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Lower Extremity Arterial Disease: Decision Making and Medical Treatment
Lower extremity peripheral artery disease (PAD) encompasses a diverse and complex set of pathologies with multiple treatment options. As a result, shared decision making between the patient, their family/caregiver, and the provider is critical. Even the definition of PAD has been debated, since presentations can range from asymptomatic to gangrene. For the purposes of research and epidemiology, a commonly accepted modern definition is based on an ankle–brachial index of less than or equal to 0.9. In 2013, Fowkes and colleagues reported that the global prevalence was 202 million people in 2010, with a dramatic increase noted in low- and middle-income countries between 2000 and 2010 ( Fig. 108.1 ). The prevalence of PAD is expected to increase in the United States and worldwide as the population ages, cigarette smoking persists, and the epidemics of diabetes mellitus, hypertension, and obesity continue.
Estimate of the number of cases, and contributing age groups, in eight WHO regions in the year 2010. LMIC, low- and middle-income countries. HIC, high-income countries.
Reprinted with permission from Elsevier. From Fowkes FGR, et al. Comparison of Global Estimates of Prevalence and Risk Factors for Peripheral Artery Disease in 2000 and 2010. Lancet. 2013;382:1329–1340.
In accordance with the increasing prevalence of PAD, the number of lower extremity revascularization procedures has been increasing; among US Medicare beneficiaries, the number of revascularizations has increased from 357 to 581 per 100,000 between 1996 and 2006. Decisions regarding the management of lower extremity PAD pose a unique challenge owing to the complex interplay of factors that must be considered, including the underlying pathology and its natural history, degree of foot ischemia and infection, availability of conduit, comorbid conditions, functional status, ambulation potential, and suitability of anatomy for successful revascularization. Appropriate management of lower extremity PAD requires a firm understanding of these factors for good decision making.
Patients with lower extremity ischemia are typically divided into two groups – those with intermittent claudication (IC) and those with chronic limb-threatening ischemia (CLTI) – depending on symptoms at presentation. The term “chronic limb-threatening ischemia” is now preferred to describe the condition previously referred to as critical limb ischemia. It is important to distinguish between IC and CLTI; they have very different natural histories in terms of limb outcomes, which makes the indications for treatment and expected risk–benefit tradeoff very dissimilar. The risk of major amputation is less than 5% over 5 years for claudicants, whereas the risk is approximately 30% in 1 year for those with CLTI. Both groups have a high prevalence of comorbid cardiovascular conditions, with 5-year estimates of all-cause mortality as high as 20% and 50% for IC and CLTI, respectively. Patients with CLTI often accept high-risk revascularization strategies because the risk of limb loss is so high, whereas the threshold to offer revascularization for IC should be far higher. That is, the indication to intervene for IC is lifestyle limitation, not limb loss; invasive measures should only be considered when other, lower-risk therapies have all failed. While the decision for revascularization is nuanced, it is clear that all patients with PAD require medical management of their cardiovascular disease.
Medical Management and Risk Factor Modification
The most important element of treatment of patients with PAD is aimed at reducing their risk of death due to cardiovascular causes. PAD is an important indirect marker for systemic atherosclerosis. PAD patients are at significantly increased risk for premature cardiovascular events, including myocardial infarction (MI), stroke, and death. , Any patient older than 40 years who is found to have an ankle–brachial index (ABI) of less than 0.90 has significant PAD, even in the absence of symptoms. Interestingly, more than 50% of patients with an abnormal ABI fail to show typical symptoms of claudication or CLTI, owing to the coexistence of other major comorbidities, a condition sometimes referred to as “chronic subclinical lower extremity ischemia.” A systematic review of screening for PAD concluded that there was no evidence for revascularization in patients with asymptomatic PAD; instead, the value of screening may be in identifying a population in whom aggressive medical therapy may be warranted to prevent cardiovascular and cerebrovascular events.
Several guidelines have been published , regarding the use of screening for PAD, including a clinical practice guideline from the Society for Vascular Surgery (SVS) Lower Extremity Guidelines Writing Group. The authors recommend accepted preventive strategies for systemic atherosclerosis and comprehensive tobacco cessation interventions, as well as education on signs and symptoms of progression of PAD to the symptomatic state. Medical management for all PAD, regardless of symptom status, should include daily antiplatelet therapy and statin therapy to target a low-density lipoprotein (LDL) goal of <100 mg/dL or to <70 mg/dL in very high-risk individuals. , Other conditions associated with cardiovascular disease should also be optimized, including use of an angiotensin-converting enzyme inhibitor for hypertension and aggressive glucose control for diabetes.
