Comprehensive Medical Management of Peripheral Arterial Disease

Progress in Cardiovascular Diseases 54 (2011) 2 – 13 www.onlinepcd.com

Comprehensive Medical Management of Peripheral Arterial Disease Sanjay Gandhi, Ido Weinberg, Ronan Margey, Michael R. Jaff ⁎ Section of Vascular Medicine, Department of Cardiovascular Medicine, Massachusetts General Hospital, Boston, MA 02114

Abstract

Peripheral arterial disease (PAD) is highly prevalent and is associated with high morbidity and mortality. The medical management of PAD involves a comprehensive approach to the patient with emphasis on cardiovascular risk factor modification in addition to therapies directed at treatment of limb symptoms. This manuscript will review the current status of medical therapy in management of patients with PAD. (Prog Cardiovasc Dis 2011;54:2-13) © 2011 Elsevier Inc. All rights reserved.

Keywords:

Peripheral arterial disease; Medical therapy

Peripheral arterial disease (PAD) is highly prevalent yet under diagnosed in the general population. Using objective measures for detection of PAD, such as the ankle-brachial index (ABI), the prevalence of PAD is maybe as high as 12% to 30% in people aged 70 or older.1 Atherosclerosis is the major cause of PAD. Conventional risk factors for atherosclerosis such as diabetes mellitus (DM), tobacco abuse, hyperlipidemia, and hypertension (HTN) increase the likelihood of developing PAD. In particular, tobacco use increases the risk of developing PAD by 2- to 6-fold, and DM increases the risk by 2- to 4fold.2 In the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) study, in primary care practices across the United States, PAD was detected in 29% of patients older than 70 years or 50 to 70 years with history of DM or tobacco use.3 A large proportion of patients with PAD have either no symptoms (20%-50%) or atypical leg pain (40%-50%). Only 10% to 35% of patients with PAD present with typical claudication and 1% to 2% progress to critical limb ischemia (CLI).2 Cardiovascular morbidity and mortality are increased in patients with PAD whether they are symptomatic or asymptomatic.4 Within 1 year of presentation, one quarter Statement of Conflict of Interest: see page 10. ⁎ Address reprint requests to Michael R. Jaff, DO, FACP, FACC, FAHA, Medical Director, Vascular Center, 55 Fruit St, GRB-800, Boston, MA 02114. E-mail address: [email protected] (M.R. Jaff).

0033-0620/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2011.02.004

of patients with CLI die of cardiovascular causes and another 25% suffer major limb amputation. Even patients with stable or no symptoms have a 20% incidence of myocardial infarction (MI) or stroke and 15% to 30% mortality in 5 years. It, therefore, follows that detection of PAD mandates aggressive treatment of cardiovascular risk factors.1,2 Notwithstanding, primary care physicians were found to treat atherosclerotic risk factors less diligently in patients with PAD than in patients with other manifestations of atherosclerosis.3,5,6 The purpose of this review is to provide a current and comprehensive review of medical therapies available for the treatment of PAD. These treatments can be seen as having 2 primary aims: (1) to reduce cardiovascular morbidity and mortality and (2) to improve function, limb outcomes, and quality of life. Medical treatments to reduce cardiovascular morbidity and mortality The current American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines recommend aggressive management of atherosclerotic risk factors (Table 1) to reduce future cardiovascular events in all patients with PAD. Diabetes mellitus management The prevalence of PAD in patients with DM has been estimated to be 20% to 30%, higher than in any other

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Abbreviations and Acronyms

7,8

matched population. The risk of developing ABI = ankle brachial index PAD correlates with the ACC = American College of duration and severity of Cardiology DM.9 Patients with DM have symptomatic PAD AHA = American Heart more often than nondiaAssociation betic patients. In the FraCAD = coronary artery mingham cohort, disease presence of DM inCLI = critical limb ischemia creased the risk of claudication by 3.5-fold in DM = diabetes mellitus men and 8.6-fold in FGF = fibroblast growth women.10 Diabetes melfactor litus also alters the distriHTN = hypertension bution of the disease, and PAD in patients with DM IC = intermittant claudication more often involves the MI = myocardial infarction arteries below the knee than in nondiabetic PAD = peripheral arterial patients.11,12 Finally, diadisease betic patients with PAD VEGF = vascular endothelial are more likely to present growth factor with tissue loss and are at higher risk for amputation compared to patients without DM.13,14 These patients also demonstrate reduced primary patency after endovascular interventions likely due to advanced and more diffuse disease.15 The effect of DM in progression of atherosclerosis is multifactorial. The metabolic abnormalities associated with hyperglycemia and insulin resistance alter endothelial function, smooth muscle vasomotor balance, and platelet aggregation, thereby promoting atherosclerosis and thrombus formation.16 Although tight glycemic control in diabetic patients reduces the risk of developing microvascular disease including retinopathy and neuropathy, it has not been shown to reduce the risk of macrovascular complications.17-19 The Veterans Affairs

