Supracardiac Atherosclerosis in Embolic Stroke of Undetermined Source

The Underestimated Source

George Ntaios; Max Wintermark; Patrik Michel


Eur Heart J. 2021;42(18):1789-1796. 

In This Article

Management of Patients With Embolic Stroke of Undetermined Source and Supracardiac Atherosclerosis

Arterial Interventions

The meta-analysis of randomized trials showed no benefit of carotid endarterectomy over best medical treatment for symptomatic patients with non-stenosing carotid plaques.[38] Accordingly, carotid revascularization is indicated for patients with stenosis >50%.[13] Still, the European Society of Vascular Surgery recommends that carotid endarterectomy or stenting may be considered in symptomatic patients with <50% stenoses if they suffer recurrent episodes despite best medical therapy and following multidisciplinary team review between the stroke physician and the vascular interventionist (Class IIb, Level C recommendation).[12,13] The presence of vulnerable plaques on imaging could inform such decision, along with other patient characteristics, e.g. patients with symptomatic peripheral arterial disease and <50% stenosis of the internal carotid artery are in higher risk of recurrence after a first non-cardioembolic stroke.[39]

Medical Treatment

Medical treatment is of outmost importance for the prevention of recurrent strokes in patients with ESUS and atherosclerotic plaques. There are no well-designed randomized trials in this specific population. Therefore, any recommendations about optimal medical management are extrapolated from the related evidence in patients with high-degree stenosis. Antithrombotic and lipid-lowering treatment constituted the cornerstone of medical treatment in these patients.

The thrombi which are formed after the ulceration of the atherosclerotic plaque consist mainly of platelets and therefore, respond better to antiplatelets. In this context, antiplatelet treatment has been the mainstay of antithrombotic treatment for several decades, and more aggressive antiplatelet treatment in the first 2–4 weeks seems of particular benefit, despite the added risk of haemorrhage.[40,41]

In the chronic phase, the role of oral anticoagulation as monotherapy in patients with ESUS and carotid plaques was investigated in a recent exploratory analysis of the NAVIGATE-ESUS cohort which did not show a beneficial effect.[25] However, the combination of low-dose rivaroxaban with aspirin seemed to have a significant beneficial effect in patients with carotid stenosis >50%[42] and is expected to change clinical practice guidelines.[43] Patients with carotid plaques causing stenosis <50% were not included in the COMPASS trial and therefore, no strong recommendations can be made about the role of this treatment strategy in this patient group. It could perhaps be considered for patients with high-risk plaques or with recurrent ischaemic strokes despite a clear increase of the haemorrhagic risk.[44]

Patients with ischaemic stroke are considered as very high-risk patients for further cerebrovascular events and death.[45] The recent guidelines of the European Society of Cardiology and the European Atherosclerosis Society recommend an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <55 mg/dL.[45] Although concerns were raised in the past about such very low LDL-C levels, there are no known adverse effects of very low LDL-C concentrations [e.g. <1 mmol/L (40 mg/dL)].[45] Lifestyle modification and intensive statin treatment are the initial steps towards this goal; if not reached, ezetimibe and PSCK9 inhibitors should be added.[45] It may be possible that supracardiac atherosclerotic plaques may respond favourably to intensive lipid-lowering treatment, similar with the effect reported in the GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) trial, in which the addition of evolocumab to statin-treated patients with coronary artery disease resulted in a greater decrease in coronary percent atheroma volume after 76 weeks of treatment compared to placebo.[46]

Diabetes mellitus is a major risk factor for atherosclerosis and is prevalent in ~25% of ESUS.[47,48] The latest guidelines of the European Society of Cardiology developed in collaboration with the European Association for the Study of Diabetes recommend treatment with sodium-glucose co-transporter-2 inhibitors (empagliflozin, canagliflozin, or dapagliflozin) or glucagon-like peptide-1 receptor agonist (liraglutide, semaglutide, or dulaglutide) are recommended in patients with Type 2 diabetes mellitus and established cardiovascular disease to reduce future cardiovascular events.[49]

Similarly, the latest ESC/ESH guidelines for arterial hypertension aim at systolic values below 130 mmHg for stroke and transient ischaemic attack (TIA) patients below age 65, and at diastolic values below 80 mmHg at any age.[50] The American Guidelines recommend a similar threshold as a therapeutic target for all hypertensive patients, regardless of the patient age.[51] Despite previous concerns that low blood pressure targets may be associated with adverse events, these recommendations are further supported by a recent meta-analysis of four randomized controlled trials.[52]

Lifestyle Interventions

After several decades of limited evidence[50] and the absence of specific data for ESUS patients, lifestyle modifications and patient education have recently developed a strong evidence base in the general stroke population. Such interventions improve the control of risk factors[53] and may reduce long-term disability[54] and cerebrovascular recurrences.[55,56]