Peripheral Artery Disease in Diabetes

Epidemiology and Prognosis of Peripheral Artery Disease and Diabetes—Overlapping Epidemics

The reported prevalence of PAD varies as a function of the population tested, the diagnostic method used, and whether symptoms are included to derive estimates. The ankle-brachial index (ABI) is the most commonly used noninvasive measurement in epidemiologic studies and is described in more detail later. The ABI is the ratio of the ankle to the brachial systolic blood pressure. For intermittent claudication, prevalence estimates range from below 2% to as high as 12%, whereas rates of noninvasively defined disease based on the ABI range from 3% to 33%. ^, The prevalence of PAD increases with age, with rates of approximately 4% documented in those 40 years and older compared with rates of 13% to 15% among those 65 years of age and older ( Fig. 27-1 ). Only a small proportion of those with ABI-defined PAD have claudication, with estimates ranging from approximately 10% to 30%. The prevalence of PAD increases with age ^, ( Fig. 27-2 ). There is less information about the true incidence of critical limb ischemia or amputation, but estimates suggest that 400 to 450 individuals per million population are affected with ischemia and approximately 112 to 250 individuals per million population require amputation.

Major risk factors for PAD overlap with, but are not identical to, those for coronary artery disease (CAD) and cerebrovascular disease. It is important to note that diabetes, smoking, older age, elevated triglyceride concentrations, and elevated systolic blood pressure are particularly potent risk factors for PAD. Data from the National Health and Nutrition Examination Survey (NHANES) suggest that cigarette smoking and diabetes are the most potent risk factors associated with the development of PAD, with odds ratios for the development of PAD of 4.5 and 2.7, respectively. In the Framingham study, the presence of diabetes increased the risk of intermittent claudication by 3.5-fold in men and 8.6-fold in women. Even in those without frank diabetes, insulin resistance has also been linked to the development of PAD.

The duration and severity of diabetes correlates with the incidence and extent of PAD. In a prospective cohort study, Al-Delaimy and colleagues found a strong association between the duration of diabetes and the risk of developing PAD. The association was particularly strong among men with hypertension or who were current smokers. Adler and colleagues estimated the prevalence of PAD up to 18 years after the diagnosis of diabetes in almost 5000 patients from the United Kingdom Prospective Diabetes Study (UKPDS). They demonstrated a higher prevalence of PAD in those with a longer duration of diabetes. The degree of diabetic glycemic control is an independent risk factor for PAD; with every 1% increase in glycosylated hemoglobin (HbA1c), the risk of PAD has been shown to increase by 28%.

Furthermore, patients with diabetes and PAD are more likely to present with an ischemic ulcer or gangrene than patients without diabetes, increasing the risk of lower-extremity amputation. Faglia and colleagues observed a positive trend between PAD severity and amputation rates in patients with diabetes. Individuals with diabetes are approximately 15 times more likely to have an amputation than those without diabetes, and an annual amputation incidence rate of 0.6% has been reported in diabetic patients. ^, Patients with diabetes often have extensive and severe PAD and a greater propensity for arterial calcification. ^, Involvement of the femoral and popliteal arteries often resembles that of nondiabetics, but distal disease affecting the tibial and peroneal arteries occurs more frequently in diabetics.

Clinical Presentation, Diagnosis, and Natural History of Peripheral Artery Disease in Diabetes

The hallmark features of clinical PAD include intermittent claudication and rest pain. The location of the symptoms often relates to the site of the most proximal stenosis. In general, buttock, hip, or thigh claudication typically occurs in patients with aortic or iliac stenoses. Calf claudication characterizes femoral or popliteal involvement. Ankle or foot claudication occurs in patients with tibial or peroneal disease. Claudication symptoms should be brought on by exertion and should resolve within minutes after cessation of effort. Leg pain that occurs at rest, such as nocturnal cramping in the calf or thigh, should not be confused with claudication.

Symptoms may occur at rest in patients with critical limb ischemia. Typically, patients complain of paresthesias or pain in the foot or toes of the affected limb. This discomfort worsens with limb elevation and often improves when the limb is lowered, as would be expected because of the increased perfusion pressure to the distal limb by the effect of gravity. The pain can be particularly severe at sites of skin breakdown, and often the skin is exquisitely sensitive to light touch. These symptoms may be absent, however, in diabetic patients with significant peripheral neuropathy, who may have important limb ischemia but experience few symptoms.

