Five-year outcomes of a multicentre, randomised controlled trial (RCT) indicate that carotid endarterectomy (CEA) or carotid artery stenting (CAS) are not superior to best medical therapy (BMT) alone for moderate-to-severe asymptomatic carotid artery stenosis.
Tilman Reiff (University Hospital of Heidelberg, Heidelberg, Germany) and colleagues recently reported this key conclusion from the SPACE-2 trial in The Lancet Neurology. The authors claim that—to the best of their knowledge—this is the first randomised trial to directly compare CEA plus BMT, CAS plus BMT, and BMT alone over a five-year period in patients with asymptomatic carotid artery stenosis.
“The optimal treatment for patients with asymptomatic CAS is under debate,” the investigators write, noting that, since BMT has improved over time, the benefit of CEA or CAS is “unclear”. They add that randomised data comparing the effect of CEA and CAS versus BMT alone are lacking, and therefore aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only in the SPACE-2 trial.
SPACE-2 was a multicentre RCT carried out at 36 study centres in Austria, Germany, and Switzerland, Reiff et al detail in their report. The researchers enrolled participants aged 50–85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70% according to European Carotid Surgery Trial criteria (equivalent to at least 50–99% according to North American Symptomatic Carotid Endarterectomy Trial [NASCET] criteria).
Reiff and colleagues note that SPACE-2 was initially designed as a three-arm trial including one group for BMT alone. However, the design was amended 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).
“Originally, we planned to recruit 3,640 patients; however, the study had to be stopped prematurely due to insufficient recruitment,” the authors write. They report that a total of 513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between 9 July 2009 and 12 December 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. The median follow-up was 59.6 months.
In their Lancet paper, Reiff and colleagues report that the cumulative incidence of any stroke or death from any cause within 30 days or an ipsilateral stroke within five years—the primary efficacy endpoint of the study—was 2.5% (95% confidence interval [CI], 1–5.8) with CEA plus BMT, 4.4% (95% CI, 2.2–8.6) with CAS plus BMT, and 3.1% (95% CI, 1–9.4) with BMT alone.
The investigators also relay that, in both the CEA and CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the five-year follow-up period, they note, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone groups, with none in the CEA plus BMT group.
Reiff et al conclude that CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of stroke or death within 30 days or ipsilateral stroke during the five-year observation period. However, they stress that their results “should be interpreted with caution” due to the small sample size.
Indeed, they note that the small sample size of the trial was its “main limitation”. They outline the crux of the issue here: “With the low number of observed outcome events, only a few further events would be needed to change the results significantly.” Despite this, they highlight that the present analysis “reveals important indications for possibly relevant existing associations, can be used for further pooled analyses, and provides data for future meta-analyses in a topic area in which currently only few randomised trials are available”.
Randomisation is key
In a commentary on Reiff and colleagues’ work, also published in The Lancet Neurology, Alison Halliday (University of Oxford, Oxford, UK) underscores the importance of randomised trials in this field of study. Halliday, who is principal investigator of the Asymptomatic Carotid Surgery Trials, remarks: “Despite its relatively small size, SPACE-2 provides important long-term follow-up data because of the randomised trial methodology. Large procedural registries usually cease follow-up within days or a few months, and patients on medical treatment alone cannot be meaningfully compared without randomisation.
“The future of interventions for carotid artery stenosis depends on randomised comparisons of different treatment approaches to ensure that bias is minimised and, at the same time, that enough patients are included. Alternatively, individual patient meta-analysis of similar trials can be used to support future interventions. SPACE-2 is of value to future individual patient meta-analyses of these three treatment options.”