Dr. John Doe is a 67-year-old vascular surgeon and is self-referred for evaluation of a carotid bruit found on a routine insurance physical examination. He has no focal neurologic symptoms and reports no history consistent with a stroke or transient ischemic attack (TIA). He has a history of hypertension, dyslipidemia, and non–insulin-dependent diabetes all well-controlled on medical therapy. Physical exam confirms a right-sided bruit in the neck, and the rest of the physical exam is unremarkable. His medications include a daily baby aspirin (81 mg), atorvastatin (20 mg), lisinopril (10 mg), hydrochlorothiazide (12.5 mg), and metformin (500 mg). Duplex ultrasound reveals an 80% to 89% stenosis of his right internal carotid artery and 20% to 49% stenosis of his left internal carotid artery. What are the consequences of Dr. Doe’s carotid artery disease? How should his case be approached?
Nearly 800,000 strokes occur each year in the United States, and over 130,000 Americans die annually from stroke.1 Stroke is the third leading cause of mortality in the United States, and among survivors, 15% to 30% are permanently disabled.1,2 Atherosclerotic carotid artery disease is responsible for 80% of new noncardioembolic strokes.3-6 Carotid plaque most often causes cerebrovascular events due to plaque rupture with atheroembolization, rather than carotid artery occlusion (<20% of ischemic strokes) with thrombosis (Figure 31-1).4
The natural history of carotid artery stenosis depends on the presence of symptoms (TIA, stroke, amaurosis fugax). Symptomatic patients have a 5- to 10-fold risk of stroke when compared to asymptomatic patients. Asymptomatic patients with carotid artery stenosis outnumber symptomatic patients by 4:1. Approximately 5% to 10% of patients over age 65 have a carotid stenosis >50%, with 1% having a stenosis ≥75%.7. Because the majority (≥80%) of ischemic strokes have no warning symptoms,4 the management of asymptomatic carotid atherosclerosis with revascularization or medical therapy is important.3,8
Transient focal neurologic symptoms are associated with a 30% risk of stroke within 6 months.9,10 TIA is currently defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction, based on pathologic, imaging, and other objective evidence and/or clinical evidence. Stroke, central nervous system (CNS) infarction, is defined by neuropathologic, neuroimaging, and/or clinical evidence of permanent injury. However, many of the initial studies that illustrated the natural history of this disease as well as our current standards of practice predated this updated definition and included only a clinical definition of infarction.11
In the 1990s, 2 larger randomized controlled trials (the Asymptomatic Carotid Atherosclerosis Study [ACAS] and the Asymptomatic Carotid Surgery Trial [ACST]) showed that carotid endarterectomy (CEA) reduced the incidence of ipsilateral stroke in patients with asymptomatic carotid artery stenosis (by ≥60%) when compared to medical therapy (eg aspirin; by 50%). However, CEA did not reduce overall stroke and death and did not show any benefit in women or in patients older than 75 years of age. It is important to note that the medical therapy provided in these trials (aspirin) has significantly improved.12-14 Currently, the risk of progression of an asymptomatic carotid artery stenosis to occlusion with modern medical therapy is very low. In a cohort of 3681 patients with yearly duplex follow-up, 316 (8.6%) asymptomatic patients had occlusion that occurred during observation. Of these, 80% (n = 254) of the occlusions occurred before the initiation of modern intensive medical therapy.15
The natural history of symptomatic carotid artery stenosis was reflected in the medical arm of the randomized North American Symptomatic Carotid Endarterectomy Trial (NASCET). The 5-year risk of ipsilateral stroke in patients medically managed was 18.7% among those with lesions <50% in severity.16 In those with 50% to 69% stenosis, the risk over the same time period was 22.2%. In those with 70% to 99% stenosis, the 2-year risk of ipsilateral stroke was 26%.17 Results were similar in the European Carotid Surgery Trial (ECST).18 The risk of stroke increased with severity of stenosis, and the 3-year risk of ipsilateral stroke in symptomatic patients with stenosis greater than 80% was 26.5%; however, as the stenosis approaches total occlusion (95%-99%), the risk of ipsilateral stroke goes down to 17.2%.4
Symptoms of carotid artery stenosis include ipsilateral transient visual defects (amaurosis fugax) from retinal emboli; contralateral weakness or numbness of an extremity or the face, or of a combination of these; visual field defect; dysarthria; and, in the case of dominant hemisphere involvement, aphasia. The National Institutes of Health Stroke Scale (NIHSS) should be performed in all symptomatic patients to quantify the neurologic deficit, which correlates with outcome.5
Digital subtraction angiography (DSA) is the gold standard for defining carotid anatomy, with the NASCET method of stenosis measurement the most widely accepted methodology (Figure 31-2). Invasive cerebral catheter-based angiography carries a risk of cerebral infarction of 0.5% to 1.2%; therefore, noninvasive imaging should be the initial strategy for evaluation.12,19 Carotid duplex imaging (Figure 31-3), transcranial Doppler imaging, computed tomography angiography (CTA), and magnetic resonance angiography (MRA) are noninvasive methods of assessment. Duplex imaging is the best initial choice given its safety profile, low cost, and wide availability. Cerebral and cervical imaging should define the aortic arch and the circle of Willis (Figures 31-4, 31-5, 31-6).