A complete cardiovascular physical examination is necessary to detect all the findings of PAD in diabetic patients. Pulse abnormalities and bruits increase the likelihood of PAD. The legs of patients with chronic aortoiliac disease may demonstrate muscular atrophy. Hair loss, thick or brittle toenails, and smooth and shiny skin on the legs can also indicate PAD. Patients with severe limb ischemia often have cool skin and may have petechiae, cyanosis or pallor, dependent rubor, skin fissures, ulceration, or gangrene. Ulcers that result from PAD often have a pale base with irregular borders and usually involve the tips of the toes, the heel of the foot, or other sites that bear chronic pressure ( Fig. 27-3 ). Overall, physical examination has a low sensitivity but high specificity for PAD.

The clinical stage of symptomatic PAD can be classified according to the Fontaine or Rutherford scoring systems. ^, Fontaine stage I represents those who have PAD but are asymptomatic. Stages IIa and IIb include patients with mild and moderate-to-severe intermittent claudication. Patients with ischemic rest pain are classified as stage III, and those with ulceration or gangrene are stage IV. In the Rutherford classification, asymptomatic patients are classified as category 0. Patients with mild claudication are category 1. Patients with moderate claudication are category 2, and patients with severe claudication are category 3. Patients with rest pain are category 4. Patients with minor tissue loss, ulceration, or gangrene are categories 5 and 6 ( Table 27-1 ).

The main reasons to diagnose PAD in diabetic individuals are to initiate therapies that decrease the risk of atherothrombotic events, to improve the overall quality of life, and to decrease disability. A diagnosis of PAD indicates the presence of systemic atherosclerosis that confers additional cardiovascular risk to the patient with diabetes, which gives further impetus to aggressively manage vascular risk factors in this high-risk group. Although the physical examination provides important information, additional noninvasive testing is necessary to ensure the diagnosis of PAD. The ABI is a reproducible and reasonably accurate measurement for the detection of PAD. The American Heart Association recently published a consensus scientific statement regarding use of the ABI and suggested standard definitions and interpretation. As mentioned earlier, the ABI is defined as the ratio of the ankle systolic blood pressure divided by the brachial systolic blood pressure. The ABI is normally between 1.00 and 1.40. ^, In PAD, the ankle systolic blood pressure is less than the brachial systolic blood pressure, and the ABI is reduced to below 1.00. PAD is defined as an ABI of 0.90 or lower, with values from 0.91 to 1.00 classified as borderline. ^, Lower ABI values indicate more severe PAD. Patients with symptoms of leg claudication often have ABIs from 0.5 to 0.8, and patients with critical limb ischemia usually have an ABI below 0.5. The ABI has been shown to correlate inversely with walking distance and walking speed ( Fig. 27-4 ). For example, less than 40% of patients with an ABI below 0.4 can complete a 6-minute walking test. One limitation of the ABI in patients with diabetes, however, is that leg blood pressure recordings cannot be reliably interpreted in patients with calcified vessels because these vessels are not reliably compressed during inflation of the blood pressure cuff. Because diabetic patients are more likely than nondiabetics to have arterial calcifications, ABI measurements in certain individuals can be difficult to interpret, and other noninvasive tests, such as a toe-brachial index, should be used to make the diagnosis. The diagnostic measurement of the ABI for the detection of lower-extremity PAD varies according to the population studied, the cutoff threshold, and the comparison gold standard test (invasive angiography or duplex ultrasound). The sensitivity and specificity of the ABI range from 0.17 to 1.0 and from 0.8 to 1.0, respectively. Overall, lower sensitivities are reported in diabetic patients.

The American Diabetes Association (ADA) consensus statement recommends that a screening ABI be performed in all diabetic individuals older than 50 years or in anyone with symptoms consistent with PAD. For the general, nondiabetic population, screening ABI testing is recommended at age 65, or at age 50 in individuals with a history of tobacco smoking. In general, PAD is underdiagnosed in the primary care setting. A large-scale PAD screening study demonstrated that only one third of patients with documented PAD had classical claudication symptoms. These data suggest that classic symptoms are inadequate in determining a person's health status with regard to PAD. Particularly in diabetic patients with peripheral neuropathy, ABI screening of asymptomatic individuals represents an important tool in diagnosing PAD and allowing for an appropriately tailored strategy for therapeutic decisions.

