circulation 2012 berger 491 500

8/20/2019 Circulation 2012 Berger 491 500

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Peripheral Arterial Disease

Medical Therapy in Peripheral Artery Disease

Jeffrey S. Berger, MD, MS, FAHA; William R. Hiatt, MD, FAHA

The epidemiology of peripheral artery disease (PAD) iswell described and related to age and, in particular, therisk factors of diabetes mellitus and smoking. Recent data

from the National Health and Nutrition Examination Survey

found a 5.9% prevalence in subjects 40 years of age

resulting in an estimated prevalence of 7.2 million affected

individuals in the United States.1 These subjects have a

significant increased risk of all-cause mortality because of the

underlying atherosclerotic disease process and general under-

treatment of PAD risk factors.2

There is a wide spectrum of clinical manifestations for

PAD: (1) the completely asymptomatic patient found to have

PAD from a screening ankle-brachial index (ABI), (2) atyp-ical leg symptoms associated with an exercise limitation, (3)

classic intermittent claudication, and (4) ischemic pain and

ulceration in the lower extremity from chronic limb ischemia.

However, despite the level and degree of limb symptoms,

even asymptomatic persons with PAD have a greatly reduced

functional capacity. This suggests that occlusive disease in

the lower extremity is associated with reduced exercise

capacity and functional status regardless of the symptomatic

state.

As noted above, symptomatic and asymptomatic PAD is

associated with an increased risk for morbidity and mortality,

and for impairment of quality of life, as well. A prospectivecohort in subjects 65 years of age found a similar high

ischemic risk in symptomatic and asymptomatic adults with

PAD.3 Pooled data from 11 studies in 6 countries found that

PAD, defined by a an ABI of 0.90 was associated with an

increased risk of subsequent all-cause mortality (relative risk

1.60), cardiovascular mortality (relative risk 1.96), coronary

heart disease (relative risk 1.45), and stroke (relative risk

1.35) after adjustment for age, sex, conventional cardiovas-

cular risk factors, and prevalent cardiovascular disease.4

The treatment of PAD has evolved over the past decade to

include a broad approach, focusing on the reduction of

adverse cardiovascular events, improving symptoms in clau-dication, and preventing tissue loss in critical limb ischemia.5

Because quality of life is severely limited in these subjects,

great emphasis is placed on ameliorating symptoms and

reducing the risk of PAD progression.

Established Therapies for Management of theSystemic Atherothrombosis in PAD

Several sets of guidelines provide physicians taking care of PAD

subjects with a list of recommendations regarding optimal

treatment recommendations.6– 8 These include the American

College of Cardiology Foundation/American Heart Association

guidelines and the international Inter-Society Consensus

(TASC) II guidelines. Both are undergoing substantial revision

at this time. However, only 15% of the American College of

Cardiology Foundation/American Heart Association PAD

guidelines come from evidence that is level A.9 Thus, there is a

paucity of high-level data to guide decision making.

Many of the medical therapeutics used in PAD target athero-thrombotic pathways. For example, statins, antiplatelets, and

angiotensin-converting enzyme inhibitors are used in PAD; yet,

much of the data supporting their use stem from data derived

from patients with coronary or cerebrovascular disease. For

example, the Heart Protection Study (HPS), which evaluated

simvastatin versus placebo, and the Clopidogrel versus As-

pirin in Patients at Risk of Ischemic Events (CAPRIE) trial

enrolled patients with atherosclerosis in several vascular

territories, including a large subgroup of patients with PAD.

Both studies found that in general PAD responds similarly to

non-PAD (except maybe somewhat better to clopidogrel than

to aspirin).10,11

Antiplatelet TherapyDespite an abundance of data demonstrating the efficacy of

antiplatelet therapy in coronary artery disease and cerebro-

vascular disease, the data in PAD are less compelling. In the

Antithrombotic Trialists’ Collaborative meta-analysis, there

was a significant 23% lowering of cardiovascular events from

a combined analysis of all antiplatelet agents, but the bene-

ficial effects were driven by picotamide (an inhibitor of

thromboxane A2 synthase and thromboxane A2 receptors).12

Although antiplatelet therapy is effective at decreasing car-

diovascular events in patients with PAD, these drugs have no

effect on symptomatic improvement in subjects with inter-mittent claudication.13

Aspirin, the most widely used antiplatelet agent in the world,

does not have compelling evidence supporting a reduction in

cardiovascular events in patients with PAD (despite a positive

From the Divisions of Cardiology and Vascular Surgery, New York University School of Medicine, New York, NY (J.S.B.); University of Colorado

School of Medicine, Division of Cardiology, and CPC Clinical Research, Aurora, CO (W.R.H.).Correspondence to William R. Hiatt, MD, Professor of Medicine/Cardiology, University of Colorado School of Medicine, c/o CPC Clinical Research,

13199 E Montview Blvd, Suite 200, Aurora, CO 80045. E-mail [email protected]

(Circulation. 2012;126:491-500.)

