Smoking Cessation

Tobacco smoking is strongly associated with development and progression of PAD, with the risk of PAD among smokers as high as threefold that of nonsmokers (see Chapter 16). Smoking cessation is a critical component of risk factor modification for patients with PAD. Epidemiological studies have established that smoking cessation improves both cardiovascular and limb-related outcomes among patients with PAD. Given the established hazards of cigarette smoking, it would be unethical to conduct a randomized clinical trial of smoking cessation.

Smoking cessation has salutary effects on claudication symptoms, exercise physiology, and limb-related outcomes in patients with symptomatic PAD. Patients with intermittent claudication who quit smoking have longer pain-free walking times and maximal walking times compared with patients who continue to smoke.³ In a prospective study of patients with intermittent claudication followed with serial noninvasive vascular testing over a period of 10 months, patients who quit smoking had significant improvements in maximal treadmill walking distance and postexercise ankle pressure, whereas ongoing smokers had no changes in these parameters.⁴ Smoking cessation is also associated with improved clinical outcomes in patients with PAD. In a Swedish study, patients with intermittent claudication who were active smokers or who had quit within 6 months were followed prospectively for development of limb-related and cardiovascular outcomes.⁵ At 7 years of follow-up, ongoing tobacco smoking was associated with development of CLI and was also an independent predictor of the need for surgical revascularization. Indeed, only patients who continued to smoke developed rest pain during the follow-up period. Ongoing smoking was also associated with development of MI and a trend toward decreased overall survival at 10 years of follow-up.

Continued cigarette smoking is associated with adverse outcome among patients with PAD referred for vascular surgery. In a prospective study of patients referred for femoropopliteal arterial bypass grafting, ongoing tobacco use was associated with a significant reduction in the 1-year cumulative patency rate of both venous and prosthetic lower-extremity bypass grafts.⁶ In an Australian study of patients who underwent lumbar sympathectomy or lower-extremity bypass grafting for symptomatic PAD, patients who quit smoking following surgery had dramatically improved 5-year survival rates compared to patients who continued to smoke.⁷ The majority of deaths that occurred in the postoperative patients were due to a major vascular event, whereas the remaining deaths were due to other smoking-related illnesses, principally chronic obstructive pulmonary disease (COPD) and lung cancer.

Degree of ongoing tobacco use following revascularization may also be predictive of adverse events. In a registry study of patients who underwent their first arterial revascularization procedure, patients categorized as heavy smokers (>15 cigarettes/day) had significantly reduced overall survival compared to moderate smokers (<15 cigarettes/day).⁸ In addition, there was a 10-fold higher amputation rate among heavy smokers compared with moderate smokers at 3 years’ follow-up.

Despite the multiple benefits of smoking cessation in patients with PAD, it is an extremely difficult goal to accomplish, and initial success rates are low. The efficacy of physician advice in achieving smoking cessation is less than 5%.⁹ The success rate is at least 10-fold higher when smoking cessation advice and encouragement are given to patients at risk for MI, or patients who have survived an MI. Intensive counseling customized to PAD patients who continue to smoke is associated with a significant improvement in confirmed tobacco abstinence at 6 months of follow-up, compared to standard clinical smoking cessation advice.¹⁰ Smoking cessation programs may be more successful when coupled with pharmacological therapy, including both nicotine and non-nicotine agents. The antidepressant bupropion has been demonstrated to improve tobacco abstinence rates at 12 months relative to placebo when used alone or in combination with the nicotine patch.¹¹ Recently, varenicline, a novel partial agonist of the nicotinic acetylcholine receptor (nAchR)  α4β, has been shown to improve tobacco abstinence rates among subjects both with and without cardiovascular disease, including patients with PAD.^12,13 Among those with cardiovascular disease, varenicline was associated with a threefold likelihood of abstinence at 1-year follow-up compared with placebo, although the absolute abstinence rate was only 19.2%.¹³ Side effects of varenicline include sleep abnormalities, nausea, and flatulence.^13,14 Both varenicline and bupropion are associated with an increased risk of neuropsychiatric side effects. Package labeling for both agents includes a black box warning recommending observation for changes in behavior or mood or development of suicidal ideation while receiving these agents for smoking cessation treatment.^14,15

Lipid-Lowering Therapy

Dyslipidemia is a well-established risk factor for development of atherosclerotic vascular disease, including coronary artery disease (CAD) and cerebrovascular disease (CVD). In addition, epidemiological studies have established dyslipidemia—specifically high total and low-density lipoprotein (LDL) cholesterol—as a risk factor for development of atherosclerosis in the peripheral circulation^16–18 (see Chapter 16). There is a less established association between low levels of high density lipoprotein (HDL) cholesterol and development of claudication.^16,19,20 The association, if any, between elevated triglycerides and PAD is controversial.^19,20 The association of dyslipidemia with vascular disease has led to extensive investigation of lipid-lowering therapy as a clinical strategy to prevent myocardial ischemia, stroke, and death in patients with systemic atherosclerosis. Some of these studies specifically addressed the use of lipid-lowering therapy in patients with PAD.

Given convincing epidemiological evidence that dyslipidemia is a risk factor for development of atherosclerosis and subsequent cardiovascular events, multiple randomized clinical trials investigated the use of lipid-lowering agents for prevention of death and other major cardiovascular events in high-risk patients. Development of highly effective and safe agents, particularly HMG-CoA reductase inhibitors (“statins”), has led to widespread application of lipid-lowering therapy for patients with hyperlipidemia and atherosclerotic vascular disease. In recent decades, multiple large randomized controlled trials established the role of lipid-lowering pharmacotherapy, primarily with statins, in secondary prevention of cardiovascular events among patients with CAD.^21–24 Although these studies were not designed to specifically investigate the long-term benefit of lipid-lowering therapy in patients with PAD, the findings are of relevance in these patients because most patients with PAD have either symptomatic or asymptomatic coronary atherosclerosis.^25–27

The Scandinavian Simvastatin Survival Study (4 S) was the first major clinical trial to demonstrate the survival benefit of aggressive lipid-lowering therapy with statins in hypercholesterolemic patients with CAD.²² In secondary analyses, the 4 S investigators examined the effect of simvastatin on development of symptoms and signs of atherosclerotic vascular disease, including claudication and the appearance of a vascular bruit, during semiannual physical examinations of the study participants.²⁸ There was no significant difference in detection of new or worsening femoral bruits, although this endpoint was likely limited by interobserver variability and the limited sensitivity of the physical examination. There was a 38% reduction in the incidence of intermittent claudication and a 30% reduction in cerebrovascular events among patients randomized to simvastatin.^22,28 Similar findings have been confirmed in subsequent studies of the use of HMG-CoA reductase inhibitors for treatment of symptomatic claudication, discussed later in this chapter.

