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