Figure 31-2
Methods of carotid stenosis assessment. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) method is the most widely used. ECST, European Carotid Surgery Trial. (Used with permission, from Kern MJ. The Interventional Cardiac Catheterization Handbook. 3rd ed. New York, NY: Elsevier; 2012. Figure 15-1.)
Figure 31-4
Aortic arch morphologies. Arch morphology is defined based on the origin of the great vessels. (A) Type I arch: all vessels originate at the superior margin of the arch. (B) Type II arch: at least 1 vessel originates between the superior and inferior margins of the aortic arch. (C) Type III arch: at least 1 vessel originates below the inferior margin of the aortic arch. (Used with permission from Krishnaswamy, A., Klein, J. P. and Kapadia, S. R. (2010), Clinical cerebrovascular anatomy. Cathet. Cardiovasc. Intervent., 75: 530-539.)
Current anti-atherosclerotic medical therapy has advanced significantly with the development of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), statin drugs, and newer antiplatelet agents.
Medical therapy for carotid atherosclerosis should focus on preventing stroke and stabilizing atherosclerotic lesions to prevent plaque rupture and atheroembolization. Blood pressure control is of paramount importance since it is a primary risk factor for stroke; it is also a risk factor for atrial fibrillation and myocardial infarction, which both increase the likelihood of stroke.20 ACEIs and ARBs seem to be of particular benefit in stroke prevention, particularly in those at higher risk for cardiovascular disease.21-23
Cholesterol lowering with statin drugs in patients treated for cardiovascular disease prevention demonstrated a lower risk of stroke.24 It is possible that statins prevent strokes through pleiotropic effects on endothelial function and plaque stabilization in addition to their lipid-lowering properties. Current American Heart Association (AHA)/American Stroke Association (ASA) stroke guidelines endorse the National Cholesterol Education Program (NCEP) III recommendations for the use of statins.25-27 New cholesterol management guidelines have been released by the American College of Cardiology (ACC)/AHA since this endorsement that recommend that high-intensity statin therapy should be initiated or continued as first-line therapy in patients ≤75 years of age who have clinical atherosclerotic cardiovascular disease unless contraindicated (Class I, Level of Evidence [LOE] A), and it should be considered in those >75 years of age if the benefit outweighs the risk (Class IIa, LOE B; Table 31-1).28 The guidelines also recognize the US Food and Drug Administration (FDA) approval of statins for stroke prevention in patients with cardiovascular disease and in high-risk hypertensive patients. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated that high-dose atorvastatin is effective for secondary stroke prevention in patients with an ischemic stroke or TIA but no coronary heart disease.29 The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study showed that rosuvastatin treatment in patients with normal cholesterol levels but elevated levels of C-reactive protein is effective in reducing the rate of stroke.30 Therefore, statins are an important component of stroke treatment and prevention and are indicated for patients with carotid artery disease.
