Recent findings about the long-term prognosis of both carotid artery stenting (CAS) and carotid endarterectomy (CEA) in asymptomatic and symptomatic carotid artery stenosis were presented at the International Stroke Conference (ISC) 2019, Honolulu, Hawaii. The insights shared from a pooled analysis of the randomized CREST and ACT I trial have reinforced the idea that both CAS and CEA could yield similar long-term outcomes in the treatment of asymptomatic carotid stenosis. In contrast, CEA is favored in symptomatic carotid artery stenosis when long term prognosis is concerned.
Clinical presentations of carotid artery disease: Asymptomatic vs. symptomatic
Carotid artery disease (CAD), moderate to severe (50%-99%), is considered a global public health issue, which leads to 10% of all strokes and affects 10% of general population by their 8th decade.1 In Hong Kong, cerebrovascular disease is the fourth leading cause of death in 2017 with stroke leads to death for around 3,000 people annually and 20% is caused by CAD.2
CAD is the most important marker of systemic atherosclerosis which is associated with a higher risk of cardiovascular events.3 Therefore, early follow up and treatment together with lifestyle modifications are recommended for all patients diagnosed with CAD.3 For many years, clinical decisions about the management of CAD have been based on the distinction between “asymptomatic” and “symptomatic” clinical presentations, which corresponds to the design and results of previous clinical trials on surgical versus medical treatment of carotid stenosis for stroke prevention as well as of current studies.3 According to the definitions of major clinical trials, carotid stenosis is defined as “symptomatic” if associated with symptoms in recent six months and “asymptomatic” if no prior symptoms can be identified or symptoms occurred more than six months ago.4 Although there are controversial facts on the above classification in clinical situations, in the latest ISC 2019, Professor Jon Matsumara, University of Wisconsin School of Medicine and Public Health, United States, stated “both symptomatic and asymptomatic patients are different enough and they should be analyzed differently, both morphologically and in terms of the future risk”.4
Recent evidence on the revascularization of carotid artery
CAS or CEA are the major treatment modalities in the revascularization of carotid artery. CAS is comparatively less invasive than CEA, with a lower risk to cranial nerve injury, wound complications or hematoma of the neck.5 In patients with “hostile neck” with recurrent stenosis or previous radiation, CAS offers more advantages over CEA.5 Furthermore, other instances such as contralateral recurrent laryngeal nerve palsy or cases of challenging surgical access, CAS is favored.6 Incidence of perioperative myocardial infarction is associated with CEA and those at a higher risk of perioperative cardiac complications may benefit from CAS.6
Among the number of randomized clinical trials (RCTs) conducted to compare CEA with CAS in asymptomatic CAD, the most noted CREST and ACT I recruited exclusively experienced interventionists and reported a death/stroke rate of 2.9% for CAS (3% is the accepted rate).5 Nevertheless, the application of these findings to real world situations are questionable as they were being performed in small number of multiple specialties.7 A systematic review conducted using dataset registries (n=1.5 million cases) indicated that 40 % of registries reported >3% of death/stroke rate and simultaneously 14% reported >5% of death/stroke rate after CAS.8
However, comparison of CAS and CEA among symptomatic patients depicts a different picture. Results of four RCTs showed that the risk of “any stroke” and “death/stroke” in symptomatic patients is 50% higher following CAS, because CAS is associated with a significantly higher rates of minor strokes.5 In CREST, CAS was performed within 14 days of the symptom onset, which led to a 5.6% increased rate of death/stroke compared with 2.6% after CEA. In symptomatic patients undergoing CAS within 15-60 days, a risk of 6.1% of death/stroke was observed compared with 2.3% after CEA.7 SPACE and International Carotid Stenting Study (ICSS) also reported significantly higher perioperative stroke levels in patients >70 years of age undergoing CAS, while CEA in contrast had a little effect on age.9
Latest guideline in the management of asymptomatic CAD
The latest guideline from the European Society of Cardiology on the treatment of CAD recommended that, in an “average surgical risk” asymptomatic patient, with 60-99% stenosis, CEA should be considered in the presence of clinical and imaging characteristics (Figure 1) that may be associated with an increased risk of late ipsilateral stroke.5 If the documented perioperative stroke/death rates are <3% and patient life expectancy is >5 years CAS may be an alternative among these patients.5 In asymptomatic patients who are categorized as “high risk” for CEA, with stenosis of 60-99%, and with imaging and clinical characteristics that may be associated with an increased risk of late ipsilateral stroke, CAS should be considered.5
Latest guideline in the management of symptomatic CAD
Revascularization of symptomatic 50-99% carotid stenoses should be performed as soon as possible (but not in patients with a <50% carotid stenosis), preferably within 14 days of symptom onset.5 In symptomatic patients with 70-99% and 50-69% carotid stenosis, CEA is recommended when documented perioperative death/stroke rate is <6%.5 Those symptomatic patients with recent 50-99% stenosis presented with adverse anatomical features or medical comorbidities are considered “high risk” for CEA, therefore CAS should be adopted provided that the documented perioperative death/stroke rate is <6%.5 CAS could be an alternative to CEA when revascularization is indicated in “average surgical risk” symptomatic patients if the documented perioperative death/stroke rate is <6%. 5
CAS demonstrated comparable short- and long-term outcomes to CEA in asymptomatic carotid stenosis
The systematic review and meta-analysis, conducted by Moresoli et al in 2014, concluded that CEA is the preferred option for the management of asymptomatic CAD.10 However with the recent and newer treatment options like CAS with embolic protection, latest findings showed that CAS has comparable short- and long-term results to CEA.
