Muhammad Rizwan Husain, MD

Keyhani S, Cheng EM, Hoggatt KJ, Austin PC, Madden E, Hebert PL, Halm EA, Naseri A, Johanning JM, Mowery D, et al. Comparative Effectiveness of Carotid Endarterectomy vs Initial Medical Therapy in Patients With Asymptomatic Carotid Stenosis. JAMA Neurol. 2020.

In this entry, I discuss a recent publication by Keyhani and colleagues regarding treatment of asymptomatic carotid stenosis. There is anecdotal evidence from randomized clinical trials (Veterans Affairs Cooperative Study Group: Efficacy of carotid endarterectomy for asymptomatic carotid stenosis NEJM 1993, Endarterectomy for asymptomatic carotid artery stenosis, JAMA 1995 and Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial (ACST), Lancet 2004) that carotid Endarterectomy (CEA) is beneficial in preventing fatal and nonfatal strokes among patients with asymptomatic carotid stenosis. However, these studies were done a long time ago, and since then, there have been great improvements in stroke prevention strategies like enhanced antiplatelet regimens, high potency statins, better diabetes and stricter blood pressure control. The authors planned to investigate that with new and improved primary stroke management strategies available in the current era, revascularization for asymptomatic carotid stenosis (by CEA or carotid stent) might not be beneficial anymore.

The authors had two hypotheses: 1) The clinical superiority seen with CEA in asymptomatic carotid stenosis has diminished and that medical management is now more favorable, and 2) In a select cohort of patients, CEA may still be the treatment of choice.

The authors looked at data from the United States Department of Veterans Affairs (VA) and Medicare. This was a retrospective study, but the authors wanted to mimic the design of a randomized control trial (RCT) to see if CEA was superior to medical therapy. To create a cohort of asymptomatic carotid stenosis patients, all patients greater than 65 years of age and a carotid imaging study that demonstrated a stenosis of greater than 70% were selected. They were further randomized to those who underwent carotid revascularization; CEA or carotid artery stenting (CAS) vs those that underwent medical management only. The authors saw that patients who had CEA/CAS were younger, had less comorbidities so in order to make the two cohorts as similar as possible, propensity score matching was done. Once the two cohorts were established (revascularization vs medical treatment), the authors interestingly further divided the cohorts into pragmatic vs RCT like sample. The pragmatic sample’s inclusion criteria tried to reflect real world practice, i.e., basically all eligible asymptomatic patients, while the RCT like sample took strict exclusion/inclusion criteria similar to that of the ACST trial (Lancet 2004). In both these cohorts, three different analyses were done: 1) estimate the crude 5-year stroke risk, 2) emulation of the ACST using target trial methods, and 3) emulation of the ACST using target trial methods and accounting for the competing risk of death. There were too few patients that underwent CAS, so the analysis evaluated CEA vs medical management only. Patients that were initially randomized to one group and later crossed into the other group were censored.

In the pragmatic sample, the observed risk of stroke or death within 30 days of CEA was 2.5% (95% CI, 2.0%- 3.1%), and the 5-year risk of fatal and nonfatal strokes was lower in the CEA group compared to initial medical management (5.6% vs 7.8%; risk difference, −2.3%; 95% CI, −4.0% to −0.3%). When incorporating the competing risk of death, the risk difference between the 2 groups was not statistically significant (risk difference, −0.8%; 95% CI, −2.1% to 0.5%).

In the RCT like sample, the observed risk of stroke or death within 30 days of CEA was 2.4% (95% CI, 1.8%-3.2%), and the 5-year risk of fatal and nonfatal strokes was 5.5% (95% CI, 4.5%-6.5%) in the CEA group vs 7.6% (95% CI, 5.7%-9.5%) in the medical management group (risk difference, −2.1%; 95% CI, −4.4% to −0.2%). Again, when including the competing risks, a risk difference of −0.9% (95% CI, −2.9% to 0.7%) that was not statistically significant was seen. The authors concluded that the benefits seen in the past with CEA for asymptomatic carotid stenosis were no longer observed and that medical management for this cohort of patients could be recommended.

There are several limitations for this study. First, this was a retrospective analysis of data which was randomized by the authors in an attempt to emulate an RCT like study. Enrollments in RCTs follows strict protocols in a controlled environment. It is possible that accurate data might have been missed/not available during the initial evaluation as the authors stated that since they used the Suicide Data Repository, there was a possibility that stroke deaths might not have been coded. Second, male veterans aged 65 years and above were included in the study, and hence the results cannot be applied to the population as a whole, especially younger patients and women. Third, the analysis censored patients that were initially randomized to one group and later crossed into the other group, and the success of this censoring depends on an assumption that an adequate set of variables were measured.

While the current paper is an interesting analysis, the ongoing CREST-2 (Carotid Revascularization Endarterectomy Versus Stenting 2) trial that attempts to answer the same question should provide further insight.