Annals of Indian Academy of Neurology
EDITORIAL
Year
: 2022  |  Volume : 25  |  Issue : 2  |  Page : 171--176

Asymptomatic carotid stenosis: Several guidelines with unclear answers


Pachipala Sudheer, Deepti Vibha, Shubham Misra 
 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Deepti Vibha
Room No 707, 7th Floor, Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi - 110 049
India




How to cite this article:
Sudheer P, Vibha D, Misra S. Asymptomatic carotid stenosis: Several guidelines with unclear answers.Ann Indian Acad Neurol 2022;25:171-176


How to cite this URL:
Sudheer P, Vibha D, Misra S. Asymptomatic carotid stenosis: Several guidelines with unclear answers. Ann Indian Acad Neurol [serial online] 2022 [cited 2022 Jul 3 ];25:171-176
Available from: https://www.annalsofian.org/text.asp?2022/25/2/171/335395


Full Text



Asymptomatic carotid stenosis (ACS) is commonly defined as the presence of atherosclerotic narrowing of the proximal internal carotid artery by ≥50% at the level of bifurcation in individuals with no history of recent (within the last six months) ischemic stroke/TIA involving ipsilateral carotid territory.[1] Although the presence of 50%–69% narrowing is considered as moderate stenosis, narrowing ≥70% is generally considered as severe stenosis.[2] However, there are no standard criteria proposed on the severity of stenosis and duration of recent ischemic event and definitions vary among studies depending on the method used for assessment of stenosis. Some criteria also use >60% definition. [Table 1] summarises the definitions of all major trials addressing the management of ACS.{Table 1}

The importance of optimal management ACS comes from the fact that it is not just a risk factor for stroke but to coronary artery disease and mortality as well. Results from the Second Manifestations of ARTerial disease (SMART) study provides evidence that patients with ACS should be treated optimally as they are at risk of vascular events (HR 1.5; 95% CI 1.1–2.1) and mortality (HR 1.8; 95% CI 1.2–2.6).[8] However, the management of ACS remains controversial, largely because only a small proportion of patients are ever destined to suffer a stroke, along with growing evidence that the risk of stroke declines with modern medical therapy, risk factors control and statin use.

 What Do the Guidelines Say?



A significant controversy in the management of patients with ACS is the selection of patients for carotid revascularisation, notably in the face of evidence that ipsilateral strokes on optimal medical therapy have declined significantly over time. [Table 2] summarises all the available guidelines published till date addressing the management of ACS.[9] The evidence supporting these recommendations is largely drawn from the randomised controlled trials (RCTs) explained below. The 2017 European Society of Vascular Surgery guidelines (ESVS) suggest that carotid endarterectomy (CEA) (class IIa recommendation, level of evidence B) or carotid stenting (class IIb, level of evidence B) should be considered for patients with ACS (60%–99%) at average surgical risk, provided the documented perioperative stroke/death rate is less than 3% and the patient's life expectancy exceeds 5 years.[10] This is in line with the other guidelines.[11],[12],[13],[14] Although all the guidelines suggest forming a multidisciplinary team for the management of these patients, the recommendations are not clear when it comes to carotid artery stenting (CAS) in both patients at average risk and high risk of complications of CEA.{Table 2}

 Carotid Revascularisation and the Evolution of Medical Management



The current evidence on management of ACS is based on several landmark trials. Three randomised controlled trials (RCTs) conducted in the 1990s investigated whether CEA could reduce the risk of stroke in patients with asymptomatic carotid stenosis, namely VA cooperative study group, Asymptomatic carotid atherosclerosis study (ACAS) and Asymptomatic carotid surgery trial 1 (ACST-1) trials.[3],[4],[15] [Table 3] These trials predominantly recruited participants with a stenosis ≥50%, although ACST-1 had no fixed minimum cut- off. All these trials reported significant benefit in favour of CEA. Although there are no direct RCTs evaluating the safety and efficacy of CAS over medical therapy, three RCTs compared the safety and efficacy of CAS with CEA, namely Stenting and angioplasty with protection in patients at high risk for endarterectomy (SAPPHIRE), Carotid revascularisation endarterectomy versus stenting trial (CREST-1) and Asymptomatic carotid trial 1 (ACT-1) trials.[5],[6],[16] [Table 4] None of the three studies showed a difference in event rates between CEA and CAS, providing evidence that carotid artery stenting with embolic protection is a reasonable alternative to endarterectomy in patients at average risk for CEA. However, the major limitation across all surgical trials in ACS is that the best medical management was not well established. Although aggressive medical treatment in ACAS trial constituted only aspirin[17], current concept of aggressive medical treatment includes lipid lowering therapy[18],[19] and optimal medical management of comorbidities like diabetes mellitus[20],[21], hypertension[22],[23], modification of life style including smoking cessation, moderation of alcohol intake, change in dietary habits and physical exercise[24],[25],[26],[27] [Table 5].{Table 3}{Table 4}{Table 5}

