Optimal Medical Management of Asymptomatic Carotid Stenosis
Abstract
Asymptomatic carotid stenosis (ACS) due to atherosclerosis is a risk factor for ipsilateral ischemic cerebrovascular events and cognitive impairment. The prognosis of ACS has improved over the past 4 decades due largely to improvements in medical management. Most patients with ACS can be managed without revascularization, but some patients with vulnerable plaque should be considered for revascularization. Regardless of the decision to refer for revascularization, all patients with ACS should receive intensive medical management. This includes lifestyle modification (Mediterranean diet, exercise, and smoking cessation) and pharmacological therapy (antiplatelets, lipid-lowering agents, blood pressure reduction, and glycemic control). Patients with ACS often have atherosclerosis in other critical locations, and thus optimal medical therapy is likely to reduce events outside the carotid arteries. The nature of optimal medical therapy is described.
Atherosclerotic carotid stenosis is an important precursor of stroke, transient ischemic attack (TIA), and cognitive impairment.1,2 It is often a harbinger of systemic atherosclerosis and frequently coexists with coronary artery disease and peripheral arterial disease.3 A recent systematic review estimated that the global prevalence of carotid stenosis between the ages of 30 and 79 is 1.5% (95% CI, 1.1–2.1), equivalent to 58 million people.4 The current prevalence has increased by 59% from the year 2000, due to aging of the population. Indeed, the prevalence of carotid stenosis is highly age-dependent, so that for men, severe asymptomatic carotid stenosis (ACS) increases in prevalence from 0.1% in age <50 to 3.1% of those age ≥80.5
Thus ACS is a commonly encountered clinical problem. Dilemmas include (1) who to refer for revascularization; (2) what lifestyle modification to suggest to affected patients; and (3) how intensively to modify atherosclerosis risk factors and with which medications. This state-of-the-art review attempts to address these questions based on the best available evidence. A search of MEDLINE, EMBASE, and the Cochrane Library (from inception up to December 20, 2020) was undertaken for prospective cohort studies, randomized controlled trials and meta-analyses on the treatment of ACS. We begin with an examination of the prognosis and natural history of this condition.
Prognosis
The risk of ipsilateral stroke, a much-feared complication of ACS, has declined over the past 4 decades.6 In the Oxford Vascular Study, published 10 years ago, the annual rate of ipsilateral ischemic stroke was 0.34% in patients with ACS and 1.78% for ipsilateral TIA.7 The accrual for this study took place between 2002 and 2009. It is likely that continuing improvements in medical therapy over the last decade have further reduced the risk of cerebrovascular events in ACS (Figure). Indeed, rates of myocardial infarction and nonstroke death likely exceed that of ipsilateral stroke in many patients with ACS.8 This is because ACS is a marker of generalized atherosclerosis in other vascular beds.9
Vulnerable plaque is prone to rupture and can lead to athero-embolism. Patients with ACS and vulnerable plaque are at higher risk of ipsilateral stroke and TIA.10 A recent systematic review found that patients with ACS who had high-risk plaques had a summary odds ratio of 3.0 (95% CI, 2.1–4.3) for ipsilateral ischemic cerebrovascular events, compared with patients without such plaques.11 Such patients have an incidence rate of 4.3% per year for combined ipsilateral stroke or TIA. One of the most discriminating features in ACS is the presence of microemboli on transcranial Doppler monitoring (summary odds ratio, 5.6 [95% CI, 2.0–15.3] for ipsilateral events).11 In a study of 319 patients with ACS who underwent transcranial Doppler embolus detection, patients with microemboli were much more likely to have a stroke during the first year of follow-up than those without microemboli (15.6% versus 1%, respectively; P<0.00001).12