The pooled analyzed results of CREST and ACT I trials also indicated that the primary end point of periprocedural death, stroke, myocardial infarction (MI), or 4-year ipsilateral stroke was 5.3% with CAS and 5.1% with CEA. The difference was nonsignificant (HR=1.02; 95% CI: 0.7-1.5; p=0.91).11
The main results of CREST were reported initially in 2010, which showed similar outcomes of CAS and CEA, but CAS induced higher stroke rate at 30 days at 4.1% vs. 2.3% with CEA.11 In ACT I, reported in ISC 2016, at the primary end point of 1-year ipsilateral stroke, CAS was non-inferior to CEA, with no difference in stroke/death at 5 years.11
The current analysis of CREST and ACT I trials involved 2,544 patients (1,637-CAS, 907-CEA), and the CAS and CEA groups did not differ significantly in associated variables such as age (mean, 67.7 vs. 68.25 years), male sex (62.4% vs. 63.3%), white race (91.8% vs. 93.2%), or presence of hypertension (89.8% vs. 88.5%), hyperlipidemia (90.3% vs. 89.9%) or diabetes (35.0% vs. 33.7%).
After a 4-year period, the rates of ipsilateral stroke were similar for CAS and CEA groups (2.3% vs. 2,2%, p=0.97). Professor Matsumara, lead investigator of the study commented “In a field where there are often very strong opinions, I think this is one where trialists across the world in their trials has found that the durability after the periprocedural hazard is very similar with both of these interventions [CAS and CEA]”.11
The stroke-free survival rate over the four years was 93.2% in the CAS group and 95.1% in the CEA group (p=0.10).11 Cumulative 4-year all-cause survival rate has also shown no difference among CAS and CEA.11 During the discussion of the results, Professor Matsumara further stated that the lower rate of periprocedural stroke compared with historic findings are likely related to the lack of embolic protection in many of the early trials. He further added that detailed information was not available to determine whether there were differences in medical management between CAS and CEA groups.11
Ipsilateral stroke: CAS versus CEA in symptomatic carotid stenosis
A decade long patient-level pooled analysis data in comparing the relative efficacy of CAS with CEA in symptomatic CAD patients was presented. The primary outcome was the composite risk of stroke or death within 120 days after randomization (periprocedural risk), or subsequent ipsilateral stroke up to 10 years after randomization (postprocedural risk) which occurred in 3% of patients with CEA and 2.9% of patients with CAS in five years (Figure 2A).12 When translated into annual rate of ipsilateral stroke per person-year, it was 0.60 % for CEA and 0.64 % for CAS (HR=1.06; 95% CI: 0.73-1.54), indicating no difference.13
Study author Professor Thomas Brott, MD, Professor of Neurology and Director for Research, Mayo Clinic, Jacksonville, Florida, United States, commented “Really what kind of [thing] surprised us with all of these studies is that once the patient underwent successful endarterectomy or stent, there was an exceptionally low rate of subsequent ipsilateral stroke”.13
But he further added that when peri- and post-procedural risks were combined (Figure 2B), the outlook is different.13 The combined risk for any stroke or death within 120 days and ipsilateral stroke after 120 days to 10 years was 8.3% with CEA and 11.4 % with CAS until 5 years.13 When the risk difference carries forward at 9 years of formal analysis, it resulted in 45% of advantage for CEA over CAS (HR=1.45; 95% CI:1.20-1.75).13
Nevertheless, in the article simultaneously published in Lancet Neurology, Professor Brott stated that if the procedures are performed safely, both CAS and CEA patients can anticipate ten years of stroke-free survival. The net long term benefits of CEA warrant further improvements in procedural safety of CAS. Although combined peri and post-procedural risks favor CEA, the similar post-procedural risks suggest that improvements in peri-procedural safety of CAS could provide similar outcomes of the two procedures in the future.12
The new emerging evidence helps further shape the choice of treatment for CAD: CAS or CEA on symptomatic and asymptomatic patients. By summarizing the main randomized clinical trials, CAS showed similar short- and long-term outcomes to CEA, although there have been more periprocedural vascular events in CAS compared with CEA. Moving forward, clinicians should integrate the currently available data to individualize better treatment paradigm for CAD patients, as the outcome varies with the level of stenosis and surgical risk of the patients.