Peripheral arterial disease (PAD) of the lower extremities affects nearly 8 to 12 million adults in the United States.¹ The age-adjusted prevalence of PAD is approximately 12% and accounts for significant morbidity and health care expenditure among the elderly. This disorder affects men and women equally.^2,3,4,5 Symptomatic PAD causes functional impairment and reduced mobility, and asymptomatic PAD may eventually progress to symptomatic PAD. Regardless of symptom status, PAD predicts future cardiovascular events such as myocardial infarction (MI), stroke, and death.

Diagnosis of Lower Extremity PAD

Although history suggestive of classic walking-induced lower extremity pain with resolution at rest and physical examination demonstrating absent or diminished pulses of lower extremities is sufficient to diagnose PAD, only 10% of patients with PAD may present with this classic presentation.^6,7 An ankle–brachial index (ABI), defined as the ratio of ankle to brachial systolic blood pressure, of ≤0.90 is 90% sensitive and 95% specific for the diagnosis of PAD.⁸ Severe PAD is defined as ABI ≤ 0.40 and is associated with rest pain or ischemic ulceration.

Risk Factors of Lower Extremity PAD

A constellation of data from several studies^{9,10,11,12,13} provides evidence that risk factors for PAD are essentially the same as those for coronary artery disease (CAD) with few exceptions. Therefore, age (>40 years), family history, diabetes, hyperlipidemia, cigarette smoking, and hypertension are the major risk factors for PAD. Cigarette smoking and diabetes are probably the most important of these risk factors. The most common form of dyslipidemia causing PAD is the combination of elevated triglycerides and low high-density lipoprotein level (HDL)—a pattern most commonly seen among patients with uncontrolled diabetes (“metabolic dyslipidemia”). Female diabetic patients are more prone to develop PAD compared to male diabetic patients, and in women, it manifests as peroneal and tibial PAD. Smoking, on the other hand, causes mostly aortoiliac disease. Women with a history of heavy smoking often develop a distinct hypoplastic aortoiliac syndrome. In addition to these traditional risk factors, several other novel risk factors are found to be associated with increased risk of PAD. Elevated levels of lipoprotein (a), homocysteine, apolipoprotein (apo) A-1, apoB-100, high sensitive C-reactive protein, and fibrinogen predispose patients to PAD.¹⁴ Impaired renal function has also been found to be a risk factor for developing PAD.¹⁵

Prevalence of Lower Extremity CAD in PAD

As the risk factors for PAD and CAD are very similar, there is a common association of these two disorders¹⁶ (Table 13-1). However, depending on the methods used to diagnose and define CAD, the prevalence of CAD in PAD has been reported from 14% to 90%. When only clinical symptoms of angina and electrocardiograms were used to diagnose CAD among PAD patients, CAD prevalence was found to be from 19% to 47%. CAD prevalence increased to >60% when stress tests were used to diagnose CAD and to >90% when conventional angiograms were used to diagnose CAD.¹⁷ In two separate reports, Hertzer¹⁸ showed that by preoperative coronary angiogram, 36% of patients with abdominal aortic aneurysm and 28% of patients with lower extremity ischemia had severe CAD, 8% had normal coronaries, and 32% had mild to moderate CAD.^18,19 Thus, presence of PAD can be a surrogate marker of coexistent CAD (Table 13-1). Identification of these patients is of critical importance as primary and secondary prevention remains the key to minimizing cardiovascular mortality and morbidity among these high-risk patients.²⁰ In the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, a total of 6979 patients aged ≥70 years or aged 50 to 69 years and with a history of diabetes or smoking from primary care practice were screened for PAD by ABI. Although PAD was present in nearly 30% of the screened patients and these patients were at a high risk of cardiovascular morbidity and mortality, the patients had less intensive treatment for their concomitant cardiovascular risk factors.²¹

ABI and Cardiovascular Outcomes

The ABI is the ratio of the ankle to brachial systolic blood pressure and a value of <0.90 indicates the presence of significant arterial disease of the lower extremities. ABI can gauge the severity of PAD in symptomatic patients and at the same time can assess the cardiovascular risk in asymptomatic patients (Figure 13-1). The lower the ABI, the worse the cardiovascular outcome^22,23 (Figure 13-2). In a large meta-analysis of nine studies, the sensitivity and specificity of ABI to predict incident CAD were 16.5% and 92.7%, respectively.²⁴ Even in primary care settings, low ABI has been shown to be associated with premature death and vascular events.²⁵ Thus, ABI should be a part of an evaluation of any patient with suspected PAD and individuals with low or borderline ABI should be targeted for follow-up and aggressive risk factor modification and secondary prevention.

PAD and Cardiovascular Morbidity

Presence of any degree of PAD (symptomatic or asymptomatic) increases the risk of cardiovascular adverse outcomes such as new angina, need for coronary artery bypass graft, nonfatal MI, congestive heart failure, and fatal MI or death.^26,27 The more severe the PAD, the more symptomatic the CAD and the worse the outcome of CAD (Figure 13-3). Symptomatic PAD is more likely to be associated with subsequent symptomatic angina (risk ratio 2.3) than is asymptomatic PAD.¹⁷ Patients with PAD, even in the absence of MI, have the same risk of death from cardiovascular causes as do patients with a history of CAD.¹⁶ PAD is thus considered to be CAD equivalent and denotes a heavy atherosclerotic burden. In addition, patients with symptomatic PAD are markedly impaired functionally and may thus limit their physical exercise, triggering weight gain and the associated comorbidities with obesity-related inactivity such as diabetes, hypertension, dyslipidemia, and metabolic syndrome. PAD has also been associated with endothelial dysfunction²⁸ as manifested by impaired endothelium-dependent vasodilatation and even by paradoxical vasoconstriction. Plasma levels of von Willebrand factors and thrombomodulin are increased in patients with PAD.²⁸ PAD patients thus have endothelial dysfunction and at the same time a heightened thrombophilic state that can be the trigger for a cardiovascular event.

