Penumbra
The Penumbra Pivotal Stroke Trial: Safety and Effectiveness of a New Generation of Mechanical Devices for Clot Removal in Intracranial Large Vessel Occlusive Disease
Clinical Question
To assess the safety and effectiveness of the Penumbra System in the revascularization of patients presenting with acute ischemic stroke secondary to intracranial large vessel occlusive disease within 8 hours of symptom onset.
Study Overview
Objective
To assess the safety and effectiveness of the Penumbra System, a new mechanical thrombectomy device, for revascularizing large vessel occlusions in acute ischemic stroke patients within 8 hours of onset.
Study Summary
- The Penumbra System achieved a very high rate of successful revascularization (TIMI 2 or 3 flow) of 81.6%.
- Symptomatic intracranial hemorrhage occurred in 11.2% of patients.
- Despite the high revascularization rate, only 25% of patients achieved a good functional outcome (mRS ≤2) at 90 days, a notable disparity.
Intervention
Mechanical thrombectomy using the Penumbra System (aspiration and/or extraction) within 8 hours of stroke symptom onset in patients with large vessel occlusion. Clinical follow-up was for 90 days.
Bottom Line
The Penumbra System demonstrated a high rate of successful revascularization (81.6%) in acute ischemic stroke patients with large vessel occlusions. While the procedure appeared safe, with rates of complications and hemorrhage comparable to historical controls, the high revascularization rate did not translate into a correspondingly high rate of good functional outcome at 90 days.
Major Points
- This was a prospective, multicenter, single-arm study that enrolled 125 patients with acute ischemic stroke due to large vessel occlusion who were treated within 8 hours of symptom onset.
- The primary effectiveness endpoint was successful revascularization (TIMI grade 2 or 3), which was achieved in 81.6% of treated vessels (95% CI 73.7–88.0).
- The rate of symptomatic intracranial hemorrhage (sICH) at 24 hours was 11.2%.
- At 90 days, 25% of patients achieved a good functional outcome (modified Rankin Scale score ≤2), and the all-cause mortality rate was 32.8% (41/125).
- Successful revascularization was associated with better neurological outcomes and a trend toward lower mortality, but the overall rate of good functional outcome was lower than might be expected given the high revascularization rate.
- The trial was designed to demonstrate substantial equivalence to the MERCI device for FDA 510(k) clearance, not superiority over medical management.
Design
Study Type: Prospective, multicenter, single-arm trial
Randomization:
Blinding: This was an open-label study. Angiographic and CT scan data were adjudicated by a blinded, independent core laboratory. Safety events were adjudicated by a Clinical Events Committee.
Enrollment Period: June 19, 2006, to June 5, 2007
Follow-up Duration: 90 days
Centers: 24
Countries: United States, Europe
Sample Size: 125
Analysis: Descriptive statistics were used. Outcomes were compared between patients with successful versus unsuccessful revascularization using a 2-tailed Fisher exact test. The primary effectiveness endpoint was compared to historical controls.
Inclusion Criteria
- Presentation within 8 hours of symptom onset
- National Institutes of Health Stroke Scale (NIHSS) score ≥8
- Angiographically verified occlusion (Thrombolysis In Myocardial Infarction [TIMI] Grade 0 or 1) of a large intracranial vessel
- Patients presenting within 3 hours must have been ineligible for or refractory to intravenous recombinant tissue plasminogen activator (tPA) therapy
Exclusion Criteria
- Extensive infarction greater than one third of the middle cerebral artery (MCA) territory
- Severe edema or intracranial hemorrhage (ICH) on baseline imaging
- Pregnancy
Arms
| Field | Mechanical Thrombectomy with Penumbra System |
|---|---|
| Intervention | Revascularization procedure using the Penumbra System, which combines thrombus debulking via aspiration with an option for direct thrombus extraction. |
| Duration | Single procedure |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Rate of successful revascularization, defined as achieving TIMI grade 2 or 3 flow in the target vessel after the procedure. | Primary | 81.6% (102/125) | |||
| Discharge NIHSS 0–1 or improved by ≥10 (overall) | Secondary | 5% (TIMI 0–1, N=23) | 32% (TIMI 2–3, N=102) | 0.0127 | |
| Good clinical outcome at 30 days (composite: discharge NIHSS 0–1 or improved by ≥10, or 30-day mRS ≤2) — overall 30% | Secondary | 9% (TIMI 0–1) | 35% (TIMI 2–3) | 0.0199 | |
| Good clinical outcome (mRS ≤2) at 90 days — overall 25% | Secondary | 9% (Not Revascularized) | 29% (Revascularized) | 0.0596 | |
| Death at 90 days — overall 33% | Secondary | 48% (Not Revascularized) | 29% (Revascularized) | 0.1384 | |
| Any procedural events | Adverse | 12.8% (16/125 patients; 19 events) | |||
| Serious procedural events | Adverse | 2.4% (3/125) | |||
| Any intracranial hemorrhage (at 24h) | Adverse | 28% (35/125) | |||
| Symptomatic intracranial hemorrhage (at 24h) | Adverse | 11.2% (14/125) | |||
| All-cause mortality at 90 days | Adverse | 32.8% (41/125) |
Subgroup Analysis
Multivariate analysis identified lower baseline NIHSS score as a predictor of good functional outcome, while higher baseline NIHSS, history of CVA, and site of occlusion were predictors of mortality.
Criticisms
- The study was a single-arm trial that lacked a concurrent control group, making it impossible to definitively conclude that the intervention improved functional outcomes compared to medical management alone.
- There was a notable disparity between the very high revascularization rate (81.6%) and the modest rate of good functional outcome at 90 days (25%), the cause of which remains unclear from this study.
- Patient selection was not guided by advanced imaging (eg, perfusion scans) to confirm the presence of salvageable ischemic penumbra, which may have contributed to the modest clinical outcomes despite successful revascularization.
Funding
Penumbra Inc.
Based on: Penumbra (Stroke, 2009)
Authors: The Penumbra Pivotal Stroke Trial Investigators
Citation: Stroke. 2009;40:2761-2768.
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