The Heart Protection Study extended use of statins to secondary prevention of cardiovascular events in patients with atherosclerosis in any major vascular bed, and to primary prevention of cardiovascular events in high-risk patients, particularly diabetics.^27,29 Patients were randomized to simvastatin or placebo and followed for a mean of 5 years. Eligible patients included those with documented CAD, CVD, or PAD, or patients without documented atherosclerotic vascular disease believed to be at high risk of a major vascular event due to diabetes or multiple cardiac risk factors. Patients enrolled in the study on the basis of PAD had intermittent claudication, had undergone lower-extremity revascularization, or had objective evidence of “leg artery stenosis.” The majority of patients randomized in the study had a history of CAD (65%); of these, 30% had PAD. There was a 13% reduction in the relative risk of all-cause mortality among patients randomized to simvastatin, due largely to a 17% reduction in the risk of vascular death. There was a 24% reduction in the first occurrence of any major vascular event among patients randomized to simvastatin. Patients enrolled on the basis of PAD alone, with no documented CAD, had a 19% reduction in incidence of first major vascular event if randomized to simvastatin. In a subsequent subset analysis of the 4588 subjects with PAD, randomization to simvastatin was associated with a 20% reduction in noncoronary revascularization procedures compared to placebo.³⁰ There was no significant benefit of simvastatin on the incidence of lower-extremity amputation.

Non-LDL cholesterol, particularly low HDL cholesterol, has been identified as an independent risk factor for development of CAD.^31,32 Pharmacological agents that raise HDL cholesterol (e.g., fibric acid derivatives, niacin) have not been as widely studied as agents that lower total and LDL cholesterol (i.e., statins) for secondary prevention of cardiovascular events in patients with atherosclerotic vascular disease, and specifically for PAD. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) investigators randomized men with documented CAD and low HDL cholesterol to gemfibrozil or placebo and found a 22% reduction in the primary composite endpoint of death from CAD or nonfatal MI in the gemfibrozil cohort after a median of 5.1 years of follow-up.²¹ The incidence of peripheral vascular surgery, the only PAD endpoint studied, was not significantly different within the treatment groups. Cardiovascular benefit has not been found in subsequent studies of other fibrates. The Bezafibrate Infarction Prevention (BIP) study was a randomized study of bezafibrate or placebo in patients with a previous MI or stable angina.³³ Bezafibrate did not significantly affect the primary endpoint of fatal or nonfatal MI or sudden death. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a randomized study of fenofibrate or placebo in patients with diabetes.³⁴ Fenofibrate did not significantly affect the primary outcome of fatal coronary heart disease (CHD) and nonfatal MI, but did decrease secondary endpoints such as nonfatal MI and coronary and peripheral revascularization. Given these limited data, the role of therapies to target non-LDL cholesterol in the management of patients with PAD is uncertain.

Treatment of Hypertension

Control of hypertension is critical for preventing stroke, MI, and congestive heart failure (CHF). Blood pressure control can be achieved with a number of pharmacological agents, either individually or in combination. Large randomized clinical trials have demonstrated the benefits of pharmacotherapy on clinical outcomes, including death.^35,36 Although patients with hypertension and PAD are at increased risk of serious vascular events, few studies have specifically addressed the benefit of blood pressure lowering in this population.

Clinical outcomes trials

Two major clinical trials have investigated the potential benefits of blood pressure–lowering therapy in preventing cardiovascular events in patients with PAD. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial studied the effect of intensive blood pressure control compared with moderate blood pressure control on the occurrence of cardiovascular events and renal insufficiency in diabetic patients.^52,53 Normotensive (diastolic blood pressure 80-90 mm Hg) and hypertensive (diastolic blood pressure > 90 mm Hg) diabetic patients were enrolled. The hypertensive patients were randomized to receive either enalapril or nisoldipine as first-line therapy. The normotensive patients were randomized to either intensive blood pressure treatment (with further randomization to one of the two study drugs) to achieve a reduction in diastolic pressure of 10 mm Hg, or standard therapy, in which case they received a placebo. Patients were followed for a mean of 5 years. In a substudy of the diabetic patients in the normotensive cohort, the effect of intensive blood pressure treatment among patients with PAD was investigated.⁵³ Among the 220 normotensive patients randomized to intensive blood pressure treatment, there was a 65% reduction in the relative risk of MI, stroke, or cardiovascular death. There was a strong inverse relationship between baseline ankle-brachial index (ABI) and risk of a cardiovascular event. Intensive blood pressure control negated this relationship and normalized the odds of a cardiovascular event toward that of patients with a normal ABI (Fig. 19-2). The benefit of intensive blood pressure control was evident even in patients with a severely decreased ABI, a subset of patients that had been excluded from prior studies.⁵⁰ There were too few patients with PAD to analyze data for enalapril and nisoldipine separately. The findings of the ABCD trial emphasize the importance of intensive blood pressure control in diabetic patients with PAD.

Figure 19-2 Intensive blood pressure control with enalapril or nisoldipine decreases the odds of a major vascular event among diabetic patients with peripheral artery disease (PAD).

Results from the Appropriate Blood Pressure Control in Diabetics (ABCD) Trial. The inverse correlation of ankle-brachial index (ABI) and odds of a major vascular event are not present among patients randomized to the intensive blood pressure control group. MI, myocardial infarction.

(Reproduced with permission from Mehler PS, Coll JR, Estacio R, et al: Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes. Circulation 107:753–756, 2003.)⁵³

The Heart Outcomes Prevention Evaluation (HOPE) investigators tested the efficacy of the ACE inhibitor ramipril for primary and secondary prevention of cardiovascular events in high-risk patients.⁴⁹ Patients were enrolled on the basis of established atherosclerotic vascular disease (CAD, prior stroke, or PAD) or diabetes mellitus with additional cardiac risk factors. Some 44% of patients randomized had evidence of PAD, as manifested by a history of claudication with an abnormal ABI of less than 0.8, limb revascularization procedure, amputation, or angiographic evidence of arterial stenosis.⁵⁴ Patients were randomized to receive ramipril or placebo. At a mean of 5 years of follow-up, there was a 22% reduction in the primary composite endpoint of MI, stroke, or cardiovascular death among patients randomized to ramipril (Fig. 19-3). In subgroup analysis, the benefit of ramipril was present regardless of baseline blood pressure. The benefit of ramipril on the composite endpoint was present among the subgroup of patients with PAD. The benefit of ramipril was likely due to cardiovascular benefits other than its blood pressure–lowering properties because the mean decrease in blood pressure among patients randomized to active therapy was very small. The findings of the HOPE trial indicate that patients with PAD should be treated with an ACE inhibitor, regardless of baseline blood pressure or the presence or absence of diabetes.