Table 1 ACC/AHA guidelines for cardiovascular risk factor modifications in patients with PAD

3

20

Diabetes Trial (VADT) was a prospective trial randomizing 1,791 people with known type 2 DM to standard and intensive treatment of DM. The primary end point was cardiovascular events defined by a composite of death; MI; stroke; congestive heart failure; operative treatment of coronary, cerebrovascular, or PAD; inoperable coronary artery disease (CAD); and amputation from PAD. New intermittent claudication (IC) and CLI were some of the secondary outcomes in the study. The median glycalated hemoglobin level was 8.4% in the standard therapy arm and 6.9% in the intensive therapy arm. However, there was no significant difference in the rate of primary or secondary outcomes or microvascular complications at a median follow-up of 5.6 years. The Epidemiology of Diabetes Interventions and Complications (EDIC) trial was a long-term follow-up of the landmark Diabetes Control and Complications Trial (DCCT) that showed cardiovascular benefit for early intensive treatment for patients with type 1 DM even after going back to standard treatment.21 In the subanalysis of the EDIC trial, assessing the development of low ABI for a period of 12 years in 1,398 persons, intensive treatment of blood glucose did not halt the development of low ABI but did reduce the occurrence of arterial calcifications (P = .02).22 In summary, tight glucose control has no significant effect on cardiovascular outcomes in patients with PAD. Therefore, to reduce macrovascular complications, the focus of therapy in diabetic patients should be on aggressive and appropriate management of their other cardiovascular risk factors including hyperlipidemia, HTN, and antiplatelet therapy, as outlined below. Of note, the current American Diabetes Association guidelines recommend targeting hemoglobin level A1c to less than 7% to reduce the incidence of microvascular events. In addition to blood glucose control, proper foot care, including use of appropriate footwear, regular podiatric foot and nail care, daily foot inspection, skin cleansing, and use of topical moisturizing creams, should be encouraged. Skin lesions and ulcerations should be addressed urgently in all diabetic patients with PAD.23 The American Diabetes Association recommends that all patients with DM older than the age of 50 years be screened for PAD.23,24

Recommendations Smoking cessation Weight reduction Hyperlipidemia Hypertension Diabetes Antiplatelet therapy

Quit smoking Counseling to reduce weight if BMI N25 LDL b100 mg/dL for all patients or b70 mg/dL if diabetes or other vascular disease BP b140/90 or b130/80 in patients with DM or renal failure Hemoglobin A1c goal of b7.0% or as close to 6% as possible ASA for all patients with symptomatic PAD. Clopidogrel may be an effective alternative to ASA

Abbreviation: LDL indicates low-density lipoprotein.

Treatment of dyslipidemia Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has demonstrated a reduction in the risk of nonfatal MI, stroke, and cardiovascular-related death in patients with prior stroke or established CAD. There are no randomized, controlled trials of statin therapy in patients with PAD alone. The Heart Protection Study25,26 randomized 20,536 high-risk patients to 40 mg/d of simvastatin or placebo, including 6,748 patients with PAD. In patients with PAD, there was