Recent data from the National Health and Nutrition Examination Study demonstrate that there are significant treatment gaps, even once patients have been identified as having abnormal ABI measurements. For example, among patients with ABI-documented PAD, statin use was reported in only 30.5% ± 2.5%, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use in 24.9% ± 1.9%, and aspirin use in 35.8% ± 2.9%. These numbers correspond to estimates of 5.0 million adults with PAD not taking statins, 5.4 million not taking ACE inhibitors or ARBs, and 4.5 million not taking aspirin. In the same study, these treatment gaps were shown to be associated with elevated mortality rates even after adjustment for other important confounding factors.

In a patient with confirmed PAD for whom further investigation is required, usually at a time when revascularization is considered, there are other modalities available for investigating the extent and nature of the PAD. Segmental pressure and pulse volume recordings are both noninvasive hemodynamic studies that aid in the localization of arterial occlusive disease. Other noninvasive imaging techniques, including magnetic resonance angiography (MRA) and computed tomographic angiography (CTA), or duplex ultrasonography can provide more precise anatomic information for revascularization planning purposes. Conventional, contrast-based angiography can still be useful, particularly when other modalities have left doubts as to the diagnosis.

Overall, patients with PAD have an increased risk of adverse cardiovascular events, as well as impaired quality of life, and an increased risk of limb loss. In addition, patients with PAD and concomitant diabetes are at risk for higher cardiovascular and cerebrovascular event rates than comparable nondiabetics. The combination of PAD and diabetes causes most nontraumatic lower-extremity amputations in the United States. The relative risk for lower-extremity amputation in patients with diabetes was 12.7 (95% confidence interval [CI] 10.9-14.9) compared with 23.5 (95% CI 19.3-29.1) for diabetic patients in the Medicare population.

Risk Factor Identification, Lifestyle Modification, and Pharmacotherapy

Once diabetic individuals with PAD have been identified, the aim of medical management is to aggressively modify cardiovascular risk factors for the prevention of adverse cardiovascular events and to relieve symptoms related to PAD to improve functional status and quality of life. These two goals should be addressed simultaneously in every patient.

Lowering Cardiovascular Morbidity and Mortality

The risk factors for PAD are identical to those for other forms of atherosclerotic vascular disease, and PAD is similarly associated with an increased risk of coronary, cerebrovascular, and renovascular disease. As a result, PAD is considered a coronary heart disease equivalent, elevating it to the highest category of cardiovascular risk. The 2005 American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines (with the 2011 focused update), the 2003 ADA consensus statement, and the 2007 TransAtlantic Inter-Society Consensus (TASC II) document on the management of PAD recommend smoking cessation, lipid-lowering therapy with statins, and the treatment of diabetes and hypertension. ^{, , ,} Data from a Dutch prospective cohort study of 2420 patients with PAD (ABI 0.90 or lower) support these conclusions and demonstrate that a comprehensive approach to risk factor modification can have additive benefits. In this study, Feringa and colleagues demonstrated that after adjustment for risk factors and propensity scores, statins (hazard ratio [HR] 0.46, 95% CI 0.36-0.58), beta blockers (HR 0.68, 95% CI 0.58-0.80), aspirin (HR 0.72, 95% CI 0.61-0.84), and ACE inhibitors (HR 0.80, 95% CI 0.69-0.94) were significantly associated with a reduced risk of long-term mortality in this cohort. The benefits of these therapies appear additive, and these data support the universal nature of atherosclerotic vascular disease, whether in the form of PAD or elsewhere.

Dyslipidemia

Several cholesterol-lowering trials in patients with dyslipidemia and CAD and/or PAD have evaluated the effects of lipid lowering on PAD. Initial studies, performed before the availability of statins, showed either regression or less progression of femoral atherosclerosis with lipid-lowering therapy. The Program on the Surgical Control of the Hyperlipidemias (POSCH) randomized men with previous MI and dyslipidemia to diet therapy or diet therapy plus surgical ileal bypass. At 5 years, those in the surgical group had better control of lipid levels, decreased overall mortality, and decreased mortality from atherosclerotic coronary heart disease.

Studies in the statin era confirm these initial results. For example, in the Heart Protection Study, which randomized 20,536 high-risk participants to 40 mg/day of simvastatin or placebo, a 24% relative risk reduction was observed in first-time cardiovascular events in the patients who received simvastatin. The subgroup of patients with PAD had similar cardiovascular benefits regardless of history of myocardial infarction (MI) or CAD. Even the subgroup population who had low-density lipoprotein cholesterol (LDL-C) levels less than 100 mg/dL at baseline benefited from statin therapy. A post hoc analysis of the Scandinavian Simvastatin Survival Study (4S), which included 4444 patients with angina or previous MI and a baseline total cholesterol level of 212 to 309 mg/dL, found that treatment with 20 to 40 mg of simvastatin per day reduced the incidence of new or worsening claudication by 38% (2.3% versus 3.6% with placebo).