Figure 19-3 Ramipril reduces the incidence of myocardial infarction (MI), stroke, or cardiovascular death among high-risk patients with atherosclerotic vascular disease or diabetes mellitus.

*, P <0.001.

(Reproduced with permission from Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145–153, 2000.) ⁴⁹

For patients with PAD who are intolerant of ACE inhibitors (e.g., development of cough), an angiotensin receptor blocker (ARB) is an acceptable alternative agent for cardiovascular risk reduction. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint (ONTARGET) Trial, 25,620 patients at high risk for cardiovascular events, a population similar to the HOPE trial, were randomized to receive ramipril, the ARB telmisartan, or a combination of the two agents.⁵⁵ The ONTARGET population included 2468 patients with symptomatic PAD. After a median follow-up of 56 months, the primary cardiovascular event rates in the ramipril, telmisartan, and combination therapy groups were statistically the same (≈︀6.5%). The combination of ramipril and telmisartan, however, was associated with higher rates of renal insufficiency and hypotension than either agent alone.

Control of Diabetes Mellitus

Multiple epidemiological studies have established a strong association between diabetes mellitus and PAD^16,17,56,57 (see Chapter 16). The relative risk of PAD is two to four times that of nondiabetic patients. Presence of diabetes is associated with adverse limb-related outcomes among patients with documented PAD, including the need for amputation.^58,59 In the Strong Heart Study, worsening glycemic control (determined by hemoglobin A_1c [HbA_1c] level) was associated with increased incidence of lower-extremity amputation among diabetic Native Americans with and without PAD.⁶⁰ In addition, diabetes is associated with a markedly increased risk of a major cardiovascular event, including myocardial ischemia, stroke, and death. Therapeutic options for achieving glycemic control in diabetic patients include insulin, sulfonylureas, metformin, the thiazolidinediones (“glitazones”), and novel agents that modify carbohydrate absorption and breakdown into glucose (α-glucosidase inhibitors) or increase insulin bioavailability through differing mechanisms (e.g., repaglinide, nateglinide, sitagliptin).⁶¹ Whereas clinical trials have established the vital importance of rigorous glycemic control for preventing microvascular complications in diabetic patients, the benefits of glycemic control for prevention of major cardiovascular events has not been definitively established. In addition, recent randomized controlled trials have indicated that certain high-risk patients may be more likely to experience adverse effects with very intensive glycemic control.⁶²

Treatment of Hyperhomocysteinemia

Hyperhomocysteinemia is a disorder associated with derangements of the metabolic pathway involved in metabolism of the essential amino acid methionine.⁸⁰ Hyperhomocysteinemia is due to an inherited defect of one of the enzymes involved in transsulfuration or remethylation of homocysteine, or can also occur as a result of malnutrition and deficiency of key cofactors for these enzymatic reactions (i.e., folic acid, vitamins B₆ and B₁₂). Hyperhomocysteinemia is associated with end-stage renal disease, although the mechanism by which this occurs is not well established.⁸⁰ Inherited homocystinuria, the most striking form of hyperhomocysteinemia, is due to homozygous deficiency of the enzyme cystathionine β-synthase, a critical enzyme of the transsulfuration pathway of homocysteine. Homocystinuria is associated with mental retardation, ectopia lentis, and premature coronary and peripheral atherosclerosis. Among heterozygotes for cystathionine β-synthase deficiency, homocysteine levels are significantly lower (on the order of 20-40 μmol/L vs. up to 400 μmol/L for homozygotes), although there is also a predisposition to premature atherosclerosis.⁸⁰ Multiple epidemiological studies have established an association between elevated plasma homocysteine levels and development and progression of CAD and CVD. Extensive epidemiological evidence has also established hyperhomocysteinemia as an independent risk factor for asymptomatic PAD and the clinical progression of symptomatic PAD.^81–84 In addition to premature atherosclerosis, elevated levels of homocysteine are associated with a hypercoagulable state characterized by a tendency toward venous and arterial thrombosis.^80,85

Because elevated plasma homocysteine levels are associated with low levels of the enzymatic cofactors folic acid, vitamin B₆, and vitamin B₁₂, vitamin supplementation is an obvious therapeutic consideration for treating hyperhomocysteinemia. One small trial of healthy siblings of patients with hyperhomocysteinemia and premature atherosclerotic vascular disease (PAD, CAD, or CVD before age 56) randomized siblings to combination vitamin therapy with 5 mg folic acid and 250 mg vitamin B₆ or placebo.⁸⁶ Siblings with and without evidence of hyperhomocysteinemia were enrolled. Subjects continued therapy for a period of 2 years and were followed for development of CAD (abnormal stress test), PAD (abnormal ABI or lower-extremity arterial duplex scan), and CVD (abnormal carotid artery duplex scan). Among patients randomized to vitamins, fasting plasma homocysteine levels fell from 14.7 to 7.4 μmol/L (a nearly 50% decline); there was an 18% decline in the placebo group. There was no significant difference in the development of PAD or asymptomatic CVD among the two groups. Among the patients randomized to aggressive vitamin therapy, there was a decrease in the incidence of an abnormal stress test.

Although the effectiveness of supplementation with folic acid and vitamin B₁₂ for lowering plasma homocysteine levels has been established, few data show a benefit of vitamin supplementation to prevent vascular events in patients with hyperhomocysteinemia or established vascular disease. In the second Heart Outcomes and Prevention Evaluation (HOPE-2) trial, patients with atherosclerotic vascular disease were randomized to receive folic acid, vitamin B₆ and B₁₂, or placebo and followed for incident cardiovascular events.^87,88 Less than 10% of patients in the study population of 5522 had known symptomatic PAD, defined as intermittent claudication or a history of bypass surgery or lower-extremity angioplasty.⁸⁸ After 5 years of follow-up and despite a mean reduction in plasma homocysteine of 2.4 μmol/L in the vitamin-treated group (compared to an increase of 0.8 μmol/L in the placebo group), there was no benefit of vitamin therapy on the primary composite outcome of fatal or nonfatal MI or stroke.

