Arterial Occlusive Disease
Jason Noble MD, FRCSC, DABO,
Mark O. Baerlocher MD, FRCPC
Background
Although atherosclerotic vascular disease is primarily appreciated as the major contributor to systemic morbidity and mortality in developed nations, it is also a significant factor in ocular disease.1,2 Furthermore, the presence of abnormalities in the ophthalmic microvasculature may reflect undiagnosed or poorly optimized systemic atherosclerotic cardiovascular disease.3 Progressive narrowing or occlusion of the carotid arteries from atherosclerosis can cause amaurosis fugax (transient monocular vision loss) and ocular ischemic syndrome or serve as a source of emboli for branch retinal artery occlusions or central retinal artery occlusions (CRAOs).4,5 Atherosclerotic changes in the more distal aspects of the ophthalmic vasculature such as the ophthalmic artery, the central retinal artery, and the branch retinal arteries can also cause central and branch retinal artery occlusions and has been implicated in the pathogenesis of retinal vein occlusion and nonarteritic ischemic optic neuropathy.5,6,7
The major risk factors for atherosclerotic vascular disease include increasing age, family history, diabetes mellitus, hypertension, smoking, and hypercholesterolemia.8 Management of these risk factors is critical in the primary and secondary prevention of the ocular and nonocular complications of atherosclerotic vascular disease.9 Patients with amaurosis fugax or retinal artery occlusions must be evaluated with carotid Doppler ultrasonography in concert with 2D echocardiography to determine if a source of the embolism can be identified.5 More commonly, atherosclerotic disease of the internal or common carotid artery disease is the source.
In this chapter, we review three major clinical trials relevant to the management of symptomatic carotid artery disease and CRAOs as relevant to an ophthalmologist.
I. CAROTID ARTERY DISEASE— THE ROLE OF CAROTID ENDARTERECTOMY
Study Objectives
The aim of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) trial was to determine the efficacy of carotid endarterectomy (CEA) in reducing the risk of stroke among patients with a recent previous adverse cerebrovascular event and stenosis within the ipsilateral carotid artery (termed “symptomatic stenosis”).10 Despite the rising popularity of the surgery from its initial publication in 1954 through the mid-1980s, the supporting data at the time were relatively limited.11,12,13,14
Methodology, Design, and Outcome Measures
The trial was multicenter, parallel group, and randomized. It was conducted in a total of 106 centers within the United States and Canada. Study groups included those with a symptomatic carotid stenosis less than 50%, 50% to 69%, and 70% to 99%. Patients were randomized to receive either medical care alone or surgical endarterectomy with medical care.
To be included within the trial, patients with a carotid stenosis of 69% or less had to have suffered an ipsilateral transient ischemic attack or nondisabling stroke (Rankin score < 3) within 180 days before study entry. A total of 1,108 (CEA) and 1,118 (medical care alone) patients were randomized within this substudy.
Patients with a stenosis of 70% to 99% had to have suffered a hemispheric or retinal transient ischemic attack or a nondisabling stroke within 120 days before study entry to be included. Patients had to be less than 80 years of age. Stenoses were assessed on selective catheter angiography. Patients were required to also have a computed tomography (CT) brain, carotid Doppler ultrasound, and a chest X-ray. A total of 328 (CEA) and 331 (medical care alone) patients were randomized within this substudy. Patients were examined by neurologists at 1, 3, 6, 9, and 12 months after study entry, and then every 4 months thereafter. The study endpoint was stroke (nonfatal or fatal) ipsilateral to the side of treatment.
Summary of Major Results and Implications for Clinical Practice
The results depended on the degree of carotid stenosis. Among patients with a stenosis of less than 50%, the failure rate of treatment for the endarterectomy group was not significantly different from that for the medical treatment group (14.9% vs. 18.7% at 5 years, p = 0.16).
Among patients with a carotid stenosis of 50% to 69%, the 5-year rate of ipsilateral stroke was 15.7% versus 22.2% for patients treated with CEA and patients treated with medical treatment alone, respectively (p = 0.045). In order to prevent a single ipsilateral stroke during the 5-year period posttreatment, 15 patients would have to be treated with endarterectomy.
Among patients with a carotid stenosis of 70% to 99%, the life-table estimate of the cumulative risk of ipsilateral stroke was 36% and 9% for the medically treated and endarterectomy groups, respectively, an absolute risk reduction (±SE) of 17% ± 3.5 (p < 0.001). Six patients would have to be treated in order to prevent a single stroke.