Medical management after revascularization greatly lacks standardization, with the evidence from the cardiology literature guiding much of these practices. While a comprehensive review is beyond the scope of this chapter, it should be noted that, in general, patients are prescribed single antiplatelet therapy at minimum after open or endovascular procedures. Other studies evaluating clopidogrel or dual anti-platelet therapy have had mixed results, specifically in terms of the trade-off between efficacy and bleeding risk. More recently, a large trial was conducted on the use of a direct oral anticoagulant (rivaroxaban); this was a randomized trial among patients who had undergone revascularization for PAD. Their results suggest the use of low-dose rivaroxaban in addition to aspirin was superior to aspirin alone in terms of the composite end point of acute limb ischemia, major amputation, MI, ischemic stroke, and death from cardiovascular causes. Whether this practice will be widely adopted is yet to be determined.
Exercise Therapy for Claudication
Multiple reports have clearly demonstrated improvements in pain-free ambulation and overall walking performance with structured exercise training. Data from more than 20 randomized trials have confirmed that exercise therapy is the best initial treatment of intermittent claudication. The benefits of exercise extend beyond improvement in the symptoms of claudication. Regular aerobic exercise reduces cardiovascular risk by lowering cholesterol and blood pressure and by improving glycemic control. In most patients, claudication initiates a downward spiral of cardiovascular deconditioning that can result in an annual mortality rate as high as 12%.
The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines support supervised exercise for the treatment of intermittent claudication as a level IA recommendation. The guidelines suggest that exercise training, in the form of walking, should be performed for a minimum of 30 to 45 minutes per session, 3 to 4 times per week, for a period not less than 12 weeks. During each session, the patient should be encouraged to walk until the limit of lower extremity pain tolerance is reached, followed by a short period of rest until pain relief is obtained, then a return to exercise. This cycle should be followed for the duration of the session. As the pain-free interval of ambulation increases, the level of exercise should be increased ( Box 108.1 ).
BOX 108.1
Key Components of a Structured Exercise Program for Claudication
From Stewart KJ, Hiatt WR, Regensteiner JG, et al. Exercise training for claudication. N Engl J Med . 2002;347:1941–1951.
ABI, ankle–brachial index; PAD, peripheral artery disease.
Role of the Primary Clinician
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Establish the diagnosis of PAD using the ABI or other objective vascular laboratory evaluations.
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Determine that claudication is the major symptom limiting exercise.
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Discuss the risks and benefits of therapeutic alternatives, including pharmacologic, percutaneous, and surgical interventions.
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Initiate systemic atherosclerosis risk modification.
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Perform treadmill stress testing.
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Provide formal referral to a claudication exercise rehabilitation program.
Exercise Guidelines for Claudication a
a These general guidelines should be individualized and based on the results of treadmill stress testing and the patient’s clinical status. A full discussion of the exercise precautions for persons with concomitant diseases can be found elsewhere for patients with diabetes (Ruderman N, Devlin JT, Schneider S, Kriska A. Handbook of Exercise in Diabetes . Alexandria, VA: American Diabetes Association; 2002); hypertension ( ACSM’s Guidelines for Exercise Testing and Prescription . In: Franklin BA, ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2000); and coronary artery disease ( Guidelines for Cardiac Rehabilitation and Secondary Prevention/American Association of Cardiovascular and Pulmonary Rehabilitation . Champaign, IL: Human Kinetics; 1999).
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Include warm-up and cool-down periods of 5–10 min each.
Types of Exercise
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Treadmill or track walking is the most effective exercise for claudication.
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Resistance training may be beneficial for individuals with other forms of cardiovascular disease, and its use (as tolerated) for general fitness is complementary to but not a substitute for walking.
Intensity
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Initially, set the treadmill to a speed and grade that elicits claudication symptoms within 3–5 min.
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Patients walk at this workload until they experience claudication of moderate severity, at which point they take a brief rest period, either standing or sitting, to permit symptoms to resolve.