In the Norwegian Vitamin Trial (NORVIT), patients with acute MI within the preceding 7 days were randomized to one of four arms in a factorial design (placebo, vitamin B₆, folic acid + vitamin B₁₂, or combination-therapy folic acid and vitamins B₆ and B₁₂).⁸⁹ There was a 27% reduction in plasma homocysteine levels among individuals who received folic acid and vitamin B₁₂. However, with a median follow-up of 40 months, there was no benefit of folic acid plus vitamin B₁₂ therapy, with or without vitamin B₆, on the composite cardiovascular endpoint. Indeed, there was a trend toward increased risk of a fatal or nonfatal cardiovascular event among individuals randomized to triple-vitamin therapy compared to placebo. The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial assessed the effect of folic acid and vitamin B₁₂ on vascular outcomes in 12,064 survivors of MI.⁹⁰ Treatment with these vitamins reduced homocysteine by 3.8 μmol/L (28%) but did not affect the primary outcome of first major vascular event, defined as a major coronary event, fatal or nonfatal stroke, or noncoronary revascularization.

Antiplatelet Therapy

The pivotal role of antiplatelet agents, particularly aspirin, in the secondary prevention of death and MI in patients with CAD has been established by large randomized clinical trials.^91,92 The role of antiplatelet therapy in the management of patients with PAD continues to evolve, with important new data gleaned from recent large clinical trials directed primarily at the prevention of cardiovascular events in patients with and without CAD.

A recent meta-analysis of six primary prevention trials of 95,000 individuals at low to average cardiovascular risk (representing 660,000 person-years) found that aspirin reduced the risk of any vascular event by 12%.⁹³ This was due primarily to a decrease in the risk of nonfatal MI, but not stroke or vascular mortality. This meta-analysis also included 16 secondary prevention trials of 17,000 individuals at high-average risk, representing 43,000 person-years. In the secondary prevention trials, aspirin reduced serious vascular events by 29%, including total stroke and coronary events, and was associated with a borderline nonsignificant 9% reduction in vascular mortality.

In 2002, the Antithrombotic Trialists’ Collaboration updated the 1994 meta-analysis of the evidence supporting the use of antiplatelet agents in the management of high-risk patients with atherosclerotic vascular disease.⁹¹ Studies with different antiplatelet agents (e.g., aspirin, dipyridamole, picotamide, ticlopidine) were included. The initial meta-analysis determined that antiplatelet therapy significantly reduced the odds of a major vascular event among high-risk patients with atherosclerosis by 27%.⁹² Also, antiplatelet therapy was effective for preventing both coronary and peripheral artery bypass graft occlusion, with a reduction in relative risk of graft occlusion of approximately one third.⁹⁴ In the updated analysis, a total of 287 randomized trials with more than 200,000 patients were included.⁹¹ Confirming the original findings, there was a 22% reduction in the odds of a serious vascular event (vascular death, nonfatal MI, or nonfatal stroke) among high-risk patients treated with antiplatelet agents. The benefit appeared to be greatest among studies that enrolled patients on the basis of high-risk criteria such as prior or acute MI, PAD, or atrial fibrillation. Among the 42 studies that enrolled 9214 high-risk patients on the basis of PAD, there was a 23% reduction in the odds of a major vascular event among patients randomized to antiplatelet therapy. The benefit of antiplatelet therapy was consistent across all PAD enrollment criteria, including intermittent claudication and surgical lower-extremity revascularization. Of note, 2304 patients in this category were enrolled in a study that randomized PAD patients to treatment with a nonaspirin antiplatelet agent, picotamide, or placebo.⁹⁵ Picotamide is an antiplatelet agent that both inhibits thromboxane A₂ (TxA₂) synthase and antagonizes the TxA₂ receptor of platelets. It is also noteworthy that none of the trials in this meta-analysis investigated the benefit of aspirin alone (i.e., not in combination with dipyridamole) in standard clinical dosage (81-325 mg daily ) versus placebo, a fact that was highlighted by an updated meta-analysis of aspirin therapy for PAD by Berger et al. in 2009 (discussed later).⁹⁶

The Critical Limb Ischaemia Prevention Study (CLIPS) randomized patients with ABI less than 0.85 or TBI less than 0.6 who were asymptomatic or had stable leg claudication (Fontaine stage I/II) to aspirin 100 mg daily or placebo.⁹⁷ Although an initial sample size of 2000 patients was planned, the trial was terminated early because of poor enrollment, and only 366 patients were randomized, with a minority followed for more than 2 years. Aspirin was associated with a 64% reduction in the relative risk of fatal and nonfatal vascular events and a 58% reduction in fatal and nonfatal vascular events or critical limb ischemia.

In contrast to the CLIPS trial, which included patients with clinically significant PAD (claudication or asymptomatic PAD with low ABI), there have been two large randomized clinical trials that investigated the efficacy of aspirin in low-risk asymptomatic PAD patients. The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial randomized 1276 patients older than 40 years of age who had type 1 or 2 diabetes mellitus and an “abnormal” ABI of less than 1.0, but who had no known cardiovascular disease and no symptoms of PAD.⁹⁸ Subjects were randomized to aspirin 100 mg daily or placebo, as well as antioxidant vitamins, in a 2 × 2 factorial design. It is important to note that this was a population that was not only asymptomatic in terms of PAD but also had relatively mild disease, with a median ABI in the study population of 0.9, barely at the lower limit of normal. After a median follow-up of 6.7 years, there was no difference between the aspirin and placebo groups in the rate of fatal or nonfatal vascular events or amputation. In subset analysis, there was a nonsignificant trend toward benefit of aspirin among patients with ABI less than 0.9.

The largest trial of aspirin therapy for prevention of cardiovascular events among patients with PAD to date was the Aspirin for Asymptomatic Atherosclerosis (AAA) Trial.⁹⁹ In this trial, nearly 29,000 Scottish patients between the ages of 50 and 75 years who had no cardiovascular disease were offered a screening ABI examination. A total of 3350 individuals with ABI below 0.95 were randomized to receive 100 mg aspirin daily or placebo and followed for an average of 8.2 years. In this study, the lower of two ankle pressures was used for calculating the ABI. There was no statistically significant difference in occurrence of the primary composite endpoint of fatal and nonfatal coronary events, stroke, or revascularization between aspirin- and placebo-treated patients (Fig. 19-4).

Figure 19-4 Aspirin therapy does not reduce the incidence of major vascular events among asymptomatic individuals with ankle-brachial index (ABI) <0.95.

Results from the Aspirin for Asymptomatic Atherosclerosis (AAA) trial. There was no statistically significant difference in the primary composite outcome of fatal and nonfatal myocardial infarction (MI) or stroke or revascularization between the two groups. CI, confidence interval; y, year.