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a 25% reduction in risk of cardiovascular events in patients randomized to simvastatin during the 5 years of follow-up regardless of their initial serum lipid levels and in addition to other treatments. In addition to the cholesterol-lowering effect, statin use also correlates with improved 6-minute walking distance and walking velocity.27 In a study of 354 patients with an ABI 0.9 or less randomized to atorvastatin 10 mg/d, atorvastatin 80 mg/d, or placebo, there was improvement in pain-free walking time for 65% of patients receiving 80 mg of atorvastatin at 12 months. However, there was no significant difference between atorvastatin 10 mg/d and placebo groups. There were also fewer vascular events (defined as worsening symptoms of claudication, development of ischemic rest pain, peripheral revascularization procedures, or limb amputation) in the treatment group as compared with placebo treated patients.28 Statin use has also been shown to reduce the risk of new or worsening claudication symptoms by 38% for 5.4 years in patients with hyperlipidemia and CAD in a retrospective analysis of the Scandinavian Simvastatin Survival Study (4S).29 The mechanism by which statins affect claudication walking speed, distance, and time is felt to be because of improved endothelium-mediated vasodilatation and reduced platelet aggregation along with modulation of plaque vulnerability.27,30 The current ACC/AHA PAD guidelines recommend a target low-density lipoprotein in patients with PAD of less than 100 mg/dL1,31 and less than 70 mg/dL in patients with evidence of other vascular bed involvement1 or those deemed to be at very high risk for ischemic events.2,31 Tobacco cessation Cigarette smoking is one of the most important preventable risk factor for PAD in both men and women.2 Both current and former smokers have 2- to 3-fold higher prevalence of symptomatic PAD compared with nonsmokers.32 In a systematic review of 17 studies, overall odds ratio for prevalence of symptomatic PAD was 2.3 times in current smokers compared to nonsmokers.32 The incidence of symptomatic PAD is directly proportional to the dose of exposure, with an increase from 2.6% in never smokers to 9.8% in heavy smokers.33 Even passive tobacco exposure with second hand smoke nearly doubles the risk of development of PAD in nonsmokers.34 Although the prevalence of symptomatic PAD is decreased in former smokers, it still remains higher than in never smokers.32 Smoking cessation not only decreases the rate of PAD progression, amputation, and CLI but also improves overall survival with lower rates of MI and stroke.35,36 Surprisingly, the role of smoking cessation in treating the symptoms of claudication is not as clear; studies have shown that smoking cessation is associated with improved walking distance in some, but not all, patients. However, these

benefits are not predictable and should not be presented with certainty of effect. Patients should therefore be encouraged to stop smoking primarily to reduce their risk of cardiovascular events as well as their risk of progression to major limb amputation and progression of PAD. Unfortunately, smoking cessation is offered to only half of patients with PAD in primary care.3 All patients with PAD should be asked strongly and repeatedly to discontinue all tobacco products. All patients should be offered proven comprehensive tobacco cessation interventions, including behavior modification therapy, nicotine replacement therapy, or bupropion. Smoking cessation counseling and treatment should be an integral part of treatment of every patient with PAD.1,2 Hypertension control Up to 55% of patients with PAD have HTN.37 In addition to reducing cardiovascular events, treatment of HTN reduces the incidence of PAD-related amputation, particularly in patients with DM. In an analysis of the UK Prospective Diabetes Study (UKPDS) data, a reduction of systolic blood pressure by 10 mm Hg conferred a 16% decrease in rate of limb amputation or death from PAD.17 All pharmacologic agents that lower blood pressure reduce the risk of cardiovascular events.38 Therefore, the choice of antihypertensive agent is less relevant than actual control of blood pressure.39 However, angiotensinconverting enzyme inhibitors have shown benefit, specifically in PAD, potentially beyond their blood pressure– lowering effect. The Heart Outcomes Prevention Evaluation (HOPE) study evaluated the effect of ramipril in patients with CAD, cerebrovascular disease, PAD, or diabetes.40 The study included 4,051 patients with PAD. In this subgroup, the reduction in risk of MI, stroke, or vascular death in patients randomized to ramipril compared to placebo approached 22%, independent of the blood pressure–lowering effect. A similar reduction of cardiovascular end points was seen in a subgroup of 883 patients with PAD treated with perindopril in the European trial on reduction of cardiac events with perindopril (EUROPA) trial.41 Therefore, angiotensin-converting enzyme inhibitors are an attractive first-line agent for management of HTN in patients with PAD. There had been concern in the past that the use of β-adrenergic antagonists in patients with PAD may worsen the symptoms of claudication. However, in a metaanalysis of 11 trials, β-blockers were shown to be safe in patients with PAD.42 Of note, the incidence of renal artery stenosis is increased in patients with PAD. This diagnosis must therefore be kept in mind when HTN resistant to medical therapy is encountered in these patients.39 The current ACC/AHA PAD guidelines recommend a goal blood pressure less than 140/90 in patients with PAD without DM and less than 130/80 in patients with DM or chronic kidney disease.

