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Introductory Analysis and Validation of CUT&RUN Sequencing Data
Published on: December 13, 2024
CREST-2 findings are unchanged using an aggregated control group for the CAS and CEA trial
Piotr Musialek1,2, Krzysztof Malinowski3,4, Lukasz Tekieli5
1Jagiellonian University Department of Cardiac and Vascular Diseases, Krakow, Poland.
Insights
Carotid artery stenting (CAS) plus intensive medical management (IMM) significantly reduced stroke risk compared to IMM alone. Carotid endarterectomy (CEA) plus IMM did not show a significant benefit, refuting control arm disparities as the cause.
Area of Science:
- Cardiovascular Medicine
- Neurology
- Interventional Cardiology
Background:
- CREST-2 evaluated carotid revascularization (stenting or endarterectomy) plus intensive medical management (IMM) versus IMM alone for asymptomatic severe carotid stenosis.
- Previous analyses showed a significant benefit for CAS but not CEA, raising questions about control arm differences.
- Asymptomatic carotid stenosis poses a risk for ischemic stroke, necessitating effective preventative strategies.
Purpose of the Study:
- To determine if divergent control arm event rates, rather than true differences in treatment efficacy, explained the outcomes in CREST-2.
- To re-evaluate the efficacy of carotid artery stenting (CAS) and carotid endarterectomy (CEA) against a single, aggregated control group.
- To confirm the effectiveness of intensive medical management (IMM) in preventing stroke in patients with asymptomatic carotid stenosis.
Main Methods:
- An aggregated control group (n=1,252) was formed by merging data from the IMM-only arms of the two CREST-2 trials.
- Kaplan-Meier analysis was used to compare outcomes between the CAS + IMM and CEA + IMM groups versus the aggregated IMM-only control group.
- The primary endpoint was peri-procedural stroke/death or ipsilateral ischemic stroke within 4 years, analyzed using an intent-to-treat approach.
Main Results:
- The aggregated control group experienced a primary endpoint event rate of 5.65%.
- CAS + IMM demonstrated a significant absolute risk reduction of 2.85% (50.4% relative risk reduction; NNT=35; p=0.0089) compared to IMM alone.
- CEA + IMM showed an absolute risk reduction of 1.95% (p=0.0871), maintaining a lack of statistical significance.
Conclusions:
- Aggregated control group analysis confirmed the efficacy of CAS + IMM in reducing stroke risk for asymptomatic carotid stenosis.
- The analysis maintained that CEA + IMM did not achieve statistical significance in preventing stroke in this patient population.
- These findings refute the hypothesis that control arm event rate disparities, rather than differential treatment efficacy, explained the divergent outcomes observed in CREST-2.
Introduction:
CREST-2 comprised two parallel observer-blinded randomised controlled trials evaluating carotid revascularisation (carotid artery stenting - CAS, or carotid endarterectomy - CEA) plus intensive medical management (IMM; supervised pharmacologic therapy and risk factor control and coached lifestyle modification) versus IMM alone in patients with asymptomatic ≥ 70% carotid stenosis. Each trial carried an independent IMM control arm. The primary endpoint (peri-procedural stroke/death or ipsilateral ischaemic stroke thereafter by 4 years) occurred, in the CAS trial, in 2.8% vs. 6.0% (IMM + CAS vs. IMM; p = 0.02). The effect of CEA did not reach significance; 3.7% vs. 5.3% (IMM + CEA vs. IMM; p = 0.24).
Aim:
To test the hypothesis that the divergent control-arm event rates - rather than true differential efficacy of the interventional treatments - could underlie the CAS efficacy and CEA failure in CREST-2, we used a single combined control group as a balanced reference for both interventional treatment arms.
Material And Methods:
An Aggregated Control Group of IMM-only (n = 1,252) was formed by merging the CREST-2 IMM control arms patient data and outcomes. Kaplan-Meier analysis was performed for the CAS and CEA treatment vs. the Aggregated Control Group, consistent with the trial statistical methodology (intent-to-treat).
Results:
In the Aggregated Control Group, the primary endpoint occurred in 5.65% of patients (95% CI: 4.47-7.12). Absolute risk reduction with CAS + IMM (n = 616) was 2.85% (relative risk reduction 50.4%; number-needed-to-treat 35, p = 0.0089). Absolute risk reduction with CEA + IMM (n = 617) was 1.95% (p = 0.0871, a maintained lack of statistical significance).
Conclusions:
Aggregated Control Group analysis of CREST-2, minimising control arms biases, confirmed CAS efficacy (50.4% relative risk reduction) and maintained failure of CEA in primary prevention of ipsilateral stroke in patients with asymptomatic carotid stenosis under intensive medical management. This refutes control-arm disparity as an explanation for the divergent outcomes with CAS vs. CEA.