(Reproduced with permission from Fowkes, FG, Price JF, Stewart, MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle-brachial index: a randomized controlled trial. JAMA 303:841–848, 2010.)⁹⁹

Berger et al. performed a meta-analysis of 18 trials comprising 5269 patients with PAD that evaluated the efficacy of aspirin (± dipyridamole) for prevention of cardiovascular events including nonfatal MI, nonfatal stroke, and cardiovascular death.⁹⁶ This meta-analysis included the trials incorporated into the Antithrombotic Trialists’ Collaboration 2002 meta-analysis, as well as new data from the POPADAD trial and CLIPS; the AAA study was not included. Aspirin therapy, with or without dipyridamole, did not significantly reduce the rate of cardiovascular events. In subset analyses, aspirin was associated with a significant reduction in the incidence of nonfatal stroke, but not cardiovascular mortality, MI, or major bleeding.

Large multicenter randomized clinical trials have investigated the use of the antiplatelet agent clopidogrel for secondary prevention of cardiovascular events. Clopidogrel is a thienopyridine derivative that inhibits platelet aggregation by antagonism of the adenosine diphosphate receptor.¹⁰⁰ Clopidogrel is less likely to cause serious adverse hematological side effects, particularly neutropenia and thrombotic thrombocytopenic purpura, than its analog ticlopidine. Pooled analysis of early clinical trials suggested a trend toward a marginal benefit of ticlopidine over aspirin in the prevention of MI, stroke, or vascular death.⁹²

The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study built on this finding and investigated the benefit of clopidogrel versus aspirin in the secondary prevention of cardiovascular events.¹⁰¹ Patients with recent MI (within 35 days), ischemic stroke (within 6 months), or symptomatic PAD were randomized to clopidogrel (75 mg daily) or aspirin (325 mg daily). Patients enrolled on the basis of PAD had intermittent claudication and an abnormal ABI (ABI ≤0.85) or had undergone leg amputation or revascularization. A total of 19,185 randomized patients were followed for development of the primary composite endpoint of first occurrence of ischemic stroke, MI, or vascular death. After a mean 1.9 years of follow-up, there was an 8.7% relative risk reduction in the annual event rate of the primary endpoint among patients randomized to clopidogrel. The benefit of clopidogrel over aspirin was greatest among the subgroup of patients enrolled on the basis of symptomatic PAD, with a relative risk reduction of the composite endpoint of 23.8% (Fig. 19-5). There was no increase in minor or major bleeding episodes associated with clopidogrel, although there was an increased incidence of gastrointestinal hemorrhage among patients randomized to aspirin.

Figure 19-5 Clopidogrel decreases the risk of the composite endpoint of stroke, myocardial infarction (MI), or vascular death relative to aspirin among high-risk patients with atherosclerotic vascular disease.

Relative risk reduction for each subgroup of patients is displayed with 95% confidence intervals. The benefit of clopidogrel is particularly pronounced among the subset of patients with peripheral artery disease (PAD).

(Adapted and reproduced with permission from the CAPRIE Steering Committee: A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events [CAPRIE]. Lancet 348:1329–1339, 1996.)¹⁰¹

Dual antiplatelet therapy, namely the combination of aspirin and clopidogrel, reduced the rate of cardiovascular events among patients with ACS in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial.¹⁰² The role of dual antiplatelet therapy for secondary prevention of cardiovascular events among patients with stable atherosclerotic vascular disease was studied in the Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) trial.¹⁰³ In this trial, 15,603 patients with symptomatic atherosclerotic vascular disease or multiple high risk features (e.g., diabetes mellitus, asymptomatic abnormal ABI) were randomized to receive either aspirin (75 to 162 mg) plus clopidogrel or aspirin plus placebo and followed for incident cardiovascular events. After a median 28 months of follow-up, there was no statistically significant difference in the primary endpoint, which was the rate of first fatal or nonfatal MI, stroke, or cardiovascular death between the two groups. Dual antiplatelet therapy increased the rate of moderate bleeding (i.e., requiring blood transfusion) but did not increase the rate of fatal bleeding or intracranial hemorrhage. A number of subset analyses were performed, including a post hoc subset analysis of patients with either symptomatic or asymptomatic PAD (N = 3096).¹⁰⁴ Among PAD patients in CHARISMA, there was no significant difference in the primary composite cardiovascular endpoint, although there was a significant 37% reduction in the rate of MI among patients randomized to dual antiplatelet therapy.

In the Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Arterial Disease (CASPAR) trial, 551 patients undergoing lower-extremity bypass surgery for claudication or CLI were randomized to dual antiplatelet therapy with aspirin (75 to 100 mg daily) plus clopidogrel (75 mg daily) or to aspirin plus placebo and followed for limb-related events (graft occlusion, repeat revascularization, major amputation) and cardiovascular events, including death, over a period of up to 2 years.¹⁰⁵ Compared to aspirin alone, dual antiplatelet therapy did not reduce the risk of clinical cardiovascular or limb-related events. In a post hoc analysis, dual antiplatelet therapy was associated with lower rates of graft occlusion and lower-extremity amputation among patients who had prosthetic (vs. venous) bypass grafting.

Anticoagulant Therapy

Several clinical trials have addressed the role of anticoagulant therapy, typically with the vitamin K antagonist warfarin, in the management of patients with PAD. These include several small studies that explored the potential effect of oral anticoagulation on limb-related outcomes. A review of three small trials found that oral anticoagulation therapy had no benefit on walking capacity or limb-related outcomes, nor on cardiovascular outcomes among patients with intermittent claudication.¹⁰⁶ Another trial, the Dutch Bypass Oral Anticoagulants or Aspirin investigators compared the efficacy of high-intensity warfarin (target international normalized ratio [INR] 3.0-4.5) with aspirin (80 mg daily) therapy on graft occlusion in patients following infrainguinal bypass grafting.¹⁰⁷ After a mean 21 months of follow-up, there was no significant difference in the rate of graft occlusion between the warfarin and aspirin groups. Subset analyses, however, demonstrated a significant reduction (31%) in the rate of graft occlusion of venous conduit bypass grafts, but not prosthetic grafts, among patients randomized to warfarin.