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Antiplatelet and antithrombotic therapy Aspirin Aspirin use has been shown to reduce the risk of stroke, MI, and vascular death by approximately 25% in patients with established coronary and cerebrovascular disease.43 In the Antithrombotic Trialists' Collaboration metaanalysis, a subgroup of 9,214 patients with PAD had benefit similar to those of patients with coronary and cerebrovascular disease, with a 23% reduction in serious vascular events.43 However, there remains uncertainty about the benefit of aspirin in patients with isolated asymptomatic PAD without involvement of other vascular beds. In a recent meta-analysis of 18 trials that included 5,269 patients with PAD, aspirin therapy alone or in combination with dipyridamole led to a 12% reduction in the primary end point of cardiovascular events; however, this did not reach statistical significance.44 Similarly, in patients with diabetes and asymptomatic PAD, no benefit with aspirin use was seen in the Japanese Primary Prevention of Atherosclerosis with aspirin in Diabetes (JPAD) trial and the prevention of progression of arterial disease and diabetes (POPADAD).45,46 The Aspirin for Asymptomatic Atherosclerosis trial, one of the largest double-blind, placebo-controlled trial of 3,350 asymptomatic subjects with ABI less than 0.95 without cardiovascular disease demonstrated no effect of aspirin in preventing fatal or nonfatal coronary event or stroke or revascularization. Although this study had a high rate of noncompliance (40%) and was underpowered, the benefits of aspirin, if any, are likely to be very small.47 Aspirin use has been shown to have benefit in patients with previous lower extremity surgical revascularization. Adjuvant aspirin therapy has also been recommended in serial Cochrane reviews to improve the patency rate after lower extremity bypass grafts.48 Thienopyridines Thienopyridine class of agents inhibit platelet aggregation via inhibition of the adenosine diphosphate pathway.49 They have been studied as an alternative to or in combination with aspirin. Ticlopidine, although shown to reduce the risk of MI, stroke, and vascular death in patients with PAD, has limited role because of the serious adverse effects of neutropenia, thrombocytopenia, and thrombotic thrombocytopenic purpura.50 The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared the use of clopidogrel in comparison to aspirin in high-risk patients (recent MI, stroke, and PAD) and included 6,452 patients with PAD. In a post hoc analysis, patients with PAD treated with clopidogrel noted a 24% reduction in the incidence of stroke, MI, or vascular death when compared to aspirin.51 The incremental benefit of clopidogrel in addition to aspirin was studied in the Clopidogrel for High Atherothrombotic Risk and Ischemia Stabilization, Management,

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and Avoidance (CHARISMA) study in a high-risk population consisting of patients with established cardiovascular disease (including PAD in 23% of enrolled patients) and patients without a history of cardiovascular disease but who had multiple atherosclerotic risk factors.52 This study demonstrated no benefit of dual antiplatelet therapy as compared to aspirin alone when studying the outcome of MI, stroke, and vascular death. In a subgroup of patients with PAD, prior MI, or stroke, the composite ischemic event rate was significantly lower at 7.3% for clopidogrel plus aspirin compared to 8.8% for aspirin alone. Moderate bleeding complications, as described by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) definition of bleeding requiring blood transfusion but not including fatal bleeds, intracranial hemorrhage, or hemorrhage culminating in hemodynamic compromise requiring resuscitation, inotropes, or surgery, were more common with dual therapy.52 Based on current data, combination therapy cannot be recommended in patients with stable PAD, and if clopidogrel is considered, it should be used as monotherapy. In the recently published clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial, the combination of clopidogrel plus aspirin did not improve limb or systemic outcomes in the overall population of patients with PAD requiring below-knee surgical bypass grafting. Subgroup analysis suggests that clopidogrel plus aspirin confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.53 Finally, newer generation thienopyridine antiplatelet agents such as prasugrel have recently been approved for use in patients with CAD and acute coronary syndromes as an alternative to clopidogrel.54,55 Although these agents have more rapid and effective antiplatelet efficacy than aspirin, they are associated with higher bleeding complication rates. No evidence currently exists describing a therapeutic role or safety for these agents in patients with PAD only, and they do not have an Food and Drug Administration–approved indication for use in this population.49,54,55 Warfarin The Warfarin Anti-platelet Vascular Evaluation (WAVE) trial has confirmed that vitamin K antagonists have no role in the prevention of cardiovascular events in patients with PAD. In this trial, patients randomized to a combination of antiplatelet and anticoagulant therapy had an increase in life-threatening bleeding.56 However, if patients have an alternative indication for anticoagulation with vitamin K antagonists, such as atrial fibrillation, venous thromboembolic disease, or prosthetic heart valves, then combination of warfarin and antiplatelet therapy can be prescribed, although the patients should be monitored closely for bleeding complications.