| High-Intensity Statin Therapy | Moderate-Intensity Statin Therapy | Low-Intensity Statin Therapy |
|---|---|---|
| Lowers cholesterol by ≥50% | Lowers cholesterol by 30%-50% | Lowers cholesterol by <30% |
Atorvastatin 40-80 mg/d Rosuvastatin 20-40 mg/d | Atorvastatin 10-20 mg/d Rosuvastatin 5-10 mg/d Simvastatin 20-40 mg/d Pravastatin 40-80 mg/d Lovastatin 40 mg/d Fluvastatin XL 80 mg/d Fluvastatin 40 mg twice a day Pitavastatin 2-4 mg/d | Simvastatin 10 mg/d Pravastatin 10-20 mg/d Lovastatin 20 mg/d Fluvastatin 20-40 mg/d Pitavastatin 1 mg/d |
Antiplatelet medications are a critical component of primary stroke prevention. In the Antithrombotic Trialists’ Collaboration meta-analysis of high-risk patients, antiplatelet therapy reduced the occurrence of any vascular event by roughly 25%, nonfatal stroke by about 25%, and death due to vascular cause by about 15%.31 Aspirin was the most widely used drug, with doses of 75 to 150 mg being as beneficial as higher doses. The Women’s Health Study found that 100 mg of aspirin every other day resulted in a significant 17% reduction in the risk of stroke over 10 years.32
In secondary prevention, aspirin reduces the risk of future strokes by 15% to 25%.33,34 High-dose aspirin (160-325 mg daily) provided no more benefit than lower doses but was associated with more side effects.31 Among patients with symptomatic vascular disease, including stroke, the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial demonstrated that clopidogrel 75 mg daily was associated with an 8.7% relative risk reduction in ischemic stroke, myocardial infarction (MI), or vascular death versus aspirin 325 mg daily (5.32% vs. 5.83%, P = .043). For the patients who presented with stroke, however, the benefit was not significant.35 Clopidogrel 75 mg daily plus aspirin 75 mg daily was compared to clopidogrel alone in the Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) trial.36 This study found that, among stroke patients, the combination regimen did not improve vascular outcomes but significantly increased the number of major and life-threatening bleeding complications. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial included over 4300 patients with a prior TIA or stroke and found that aspirin 75 to 162 mg daily was as effective as aspirin plus clopidogrel in preventing future MI, stroke, or cardiovascular death in patients with multiple risk factors or with clinically evident cardiovascular disease.37 This study also found that aspirin 81 mg is the optimal dose for safety and efficacy for prevention.38 The European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) compared aspirin plus dipyridamole to aspirin alone in patients who presented within 6 months of a minor stroke or TIA.39 The primary outcome of vascular death, nonfatal MI or stroke, and major bleeding occurred in 13% of the aspirin plus dipyridamole patients and 16% of the aspirin alone patients (P = not significant [NS]). The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study found no difference between clopidogrel and aspirin/dipyridamole in the secondary prevention of stroke.40
AHA/ASA guidelines recommend that all patients with carotid atherosclerosis be placed on antiplatelet medications.25 Aspirin 50 to 325 mg daily, aspirin/dipyridamole, or clopidogrel alone in patients who cannot tolerate aspirin should be initiated for secondary prevention of stroke.
There is uncertainty regarding the best therapy for asymptomatic carotid artery disease. The CREST-2 trial (ClinicalTrials.gov identifier: NCT02089217) is currently enrolling and features 2 parallel arms (Figure 31-7): one compares CEA with best medical management versus best medical management alone and the other compares carotid artery stenting (CAS) and best medical management versus best medical management alone. CREST-2 medical management goals include systolic blood pressure <140 mm Hg (<130 mm Hg for patients with diabetes mellitus), low-density lipoprotein <70 mg/dL, hemoglobin A1c <7.0%, smoking cessation, targeted weight management, and more than 30 minutes of moderate exercise 3 times per week. Clinicians need to vigorously support enrollment in CREST-2 in order to answer the question of whether carotid revascularization for asymptomatic stenosis is superior to contemporary medical therapies for stroke prevention.41
The purpose of carotid revascularization is to prevent ischemic stroke. There have been 3 large randomized studies comparing CEA to antiplatelet (aspirin) therapy in the treatment of at least moderate (≥50%-60%) carotid stenosis in patients without focal neurologic symptoms. The Veterans Affairs Cooperative Study (VACS) randomized 444 men with asymptomatic carotid stenosis of ≥50% by angiography to medical therapy plus CEA or medical therapy alone.42 All patients were assigned aspirin 650 mg twice daily, although many did not tolerate that dose. The 30-day risk of stroke or death in the CEA group was 4.7%. At nearly 4 years of follow-up, the ipsilateral neurologic event rate (including TIA, transient monocular blindness, and fatal and nonfatal stroke) was 8% in the surgical arm and 20.6% in the medical arm (P <.001). The risk of ipsilateral stroke alone was reduced from 9.4% with medical treatment to 4.7% (P <.06) with CEA. Notably, there was no difference between surgery and medical therapy for combined stroke or death.
ACAS randomized 1662 asymptomatic patients with carotid stenosis ≥60% to medical therapy or medical therapy with CEA.12 All patients received aspirin 325 mg daily. Angiography was performed only in the CEA group and was associated with a 1.2% risk of stroke. The 30-day risk of stroke or death in the surgical group, including the risk associated with angiography, was 2.7%. The projected 5-year risk of ipsilateral stroke and any perioperative stroke or death was reduced from 11% in the medical arm to 5.1% with CEA. The number of patients needed to treat (NNT) with surgery to prevent 1 ipsilateral stroke at 5 years was 19. The benefit for women (17% reduction in events) was less than for men (66% reduction).