© 2012 American Heart Association, Inc.Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.111.033886

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trend).14 In a recent meta-analysis of 18 prospective randomized

trials comprising 5269 subjects with PAD, aspirin resulted in a

12% reduction of the combined end point of nonfatal myocardial

infarction, nonfatal stroke, and cardiovascular death that failed to

reach statistical significance.14 Whether a larger sample would

provide more convincing benefit is unknown, but recent studies

of aspirin in subjects with asymptomatic PAD or PAD with

diabetes mellitus were entirely negative.15,16 However, the scar-

city of randomized data investigating aspirin in symptomatic

PAD compared with coronary artery disease or cerebrovascular

disease remains a major limitation in clinical decision making.

There is some evidence that clopidogrel monotherapy may

be particularly effective in PAD. In a subgroup analysis of

CAPRIE, clopidogrel (versus aspirin) had its greatest effect

on reducing cardiovascular events in subjects with PAD (P for

heterogeneity0.045).11 Subsequently, the Clopidogrel for HighAtherothrombotic Risk and Ischemic Stabilization, Management

and Avoidance (CHARISMA) trial evaluated the effect of

aspirin plus clopidogrel versus aspirin alone in patients with

established and at risk for cardiovascular disease. In a subgroup

analysis of PAD patients, no benefit was observed for dual-

antiplatelet therapy with aspirin plus clopidogrel.17

Current guidelines recommend antiplatelet therapy in patients

with PAD. Because the majority of patients with PAD have

concomitant symptomatic coronary artery disease or cerebrovas-

cular disease, aspirin is an acceptable antiplatelet agent in this

setting. In addition to aspirin, clopidogrel monotherapy is a

reasonable alternative strategy. Implicit in these recommenda-

tions is that a large prospective randomized trial investigating the

optimal antiplatelet strategy in patients with PAD is long

overdue.

Established Therapies forSymptomatic Improvement

Over the past decade there has been a tremendous growth of

PAD limb-specific clinical studies suggesting that treatment

with metabolic agents, antimicrobials, cell therapy, and gene

therapy would result in improved lower-extremity function

and viability in subjects with PAD. Trials in humans have led

to inconsistent results. This review will provide the current

state of medical therapy in subjects with PAD (Table 1). Thiswill include the evidence for and against these new modalities

with a focus on medical treatments including drugs and

biological agents. Revascularization trials are not within the

scope of this review.

Exercise TrainingExercise rehabilitation is a class I, level of evidence A, recom-

mendation for the treatment of claudication in patients with

PAD.7,8 A landmark meta-analysis in 1995 demonstrated that

supervised exercise improves claudication symptoms and in-

creases pain-free walking distance on a treadmill by 100%.18

In 2008, a rigorous systematic review by the Cochrane group19

involving 1200 participants from 22 randomized trials with

stable claudication demonstrated a significant benefit in improv-

ing treadmill walking time and walking distance with a super-

vised exercise program. Although no benefit was seen in

reducing major adverse cardiovascular events or on improving

the ABI, subjects randomly assigned to exercise had improve-

ment in claudication symptoms out to 2 years.19

Although supervised exercise is very effective in PAD sub-

jects with claudication, several questions remain: (1) is exerciseeffective in PAD subjects without claudication and (2) what is

the role of a nonsupervised exercise program? Two recent

randomized trials address these issues.21,22 The effect of

supervised treadmill exercise or lower-extremity resistance

training on functional performance and quality of life was

evaluated in a randomized trial of 156 PAD patients, of whom

20% had symptoms of classic claudication.20 Although any

exercise (treadmill or resistance training) improved func-

tional performance, the treadmill exercise group had greater

increases in the 6-minute walk distance and in the maximum

treadmill walking time in comparison with the resistance

group. Of note, the changes in the primary outcomes were

similar between subjects with and without claudication andbetween asymptomatic and symptomatic participants. Despite

the efficacy of a supervised exercise program in PAD, lack of

reimbursement in the United States remains a major barrier to

utilization of this treatment.

Evaluating the role of home-based exercise, Gardner and

colleagues randomly assigned 119 subjects with claudication

to either home-based exercise, supervised exercise, or a usual

care control group.21 Both exercise programs increased clau-

dication onset time and peak treadmill walking time versus

the control group; however, the changes in average walking

cadence time were greater in the home-based exercise group.

Although this study was small, and nearly 25% of subjects

did not complete follow-up, it suggests that a quantified

home-based approach may be useful in this high-risk popu-

lation with impaired quality of life. However, a meta-analysis

of home-based exercise training in PAD was negative.22

Future exercise studies with improved home-training meth-

ods, larger populations, and clinically meaningful end points

are certainly warranted. In the meantime, subjects with PAD

(symptomatic or not) are likely to benefit from an aggressive

exercise regimen.