PAD and Mortality

Patients with PAD, even in the absence of MI or cerebrovascular disease, have similar risk of death from cardiovascular causes as do patients with a history of CAD or cerebrovascular disease (Table 13-2). The all-cause mortality among PAD patients is similar between men and women. In a prospective cohort study of patients with PAD more than 10 years of follow-up, the relative risk of death from all causes among PAD patients was 3.1 (95% CI 1.9–4.9) compared to those with no PAD, 5.9 for all cardiovascular deaths (95% CI 3.0–11.4), and 6.6 (95% CI 2.9–14.9) for death from CAD.²⁶ The 10-year absolute mortality among patients with large vessel lower extremity arterial diseases was 61.8% for men and 33.3% for women as compared to 16.9% and 11.6% among men and women respectively if they had no PAD.²⁶ Severe and symptomatic PAD can thus cause up to several-fold increase in cardiovascular mortality compared to patients with no PAD. Patients with severe PAD as manifested by critical limb ischemia have an annual mortality rate of 25%.²⁹

Effects of PAD on the Outcomes of ACS Patients

One study reviewed the medical records of patients admitted for ACS and it was found that patients with prior PAD have low rates of prehospital use of ACE inhibitors, beta-blockers, aspirin, and lipid-lowering therapy.³⁰ Patients with PAD also have higher risk of adverse events and higher comorbidities. But they are again less likely to receive aggressive treatment for reperfusion therapy, and less likely to undergo interventional procedures and revascularization during hospitalization for ACS. As such, the hospital outcomes of these patients in death, MI, stroke, and cardiogenic shock were also poorer compared to patients with no PAD.³⁰ In another study of acute coronary syndrome, the presence of extracardiac vascular disease appeared to portend a worse outcome and low likelihood of less aggressive treatment.³¹ PAD has also been associated with lower long-term survival while recovering from acute MI.³²

Outcome of Percutaneous Coronary Intervention Among Patients with PAD

The presence of PAD may lead to higher short- and long-term mortality and lower procedural success among patients undergoing percutaneous coronary interventions (PCI). In a review of >10 000 patients undergoing PCI, PAD was identified in nearly one-fifth of patients and was associated with lower rates of procedural success, worse procedural, and in-hospital outcomes, and with higher rates of in-hospital and 1-year mortality. PAD was also an independent predictor of increased 1-year mortality.^33,34 In a pooled analysis of eight large randomized PCI trials of nearly 20 000 patients, PAD was present in 8% of patients. The presence of PAD was associated with higher incidences of death and MI as well as increased risk of bleeding.³⁵ PAD patients undergoing PCI thus remain to be a very high-risk group with higher post-PCI death and MI compared to non-PAD subjects, and they may benefit from aggressive treatment strategy and closer monitoring.

Effects of PAD on CABG Outcomes

Patients with PAD are also at risk of adverse outcomes after undergoing CABG. Data from the Coronary Artery Surgery Study (CASS)³⁶ revealed that patients with PAD had a 25% greater likelihood of mortality than patients with no PAD (95% CI 1.15–1.36, p < 0.001). In another prospective analysis of 1022 patients³⁷ undergoing CABG, preoperative ABI were obtained. Among all enrolled patients, 14% had clinical PAD and 25% had subclinical PAD (ABI < 0.85 or incompressible arteries with ABI >1.5). Patients were prospectively followed up for 4.4 years. Besides having higher adverse cardiovascular events among PAD patients, clinical and subclinical PAD were independent predictors of overall and cardiovascular deaths.

Lower Extremity PAD and Preoperative Risk Stratification

As CAD is very highly prevalent among patients with PAD, optimal preoperative risk stratification is imperative in adequate management of these patients during their perioperative period. According to the current American College of Cardiology/American Heart Association guidelines,³⁸ peripheral vascular surgery is considered a high-risk surgery and patients should have their surgery deferred if they have any of the four major clinical predictors (acute coronary syndrome or Canadian Cardiovascular Class (CCS) III or IV angina, de-compensated heart failure, severe valvular disease, and significant ventricular or supraventricular arrhythmia). On the other hand, patients with any of the five intermediate clinical predictors (CCS I or II angina, previous MI, compensated heart failure, renal insufficiency, and diabetes mellitus) or limited functional capacity should have perioperative noninvasive stress testing in addition to adequate perioperative beta blockade during this time. Guidelines recommend preoperative coronary angiography and revascularization preceding surgery for patients undergoing peripheral vascular surgery if noninvasive stress tests show high-risk results, unstable angina or medically refractory angina, or inconclusive noninvasive test results. These recommendations were adopted in the guidelines based mostly on consensus expert opinions and observational studies.