In addition to microemboli, a number of other high-risk features predict an increased incidence of ipsilateral stroke in patients with ACS (Table 1).13 These include plaque echolucency on Duplex ultrasound, progression in the severity of ACS, silent embolic infarcts on brain imaging, reduced cerebrovascular reserve, large juxta-luminal hypoechoic area, intraplaque hemorrhage, and carotid ulceration. The 2017 European Society for Vascular Surgery guidelines for the management of carotid disease suggest these features might be useful for selecting patients for revascularization.14 More information on the risk-benefit ratio of using these features to guide revascularization will be forthcoming from 4 ongoing clinical trials of revascularization plus optimal medical therapy versus optimal medical therapy alone for ACS.15–18
Imaging/clinical parameter and stenosis severity | Annual rate of ipsilateral stroke | OR/HR (95% CI) P value |
---|---|---|
Type of study | ||
Silent infarction on CT | Yes=3.6% | 3.0 (1.46–6.29) P=0.002 |
No=1.0% | ||
Multicenter, observational | ||
Stenosis progression | Regression=0.0% | 1.92 (1.14–3.25) P=0.05 |
50%–99% stenoses | Unchanged=1.1% | |
Multicenter, observational | Progression=2.0% | |
Stenosis progression | Regression | 0.7 (0.4–1.3) |
70%–99% stenoses | No change | Comparator |
Progression 1 stenosis grade | 1.6 (1.1–2.4) | |
Multicenter, RCT | ||
Progression 2 stenosis grades | 4.7 (2.3–9.6) | |
Plaque area on computerized plaque analysis | <40 mm2=1.0% | HR, 1.0 |
70%–99% | 40–80 mm2=1.4% | 2.08 (95% CI, 1.05–4.12) |
Multicenter, observational | >80 mm2=4.6% | 5.81 (95% CI, 2.67–12.67) |
JBA on computerized plaque analysis | <4 mm2=0.4% | Trend P<0.001 |
50%–99% stenoses | 4–8 mm2=1.4% | |
Multicenter, observational | 8–10 mm2=3.2% | |
>10 mm2=5.0% | ||
Intraplaque hemorrhage on MRI | Yes vs no | OR, 3.66 (2.77–4.95) P<0.01 |
50%–99% stenoses | ||
Meta-analysis | ||
Impaired CVR | Yes vs no | OR, 6.14 (95% CI, 1.27–29.5) P=0.02 |
70%–99% stenoses | ||
Meta-analysis | ||
Plaque lucency on Duplex US | Predominantly echolucent 4.2% | OR, 2.61 (95% CI, 1.47–4.63) P=0.001 |
50%–99% stenoses | ||
Predominantly echogenic 1.6% | ||
Meta-analysis | ||
Spontaneous embolization on TCD | Yes vs no | OR, 7.46 (95% CI, 2.24–24.89) P=0.001 |
50%–99% stenoses | ||
Meta-analysis | ||
Spontaneous embolization plus uniformly or predominantly echolucent plaque | Yes=8.9% | OR, 10.61 (95% CI, 2.98–37.82) P=0.0003 |
70%–99% stenoses | ||
Multicenter, observational | No=0.8% | |
Contralateral TIA/stroke | Yes=3.4% | OR, 3.0 (95% CI, 1.9–4.73) P=0.0001 |
50%–99% stenoses | No=1.2% | |
Multicenter, observational |
CT indicates computed tomography; CVR, cerebrovascular reserve; HR, hazards ratio; JBA, juxta-luminal black area; OR, odds ratio; RCT, randomized controlled trial; TCD, transcranial Doppler; TIA, transient ischemic attack; and US, ultrasound.
Adapted from Naylor et al14 with permission. Copyright ©2018, Elsevier.
Optimal Medical Therapy: Lifestyle Modification
Regardless of whether patients with ACS undergo revascularization or not, all patients with ACS should receive intensive medical management to control their risk factors and comorbidities (Table 2). Such treatment not only reduces the risk of ipsilateral cerebrovascular events; crucially, it also prevents atherosclerotic events in other vascular beds. Lifestyle modification is foundational to this approach and will be discussed first.