The Warfarin Antiplatelet Vascular Evaluation (WAVE) trial studied the potential benefit of oral anticoagulation therapy in addition to aspirin for patients with noncoronary atherosclerotic vascular disease.¹⁰⁸ The study included 2161 patients with atherosclerotic vascular disease (symptomatic lower-extremity PAD, symptomatic or asymptomatic carotid artery disease (CAD), or subclavian artery stenosis) who were randomized to receive aspirin (dose 81-325 mg) or aspirin plus warfarin (INR goal of 2-3). More than 80% of patients enrolled had lower-extremity PAD. The co-primary endpoints of the trial were: (1) cardiovascular death, nonfatal MI, and nonfatal stroke, and (2) the above plus need for urgent coronary or peripheral revascularization. Over a follow-up period of 35 months, there was no significant benefit of oral anticoagulation therapy in either of the two co-primary endpoints. There was 3.4-fold relative risk of life-threatening bleeding, and a 15.2-fold relative risk for hemorrhagic stroke among patients randomized to oral anticoagulation therapy.

Care and Protection of the Feet

Careful attention to foot care is indicated to reduce the likelihood of skin breakdown and infection, and is particularly important in diabetic persons with vascular disease and in patients with critical limb ischemia. Treatment of lower-extremity ulcers is discussed in Chapter 60. The feet of patients with PAD should be kept clean, and moisturizing lotion applied to prevent drying and fissuring. Stockings should be made of absorbent natural fibers. Well-fitted shoes are recommended to reduce the risk of pressure-induced necrosis. In some patients, customized footwear or orthotic devices (e.g., for the patient with excessive callous formation or bony deformities) are indicated. The patient is advised to inspect the skin of the feet frequently so minor abrasions can be addressed promptly. High-grade graduated elastic stockings should generally be avoided because they can restrict cutaneous blood flow.

In patients with ischemia at rest, conservative measures include placing the affected limb in a dependent position (i.e., below heart level) to increase perfusion pressure and oxygen tension in ischemic tissues. If there is edema, which may impair healing, the limb is kept horizontal instead. Sheepskin should be placed beneath the heels of the feet to prevent skin breakdown at these sites. A footboard should be used to cradle the blankets over the feet in a fashion that minimizes frictional trauma. Alternatively, protective boots may be used. Wisps of cotton or lambswool inserted between the toes help protect the digits from intertriginous friction and moisture. Gentle warmth is recommended to minimize vasoconstriction, but excessive heat should be avoided. Tinea pedis should be treated with appropriate antimicrobial preparations to reduce the risk of cutaneous breakdown leading to bacterial superinfection. Caution is advised in the use of topical medications because of the possibility of local inflammatory reactions. Open sores should be kept clean, and deep cultures should be obtained (also see Chapter 60). Antibiotic medications are not always effective, in part because of impaired delivery to ischemic tissue. Plain roentgenographic examinations or magnetic resonance imaging (MRI) of underlying bone may be helpful in assessing the possibility of osteomyelitis, for which antibiotic therapy generally is given.

Treatment of Intermittent Claudication and Critical Limb Ischemia

Physical and pharmacological therapies should be considered in the treatment plan of patients with symptomatic PAD. These include supervised exercise rehabilitation and pharmacotherapy. Drugs available for the treatment of intermittent claudication include cilostazol and pentoxifylline. Investigative pharmacotherapies include prostaglandins (PGs), metabolic agents, angiogenic growth factors, stem cell therapy, and statins. The evidence supporting and refuting the efficacy of drug therapy for intermittent claudication and CLI is reviewed subsequently. Endovascular and surgical reconstructions for the treatment of disabling claudication are reviewed in Chapters 20 and 21.

Exercise Training

Supervised exercise training programs improve walking duration, speed, and walking distance in patients with intermittent claudication. Although supervised exercise therapy has been shown to be highly cost-effective compared to catheter-based revascularization for treatment of lower-extremity claudication, it is not widely available owing to a lack of reimbursement by most third-party payers in the United States.^110,111 Two separate meta-analyses have supported the efficacy of supervised exercise training. One meta-analysis of 21 randomized and nonrandomized trials found that pain-free walking distance and maximal walking distance increased by 180% and 120%, respectively.¹¹² Another meta-analysis that included 10 randomized trials found that supervised exercise training improved maximal walking distance by 150%.¹¹³ Strength or resistance training is not as effective as treadmill training in improving walking distances in patients with claudication.^114, In the recently published Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) study, randomization to supervised exercise training was associated with improved maximal walking time at 6 months follow-up compared to endovascular therapy or optimal medical therapy among patients with aortoiliac occlusive disease¹¹⁵. Supervised exercise training has also been shown to improve quality of life among patients with PAD and either claudication or atypical leg symptoms.¹¹⁴ Unsupervised exercise training programs are not as effective as supervised programs.^116,117 Most comparative studies have found that home-based unsupervised exercise is not as effective as supervised exercise training. A recent study, however, did observe comparable improvement in walking time between home-based exercise coupled with activity monitoring and supervised exercise training.¹¹⁶

Several mechanisms have been proposed to explain the improvement in walking distance that results from exercise training. These include collateral blood vessel development, enhancement in endothelium-dependent nitric oxide (NO)-mediated vasodilation of the microcirculation, improved hemorrheology, increased oxidative capacity of calf skeletal muscle, and better walking biomechanics.¹¹⁹ Exercise training has been found to improve collateral blood flow in animal models of hindlimb ischemia, as well as capillary density in humans.^120–122 Exercise-induced angiogenesis has been attributed to up-regulation of angiogenic growth factors such as vascular endothelial growth factor (VEGF).^123,124 Increased expression and activity of endothelial nitric oxide synthase (eNOS) and production of NO may contribute to angiogenesis.^{121,123,125,126} In humans, several studies have found that exercise training improves maximal calf blood flow following exercise.^127,128 Similarly, exercise training improves calf blood flow during reactive hyperemia following an ischemic stimulus. There was no effect of exercise training on resting calf blood flow in these studies. Exercise training enhances endothelium-dependent vasodilation in peripheral conduit arteries, and thereby may contribute to improved blood flow and walking time in claudicants.^114,129,130 Improvement in skeletal muscle metabolic function, and specifically oxidative capacity, occurs with exercise training and may be relevant to the improvement in walking capacity experienced by patients with intermittent claudication.^131,132 Also, exercise training may improve walking distance by altering biomechanics and adapting patterns of walking that are more efficient, engaging skeletal muscle less affected by ischemia, and improving gait stability.¹³³

A number of novel approaches to exercise training for improvement of functional capacity for patients with PAD are currently under investigation, including supervised interval training, home-based monitored exercise programs, and arm ergometry.^{118,134–137}

Vasodilator Drugs

Vasodilator drugs have undergone extensive investigation for treatment of patients with claudication and critical limb ischemia. It is tempting to assume that treatment with a medication that reduces arteriolar resistance would be as effective for patients with PAD as nitrates and calcium channel blockers are for patients with angina. In general, however, vasodilator drug therapy has been disappointing for relief of intermittent claudication. Differences in the pathophysiology of limb and myocardial ischemia may promote insight into the disparate efficiency of vasodilator drugs. Vasodilator therapy may decrease myocardial oxygen demand, but is not likely to affect skeletal muscle oxygen demand. Therefore, to be effective, vasodilators would have to improve the blood supply to exercising muscle.