In 1995, ACAS trial reported 5-year risk of “ipsilateral” stroke of 11.0% (2.2% per annum) in patients receiving medical treatment with aspirin.[3] By 2004, the 5-year risk in ACST was reduced to 5.3% (1.1% per annum), whereas in years 6 to 10, the risk of “ipsilateral stroke” has decreased further to 3.6% (0.7% per annum) with modern medical treatment.[4] Evolution of medical treatment in the last two decades, especially with the introduction of intensive lipid lowering therapy has revolutionised the management of these patients.[18],[29],[30] A meta-analysis of the three most recently published studies on ACS patients receiving the best medical treatment showed an annual risk of 0.49% which is even less compared to the annual risk recorded in the 6-10 years results of ACST-1 trial.[31] These results signify that RCTs done so far have not included the best medical treatment. To support this notion, use of lipid lowering therapy and antihypertensive drugs increased significantly towards the end of study period in ACST-1 trial.[4] In the OxVasc study, the risk of ipsilateral stroke was only 0.34% per year in ACS patients receiving contemporary medical therapy.[32] Spence et al.[33] showed that intensive medical therapy based on treating arteries instead of treating risk factors was associated with lower risk of stroke and myocardial infarction (MI).

So had the medical treatment been optimal in the earlier RCTs, the results might have been different. There have been claims that advances in technology and increased experience may have led to reduction in risks following CAS and CEA which may increase the benefit of intervention in these patients. Naylor et al.[34] reanalysed the 5 and 10-years data from the ACAS and ACST trial with an assumption of 0% procedural risk. Modelling for a 0% procedural risk meant that more than 90% of these procedures were still unnecessary. On the contrary, in some cohort studies that included all three treatment groups, the results are conflicting [Table 6]. All these factors highlight the need for studies that can evaluate the efficacy of optimal medical management in comparison with CEA and CAS.{Table 6}

 Risk Stratification



Offering routine carotid revascularisation to every patient with asymptomatic carotid artery stenosis is no longer considered as the optimal management. Equally suboptimal, however, is the policy of offering only best medical treatment to these patients and not considering any of them for revascularisation. Some patients may not respond to medical management, and they may benefit from carotid revascularisation. It is essential to identify these subsets of patients who are at high risk of recurrence of events. Degree of stenosis alone may not be the best approach for identification of these patients. In the last few years, several methods have been proposed as reliable predictors for the identification of patients at high risk of stroke.[39] For some of these predictors, the evidence is adequate and robust, whereas for others it is weaker. Micro embolic signals detected on transcranial Doppler is a simple, convenient and cost-effective method that can help in risk stratification of these patients.[40]

[Table 7] summarises the clinical and imaging features that are associated with increased risk of stroke/TIA in ACS patients.[41]{Table 7}

 Need for Future Trials



Although there are trials supporting revascularisation and emerging evidence towards best medical therapy, there is a lack of consensus as reflected in the guidelines addressing the management of these patients. Though guidelines recommend CEA in management of ACS patients, the data is based on trials that appear to be of only historical importance. However, intervention in every patient with ACS is not worthwhile. AHA recognises that only highly selected patients should undergo carotid revascularisation but have not defined what is highly selected population.[13] Risk stratification through various methods has been proposed for identifying the high risk population but there are no studies to suggest that selective screening will reduce fatal or disabling strokes. Finally, the recent decline in stroke rates with optimal medical management has not been evaluated in an RCT. It is difficult to frame guidelines for management of these patients with the existing controversies. With the recent publication of studies suggesting an association between ACS and cognitive decline the clinical decision-making is going to become worse.[43] Hence there is a need for trials which can clear the existing controversies. CREST-2,[44] ECST-2,[45] and ACST-2[46] are some of the ongoing RCTs in patients with ACS. [Table 8] provides characteristics of these ongoing trials. The results of these trials should answer the role of optimal medical treatment, indications for revascularisation (CEA/CAS) and risk stratification of patients with ACS. In the meantime, patients referred for revascularisation should have evidence of vulnerable plaque.{Table 8}

 Conclusion



Asymptomatic carotid stenosis is a risk factor for stroke, myocardial infarction and mortality. Improvements in medical therapy have reduced the risk of cerebrovascular events possibly below a threshold where carotid revascularisation would still benefit the average risk patient. Although the results of the ongoing trials CREST-2,[44] ECST-2,[45] and ACST-2[46] awaited, all patients with ACS should receive optimal medical management for control of risk factors and comorbidities and patients with vulnerable plaque should be considered for revascularisation.