Modality | Details |
---|---|
Diet | Mediterranean diet |
Exercise | Moderate intensity (such as brisk walking, jogging, swimming, or cycling) 4 to 7 days per week, for a total of at least 150 min per week |
Smoking | Smoking cessation with varenicline or bupropion and nicotine replacement therapy |
Antithrombotic therapy | Options |
ASA 75–325 mg/d | |
ASA+rivaroxaban 2.5 mg bid | |
Clopidogrel 75 mg OD or ticagrelor 90 mg BID (if ASA-intolerant or allergic to ASA) | |
Lipid-lowering therapy | Goal LDL <1.8 mmol/L (70 mg/dL; <1.4 mmol/L [54 mg/dL] for very high risk) |
High-dose statin | |
Add ezetimibe or | |
Add PCSK9 inhibitor | |
Consider icosapent ethyl (high-dose EPA) for fasting triglycerides 1.52–5.63 mmol/L | |
Antihypertensive therapy | Goal BP <130/80 |
Prefer ACE inhibitor/ARB due to high prevalence of renovascular hypertension | |
May require combination therapy | |
Glucose-lowering therapy | Goal HbA1c <7.0% |
Metformin, GLP-1 agonist, SGLT-2 antagonist are preferred | |
Consider referral for carotid revascularization | TCD+ for microemboli, plaque ulcer, reduced cerebrovascular reserve, intraplaque hemorrhage, silent embolic infarcts on CT/MRI, plaque echolucency, large JBA, progression in severity of stenosis |
ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid; BP, blood pressure; CT, computed tomography; EPA, eicosapentaenoic acid; GLP-1, glucagon-like peptide 1; HbA1c, hemoglobin A1c; JBA, juxta-luminal black area; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; PCSK9, proprotein convertase subtilisin/kexin type 9; SGLT2, sodium-glucose cotransporter 2; and TCD, transcranial Doppler.
Recently, the US Preventive Services Task Force issued a positive recommendation that adults at cardiovascular risk should be offered behavioral counseling interventions to promote a healthy diet and physical activity.19 This recommendation is based on a systematic review which found such interventions lowered the risk of cardiovascular events based on 9 randomized trials (pooled relative risk, 0.80 [95% CI, 0.73–0.87]).20 Behavioural counseling interventions were also associated with statistically significant reductions in physiological risk factors such as blood pressure, LDL-C (low-density lipoprotein cholesterol), fasting glucose, and adiposity. In the ongoing CREST2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis), all patients receive frequent lifestyle coaching using a telephone-based lifestyle modification program.15 Goals include complete smoking cessation, a target body mass index <25 kg/m2 or 10% weight loss, and ≥30 minutes of moderate exercise ≥3× per week.
Two randomized trials found that a Mediterranean-type diet reduced cardiovascular events in patients in primary and secondary prevention settings.21,22 In the Lyon Diet Heart Study, de Lorgeril et al22 documented a large reduction in cardiovascular events (relative risk, 0.28 [95% CI, 0.15–0.53]) and all-cause mortality (relative risk, 0.44 [95% CI, 0.21–0.94]) for a Mediterranean diet in patients enrolled after a first myocardial infarction. The PREDIMED trial (Prevención con Dieta Mediterránea) found a 30% reduction in the risk of cardiovascular events (hazard ratio [HR], 0.70 [95% CI, 0.55–0.89]) in primary prevention patients assigned a Mediterranean diet supplemented with extra virgin olive oil or nuts.21 This was especially driven by reduction in stroke (HR, 0.58 [95% CI, 0.42–0.82]).