When an obstructive arterial lesion produces critical stenosis, distal perfusion pressure is reduced (see Chapter 17). Intramuscular (IM) arterioles normally dilate in response to the metabolic demands of limb exercise, but flow augmentation is blunted in patients with proximal stenotic disease. Also, distal pressure falls during exercise, leading to accumulation of the ischemic metabolites believed to mediate the symptom of claudication. These substances potentiate local vasodilation and perfusion pressure falls, no longer balancing the extravascular compressive force exerted by exercising muscle within the tissue compartment. The distal vasculature virtually collapses under these circumstances, and this mechanism may not be mitigated by vasodilator therapy. Indeed, vasodilator drugs, including β-adrenergic agonists (isoproterenol, nylidrin), α-adrenergic antagonists (reserpine, guanethidine, tolazoline), calcium channel blockers, nitrates, and others (isoxsuprine, cyclandelate) have been evaluated in clinical trials. None increases blood flow in exercising skeletal muscle subtended by significant arterial obstructive lesions, nor do any of these improve symptoms of intermittent claudication or objective measures of exercise capacity. Nonetheless, one drug with vasodilator properties, cilostazol, has been reported to improve walking distance in patients with claudication.

Cilostazol

Cilostazol was approved by the U.S. Food and Drug Administration (FDA) in 1999 for use in patients with intermittent claudication. As a phosphodiesterase (PDE) III inhibitor, cilostazol increases cyclic adenosine monophosphate (cAMP), causes vasodilation, and inhibits platelet aggregation.^138–141 The precise mechanism of action whereby cilostazol may improve symptoms of claudication, however, is not known. In a pooled analysis of 2491 patients in nine trials, cilostazol (100 mg twice daily) increased maximal walking distance by approximately 50% compared to 24% for placebo, corresponding to an absolute improvement of 42 meters more than the improvement with placebo¹⁴² (Fig. 19-6). The efficacy of cilostazol compared to placebo among patients with CLI has not been evaluated, although observational studies have reported improvements in lower-extremity microcirculation and amputation-free survival among cilostazol-treated patients.^143,144

Figure 19-6 Cilostazol improves maximal walking distance in patients with claudication.

Meta-analysis of nine randomized controlled trials including 1258 subjects. Shown are random effects–weighted differences in maximal walking distance, with 95% confidence intervals (CI) for the nine trials and the pooled treatment effect. There was a pooled improvement of 42.1 meters in maximal walking distance compared to placebo over a mean follow-up of 20.4 weeks.

(Reproduced with permission from Pande RL, Hiatt WR, Zhang P, et al: A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication. Vasc Med 15:181–188, 2010.)¹⁴²

Cilostazol is primarily metabolized in the liver by the CYP3A4 and CYP2C19 isoenzymes. Prescription of low-dose (50 mg twice daily) cilostazol is recommended for patients who concurrently take medications that are known to inhibit CYP3A4 or CYP2C19, including diltiazem, fluoxetine, fluconazole, erythromycin, and other macrolide antibiotics (CYP3A4), as well as omeprazole (CYP2C19).¹⁴⁵ Side effects of cilostazol are relatively common and include headache in approximately 25%, palpitations in approximately 15%, and diarrhea or abnormal stool in 15% to 20%.¹⁴⁶ The FDA has advised that cilostazol not be administered to patients with CHF of any severity.¹⁴⁵ The reason for this advisory is that when studied in patients with congestive heart failure, other PDE III inhibitors, such as milrinone or vesnarinone, were associated with increased mortality.^147,148 Cilostazol has not been associated with increased mortality rates, but it has not been studied in a heart failure population.

In the Cilostazol: A Study in Long-Term Effects (CASTLE) trial, 1435 patients with claudication were randomized to receive cilostazol (100 mg twice daily) or placebo and followed for adverse events.¹⁴⁹ At approximately 3 years of follow-up, there was no excess of death or serious bleeding events among those randomized to cilostazol compared to placebo. Importantly, the discontinuation rate of study medication was very high in this trial (>60%), perhaps reflective of the side effect profile of cilostazol.

Recommendations

Cilostazol is an effective therapy to improve walking distance in patients with intermittent claudication, and a therapeutic trial of cilostazol is recommended in the ACC/AHA PAD guidelines (class I).¹ Physicians should be aware of the side effect profile of this drug and are advised not to administer this medication to patients with congestive heart failure.

Hemorrheological Agents

Metabolic Agents

Symptoms of intermittent claudication may be related in part to abnormalities in skeletal muscle metabolism (see Chapter 17). Therefore, drugs that favorably affect oxidative metabolism may confer benefit by enhancing skeletal muscle function even without improving blood supply. For example, L-carnitine and its derivative propionyl-L-carnitine enhance glucose oxidation and oxidative metabolism via the Krebs cycle by providing a source of carnitine.¹⁶⁷ Three placebo-controlled trials have assessed the efficacy of propionyl-L-carnitine in patients with intermittent claudication.^168–170 In these studies, propionyl-L-carnitine administered as a 1-g oral dose twice daily improved maximal walking distance by 54% to 73%, whereas those randomized to placebo increased maximal walking distance 25% to 46%. Propionyl-L-carnitine improved physical function, walking speed, and distance as assessed by quality-of-life questionnaires.^168,171 Propionyl-L-carnitine was not associated with any significant adverse side effects.

A recent trial assessed the potential benefit of propionyl-L-carnitine therapy (vs. placebo) as adjunctive treatment to home-based monitored exercise training for patients with intermittent claudication.¹⁷² In this trial, maximal walking time increased in both the propionyl-L-carnitine and placebo groups after 6 months of exercise training, with a nonsignificant trend toward improved walking in the propionyl-L-carnitine group. Propionyl-L-carnitine has potential merit for treating intermittent claudication, but should be considered investigational at this time.

