ISCHEMIC STROKE / PREVENTION

Management of asymptomatic carotid stenosis

Created 03/01/2022, last revision 27/02/2023

carotid artery atherosclerotic disease is a substantial stroke risk factor (TOAST 1)
classification of carotid artery disease
- asymptomatic x symptomatic (signs/symptoms of cerebral or ocular ischemia in the past 6 months)
- low risk x high risk
high risk features:
- significant carotid stenosis of ≥ 50% or an increased carotid IMT of 1.5 mm
- detection of vulnerable plaque (characteristics are discussed below)
- additional uncontrolled CV risk factors (atrial fibrillation, diabetes mellitus, metabolic syndrome, etc.)

Stroke risk and prevalence of asymptomatic carotid stenosis

Carotid artery stenosis (ultrasound, CTA, MRA, DSA)

the prevalence of carotid artery atherosclerotic disease depends on the population studied and the stenosis threshold used for inclusion
- the prevalence of asymptomatic stenosis > 50% is 2-8%, and the prevalence of asymptomatic stenosis > 80% is 1-2%
- the prevalence of stenosis > 50% increases with age
  - < 60 years – 0.5% , > 80 years – 10%
the risk of stroke in patients with asymptomatic carotid stenosis > 50% is about 1-2%/year (rate of coronary events is 7%)
- compared to symptomatic stenosis, the risk is much lower
- according to a population-based study and meta-analysis, the risk of stroke increases with the degree of stenosis – the risk of 80-99% stenosis is higher than that of 50-79% stenosis [Howard, 2021]
- see below for individual parameters of high-risk plaques
in addition to the increased risk of stroke, patients with asymptomatic carotid stenosis also have an increased risk of MI ⇒ intensive systemic therapy is essential

Revascularization trials for asymptomatic carotid stenosis

Management of patients with carotid artery stenosis undergoing surgical intervention

in general, prophylactic CEA is not required before surgery using general anesthesia (GA) or extracorporeal circulation (ECC) → carotid endarterectomy

Screening for asymptomatic carotid stenosis

screening for asymptomatic carotid stenosis in the general population is not recommended by the U.S. Preventive Services Task Force (unknown cost-benefit)
- the situation may vary from country to country.
it is recommended to screen selected patients with:
- symptomatic peripheral artery disease (PAD), coronary artery disease (CAD), or atherosclerotic aortic aneurysm
- ≥ 2 of the following CV risk factors, including arterial hypertension, hyperlipidemia, smoking, family history of early-onset atherosclerotic disease in a first-degree relative, or family history of ischemic stroke
repeated duplex examination:
- annually assess patients with carotid stenosis >50% for progression or regression and response to therapeutic intervention
- patients with normal/mildly increased baseline IMT should not have repeat carotid Doppler (because of the very slow rate of IMT increase)

Best medical therapy

best medical therapy (BMT) is the mainstay of carotid stenosis management (it also leads to a reduced risk of MI)
- antiplatelet drugs
- intensive management of vascular risk factors
the relatively low risk of stroke was reported with such an approach (~1.68%/year) [Raman, 2013]

Antithrombotic therapy

Antiplatelet drugs

aspirin 75-325 mg/d
aspirin intolerance or contraindication: clopidogrel (75mg) or ticlopidine
clopidogrel resistance/allergy: consider ticagrelor (BRILIQUE)

→ antiplatelet drugs

Anticoagulant drugs

antiplatelet + low-dose anticoagulant:
- ASA + rivaroxaban 2×2.5 mg in selected patients
  - in the COMPASS trial, carotid disease included both asymptomatic stenosis and patients with previous revascularization. The combination was maximally effective in patients with ‘symptomatic PAD’ defined as the co-existence of symptomatic peripheral artery disease of lower
    extremities and carotid artery disease

anticoagulants alone: not recommended
antiplatelets + standard-dose anticoagulants: not recommended

Vascular risk factors management

target BP < 120/80 mm Hg (if possible concerning comorbidities)
- in therapy, prefer ACE-I or sartans
lipid-lowering therapy
- LDL cholesterol target according to cardiovascular risk → target lipid values
tight glycemic control
- target glycosylated Hb < 53 mmol/mol in diabetes + management of insulin resistance
lifestyle interventions:
- smoking cessation
- obesity control
  - according to some recommendations, the target BMI <20-24!
  - waist circumference female/ male <80/<94 cm
- a healthy diet (i.e. Med-Diet)
- physical activity
  - 150 min/wk of moderate aerobic or 75 min/wk of vigorous aerobic activity