Duration
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The exercise–rest–exercise pattern should be repeated throughout the exercise session.
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The initial duration usually consists of 35 min of intermittent walking. This should be increased by 5 min each session until 50 min of intermittent walking can be accomplished.
Frequency
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Perform treadmill or track walking 3–5 times per week.
Role of Direct Supervision
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As walking ability improves, the exercise workload should be increased by modifying the treadmill grade or speed (or both) to ensure the stimulus of claudication pain during the workout.
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As walking ability improves, it is possible that cardiac signs and symptoms (e.g., dysrhythmia, angina, ST-segment depression) may appear. These events should prompt physician re-evaluation.
Although exercise therapy would appear easy to implement, effectiveness is often limited by poor patient compliance. Studies have shown the superiority of clinic-based exercise programs over home-based programs, , but this can be overcome with the addition of behavioral change techniques. Effective exercise training is not possible in up to 34% of patients because of comorbid medical conditions, and an additional 30% of patients simply refuse to participate in exercise training. In addition, while Medicare has recently begun covering supervised exercise training programs (for up to 12 weeks, 36 sessions), there are still barriers such as the need for transportation and an appointment with the facility. Therefore, even though exercise therapy in motivated patients offers proven benefits, its effectiveness is applicable to only approximately one-third of patients presenting with intermittent claudication. The use of either consumer-grade or research-grade activity trackers and other health technologies are areas of active investigation for overcoming some of these barriers. Along these lines, the SVS has recently partnered with a private telehealth company (CellEd, Palo Alto, CA) to pilot an app that leverages Apple Health-based mobility metrics to virtually prescribe and monitor progress along a supervised exercise therapy program. In the future, technology-based at-home exercise therapy may have greater adherence rates, and therefore success, than other approaches.
Pharmacologic Treatment of Claudication
Pharmacologic therapy for intermittent claudication has been the subject of intense research for more than 30 years. To date, only two drugs (pentoxifylline and cilostazol) have achieved FDA approval for the treatment of intermittent claudication in the United States; cilostazol is the only drug used in current practice. However, a number of other medications have been investigated, with varying degrees of evidence supporting their efficacy. These include several drugs and supplements with various reported mechanisms of action such as changes in tissue metabolism (naftidrofuryl, levocarnitine), enhanced nitric oxide production (l-arginine), and vasodilatory effects (statins, buflomedil, prostaglandins, angiotensin-converting enzyme inhibitors, K-134).
Cilostazol
Cilostazol (Pletal) gained FDA approval in 1999 for the treatment of intermittent claudication. Oral administration of this phosphodiesterase III inhibitor increases cyclic adenosine monophosphate (cAMP) and results in a variety of physiologic effects, including the inhibition of smooth muscle cell contraction and platelet aggregation. Finally, cilostazol has a beneficial effect on plasma lipid concentrations, resulting in a decrease in serum triglycerides and an increase in HDL. Although the precise mechanism by which cilostazol improves the symptoms of intermittent claudication is unknown, it is likely a combination of these effects.
Several controlled clinical trials, including a meta-analysis, have confirmed the efficacy of cilostazol. Results have shown increased maximal walking distances up to 50%, as well as significant improvements in health-related quality of life (QoL) measures. There is also increasing evidence that cilostazol may modulate the synthesis of vascular endothelial growth factor (VEGF), potentially stimulating angiogenesis in patients with chronic lower extremity ischemia.
The benefits of cilostazol in the treatment of intermittent claudication were compared with those of pentoxifylline in a randomized controlled trial performed by Dawson and associates. They found that cilostazol therapy significantly increased maximal walking distance by 107 m (54% increase), compared with a 64-m improvement in the pentoxifylline group (30% increase). There was no difference in maximal walking distance improvement between the pentoxifylline and placebo groups. Regarding the durability of the effect, a recent pooled analysis of nine randomized controlled trials demonstrated a significant benefit in maximal walking distance compared with placebo at 6 months.
Cilostazol has a moderate but notable adverse effect profile that includes headache, diarrhea, and gastrointestinal discomfort. Its use is contraindicated in patients with congestive heart failure. High plasma drug levels may result when taken in combination with other medications metabolized by the liver via the cytochrome P-450 pathway.
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