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EXPERT COMMENTARY
Year : 2018  |  Volume : 5  |  Issue : 1  |  Page : 6-8

Expert commentary on “asymptomatic carotid stenosis” less is more!


The Leicester Vascular Institute, Glenfield Hospital, Leicester, UK

Date of Web Publication31-Jan-2018

Correspondence Address:
A Ross Naylor
The Leicester Vascular Institute, Glenfield Hospital, Leicester
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijves.ijves_84_17

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How to cite this article:
Naylor A R. Expert commentary on “asymptomatic carotid stenosis” less is more!. Indian J Vasc Endovasc Surg 2018;5:6-8

How to cite this URL:
Naylor A R. Expert commentary on “asymptomatic carotid stenosis” less is more!. Indian J Vasc Endovasc Surg [serial online] 2018 [cited 2018 Dec 11];5:6-8. Available from: http://www.indjvascsurg.org/text.asp?2018/5/1/6/224461



The management of asymptomatic carotid disease remains enduringly controversial, largely because only a relative minority of patients is ever destined to suffer a stroke, along with growing evidence that the risk of stroke on modern medical therapy appears to be declining. The 2017 European Society for Vascular Surgery (ESVS) guidelines on the management of atherosclerotic carotid and vertebral artery disease became the first to recommend that asymptomatic patients with 60%–99% stenoses who exhibit one or more imaging and/or clinical criteria which might make them “higher risk for stroke on medical therapy” should be considered for carotid endarterectomy (CEA) or carotid artery stenting (CAS), with the remainder being treated medically.[1] This revised recommendation has generated debate,[2] but it has also been adopted by the European Society of Cardiology.[3] By contrast, the latest American Heart Association (AHA) guidelines still continue to advise that only “highly selected” asymptomatic patients should be considered for a carotid intervention.[4] However, like all of its predecessor guidelines, the AHA does not define what is meant by “highly selected.” Accordingly, and possibly because of a fear of medicolegal censure, patients with 60%–99% asymptomatic stenoses in many health systems around the world (especially those that are “fee per case” funded [5]) have tended to be offered CEA or CAS.

So why is this still such a contentious issue, especially as two large randomized trials comparing CEA with best medical therapy (BMT) reported that CEA conferred a small but significant reduction in stroke at 5 and 10 years?[6],[7] Surely, level I evidence trumps all other opinion?

The fact is there were rumblings of discontent from the time that the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST) first published their 5-year data.[6],[7] Surgeons expressed surprise that CEA conferred much less benefit (in ACAS) than had been expected, based on historical observational study data,[8] while leading neurologists questioned whether the small but significant benefit conferred by CEA justified a 10-fold increase in CEA rates in asymptomatic patients.[9] Attitudes around the world (particularly amongst neurologists) were further polarized by a growing awareness that 30-day death/stroke rates after CEA in “real world” practice were significantly higher than had been observed in ACAS and ACST,[10] thereby casting doubt on the external validity of randomized trial outcomes in terms of application within routine clinical practice. Inevitably, focus has now turned toward CAS practitioners, regarding their outcomes in asymptomatic patients. In a recent systematic review, 9/21 administrative dataset registries (43%) reported 30-day death/stroke rates which exceeded 3% after CAS in asymptomatic patients, while 7/21 registries (33%) reported 30-day death strokes which exceeded 4%.[11]

The most controversial issue, however, is the growing body of evidence that the risk of stroke in asymptomatic patients treated medically may be declining.[12] In a systematic review, this observation was consistent across all stenosis severities, as well as for both ipsilateral and “any” stroke and (most importantly) it was also apparent in the randomized trials. In ACAS and ACST, the sequential 5-year risks of stroke in patients randomized to BMT declined by 70% from when ACAS reported its first 5-year data in 1995, compared to what was reported in the first 5-year data in ACST (2004) and then the 5–10 years' ACST data published in 2010.[12] In another large meta-analysis of 41 studies, the rate of ipsilateral stroke was 2.3/100 person-years in studies which completed recruitment before 2000, compared with 1.0/100 person-years in studies which published between 2000 and 2010 (P < 0.001).[13] The 39% decline in ipsilateral stroke per decade was attributed to improvements in medical therapy and smoking cessation. Interestingly, in studies where >25% of patients took statins, the rate of ipsilateral stroke was 1.2/100 person-years, compared with 2.3/100 person-years where <25% of participants took statins (P = 0.009).[13] The apparent decline in stroke in patients treated medically is now being tested in CREST-2, where asymptomatic patients are being randomized to either CEA versus BMT alone or CAS versus BMT alone.[14] The SPACE-2 randomized trial (Germany, Austria, and Switzerland) had a similar methodology to CREST-2 (in that it included a limb for medical therapy). Sadly, this trial stopped prematurely because of problems with recruitment after only randomizing 500 patients.[15],[16]

