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2296 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2297

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immunosuppressive macrocyclic lactone rapamycin (sirolimus) and vorapaxar, is approved to prevent cardiovascular events in patients
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the chemotherapeutic agent paclitaxel (Taxol), significantly reduce with PAD. The clinical consensus is that antiplatelet therapy should
the rate of restenosis. Because drug-eluting stents were not available at be offered to all patients with PAD unless contraindicated by allergy
the time of the previous clinical trials, extrapolating the benefits of PCI or comorbidities. 263
versus CABG or over medical therapy is difficult. The medical manage- The options for treating claudication symptoms include exercise
ment of patients with stable angina pectoris should include antiplatelet rehabilitation, pharmacologic agents, and a revascularization pro-
therapy, statin drug treatment, a β-blocker, an angiotensin-converting cedure. Several studies indicate exercise rehabilitation improves the
enzyme inhibitor, and a long-acting nitrate. symptoms of claudication, and a supervised program is better than an
unstructured program, and comparable to percutaneous revasculariza-
tion. 264,265 Two drugs are approved by the FDA for treatment of claudi-
PERIPHERAL ARTERY DISEASE cation symptoms: pentoxifylline, a methylxanthine derivative that may
PAD is a term that encompasses any arterial disease of the lower extrem- improve abnormal red cell deformability and reduce blood viscosity,
ities, upper extremities, and iliac vessels. It most commonly results from and cilostazol, a type III phosphodiesterase inhibitor with antiplatelet
atherosclerosis. Patients who have atherosclerotic disease that compro- and vasodilating properties. Cilostazol is generally considered more
mises blood flow to the extremities may present with exertional pain in effective than pentoxifylline for improving walking distance in patients
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a muscle group, called claudication (derived from the Latin claudicare with claudication. The addition of cilostazol to either aspirin or
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meaning “to limp”). Claudication is an intermittent but reproducible clopidogrel does not increase the bleeding risk. A revascularization
discomfort of a defined group of muscles that is induced by exercise procedure in patients with stable, intermittent claudication generally is
and relieved with rest. Acute limb ischemia is a relatively rare prob- reserved for those with severe lifestyle-limiting symptoms or manifes-
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lem in patients with PAD. In general, it is caused by in situ thrombo- tation of critical limb ischemia.
sis or an embolic event from arrhythmias, such as atrial fibrillation, or
after manipulation of an artery or aorta with a catheter. Approximately
4 percent of patients with claudication progress to critical limb ischemia, CEREBROVASCULAR DISEASE
which is defined as rest pain and/or foot ulceration that heralds impending The etiology of ischemic stroke is multifactorial and can be categorized
tissue loss. into embolic, small-vessel disease, large-vessel disease, and crypto-
The 5-year mortality rate is estimated to be 30 percent in patients genic. Carotid artery disease accounts for approximately 30 percent of
with lower-extremity PAD. Approximately 75 percent of mortal- strokes. Major risk factors for developing carotid artery atherosclero-
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ity results from a cardiovascular event, such as MI or stroke. The sis are hypertension, diabetes, smoking, and dyslipidemia. Emerging
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ankle-brachial index is a noninvasive measure of limb vascular pressure risk factors for stroke include hyperhomocysteinemia and an elevated
in the lower extremities and has been noted in several studies to be pre- plasma level of lipoprotein(a). An elevated hsCRP level is a risk factor
dictive of cardiovascular events. However, a decreased index is not associated with ischemic stroke in both men and women. However, at
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just a predictor; it also is a physical finding that indicates significant ath- this time hsCRP is not routinely measured as an additional marker for
erosclerotic plaque burden is present. Other noninvasive imaging stud- increased risk of stroke. Similar to CAD and PAD, control of athero-
ies for PAD include the combination of segmental pressures and pulse sclerotic risk factors is essential in the primary prevention of stroke in
volume recordings, duplex Doppler ultrasound, computed tomographic patients with evidence of carotid atherosclerosis and for those who have
angiography and magnetic resonance imaging. 256,257 undergone carotid endarterectomy. 269,270
Medical therapy for patients with PAD includes risk-factor mod- Carotid endarterectomy is indicated for patients with symptoms
ification, antiplatelet therapy, and treatment of claudication symptoms and a greater than 50 percent stenosis or for patients who are asymp-
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with exercise rehabilitation and possible pharmacologic agents. The tomatic with a greater than 60 to 99 percent stenosis of the common
risk factors for development of peripheral atherosclerosis include cig- carotid or internal carotid arteries. Carotid stent with embolic protec-
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arette smoking, diabetes mellitus, hypertension, and dyslipidemia. tion is a therapy used for treatment of carotid atherosclerosis in selective
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Aggressive management of risk factors for PAD is recommended to patients. 273
prevent disease progression. Treatment with antiplatelet agents Two antiplatelet drug regimens are approved for prevention of
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reduces the risk of cardiovascular events, such as MI and stroke, in stroke: clopidogrel (Plavix) and the combination of aspirin 25 mg and
patients with PAD. The Antithrombotic Trialists’ Collaboration dipyridamole 200 mg daily. Approval of clopidogrel is based on the
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evaluated 9214 patients with PAD enrolled in 42 trials and found that CAPRIE study, which showed a reduction in the combined end point
use of antiplatelet drugs, such as aspirin 75 to 325 mg/day, resulted in of stroke, MI, and death in patients treated with clopidogrel 75 mg/
a proportional reduction of 23 percent in serious vascular events. day compared to those treated with aspirin 325 mg/day. The FDA
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Evaluation of patients with PAD in the Physicians’ Health Study found indication for dipyridamole/aspirin is primarily based on the European
that aspirin 325 mg every other day decreased the need for peripheral Stroke Protection Study 2, which noted a reduction in stroke with
artery surgery. However, no difference between the aspirin and pla- the combination of dipyridamole 200 mg and aspirin 25 mg given
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cebo groups with regard to development of claudication was observed. together (Aggrenox) twice per day. The Prevention Regimen for
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Several studies have evaluated the ADP receptor blockers ticlopidine Effectively Avoiding Second Strokes (PRoFESS) trial was a second-
and clopidogrel. Clopidogrel was evaluated in 19,185 patients in the ary stroke–prevention trial comparing the combination of aspirin
Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events and extended-release dipyridamole (Aggrenox) versus clopidogrel
(CAPRIE) study. A dose of clopidogrel 75 mg/day had a modest but (Plavix) in preventing stroke recurrence after a first event. The
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significant advantage over aspirin 325 mg/day in preventing stroke, difference between the agents was not statistically significant for the
MI, and peripheral vascular disease. Subgroup analysis revealed that primary outcome of recurrent stroke. Fish oil (omega-3 fatty acids)
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the patients with PAD benefited the most with clopidogrel treatment. lowers triglycerides and VLDLs and may reduce serum viscosity by
One study evaluating the effect of aspirin, 100 mg, compared to pla- lowering fibrinogen. Some studies suggest that fish oil consumption
cebo in asymptomatic patients with diabetes mellitus and PAD found lowers the risk of ischemic stroke. The effect of fish oils on carotid
no benefit in reducing cardiovascular events. The PAR-1 antagonist, atherosclerosis is unknown. 276
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