Smoking is a major risk factor for carotid stenosis and amplifies progression of severity, ipsilateral cerebrovascular events, and the occurrence of carotid revascularization.23 Current smokers are more likely to have vulnerable plaques with intraplaque hemorrhage and plaque ulcers.24,25 All patients with ACS who smoke should be offered smoking cessation counseling as well as effective pharmacotherapy for achieving cessation (varenicline or bupropion with nicotine replacement therapy). Although randomized trials of smoking cessation in patients with ACS do not exist, and likely would be unethical, it is probable that smoking cessation markedly reduces the risk of ipsilateral stroke and TIA, as well as other vascular events.26 Showing smokers ultrasound photographs of their atherosclerotic plaque improves their cessation rate by >6-fold.27
Physical activity is an essential component of lifestyle modification. Poor cardiopulmonary fitness is a strong predictor of long-term vascular events and mortality.28 The Canadian Stroke Best Practice Recommendations suggest that individuals with cerebrovascular disease should be counseled to participate in dynamic exercise of moderate intensity (such as brisk walking, jogging, swimming, or cycling) 4 to 7 days per week, to accumulate at least 150 minutes in episodes of 10 minutes or more, in addition to routine activities of daily living.29 Effects of exercise on cardiovascular risk factors are well documented, and imaging trials suggest that the progression of carotid atherosclerosis can be slowed in patients who adopt exercise programs.30,31
Optimal Medical Therapy: Pharmacological Strategies
Antiplatelet Therapy
Oral antiplatelet agents remain a cornerstone of treatment for atherosclerosis, including ACS. In the Antithrombotic Trialists Collaboration’s third systematic overview, acetylsalicylic acid (ASA) reduced the risk of serious vascular events by 17% in patients following TIA or ischemic stroke (rate ratio, 0.83 [95% CI, 0.75–0.93]).32 Many of the patients in these trials likely had carotid stenosis.
The evidence for ASA in ACS is significantly weaker. The Asymptomatic Cervical Bruit Study randomly assigned 372 asymptomatic patients with ≥50% carotid stenosis (defined by duplex ultrasound) to ASA 325 mg/d or identical placebo.33 The primary outcome was the composite of TIA, stroke, myocardial infarction, unstable angina, or death. During a median follow-up of 2.3 years, the adjusted HR for ASA versus placebo for the primary outcome was 0.99 (95% CI, 0.67–1.46); for vascular events only, the adjusted HR was 1.08 (95% CI, 0.72–1.62). ASA was also ineffective in a larger randomized trial of patients with asymptomatic atherosclerosis detected by ankle-brachial index testing (the Aspirin for Asymptomatic Atherosclerosis trial).34
Nevertheless, ASA is likely the most commonly employed antiplatelet agent in ACS.35 A recent large randomized trial (COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies]) tested whether the addition of low-dose rivaroxaban (a factor Xa inhibitor) to ASA, would improve the outcome of 27 935 patients with stable atherosclerotic vascular disease (including nearly 2000 patients with ACS ≥50% or previous carotid revascularization).36 There were 3 treatment arms: ASA 100 mg/d (monotherapy), ASA 100 mg/d plus rivaroxaban 2.5 mg BID, and rivaroxaban 5 mg BID (monotherapy). In the entire sample, dual therapy with ASA and rivaroxaban reduced the primary outcome by 24% (HR, 0.76 [95% CI, 0.66–0.86]) in comparison with ASA alone. A similar but not statistically significant reduction (P=0.07) occurred in the carotid disease subgroup (HR, 0.63 [95% CI, 0.38–1.05]). No reduction was seen with rivaroxaban 5 mg BID.37 In patients with carotid disease, major bleeding was not increased in the dual therapy group (HR, 1.18 [95% CI, 0.55–2.51]) but was more than doubled with rivaroxaban 5 mg BID (HR, 2.34 [95% CI, 1.21–4.52]). These results suggest that low-dose rivaroxaban (2.5 mg BID) could be used to prevent vascular events in patients with ACS on top of ASA, but prospective replication in ACS would be valuable.