Study Limitations
One of the criticisms of the NASCET trial is the method by which the percent stenosis was calculated. Authors have subsequently shown that there is a potential for variability in the ratio measurement depending on the assessor, in some cases leading to an overestimation of degree stenosis, and therefore potentially overtreatment of patients.15 The definition of stroke has also been questioned—while the NASCET trial considered any neurological deficit lasting greater than 24 hours as a stroke, another major CEA trial, the European Carotid Surgery Trial (ECST), used 7 days as the threshold.16 Finally, surgeon experience and operator volume have been shown to affect patient outcome following CEA (perhaps surprisingly, greater years since licensure was associated with poorer patient outcomes).17
Conclusions
In patients with a recent transient ischemic attack or nondisabling stroke and ipsilateral carotid artery stenosis, the benefit of endarterectomy over medical treatment alone depended upon the severity of stenosis. Patients with a severe stenosis (70% to 99%) had a significant and durable benefit from endarterectomy. Patients with a stenosis of 50% to 69% appreciated a moderate reduction in the risk of subsequent stroke, and therefore the potential benefit and indication for endarterectomy in such patients must take into account other risk factors such as surgical difficulty and patient expectations. Finally, patients with a stenosis of less than 50% did not benefit significantly from endarterectomy.
II. CAROTID ARTERY DISEASE—CAROTID ENDARTERECTOMY VERSUS CAROTID STENTING
Background
The NASCET trial, along with other landmark trials, established CEA as an effective preventive treatment for symptomatic and asymptomatic carotid artery disease
fulfilling certain criteria.10,16,18,19 More recently, carotid artery stenting (CAS) has been used as an alternative method of restoring normal carotid blood flow via a minimally invasive, endovascular technique. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) was undertaken to directly compare CAS with traditional CEA.20
fulfilling certain criteria.10,16,18,19 More recently, carotid artery stenting (CAS) has been used as an alternative method of restoring normal carotid blood flow via a minimally invasive, endovascular technique. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) was undertaken to directly compare CAS with traditional CEA.20
The Carotid Revascularization Endarterectomy versus Stenting Trial
Study Objectives
The CREST study was a large, prospective, randomized clinical trial with blinded endpoint adjudication undertaken to compare the safety and efficacy of CAS to CEA in patients with both symptomatic and asymptomatic carotid artery disease.
Methodology, Design, and Outcome Measures
The CREST trial involved 117 centers from the United States and Canada. Patients were randomized to receive either traditional CEA or CAS using the Acculink stent (Abbott Vascular, Redwood City, CA). Inclusion criteria for symptomatic patients included a history of transient ischemic attack, amaurosis fugax, or minor nondisabling stroke in the distribution of the study artery within 180 days of randomization, along with carotid artery stenosis of at least 50% by angiography, 70% by ultrasound, or 70% by CT or magnetic resonance (MR) angiography (if ultrasound was 50% to 69%). Inclusion criteria for asymptomatic patients included carotid artery stenosis of at least 60% by angiography, 70% by ultrasound, or 80% by CT or MR angiography (if ultrasound was 50% to 69%). Exclusion criteria for all patients included a history of previous disabling stroke or chronic atrial fibrillation.
The primary endpoint was a composite of any stroke, myocardial infarction (MI), or death during the periprocedural period or any postprocedural ipsilateral stroke within a 4-year time period.
Summary of Major Results and Implications for Clinical Practice
In total, 2,502 patients participated in the study, of which 53% were symptomatic and 47% were asymptomatic. There was no significant difference in the primary endpoint between CAS and CEA at 4 years (7.2% vs. 6.8%, p = 0.51). During the periprocedural period, there was also no significant difference in the composite primary endpoint; however, significant differences in the components of the endpoint did exist. During the periprocedural period, a higher risk of stroke was observed with CAS compared with CEA (4.1% vs. 2.3%, p = 0.01), while a higher risk of MI was observed with CEA compared with CAS (2.3% vs. 1.1%, p = 0.03). No significant difference in death rates was found during the periprocedural period between the two groups (CAS = 0.7% versus CEA = 0.3%, p = 0.18). The study outcomes were slightly better after CAS for patients less than 70 years and better after CEA for patients older than 70 years. Symptomatic versus asymptomatic status did not influence the outcomes.
Study Limitations
The CREST study has been criticized for grouping all the varied components of the primary endpoints together (i.e., death, stroke, and MI).21 Also, the inclusion of an asymptomatic group potentially confounds the overall results as this group has a different natural history than the symptomatic group.21 Finally, the CAS and CEA groups received different antiplatelet regimens periprocedurally, with the CAS group receiving double-antiplatelet therapy (aspirin in concert with clopidogrel or ticlopidine) compared with monotherapy (aspirin or clopidogrel or ticlopidine) for the CEA group. This may explain the lower MI rate observed in the CAS group.21
