot burden ≥8mm).
- The definition of sICH was broader than in other trials, not requiring relatedness to neurological decline, potentially leading to higher reported rates compared to other studies (though no difference was found between groups).
Subgroup Analysis
Not explicitly detailed, but multivariate adjusted ordinal analyses were performed, suggesting benefit for thrombectomy after accounting for baseline imbalances (sex, history of atrial fibrillation, smoking status, and clot location).
Funding
Penumbra, Inc.
Based on: THERAPY (Stroke, 2016)
Authors: J Mocco, MD; Osama O. Zaidat, MD; Rüdiger von Kummer, ..., MD; Pooja Khatri
Citation: Stroke. 2016;47:2331-2338. DOI: 10.1161/STROKEAHA.116.013372.
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