P2Y12 (purinergic receptor P2Y, G-protein coupled, 12) receptor antagonists (clopidogrel, ticagrelor, and prasugrel) have not been studied in patients with ACS. Short-term dual antiplatelet therapy with ASA and clopidogrel or ticagrelor prevents recurrent ischemic strokes in acute noncardioembolic TIA or ischemic stroke.38–40 Longer-term trials of dual antiplatelet therapy have reported an unfavorable risk-benefit ratio in patients with symptomatic cerebrovascular disease.41–43 The main role of P2Y12 receptor antagonists in ACS is, therefore, limited to patients who are allergic to or intolerant of ASA. Given the uncertainty regarding the benefits and risks of antiplatelet therapy in ACS, one approach is to provide antiplatelet therapy only to patients with high-risk plaque, as determined by imaging (Table 1).
Lipid-Lowering Therapy
The American Heart Association 2018 guidelines on management of blood cholesterol promote an LDL-C goal of <1.8 mmol/L (70 mg/dL) in patients with atherosclerosis, including ACS.44 The 2019 European Society of Cardiology/European Atherosclerosis Society guidelines suggest treatment with a maximum tolerated dose of statin, plus ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, to reduce the risk of vascular events in patients with carotid disease.45 For very high-risk patients, an LDL-C target of <1.4 mmol/L (54 mg/dL) is recommended. High-dose statins are more effective than low or moderate doses at regressing carotid atherosclerosis and preventing stroke.46 In addition, high-dose atorvastatin reduced stroke (HR, 0.67 [95% CI, 0.47–0.94]), major coronary events (HR, 0.57 [95% CI, 0.32–1.00]), and carotid revascularization (HR, 0.44 [95% CI, 0.24–0.79]) among patients with stroke/TIA with documented carotid stenosis.47 PCSK9 inhibitors and ezetimibe also prevent stroke and other cardiovascular events in patients with atherosclerosis, and these effects are incremental to statins.48,49
A recent large randomized trial (REDUCE-IT [Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial]) documented the efficacy of highly purified eicosapentaenoic acid for preventing cardiovascular events in patients with elevated fasting triglycerides (1.52–5.63 mmol/L) and established cardiovascular disease (including ACS with ≥70% severity) or diabetes plus additional risk factors.50 The primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina) was reduced by 25% (HR, 0.75 [95% CI, 0.68–0.83]). Ischemic stroke was reduced by 36% (HR, 0.64 [95% CI, 0.49–0.85]) with no increase in hemorrhagic stroke (HR, 1.28 [95% CI, 0.56–2.93]). Although no subgroup analysis is available for ACS, treatment with eicosapentaenoic acid was highly effective in the secondary prevention cohort (HR, 0.72 [95% CI, 0.63–0.82]). All patients received statins, so reductions are additive to statin therapy. A second smaller trial showed that high-dose eicosapentaenoic acid reduced coronary plaque volume, as measured by serial multidetector computed tomography.51
ACS is not a homogenous disorder with respect to patient risk; as discussed above, some patients have vulnerable plaque features (Table 1) which call for particularly intensive lipid-lowering therapy to reduce risk. Serial ultrasound to assess progression of plaque area and stenosis severity is warranted in ACS and can be used to titrate lipid-lowering therapies.52 Given the current high cost of PCSK9 inhibitors, their use may need to be restricted to patients at highest risk for atherosclerotic events (such as those with polyvascular disease).