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In conclusion, the current ACC/AHA PAD guidelines recommend antiplatelet therapy for all symptomatic patients with PAD with or without cardiovascular disease to reduce the risk of cardiovascular morbidity and mortality. Aspirin is effective in patients with PAD in whom there is evidence of other forms of cardiovascular disease. The use of aspirin in patients with PAD without overt cardiovascular disease can be considered, but the evidence is controversial. Clopidogrel, as an alternative to aspirin, is effective in decreasing cardiovascular events in symptomatic patients with PAD with or without other cardiovascular disease. Finally, oral anticoagulation therapy with warfarin is not indicated to reduce the risk of adverse cardiovascular ischemic events in individuals with atherosclerotic PAD.

Medical therapy to treat limb symptoms Treatment of IC is dependent on the severity of presenting symptoms and the associated impact of those symptoms on the individual lifestyle. Patients with a mild to moderate disability from IC have traditionally been treated with a regimen of risk-factor modification and exercise. Patients with more severe symptoms are offered revascularization by either endovascular or surgical approaches. These treatment options are being compared prospectively in the Claudication: Exercise Vs. Endoluminal Revascularization (CLEVER) study funded by the National Heart, Lung, and Blood Institute. It is a prospective, multicenter, randomized, controlled clinical trial evaluating the relative efficacy, safety, and health economic impact of exercise, pharmacologic therapy, endovascular, and surgical revascularization strategies for people with aortoiliac PAD and claudication.57 Although all therapies have been compared in a head-to-head study, Fig 1 summarizes the relative effect of different noninvasive modalities on walking distance in patients with IC.

This section reviews the current status of exercise and pharmacologic therapy for IC. Exercise therapy People with PAD have markedly impaired exercise capacity that is commonly associated with impaired quality of life.58,59 Furthermore, patients with PAD have an increased rate of mobility loss at 4-year follow-up compared to those without PAD.60 In patients with PAD, supervised exercise program improve the speed, distance, and duration walked, with decreased limb symptoms at each workload or distance.61 Supervised exercise programs have also been shown to improve quality of life in these patients.62 Supervised exercise programs are as effective as endovascular revascularization in their effectiveness to improve functional capacity and do so at a much lower cost.63 A meta-analysis of 21 studies of exercise training by Gardner and Poehlman64 demonstrated that walking time improved by an average of 180% and that maximal walking time increased by 120% in patients with IC who underwent exercise training. Supervised treadmill exercise programs are more effective than lower extremity resistance training.62 However, due to lack of reimbursement and therefore limited availability of such programs, supervised exercise programs are underused or unavailable to patients. The benefits of unsupervised exercise regimens remain unproven. There is inadequate evidence to attribute the functional benefit from exercise, as is often believed, to the growth of new arterial collaterals (angiogenesis); in contrast, clinical improvement is more likely to be due to alterations in skeletal muscle metabolism, muscle hypertrophy, improvements in endothelial function, improved cellular or subcellular function, or altered gait.2 In addition, regular physical activity has also been shown to reduce the risk of cardiovascular disease by reduction in blood pressure, lipids, blood glucose, and also reduction in inflammatory markers.65 The recommended exercise regimen is

Fig 1. Comparative improvement in walking distance with non-invasive interventions.