Notwithstanding previous comments about external validity, there is a perception among surgeons that procedural risks following CEA have been declining and this perception would appear to be supported by a recent meta-analysis involving >60,000 asymptomatic patients which reported that the 30-day risk of stroke after CEA had declined from 3.2% (in studies published before 2005), down to 1.5% thereafter.[17] It is assumed (by many surgeons) that this reduction in procedural risk will translate into much greater long-term benefit for the asymptomatic patient (in terms of stroke prevention), which may offset any potential reduction in stroke rates associated with improvements in BMT.[12] However, this assumption does not stand up to scrutiny. ACAS and ACST observed that CEA conferred small but significant absolute risk reductions (ARR) in stroke at 5 years over medical therapy alone (ACAS ARR = 5.9%; ACST ARR = 5.4%).[6],[7] With an ARR of 5.9% (in ACAS), this means that 59 strokes would be prevented per 1000 CEAs at 5 years. The corresponding value for ACST is 54 strokes prevented at 5 years/1000 CEAs. Simple mathematics then shows that 941 patients in ACAS (94%) and 946 (95%) in ACST, therefore, underwent an ultimately unnecessary CEA. If one looks at the 10-year ACST data (where the ARR in stroke conferred by CEA was 4.6%), this means that 46 strokes would be prevented at 10 years/1000 CEAs, i.e., 954 (95%) underwent an ultimately unnecessary CEA at 10 years.

If one now remodels these ACAS and ACST data for a 0% perioperative death/stroke risk, to see if declining perioperative stroke rates significantly increase the efficacy of CEA, the evidence suggests that the benefits (in terms of strokes prevented) hardly change at all. With a remodeled ARR of 8.2% (using ACAS data and assuming a 0% operative risk), 82 strokes will now be prevented per 1000 CEAs at 5 years. The corresponding value for ACST is 83 strokes prevented. This means that 918 ACAS patients (92%) and 917 ACST patients (92%) would still undergo an ultimately unnecessary CEA (despite having a 0% procedural risk). If one remodels the 10-year ACST data (where the ARR in stroke conferred by CEA would increase to 7.4% if there was a 0% operative risk), 926 (93%) of patients would still undergo an ultimately unnecessary CEA at 5 years. Simply put, reducing perioperative death/stroke rates is nothing but good news for the individual patient, but it actually does little to reduce the number of patients who will ultimately undergo an unnecessary CEA.[12]

The goal for the future is to identify a smaller cohort of “higher risk patients for stroke” in whom to target CEA or CAS. The 2017 ESVS guidelines are the first to try and translate this principle into practice. The guidelines identified a number of clinical and/or imaging features which have been shown in meta-analyses, subgroup analyses from randomized trials, or multicenter observational studies (i.e., not single-center studies) to be associated with an increased risk of late stroke on medical therapy. The guidelines detail the magnitude of stroke reduction for each imaging/clinical parameter, for those interested in seeing how they compare.[1] These imaging/clinical criteria include a history of contralateral transient ischemic attack/stroke, silent infarction on computed tomography/magnetic resonance (MR), stenosis progression, large volume plaque area on computerized plaque analysis, a large juxtaluminal hypoechoic area on computerized plaque analysis, plaque lucency, intraplaque hemorrhage on MR image, impaired cerebral vascular reserve, and spontaneous embolization on transcranial Doppler ultrasound monitoring.[1]

Finally, concerns over external validity of trial data, the limited benefit conferred by CEA, the declining rate of stroke on modern medical therapy, and the potential for patients with false positive scans undergoing CEA and then suffering a perioperative stroke led the United States Preventive Services Taskforce to once again recommend against any form of screening for asymptomatic carotid disease.[18] However, if it proved possible to identify a smaller cohort of “higher risk for stroke patients on medical therapy,” the benefits of screening might prove more advantageous. While a smaller proportion of asymptomatic patients would ultimately undergo CEA (or CAS), everyone would benefit from institution of BMT, which will significantly reduce fatal cardiac events, which are the most common cause of late death in patients with asymptomatic carotid disease.[19]