Blood Pressure Reduction
In a chart review of all patients from an academic center participating in the North American Symptomatic Carotid Endarterectomy Trial and the Asymptomatic Carotid Artery Study, 84% had stage II hypertension or worse (systolic >160 or diastolic >90 mm Hg).53 Of these patients with hypertension, 17% had renovascular hypertension, which was even more prevalent (25%) in those with treatment-resistant hypertension. This suggests a high degree of concomitant renal artery stenosis in patients with ACS, a finding which is supported by the literature.54 This is important, because drugs that interrupt the renin-angiotensin system effectively lower blood pressure in renovascular hypertension. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers also appear to reverse the progression of carotid atherosclerosis and prevent vascular events in patients with atherosclerotic cardiovascular disease.55,56
The American Heart Association/American College of Cardiology 2017 hypertension guidelines recommend a blood pressure target of <130/80 mm Hg in patients with hypertension and cardiovascular disease.57 One caveat is that patients with hypertension with severe bilateral ACS (≥70%) may not tolerate blood pressure lowering to this degree, due to impaired cerebral perfusion.58 However, a pooled analysis of 4 trials of intensive blood pressure lowering (to a target <130/80 mm Hg) in patients with a history of stroke found a significant benefit on stroke recurrence (relative risk, 0.78 [95% CI, 0.64–0.96]).59 The ACE (angiotensin-converting enzyme) inhibitor perindopril lowers blood pressure without lowering cerebral blood flow in patients with hypertensive stroke with moderate to severe internal carotid artery disease or internal carotid artery occlusion.60
Glucose-Lowering Therapies
The American Diabetes Association 2021 guidelines suggest a goal hemoglobin A1c of <7.0% for most patients with type 2 diabetes without significant hypoglycemia.61 Glucose-lowering therapies with proven cardiovascular benefits are preferred, namely metformin, SGLT2 (sodium-glucose cotransporter-2) inhibitors, and GLP-1 (glucagon-like peptide-1) receptor agonists. Recently published American Heart Association/American College of Cardiology guidance on the use of these therapies for cardiovascular protection are available.62
Selecting Patients for Revascularization
A significant controversy is the selection of patients with ACS for revascularization, notably in the face of evidence that ipsilateral strokes on optimal medical therapy have declined significantly over time.63 The 2017 European Society for Vascular Surgery guidelines suggest that carotid endarterectomy (class IIa recommendation, level of evidence B) or carotid stenting (class IIb recommendation, level of evidence B) should be considered for average surgical risk patients with an asymptomatic 60% to 99% stenosis, who have one or more imaging characteristics associated with an increased risk of late ipsilateral stroke (Table 1), provided documented perioperative stroke/death rates are <3% and the patient’s life expectancy exceeds 5 years.14 The evidence supporting these recommendations is largely drawn from 3 randomized trials of carotid endarterectomy for ACS with enrollment in the 1980s, 1990s, and early 2000s.64–66
As mentioned above, it is likely that further improvements in medical therapy have reduced the risk of ipsilateral stroke in ACS, possibly below a threshold whereby carotid revascularization would still benefit the average risk patient.7 This hypothesis is being tested in 4 ongoing randomized trials.15–18 In the meantime, patients referred for revascularization should have evidence of vulnerable plaque. Otherwise, given the uncertain risk-benefit ratio, patients should be enrolled in one of the ongoing trials.
Conclusions
There is considerable evidence to support lifestyle modification and pharmacological therapy for preventing cardiovascular events in patients with atherosclerotic ACS. A Mediterranean diet, exercise, and smoking cessation are foundational practices that should be promoted by treating clinicians. In addition, antiplatelet therapy, lipid-lowering therapy, blood pressure reduction, and glucose-lowering therapy (the latter 2 where appropriate) further reduce the risk of vascular events. Patients with vulnerable plaque should be considered for revascularization or enrolled into one of the ongoing trials studying revascularization to improve outcomes in ACS.
Footnote
Nonstandard Abbreviations and Acronyms
- ACE
- angiotensin-converting enzyme
- ACS
- asymptomatic carotid stenosis
- ASA
- acetylsalicylic acid
- COMPASS
- Cardiovascular Outcomes for People Using Anticoagulation Strategies
- CREST-2
- Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis
- GLP-1
- glucagon-like peptide-1
- HR
- hazard ratio
- LDL-C
- low-density lipoprotein cholesterol
- P2Y12
- purinergic receptor P2Y, G-protein coupled, 12
- PCSK9
- proprotein convertase subtilisin/kexin type 9 inhibitor
- PREDIMED
- Prevención con Dieta Mediterránea
- REDUCE-IT
- Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial
- SGLT2
- sodium-glucose cotransporter 2
- TIA
- transient ischemic attack
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