← Back

THERAPY

The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke (THERAPY)

Share Share Copied! Compare

Year of Publication: 2016

Authors: J Mocco, MD; Osama O. Zaidat, MD; Rüdiger von Kummer, ..., MD; Pooja Khatri

Journal: Stroke

Citation: Stroke. 2016;47:2331-2338. DOI: 10.1161/STROKEAHA.116.013372.

Link: http://stroke.ahajournals.org/lookup/sup...16.013372/-/DCL

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

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.

Content summarized and formatted by NeuroTrials.ai.

THERAPY

(2016)

Objective

Aspiration thrombectomy plus IV alteplase versus alteplase alone to improve outcomes in large vessel occlusion stroke with ≥8 mm clot.

Study Summary

• The trial was underpowered due to early termination, but aspiration thrombectomy showed a consistent trend toward benefit across all prespecified outcomes.

Intervention

IV alteplase (0.9 mg/kg) plus aspiration thrombectomy using the Penumbra system vs. IV alteplase alone. Randomization within 3 hours of symptom onset; thrombectomy initiated after alteplase.

Inclusion Criteria

Age 18–85 years, NIHSS ≥8, occlusion of intracranial ICA or MCA (M1/M2), clot length ≥8 mm, treatment within 3 hours, no significant infarct (>1/3 MCA territory), and mRS ≤1 before stroke.

Study Design

Arms: Aspiration Thrombectomy + Alteplase vs. Alteplase Alone

Patients per Arm: Thrombectomy: 55, Alteplase: 53

Outcome

• Primary outcome (mRS 0–2 at 90d): 38% vs. 30%, OR 1.4, P=0.44.• Ordinal shift analysis (adjusted ITT): OR 2.4, 95% CI 1.1–5.1, P=0.02.• Per-protocol mRS 0–2: 41% vs. 29%.• 90d mortality: 12% vs. 24%.• Symptomatic ICH: 9.3% vs. 9.7%.• Serious adverse events: 42% vs. 48%.

Bottom Line

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.

Study Design

Study Type: International, multicenter, prospective, randomized (1:1), open label, blinded end point evaluation, concurrent controlled clinical trial
Randomization: Yes
Blinding: Blinded end point evaluation by independent adjudicators and neuroradiologists, and NIHSS-certified assessors.
Sample Size: 108
Follow-up: 90 days
Centers: 36
Countries: United States, Germany

Primary Outcome

Definition: Proportion of patients achieving functional independence (modified Rankin Scale score, 0-2) by 90 days.

Control	Intervention	HR/OR	P-value
30% (14/46)	38% (19/50)	- (0.60-3.3)	0.44

Limitations & 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).

Citation

Stroke. 2016;47:2331-2338. DOI: 10.1161/STROKEAHA.116.013372.

View Original Publication →

THERAPY

The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke (THERAPY)

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Criticisms

Subgroup Analysis

Funding

Ask about THERAPY