References

1den Hartog AG, Achterberg S, Moll FL, Kappelle LJ, Visseren FL, van der Graaf Y, et al. Asymptomatic carotid artery stenosis and the risk of ischemic stroke according to subtype in patients with clinical manifest arterial disease. Stroke 2013;44:1002-7.
2Chatzikonstantinou A, Wolf ME, Schaefer A, Hennerici MG. Asymptomatic and symptomatic carotid stenosis: An obsolete classification? Stroke Res Treat 2012;2012:340798. doi: 10.1155/2012/340798.
3Walker MD, Marler JR, Goldstein M, Grady PA, Toole JF, Baker WH, et al. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421-8.
4Halliday A, Harrison M, Hayter E, Kong X, Mansfield A, Marro J, et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): A multicentre randomised trial. Lancet 2010;376:1074-84.
5Brott TG, Hobson RW 2nd, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363:11-23.
6Rosenfield K, Matsumura JS, Chaturvedi S, Riles T, Ansel GM, Metzger DC, et al. Randomized trial of stent versus surgery for asymptomatic carotid stenosis. N Engl J Med 2016;374:1011-20.
7Reiff T, Eckstein HH, Mansmann U, Jansen O, Fraedrich G, Mudra H, et al. Angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy compared to best medical treatment: One-year interim results of SPACE-2. Int J Stroke 2019;15:1747493019833017. doi: 10.1177/1747493019833017.
8Goessens BM, Visseren FL, Kappelle LJ, Algra A, van der Graaf Y. Asymptomatic carotid artery stenosis and the risk of new vascular events in patients with manifest arterial disease: The SMART study. Stroke 2007;38:1470-5.
9Beckman JA, Ansel GM, Lyden SP, Das TS. Carotid artery stenting in asymptomatic carotid artery stenosis: JACC review topic of the week. J Am Coll Cardiol 2020;75:648-56.
10Eckstein HH. European Society for Vascular Surgery guidelines on the management of atherosclerotic carotid and vertebral artery disease. Eur J Vasc Endovasc Surg 2018;55:1-2
11Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, Cohnert T, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: The European Stroke Organization (ESO) The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J 2018;39:763-816.
12Ricotta JJ, Aburahma A, Ascher E, Eskandari M, Faries P, Lal BK, et al. Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease: Executive summary. J Vasc Surg 2011;54:832-6.
13Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guidelines for the primary prevention of stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:517-84.
14Carotid Stenting Guidelines Committee: An Inter-collegiate Committee of the RACP (ANZAN, CSANZ), RACS (ANZSVS) and RANZCR. Guidelines for patient selection and performance of carotid artery stenting. Intern Med J 2011;41:344-7.
15Hobson RW 2nd, Weiss DG, Fields WS, Goldstone J, Moore WS, Towne JB, et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. N Engl J Med 1993;328:221-7.
16Gurm HS, Yadav JS, Fayad P, Katzen BT, Mishkel GJ, Bajwa TK, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med 2008;358:1572-9.
17Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, et al. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849-60.
18Sillesen H, Amarenco P, Hennerici MG, Callahan A, Goldstein LB, Zivin J, et al. Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis: A secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke 2008;39:3297-302.
19Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
20American Diabetes Association. 6. Glycemic targets: Standards of medical care in diabetes-2021. Diabetes Care 2021;44(Suppl 1):S73-84.
21Rangaswami J, Bhalla V, de Boer IH, Staruschenko A, Sharp JA, Singh RR, et al. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: A scientific statement from the American Heart Association. Circulation 2020;142:e265-86.
22Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Hypertension 2018;71:1269-324.
23Kitagawa K, Yamamoto Y, Arima H, Maeda T, Sunami N, Kanzawa T, et al. Effect of standard vs intensive blood pressure control on the risk of recurrent stroke: A randomized clinical trial and meta-analysis. JAMA Neurol 2019;76:1309-18.