Independent of cholesterol-lowering effects, statin use improves pain-free walking distance and walking speed in patients with PAD and claudication. Two studies randomized patients with claudication to simvastatin 40 mg daily or placebo. Aronow and colleagues reported an improvement in pain-free walking distance of 24% increase at 6 months and of 42% increase at 1 year after initiation of treatment. It is interesting to note that total walking distance and ABI did not improve. In contrast, Mondillo and colleagues reported increases in ABI, total walking distance, and pain-free survival in patients randomized to simvastatin ( Fig. 27-5 ). Mohler and colleagues randomized 354 patients with claudication to atorvastatin 10 mg or 80 mg or placebo. Patients receiving atorvastatin had an increased pain-free walking distance, but not total walking distance or ABI. Patients with PAD who take statins have been shown to have less annual decline in lower-extremity performance than those that do not. Overall, the aggregate data suggest that statin use may increase the walking distance until the onset of pain, but statin use does not clearly affect total walking time or change lower-extremity blood flow as measured by ABI.

The current recommendations advocate a goal LDL-C of less than 100 mg/dL for patients with PAD; for very high-risk patients, the goal is an LDL-C below 70 mg/dL. All patients with PAD should be treated with statins as first-line lipid-lowering therapy, if tolerable. ^,

There is also a role for fibrate therapy in the treatment of PAD. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study randomized 9795 patients aged 50 to 75 years with type 2 diabetes to either fenofibrate 200 mg/day or placebo for 5 years' duration. The risks of first amputation (45 versus 70 events; HR 0.64, 95% CI 0.44-0.94; P = .02) and minor amputation events without known large-vessel disease (18 versus 34 events; 0.53, 0.30-0.94; P = 0.027) were lower for patients assigned to fenofibrate than for patients assigned to placebo, with no difference between groups in risk of major amputations. A reduction in amputation events has not been similarly shown with statin therapy.

Smoking Cessation

Several nonrandomized studies have shown that patients who successfully quit smoking have decreased rates of PAD progression, critical limb ischemia, amputation, MI, and stroke, and have increased survival. ^, Unfortunately, the spontaneous cessation rates without intervention range from 2% to 5% in the United States, despite nearly 75% of smokers expressing a desire to stop. Given the importance of smoking cessation, it is important for health care providers to consistently convey to patients that discontinuation of tobacco products is extremely important to overall survival, well-being, and limb preservation. ^, Behavioral interventions can improve cessation rates, but only modestly. Only 5% of patients who receive physician advice, follow-up correspondence, phone calls, and supplementary visits will quit smoking. Randomized trial evidence, however, has demonstrated that a 10-week intervention that results in just a 21.7% smoking cessation rate at 5 years significantly improves survival in patients with chronic lung disease compared with those treated with usual care. Thus, efforts at cessation should be made.

Hennrikus and colleagues have specifically demonstrated that individuals with PAD respond to intensive counseling and education in a randomized trial of 124 patients. These researchers compared an intensive tobacco cessation counseling program with a minimal educational program over 6 months. Study participants assigned to the intensive intervention group were significantly more likely to be abstinent from tobacco at 6-month follow-up: 21.3% versus 6.8% in the minimal intervention group ( P = 0.023).

Smoking cessation can be aided in many ways, including the use of pharmacotherapy such as short-term nicotine replacement products including gums, long-acting nicotine replacement patches, bupropion, or varenicline. Pharmacologic interventions are more effective than medical advice alone. In controlled studies, the rates of stopping smoking with use of pharmacologic treatment interventions has varied from 17% to 48% at 6 months and from 11% to 34% at 1 year. Bupropion, via a poorly understood mechanism, diminishes the desire for smoking. It is associated with cessation rates of 27% to 35% at 6 months and 23% to 30% at 1 year. Varenicline, a partial agonist selective for the alpha ₄ , beta ₂ nicotinic acetylcholine receptor, is a newer agent than bupropion. Two large, randomized trials have suggested that varenicline performs better when the two are compared directly. In a study of 1025 smokers where patients were randomized to placebo, sustained-release bupropion, or varenicline, abstinence rates from weeks 9 to 52 were significantly elevated in the two drug arms compared with placebo. Cessation rates were 8.4%, 16.1%, and 21.9% respectively for individuals taking placebo, bupropion, and varenicline. In a second large randomized trial, Jorenby and colleagues found similar abstinence rates in individuals treated with placebo, bupropion, or varenicline.