Ranolazine is a piperazine derivative that inhibits fatty acid oxidation, activates pyruvate dehydrogenase, and shifts metabolism toward carbohydrate oxidation, thereby increasing efficiency of oxygen utilization.¹⁷³ Ranolazine improves exercise capacity and decreases angina frequency in patients with CAD and was associated with improvement in pain-free walking time (vs. placebo) among patients with intermittent claudication in a single-center pilot study.^174–176

Angiogenic Growth Factors

Angiogenic growth factors have undergone investigation for treatment of PAD. This class of drugs includes VEGF, fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and hypoxia-inducible factor-1α (HIF-1α). They may be administered as recombinant proteins or by gene transfer using plasmid deoxyribonucleic acid (DNA) or an adenoviral vector that encodes the angiogenic growth factor.¹⁷⁷ Vascular endothelial growth factor, FGF, and HIF-1α increase collateral blood vessels and improve blood flow in animal models of hindlimb ischemia.^178–181 Therefore, angiogenic growth factors have the potential to promote collateral blood vessel formation and thereby increase blood flow to the ischemic limbs of patients with PAD.

Stem Cell Therapy

Infusion of endothelial progenitor cells into mice in an experiment model of hindlimb ischemia has been shown to improve blood flow and capillary density in the ischemic hindlimb and reduce the rate of limb loss.¹⁹⁵ Bone marrow mononuclear cells include endothelial progenitor cells. Intramuscular injection of autologous bone marrow–derived mononuclear cells improved collateral blood vessel formation in animal models of myocardial and hindlimb ischemia.^196,197 Consequently, the effect of autologous implantation of bone marrow–derived mononuclear cells was studied in patients with PAD manifested as limb ischemia.¹⁹⁸ Injection of bone marrow mononuclear cells, compared with peripheral blood mononuclear cells, reduced rest pain and improved pain-free walking time. The improvement was sustained for 24 weeks. Angiographic evidence of collateral blood vessel formation was present in many of the patients who received bone marrow–derived mononuclear cells. Additional data supporting potential angiogenic benefit of IM injection or IA infusion of bone marrow–derived mononuclear cells or bone marrow–derived mesenchymal cells for patients with CLI and limited revascularization options have been reported in multiple small single-center early phase trials.^199–204 Many of these studies reported noninvasive testing (e.g., ABI, TBI, plethysmography) rather than angiography to document evidence of angiogenesis.

Several trials are planned or are in progress. The Use of Vascular Repair Cells in Patients with Peripheral Arterial Disease to Treat Critical Limb Ischemia (RESTORE-CLI) trial has randomized 86 patients to stem and progenitor cell therapy with lower-extremity (IM injection) versus a sham control procedure (injection of an electrolyte solution) at 18 U.S. centers.²⁰⁵ In a published interim analysis, stem cell therapy was associated with improved amputation-free survival, and the results of the completed study are awaited. The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intraarterial Supplementation (JUVENTAS) trial is another multicenter randomized controlled trial of stem cell therapy in CLI that is currently underway.²⁰⁶ In JUVENTAS, bone marrow–derived mononuclear cells (vs. placebo) will be administered to the lower extremities through IA infusion, and patients will be followed for the primary endpoint of lower-extremity amputation at 6 months.

Statins

As discussed earlier in this chapter, lipid-lowering therapy with statins reduces the risk of adverse cardiovascular events in patients with atherosclerosis, including those with PAD. Post hoc analysis of the 4S found that simvastatin reduced the risk of new or worsening claudication.²⁸ Several prospective studies found that statin therapy improved symptoms of claudication in patients with intermittent claudication. One placebo-controlled trial found that atorvastatin (80 mg/day) for 12 months improved pain-free walking time by 63%, compared with 38% in the placebo group²⁰⁷ (Fig. 19-7). In other studies, 6 and 12 months of treatment with simvastatin (40 mg/day) improved pain-free and maximal walking distance.^208,209 The efficacy of lipid lowering therapy on walking time was not demonstrated, however, in another trial of patients with claudication who were randomized to lovastatin (40 mg) plus niacin 2000 mg daily, lovastatin plus niacin 1000 mg daily, or diet intervention.²¹⁰ After 28 weeks of follow-up, there was no significant difference in treadmill walking times among the three treatment groups.

Figure 19-7 Atorvastatin improves pain-free walking time (PFWT) in patients with intermittent claudication.

*, P = 0.025 for 80-mg dose at 12 months.

(Reproduced with permission from Mohler ER 3 rd, Hiatt WR, Creager MA: Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation 108:1481–1486, 2003.)²⁰⁷

There are several potential mechanisms whereby statin therapy may improve symptoms of claudication. These include reduction in plaque size, improvement in vasomotor regulation of blood flow (particularly in the microcirculation), promotion of angiogenesis, and increased skeletal muscle metabolic function. It is not likely that reduction of plaque size accounts for the improvement in symptoms. This is because angiographic studies have shown that treatment with statins induces only very mild changes in vascular lumen size, and these are unlikely to affect blood flow through a stenotic artery.²¹¹ In the studies that have examined the effect of statins on patients with claudication, there have been no, or only very minor, changes in the ABI.^207,209 Endothelial function, particularly in the peripheral resistance vessels, is impaired in patients with atherosclerosis, including those with PAD.²¹² Statin therapy has been shown to improve endothelial function in patients with CAD.^213,214 Therefore, statin therapy may improve blood flow to the microcirculation and thereby ameliorate symptoms of claudication. Animal studies have found that hypercholesterolemia inhibits angiogenesis.²¹⁵ This inhibition may be reduced when cholesterol concentration is reduced by statin therapy, enabling collateral formation to occur. In addition, statins have been shown to increase circulating endothelial progenitor cells independent of cholesterol reduction, and thereby may have a proangiogenic effect.²¹⁶ Favorable effects on metabolic function are not likely to account for the observed effects on walking time. Therapy with simvastatin, alone or in combination with ezetimibe, did not improve phosphocreatine recovery time, as assessed by phosphorus-31 magnetic resonance spectroscopy (MRS).²¹⁷

Miscellaneous Pharmacological Agents

A number of additional pharmacological agents have been studied as potential therapies for intermittent claudication in recent clinical trials, but unfortunately none has yielded a consistently positive efficacy signal. Multiple serotonin receptor antagonists have been studied with mixed, and largely negative, clinical results to date.^218,219 The antichlamydial antibiotic rifalazil had no significant effect on treadmill walking times or quality-of-life parameters compared to placebo.²²⁰

Nutraceuticals and Alternative Therapies

Dietary supplements with nutrients, herbs, and vitamins such as L-arginine, ginkgo biloba, and vitamin E, as well as ethylenediaminetetraacetic acid (EDTA), have been studied as complementary therapeutic strategies to improve functional capacity in patients with intermittent claudication. The available evidence supporting and refuting these holistic therapies is reviewed here because vascular specialists are frequently queried by their patients about these remedies.