Carotid Endarterectomy or Stenting or Best Medical Treatment Alone for Moderate to Severe Asymptomatic Carotid Artery Stenosis: 5-Year Results of a Multicenter Randomized Controlled Trial
Background
The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. As best medical therapy (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. There are no randomized data comparing the effect of CEA and CAS versus BMT alone.
The objective was to directly compare CEA plus BMT with CAS plus BMT and both with BMT alone.
Methods
SPACE-2 was a multicenter, randomized, controlled trial at 36 study centers in Austria, Germany, and Switzerland. We enrolled participants aged 50 to 85 years with asymptomatic carotid artery stenosis in the distal common carotid artery or extracranial internal carotid artery of at least 70%, according to the European Carotid Surgery Trial criteria.
Initially designed as a three-arm trial including a BMT-only group (with a randomization ratio of 2·9:2·9:1), the design of the SPACE-2 study was modified (due to slow recruitment ) to become two substudies with two arms, each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomization. Participants and clinicians were not blinded to allocation.
The primary measure of efficacy was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischemic stroke within 5 years.
The primary safety endpoint was any stroke or death from any cause within 30 days of CEA or CAS.
The primary analysis was intention-to-treat, including all patients randomized into SPACE-2, SPACE-2a, and SPACE-2b, analyzed by individual patient data meta-analysis.
We did a two-step hierarchical test to first show the superiority of CEA and CAS versus BMT alone and then to evaluate the noninferiority of CAS versus CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5 years of follow-up.
Results
513 patients were recruited and surveyed in SPACE-2, SPACE-2a, and SPACE-2b between July 9, 2009 and December 12, 2019, of whom 203 (40%) were assigned to CEA plus BMT, 197 ( 38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59.9 months (IQR 46.6-60.0).
The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischemic stroke within 5 years (primary efficacy endpoint) was 2.5% (95% CI 1.0–5 .8) with CEA plus BMT, 4·4% (2·2–8·6) with CAS plus BMT, and 3·1% (1·0–9·4) with BMT alone.
The Cox proportional hazard test showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0.93, 95% CI 0.22–3.91; p=0.93) or for CAS plus BMT versus BMT alone (1·55, 0·41–5·85; p=0·52).
Superiority of CEA or CAS over BMT was not demonstrated, so noninferiority testing was not performed. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure.
During the 5-year follow-up period , three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone groups, and none in the CEA plus BMT group.
Interpretation
CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone with respect to the risk of stroke or death within 30 days or ipsilateral stroke over the 5-year observation period. Due to the small sample size, the results should be interpreted with caution.
This trial is registered with ISRCTN, number ISRCTN78592017.
Comments
Optimal treatment of asymptomatic carotid stenosis
In studies conducted more than 25 years ago, a modest benefit was observed with carotid endarterectomy relative to medical therapy for patients with asymptomatic 60% to 99% internal carotid artery stenosis. However, observational studies have shown that with advances in medical therapy, including the widespread use of statins, the rate of stroke with medical treatment has decreased.
Therefore, it is unclear whether carotid revascularization remains beneficial. These authors conducted a two-arm randomized trial: they compared carotid endarterectomy (CEA) plus best medical therapy (BMT) with BMT alone, and they separately compared carotid artery stenting (CAS) plus BMT with BMT alone.
Eligible patients were between 50 and 85 years old and had stenosis ≥70%. The primary endpoint was stroke or death within 30 days or ipsilateral stroke from 30 days to 5 years.
The initial enrollment goal was 3640 patients, but due to slow enrollment it stopped after 513 patients (mean age, 69 years; 75% men). About 90% of the participants had hypertension and about a third had heart disease.
During follow-up, the primary endpoint occurred in 2.5% of the CEA+BMT group, 3.1% of the BMT alone group, and 4.4% of the CAS+BMT group. There was no clear superiority of either revascularization procedure over BMT alone.
This study provides useful evidence that the stroke rate with contemporary medical therapy has decreased considerably, averaging less than 1% per year in the trial.
Because the study was stopped prematurely, it is unclear whether carotid revascularization provides any benefit. The CREST 2 trial (www.crest2trial.org) is expected to enroll nearly 2,500 asymptomatic patients and provide more definitive data on whether CEA or CAS plays a role in patients with asymptomatic carotid stenosis.