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supervised exercise for 30 minutes 3 times a week for at least 12 weeks, with further increase of exercise time to an hour each session. Intensity should be submaximal in such a way that induces pain within 3 to 5 minutes.1,66 The AHA and American College of Sports Medicine also recommend 30 minutes or more of moderate intensity physical activity, preferably daily, for reduction in cardiovascular risk.66 Weight loss Obesity and metabolic syndrome are highly prevalent among patients with PAD. In the subgroup of patients with PAD in the Reduction of Atherothrombosis for Continued Health (REACH) registry, nearly half of the patients with PAD had abdominal obesity.5 Similarly, in another study, metabolic syndrome as defined by adenosine triphosphate III report was present in 41% of patients with PAD.67 Both obesity and metabolic syndrome are independent predictors of adverse cardiovascular events in these patients.67,68 Obesity also correlates with reduced ability to walk and shorter time to onset of IC symptoms. A 6year, ongoing longitudinal study examined the prevalence of self-reported effort-related calf pain in 4,047 obese Swedish people and a reference group of 1,135 subjects. Obese people experienced more calf symptoms than nonobese (odds ratio for symptoms was 4.4 and 6.8 for men and women, respectively) counterparts. Calf symptoms improved as patients lost weight in a dose-response fashion. The most prominent recovery occurred in persons who had lost the most weight secondary to bariatric surgery.69 Obese patients also experience a higher rate of postoperative surgical site infections after lower extremity bypass surgery.70 Therefore, all overweight or obese patients with PAD should be encouraged to lose weight. Pharmacologic therapy for IC Cilostazol Cilostazol is a type 3 phosphodiestherase inhibitor that increases cyclic adenosine monophosphate. The precise mechanism whereby cilostazol improves walking distance in patients with IC is unclear. The putative mechanisms include a favorable effect on platelet aggregation, vasodilation, and modification of the lipid profile (raising high-density lipoprotein, lowering triglyceride levels).71,72 Besides effect on claudication, cilostazol reduces vascular smooth muscle cell proliferation73 and may decrease chronic inflammation and atherogenic cytokines.74 In a small randomized trial of 78 patients undergoing femoropopliteal intervention, patients assigned to cilostazol plus aspirin (n = 39) had lower rate of restenosis (46.3% vs 70.3%) and repeat revascularization (18% vs 43.6%) at 2 years compared to patients randomized to aspirin alone.75 Several trials have demonstrated the efficacy of cilostazol in improving walking distance and quality of

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life in patients with IC compared with placebo or pentoxifylline. In a pooled analysis of data from 9 randomized, controlled trials of cilostazol at 100 mg BID, cilostazol was associated with a 50.7% improvement from baseline in maximal walking distance compared to placebo (24.3%) for a mean follow-up period of 20.4 weeks. These benefits were sustained during the 24-week treatment period.76 These findings are similar to those of a previous metaanalysis by Thompson et al77 and Cochrane review in 2008,78 both of which showed significant benefit of cilostazol at a dose of 100 mg BID. A 50-mg twice daily dosing of cilostazol led to a lower (44%) improvement in mean walking distance from baseline.77 Patients treated with cilostazol improved far better than patients randomized to either pentoxifylline (38%) or placebo (21%). The most common adverse effects noted by patients treated with cilostazol were related to the vasodilatory properties of the agent, notably headaches, diarrhea, dizziness, and palpitations.71,78 Because cilostazol is structurally similar to milrinone, which has been shown to increase mortality in patients with congestive heart failure, cilostazol's use is contraindicated in patients with congestive heart failure and/or left ventricular ejection fraction less than 40%. However, there is little direct evidence of increased mortality with cilostazol. The Cilostazol: A Study in Long-term Effects (CASTLE) study79 was a randomized multicenter placebo-controlled post market study to evaluate the safety of cilostazol for a period of 3 years. It randomized assigned 718 patients to cilostazol and 717 patients to placebo. However, the study was discontinued prematurely because of a low event rate and a high rate of drug discontinuation (N60%) at 3 years. Notwithstanding these limitations, the study showed that the all-cause (1.72 events per person-year of follow-up) and cardiovascular mortality (1.34 events per person-year) rates were low and similar to that of the placebo arm. There was no increase in bleeding in patients treated with cilostazol. The current ACC/AHA PAD guidelines recommend cilostazol 100 mg orally twice daily to improve IC symptoms in the absence of heart failure.