 
  References Top

1.
Writing Group, Naylor AR, Ricco JB, de Borst GJ, Debus S, de Haro J, et al. 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.  Back to cited text no. 1
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Eckstein HH. Editorial: 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.  Back to cited text no. 2
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3.
Authors/Task Force Members, Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European society for vascular surgery (ESVS). Eur J Vasc Endovasc Surg 2017. pii: S1078-5884(17)30454-9.  Back to cited text no. 3
    
4.
Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, et al. Guidelines for the primary prevention of stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:3754-832.  Back to cited text no. 4
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Venermo M, Wang G, Sedrakyan A, Mao J, Eldrup N, DeMartino R, et al. Editor's choice – Carotid stenosis treatment: Variation in international practice patterns. Eur J Vasc Endovasc Surg 2017;53:511-9.  Back to cited text no. 5
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7.
Halliday A, Mansfield A, Marro J, Peto C, Peto R, Potter J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: Randomised controlled trial. Lancet 2004;363:1491-502.  Back to cited text no. 7
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Hertzer NR. A personal view: The asymptomatic carotid atherosclerosis study results – Read the label carefully. J Vasc Surg 1996;23:167-71.  Back to cited text no. 8
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Barnett HJ, Eliasziw M, Meldrum HE, Taylor DW. Do the facts and figures warrant a 10-fold increase in the performance of carotid endarterectomy on asymptomatic patients? Neurology 1996;46:603-8.  Back to cited text no. 9
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Rothwell PM, Goldstein LB. Carotid endarterectomy for asymptomatic carotid stenosis: Asymptomatic carotid surgery trial. Stroke 2004;35:2425-7.  Back to cited text no. 10
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Paraskevas KI, Kalmykov EL, Naylor AR. Stroke/Death rates following carotid artery stenting and carotid endarterectomy in contemporary administrative dataset registries: A Systematic review. Eur J Vasc Endovasc Surg 2016;51:3-12.  Back to cited text no. 11
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Naylor AR. Time to rethink management strategies in asymptomatic carotid artery disease. Nat Rev Cardiol 2011;9:116-24.  Back to cited text no. 12
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Hadar N, Raman G, Moorthy D, O'Donnell TF, Thaler DE, Feldmann E, et al. Asymptomatic carotid artery stenosis treated with medical therapy alone: Temporal trends and implications for risk assessment and the design of future studies. Cerebrovasc Dis 2014;38:163-73.  Back to cited text no. 13
    
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Howard VJ, Meschia JF, Lal BK, Turan TN, Roubin GS, Brown RD Jr., et al. Carotid revascularization and medical management for asymptomatic carotid stenosis: Protocol of the CREST-2 clinical trials. Int J Stroke 2017;12:770-8.  Back to cited text no. 14
    
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Eckstein HH, Reiff T, Ringleb P, Jansen O, Mansmann U, Hacke W, et al. SPACE-2: A Missed opportunity to compare carotid endarterectomy, carotid stenting, and best medical treatment in patients with asymptomatic carotid stenoses. Eur J Vasc Endovasc Surg 2016;51:761-5.  Back to cited text no. 15
    
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Naylor AR. Lost in SPACE! Eur J Vasc Endovasc Surg 2016;51:759-60.  Back to cited text no. 16
    
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Lokuge K, de Waard DD, Halliday A, Gray A, Bulbulia R, Mihaylova B, et al. Meta-analysis of the procedural risks of carotid endarterectomy and carotid artery stenting over time. Br J Surg 2018;105:26-36.  Back to cited text no. 17
    
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LeFevre ML; U.S. Preventive Services Task Force. Screening for asymptomatic carotid artery stenosis: U.S. Preventive services task force recommendation statement. Ann Intern Med 2014;161:356-62.  Back to cited text no. 18
    
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Giannopoulos A, Kakkos S, Abbott A, Naylor AR, Richards T, Mikhailidis DP, et al. Long-term mortality in patients with asymptomatic carotid stenosis: Implications for statin therapy. Eur J Vasc Endovasc Surg 2015;50:573-82.  Back to cited text no. 19
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