The U.S. Public Health Service task force smoking cessation guidelines do not recommend any one of the first-line agents over another. Instead, they recommend that patient preference and previous experience with the medications guide the choice of the first-line therapy (nicotine replacement, bupropion, and varenicline). Meta-analyses done for the guideline update addressed the question of whether any drug was more effective than the nicotine patch. In this analysis, there was no statistically significant difference between the patch and other nicotine replacement products or bupropion, but varenicline had a higher efficacy than the nicotine patch (OR 1.6, 95% CI 1.3-2.0). The analysis also compared the nicotine patch with combinations of drugs. The combination of nicotine patch and short-acting nicotine replacement products, used for an extended period of time, was more effective than the patch alone (OR 1.9, 95% CI 1.3-2.7), as was the combination of nicotine patch and sustained-release bupropion (OR 1.3, 95% CI 1.0-1.8).

Until further trials have been performed, varenicline and the combination of long-acting patch plus short-acting nicotine replacement therapies appear to be roughly equivalent first-line choices. Patients treated with varenicline should be monitored for possible adverse neuropsychiatric events.

Despite multiple options for the approach to tobacco cessation in individuals with PAD, there appears to be continued risk in individuals who successfully become abstinent. Data from the Women's Health Study demonstrate that although smoking cessation substantially reduces risk for PAD events in women, there remains an increased occurrence of PAD events in former smokers compared with individuals who never smoked.

Hypertension

In a large number of clinical trials involving thousands of patients, antihypertensive drug therapy has been associated with a 35% to 40% mean reduction in the rate of stroke, a 20% to 25% reduction in MI, more than a 50% reduction in heart failure, and a significant reduction in the development of chronic kidney disease. Although treatment of hypertension has been studied in many contexts, there are limited data available to determine whether treatment of hypertension will prevent the development of claudication or alter the course of PAD itself.

The Treatment of Mild Hypertension Study (TOMHS) showed that drug treatment in addition to nutritional interventions was superior to nutritional interventions alone in preventing the development of intermittent claudication and PAD over an average follow-up of 4.4 years. Reports on the effect of blood pressure lowering on the ability to walk in patients with intermittent claudication are mixed. However, these small studies have demonstrated that the ACE inhibitor captopril maintains and may increase walking distance in patients with claudication. Alpha-adrenergic blockers, beta blockers, and calcium channel blockers may adversely affect walking distance, particularly if there is a substantial decrease in systolic blood pressure. In a 6-month crossover trial of 20 hypertensive patients with PAD randomized to atenolol, labetalol, pindolol, captopril, or placebo, only individuals treated with captopril maintained walking distance. This appears to be a class effect, as enalapril and ramipril also seem to improve lower-extremity blood flow in patients with claudication. ^,

Antihypertensive therapy should be administered to hypertensive patients with PAD to achieve a goal of less than 140/80 mm Hg to reduce the risk of MI, stroke, heart failure, and cardiovascular death. ^,

In PAD patients with diabetes, the Appropriate Blood Pressure Control in Diabetes (ABCD) study supports intensive management of hypertension. The ABCD study randomized 480 normotensive patients (baseline diastolic blood pressure of 80 to 89 mm Hg) with type 2 diabetes to either an intensive blood pressure regimen with enalapril or nisoldipine or placebo. Individuals were followed for 5 years. Fifty-three of the patients had PAD as defined by an ABI below 0.90. In patients with PAD, there were 3 cardiovascular events (13.6%) in the intensive treatment group compared with 12 events (38.7%) in patients taking placebo ( P = .046). After adjustment for multiple cardiovascular risk factors, an inverse relationship between ABI and cardiovascular events was observed with placebo ( P = .009), but not with intensive treatment ( P = .91). Thus, with intensive blood pressure control, the risk of an event was not increased, even at the lowest ABI values, and was the same as in patients without PAD. The conclusion from the trial was that intensive blood pressure lowering to a mean of 128/75 mm Hg resulted in a marked reduction in cardiovascular events.

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