24Lin JS, O'Connor E, Evans CV, Senger CA, Rowland MG, Groom HC. Behavioral counseling to promote a healthy lifestyle in persons with cardiovascular risk factors: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2014;161:568-78.
25de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon Diet Heart Study. Circulation 1999;99:779-85.
26Paraskevas KI, Mikhailidis DP, Veith FJ, Spence JD. Definition of best medical treatment in asymptomatic and symptomatic carotid artery stenosis. Angiology 2016;67:411-9.
27Hackam DG. Optimal medical management of asymptomatic carotid stenosis. Stroke 2021;52:2191-8.
28Kolos I, Loukianov M, Dupik N, Boytsov S, Deev A. Optimal medical treatment versus carotid endarterectomy: The rationale and design of the Aggressive Medical Treatment Evaluation for Asymptomatic Carotid Artery Stenosis (AMTEC) study. Int J Stroke Off J Int Stroke Soc 2015;10:269-74.
29Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
30Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
31Rothwell PM. Carotid stenting: More risky than endarterectomy and often no better than medical treatment alone. Lancet 2010;375:957-9.
32Marquardt L, Geraghty OC, Mehta Z, Rothwell PM. Low risk of ipsilateral stroke in patients with asymptomatic carotid stenosis on best medical treatment: A prospective, population-based study. Stroke 2010;41:e11-7.
33Spence JD, Coates V, Li H, Tamayo A, Muñoz C, Hackam DG, et al. Effects of intensive medical therapy on microemboli and cardiovascular risk in asymptomatic carotid stenosis. Arch Neurol 2010;67:180-6.
34Naylor AR. Why is the management of asymptomatic carotid disease so controversial? Surgeon 2015;13:34-43.
35Libman RB, Sacco RL, Shi T, Correll JW, Mohr JP. Outcome after carotid endarterectomy for asymptomatic carotid stenosis. Surg Neurol 1994;41:443-9.
36Lim S, Mora-Pinzon M, Park T, Yoon W, Crisostomo PR, Cho JS. Medical therapy does not confer stroke prevention for all patients: Identification of high-risk patients with asymptomatic carotid stenosis is still needed. Int Angiol 2019;38:372-80.
37Kang J, Kim YW, Kim DI, Woo SY, Park YJ. Outcomes of carotid revascularization versus optimal medical treatment alone for asymptomatic carotid stenosis: Inverse-probability-of-treatment weighting using propensity scores. World Neurosurg 2021;146:e419-30.
38Keyhani S, Cheng EM, Hoggatt KJ, Austin PC, Madden E, Hebert PL, et al. Comparative effectiveness of carotid endarterectomy vs initial medical therapy in patients with asymptomatic carotid stenosis. JAMA Neurol 2020;77:1110-21.
39Paraskevas KI, Veith FJ, Spence JD. How to identify which patients with asymptomatic carotid stenosis could benefit from endarterectomy or stenting. Stroke Vasc Neurol 2018;3:92-100.
40Markus HS, King A, Shipley M, Topakian R, Cullinane M, Reihill S, et al. Asymptomatic embolisation for prediction of stroke in the Asymptomatic Carotid Emboli Study (ACES): A prospective observational study. Lancet Neurol 2010;9:663-71.
41Naylor AR, Ricco JB, de Borst GJ, Debus S, de Haro J, Halliday A, et al. Editor's choice-management of atherosclerotic carotid and vertebral artery disease: 2017 clinical practice guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 2018;55:3-81.
42Kamtchum-Tatuene J, Noubiap JJ, Wilman AH, Saqqur M, Shuaib A, Jickling GC. Prevalence of high-risk plaques and risk of stroke in patients with asymptomatic carotid stenosis: A meta-analysis. JAMA Neurol 2020;77:1524-35.
43Gray VL, Goldberg AP, Rogers MW, Anthony L, Terrin ML, Guralnik JM, et al. Asymptomatic carotid stenosis is associated with mobility and cognitive dysfunction and heightens falls in older adults. J Vasc Surg 2020;71:1930-7.
44Mott M, Koroshetz W, Wright CB. CREST-2: Identifying the best method of stroke prevention for carotid artery stenosis: National Institute of Neurological Disorders and Stroke organizational update. Stroke 2017;48:e130-1.
45ISRCTN-ISRCTN97744893: European Carotid Surgery Trial 2. Available from: https://www.isrctn.com/ISRCTN97744893. doi: 10.1186/ISRCTN97744893.
46Bulbulia R, Halliday A. The asymptomatic carotid surgery trial-2 (ACST-2): An ongoing randomised controlled trial comparing carotid endarterectomy with carotid artery stenting to prevent stroke. Health Technol Assess 2017;21:1-40.