→ overview of most important vascular risk factors

Carotid artery revascularization

carotid artery revascularisation (CAR) = carotid endarterectomy (CEA) or carotid angioplasty and stenting (CAS)
carotid revascularisation should only be performed in a unit with low perioperative complications (<3% for asymptomatic stenosis)
CEA and CAS have similar safety, but CEA seems to be a little safer (ACST-2)
- the SAPPHIRE and CREST trials demonstrated the similar safety of CAS and CEA
- ACT 1 and ACST-2 trials demonstrated comparable safety even in asymptomatic stenoses [Rosenfield, 2016]
- on the other hand, CEA appears somewhat safer than CAS according to an analysis of 5 randomized trials [Moresoli, 2017]
patients with more extensive white matter lesions on CT/MRI (ARWMC score ≥ 7) should be treated with CEA (ICSS trial)
when considering any intervention, several aspects should be considered that may help to select patients with the highest benefit from revascularisation (→ see here)
- degree of stenosis + plaque vulnerability should be evaluated (Brinjikji, 2016)

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All cited markers of high stroke risk associated with asymptomatic carotid stenosis:

lack specificity
have not been assessed in conjunction with the current optimal medical therapy
have not been shown in randomized trials to identify those who will benefit from a carotid revascularization procedure in addition to optimal medical therapy

Stenosis degree

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Progression over time

risk of stenosis progression is substantial and increases with time
several studies showed a higher risk of stroke in progressive stenoses > 80%
rapidly progressive stenoses, in particular, seem to be associated with a higher risk of ischemic stroke
the data justify the use of serial duplex scans to follow carotid stenosis; there is no consensus on the appropriate intervals
- according to various recommendations, the scan should be repeated every 6-12 months for stenosis > 50% (AHA/ASA 2014 IIa/C)

Plaque morphology

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Proof of microembolization on TCD/TCCD

the association of embolic signals with the risk of infarction has been demonstrated in both symptomatic and asymptomatic stenoses [Markus, 2017]
- detection of ≥ 2 embolic signals per hour indicates an unstable plaque or a plaque with concurrent thrombosis
- annual stroke risk is up to 8% in such condition
embolic signals are more common in unstable, hypoechoic, exulcerated, poorly calcified plaques
the use of TCD Holter may be helpful in these conditions

Evidence of silent ischemia

according to some authors, the incidence of silent ischemia on CT/MRI correlates with the degree of stenosis and the type of plaque (especially exulcerated plaques)
- MRI is more sensitive than CT
- according to the ACSRS trial, for stenosis > 60%, the average incidence of stroke in patients with silent ischemia is 3.6%/year compared to 1.3%/year in those without silent ischemia
- no difference was seen for stenosis < 60%
in contrast, silent ischemia was not related to stenosis severity in the ACAS trial
although the benefit of revascularisation in patients with silent lesions has not been demonstrated in trials, their detection is a supportive factor for the indication of CEA/CAS in clinical practice

Impact of contralateral carotid stenosis or occlusion

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Gender

in the ACAS trial, women had a higher surgical risk than men ( 3.6% vs. 1.7%); some other smaller studies have reported similar results
other studies have not confirmed those findings
there is no solid consensus, but there is a tendency toward greater restraint in women

Age

advanced age is not an absolute contraindication to CEA/CAS; the patient’s biological status, life expectancy, and other factors must be considered
surgery is more common in patients < 75 years of age
- in the ACAS trial, age > 80 years was a contraindication
- in the ACST trial, the benefit was relatively small in patients > 75 years (ARR 3.3%/5 years)
- for asymptomatic stenoses, a higher mortality rate was reported in patients >75 years compared to those <75 years [Rajamani, 2013]

Intracranial flow and vasomotor reactivity (CVR)

data indicate a higher risk of stroke in patients with impaired cerebral vasomotor reactivity (VMR or CVR) and impaired intracranial flow [Gupta, 2012]
- ~4x higher risk of stroke/TIA (5.7% per year with an average follow-up of 24 months)
methods used to assess VMR:
- neurosonologic examinations
  - hyperventilation/apnea test during TCCD examination
  - acetazolamide (ACZ) test
- MRA+MR perfusion
- CT perfusion performed after IV acetazolamide challenge [Kang, 2008]
  - severe stenosis may sometimes manifest as false ischemic penumbra (FIP) on baseline CTP [Mosqueira, 2017]
- SPECT performed after IV acetazolamide challenge