Pentoxifylline Pentoxifylline is a methylxanthine derivative that is believed to exert hemorrheologic effects by decreasing blood viscosity, increasing red blood cell deformability, inhibiting neutrophil adhesion and activation, and lowering plasma fibrinogen concentrations in some studies but not in others.2 The clinical data regarding benefits of pentoxifylline are inconsistent. Pentoxifylline does not improve ABI at rest or after exercise. A 3-arm comparison of cilostazol, pentoxifylline, or placebo in 698 patients did not prove a statistically significant advantage for pentoxifylline over placebo.80

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The current ACC/AHA PAD guidelines recommend using pentoxifylline as an alternative in patients who cannot tolerate cilostazol or in whom cilostazol is contraindicated.2 Naftidrofuryl Naftidrofuryl is a 5-hydroxytryptamine type 2 antagonist used predominantly in Europe. It may improve muscle metabolism and reduce erythrocyte and platelet aggregation. In a meta-analysis of 5 studies involving a total of 888 patients with IC, naftidrofuryl increased pain-free walking distance by 26% compared to placebo (P = .003).81,82

Naftidrofuryl is not included in the ACC/AHA PAD guidelines, although it is recommended at a similar level of evidence to cilostazol in the The TransAtlantic InterSociety Consensus (TASC) II guidelines.1 A study sponsored by the National Health Services, expected to be analyzed in 2011, is comparing pentoxifylline, cilostazol, inositol nicotinate, and naftidrofuryl in patients with claudication and ischemic rest pain.83 Prostanoids Intravenous prostanoids have been used to treat severe manifestations of PAD. Prostanoids include prostaglandin E1 and prostaglandin I2 and their synthetic analogs such as

Table 2 Medications with little or no evidence

Medication

Proposed Mechanism

Agents with insufficient evidence Ginkgo biloba Vasodilatation and inhibition of platelet aggregation L-arginine L-arginine is a precursor of nitric-oxide. Nitric oxide is a vasoprotective vasodilator. Omega-3 fatty Delay of atherosclerosis acids Buflomedil α1/α2 antagonist, decreased platelet aggregation, and increased red blood cell deformability Sarpogrelate 5-hydroxytryptamine 2A antagonist that inhibits platelet aggregation and vasoconstriction and increases red cell deformity Glutathione Antioxidant that reduces hydroperoxidase and increases nitric oxide–mediated platelet aggregation Mesoglycan Indirect local thrombin inhibition

Agents not recommended or recommended against Oral vasodilators Vasodilatation and antiplatelet aggregation

EDTA

Vitamin E

Rifalazil

Chelation of calcium, free radical scavenging, inhibition of lipid peroxidation, cell membrane stabilization Antioxidant that may oppose exerciseinduced ischemia and counterbalance atherosclerosis Antibiotic with anti–Chlamydophila pneumonia action

Comments

AHA/ACC Level of Recommendation/Evidence (Hirsch, JVIR 2006—TASC Guidelines) Reference IIb/B

86,87

N/A

88

N/A

89

N/A

90

N/A

91

Need for intravenous administration. Only short-term results are available

N/A

92

Single study; trend toward significant improved maximal and pain-free walking distance. No effect on aPTT.

N/A

93

Insufficient data. Most publications suggest efficacy. Early small scale, short-term studies showed benefit; however, oral L-arginine had no clinical effect at 6 mo and may hamper vascular reactivity Probable favorable vascular effect but no clinical efficacy proven Objective high-quality data are lacking; publication bias exists, and the therapeutic window is narrow (letter circulation 2008) No proven clinical effect to date.

III/A Vasodilators may increase ischemia via a steal phenomenon. There are some encouraging results; however, they are recommended against by the AHA/ACC and the ACCP. Some may need to be administered intravenously for effect. Treatment did not prove effective in a pilot study. III/A

94,95

Possible unproven benefit and no general mortality, coronary, or cognitive benefit

III/C

97,98

Chronic infection with Chlamydia pneumonia proposed to play a role in atherosclerosis

N/A

99

96

Abbreviations: aPTT, activated Partial Thromboplastin Time; ACCP, The American College of Chest Physicians. Class I evidence is defined as evidence, general agreement, or both that the treatment is beneficial, useful, and effective; class IIb, as conflicting evidence or divergence of opinion about efficacy or usefulness (or efficacy that is less well established by evidence or opinion); and class III, as evidence, general agreement, or both that the treatment is not beneficial, useful, and effective. Levels of evidence are classified as follows: level A, data derived from multiple randomized trials or meta-analyses; level B, data derived from a single randomized trial or from nonrandomized studies; and level C, the consensus opinion of experts, data from case studies, or the standard of care.