ACST evaluated 3120 asymptomatic patients with ≥60% carotid stenosis by ultrasound.43 Patients were randomized to CEA with medical management or medical management alone. Drug treatment was left to the discretion of the patients’ primary physicians—this usually included antiplatelet medications, antihypertensive therapy, and, in the later years of the study, lipid-lowering agents. The 30-day perioperative risk of stroke or death was 3.1%. The 5-year risk of perioperative death or total stroke was reduced from 11.8% to 6.4% with CEA; roughly half the strokes were disabling. The benefit of surgery was significant across varying degrees of stenosis (60%-90% stenosis); however, CEA did not reduce overall stroke and death and did not show any benefit in women or in patients older than 75 years of age.
Three large randomized controlled studies have evaluated the benefit of CEA compared to medical therapy in symptomatic patients with moderate to severe carotid artery disease. The Veterans Affairs (VA) 309 trial screened 5000 men who presented within 4 months of a small stroke, TIA, or transient monocular blindness and randomized 189 to either CEA with best medical therapy or best medical therapy alone.44 The patients had angiographically defined internal carotid stenosis >50%. The trial was ended prematurely when early results from NASCET and ECST confirmed the significant benefit of CEA. At a mean follow-up of almost 1 year, there was a reduction in ipsilateral stroke or TIA from 19.4% in the medical treatment arm to 7.7% in the surgical arm, an absolute reduction in risk of 11.7%. The benefit of surgery was most profound in patients with stenosis >70% (absolute risk reduction of 17.7%).
The NASCET investigators randomized patients with a TIA or nondisabling stroke within 180 days to CEA with medical therapy (including aspirin) or medical therapy alone. Patients were originally stratified according to the degree of stenosis: <50%, 50% to 69%, or 70% to 99%. After randomizing 659 patients with ≥70% stenosis, that portion of the study was terminated. CEA demonstrated an absolute risk reduction of 17% (26% vs. 9%) in the rate of ipsilateral stroke at 2 years.17,45 CEA lowered the 2-year risk of major or fatal stroke from 13.1% to 2.5%. Among patients with a 50% to 69% stenosis, the 30-day perioperative stroke or death rate was 6.7% in patients treated with CEA.16 The 5-year rate of ipsilateral stroke was 22.2% in those treated medically and 15.7% in those treated with CEA, for an absolute risk reduction of 6.5% for those treated with CEA. In patients with <50% stenosis, there was no benefit for stroke prevention with CEA and medical therapy compared to medical therapy alone.
ECST studied 3024 symptomatic patients with carotid stenosis; 60% of patients were randomized to CEA and 40% to medical therapy.18 All patients received optimal medical therapy that usually consisted of antihypertensives, antiplatelet agents, and antismoking counseling. The 30-day perioperative risk of major stroke or death with surgery was 7%. Although there was no benefit to surgery for stenosis below the 70% to 80% range, among patients with a stenosis ≥80%, the rate of major stroke or death at 3 years was 26.5% in the medical therapy group and 14.9% in the CEA group, an absolute reduction of 11.6% favoring surgery. There was no benefit for patients who had near occlusion of the carotid artery.46 Of note, ECST defined the degree of stenosis differently than NASCET. An 80% stenosis in this trial was similar to a 60% stenosis in NASCET.
A meta-analysis of these 3 studies found that for lesions <30% as measured by NASCET criteria, surgery increased the 5-year risk of ipsilateral stroke. CEA provided a marginal benefit in patients with 50% to 69% stenosis (absolute risk reduction of 4.6%) and was highly beneficial for patients who had ≥70% stenosis (16% absolute risk reduction; P <.001). In patients with near occlusion, defined as a stenosis causing reduced flow to the distal internal carotid artery (ICA) and narrowing of the poststenotic ICA, there was no benefit for CEA.47
Current AHA/ASA guidelines recommend CEA in symptomatic patients with stenosis of 50% to 99% if the risk of perioperative stroke or death is <6%.26 In asymptomatic patients, guidelines recommend CEA for stenosis of 60% to 99% if the perioperative risk of stroke is <3% and life expectancy is at least 5 years.25 Some have recommended delaying revascularization in asymptomatic patients until the stenosis has reached 80%, but the evidence from ACST demonstrated equal benefit for moderate and severe stenosis.43,48