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iloprost. They are proposed to cause vasodilatation and inhibit platelet activation, adhesion, and aggregation and may have antithrombotic and profibrinolytic actions. They may also improve endothelial function.84 The results concerning their efficacy are contradictory. A recent Cochrane database review of 20 trials with a total of 2,724 patients concluded that despite positive results regarding pain relief, ulcer healing, and amputation rate reduction, there was not enough data to recommend the use of prostanoids for CLI.85 The AHA/ACC guidelines2 for the management of patients with PAD recommended against the use of prostanoids for claudication (level of evidence III/A) or for reducing the risk of amputation in patients with CLI (level of evidence III/B). Parenteral prostanoids may be considered to facilitate the healing of ulcers or reduction of rest pain (level of evidence IIb/A). Other agents There have been many other pharmacologic agents studied to improve physical functioning in patients with IC, all demonstrating limited or no benefit. These are summarized in Table 2. Regenerative therapies Several trials are evaluating the role of protein and gene transfer therapies for patients with PAD. Despite the vast

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array of animal, experimental, and preclinical research, the efficacy of these therapies in stimulating angiogenesis remains unproven.2,100,101 The 2 most widely studied growth factors include vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF).102-104 The Regional Angiogenesis with VEGF (RAVE) trial, the first randomized study of intramuscular VEGF, demonstrated no difference in peak walking time or ABI measurement when compared to placebo.105 In the Therapeutic Angiogenesis with Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (TRAFFIC) trial,104 a phase II double-blinded, placebo-controlled clinical trial, 190 patients with IC were randomized to intra-arterial FGF-2 vs placebo. In this study, peak walking distance increased significantly in those randomized to intraarterial FGF-2, but only a small increase in ABI was noted. Another randomized controlled trial of FGF, Therapuetic Angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with CLI (TALISMAN), showed no difference in the primary end point of ischemic ulcer healing.106 Recently, Efficacy and Safety of XRP0038/NV1FGF in Critical Limb Ischemia Patients With Skin Lesions (TAMARIS), a randomized double-blinded, placebo-controlled trial disappointingly did not demonstrate any difference in amputation or amputation and mortality rates between those treated with gene therapy vs placebo.107

Fig 2. Management goals and treatment strategies for patients with peripheral arterial disease.

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There are also several studies looking at the role of bone marrow progenitor or peripheral blood progenitor cells in patients with PAD. The Therapeutic Angiogenesis using Cell Transplantation (TACT) trial initially studied 25 patients with unilateral limb ischemia. In this study, patients were administered autologous bone marrow– derived mononuclear cells injected intramuscularly.108 At 25 weeks, there were markedly improved transcutaneous oxygen pressure gradients, pain-free walking time, and reduction in ischemic rest pain. From this pilot study, a further 22 patients were randomized to bone marrow– derived cells in 1 leg and peripheral blood derived cells in the other. The same clinical improvements were noted in this segment of the study, and safety has been reported out to 3 years of follow-up. Multiple clinical series have reported similar positive findings in contrast to the largely disappointing results from gene therapy. Huang et al109,110 have published small series demonstrating the clinical efficacy of peripherally harvested mononuclear progenitor cells for angiogenesis therapy in diabetic patients with PAD without surgical or endovascular options. Although promising, these therapies need to be evaluated in rigorous well-controlled randomized trials before considered for clinical use.

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Conclusion Peripheral arterial disease is the most underrecognized and undertreated atherosclerotic syndrome in the general population. Clinicians should actively seek out patients at risk for PAD because they are at very high risk for future cardiovascular events and mortality. Once the diagnosis of PAD is established, all patients must receive a comprehensive program to lower their risk for future cardiovascular events. Our approach to manage these patients is summarized in Fig 2. This includes aggressive atherosclerotic risk factor modification including tobacco cessation, weight loss, antiplatelet therapy, lipid-lowering therapy, control of DM, and high blood pressure. For patients who are symptomatic, participation in a supervised exercise program and pharmacologic therapy should be advised to improve quality of life.

Statement of Conflict of Interest

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All authors declare that there are no conflicts of interest. 16.

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