CilostazolCilostazol is a phosphodiesterase type 3 inhibitor approved in

the United States in 1999 to treat intermittent claudication. Itspossible mechanism of action includes increasing intracellu-

Table 1. Effect of Medical Therapies in Subjects With

Peripheral Artery Disease

Symptomatic

Improvement

Reduced

Cardiovascular Risk

Exercise Not studied

Cilostazol Neutral

Statins /

Antiplatelets

L-Carnitine and

propionyl-L-carnitine

Not studied

Pentoxifylline Not studied

Naftidrofuryl Not studied

Gene therapy / Neutral

Cell therapy / Not studied

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lar concentrations of cAMP, thereby causing vasodilation and

inhibiting platelet aggregation.23 Although other drugs with

vasodilating and platelet-inhibiting properties have not been

demonstrated to improve claudication symptoms, cilostazol is

effective in ameliorating symptoms. A meta-analysis of 8

randomized trials including 2702 PAD subjects with claudi-

cation found that cilostazol improved maximum and pain-free

treadmill walking distance and quality-of-life measures.24 Of

note, cilostazol decreased triglyceride concentration by 16%

and increased high-density lipoprotein levels by 13%, but

also increased the incidence of headache, bowel concerns,

and palpitations.

Cilostazol may have an additional benefit of reducing reste-

nosis and repeat revascularization following endovascular ther-

apy.25 Similar to patients with coronary artery disease,26–28

patients with PAD have lower rates of target vessel revascular-

ization following cilostazol therapy.29,30 However, these studies

have been small and open label in design, thus hypothesis

generating.

Milrinone, another phosphodiesterase type 3 inhibitor, wasnoted to increase mortality in subjects with heart failure.31 In

response, the US Food and Drug Administration mandated a

long-term safety study of cilostazol. Hiatt and colleagues per-

formed a phase 4 (postmarketing) randomized, double-blind,

placebo-controlled trial of cilostazol in 1435 PAD subjects with

claudication.32 Although underpowered because of a lower

mortality than projected and poor study drug adherence, this is

the largest study to date that has evaluated serious adverse events

and mortality. No difference was observed for overall mortality

or serious bleeding events between the cilostazol and placebo

groups; however, the study could not exclude a modest increased

risk. In comparison with milrinone, cilostazol has fewer cardiac

inotropic effects but equivalent vasodilating and platelet-inhibiting properties.33 Nonetheless, an advisory from the US

Food and Drug Administration stated that cilostazol should not

be used in subjects with congestive heart failure.

Statin TherapySubgroup analyses of PAD patients from large randomized

trial data in subjects with PAD found a reduction in cardiovas-

cular events from statin therapy. Exploratory analyses suggested

an improvement of claudication symptoms in subjects with

PAD.34 In a randomized trial of 354 PAD subjects with claudi-

cation, Mohler and colleagues35 demonstrated that atorvastatin

(10 or 80 mg daily) improved pain-free walking distance and

community-based physical activity. However, the functional

benefits of statins on claudication have not been proven.

Carnitine and Propionyl-L-Carnitine TherapyL-Carnitine and propionyl-L-carnitine may improve muscle

metabolism and exercise performance in patients with PAD.

Initial studies evaluated L-carnitine given orally as 2 g twice

daily, and also given as a single 3-g dose intravenously.36

These early studies in PAD were indicative of clinical benefit

and therefore led to the development of propionyl-L-carnitine,

an acyl form of L-carnitine.

In 2 published phase 3 trials, propionyl-L-carnitine had a

significant improvement on claudication-limited treadmillexercise performance. In Europe, a total of 501 subjects were

randomly assigned to propionyl-L-carnitine 2 g/d for 12 months

(n248) or placebo (n253).37 The primary analysis was the

subgroup of 171 patients who had a maximum walking distance

between 50 and 250 m and baseline variability 25%. After

12 months of treatment, patients randomly assigned to pla-

cebo increase maximal walking distance 44% versus 61% on

drug. This difference had a probability value of 0.055 by the

primary analysis and 0.048 with a secondary analysis. The

quality-of-life questionnaire was also positive in favor of

drug (P0.002). In the second pivotal trial, a total of 161

subjects were randomly assigned to propionyl-L-carnitine, 2

g/d (n85), or placebo (n76).38 After 6 months of therapy,

treated patients increased peak walking time 78% with a 37%

increase in controls (P0.002). Patients randomly assigned

to propionyl-L-carnitine also had significant improvements in

the physical function scores of the SF-36 (P0.31), but not

with the Waling Impairment Questionnaire (P0.26). How-

ever, more recent studies in which propionyl-L-carnitine was

given on a background of exercise training, although showing

favorable trends, were not statistically significant on theprimary end point.39 Thus, the overall incremental benefit of

propionyl-L-carnitine in PAD remains to be determined.

Other Medical Therapies

PentoxifyllinePentoxifylline is a xanthine derivative used to treat patients

with intermittent claudication. Its mechanism of action is

thought to be a rheological modifier that includes improving

the deformability of red blood cells and white blood cells, and

decreasing fibrinogen concentration, platelet adhesiveness,

and whole-blood viscosity. A meta-analysis demonstrated a

modestly improved walking distance, substantially less effec-

tive than either cilostazol or a supervised exercise program.40

NaftidrofurylNaftidrofuryl is a serotonin 5-hydroxytryptamine 2 receptor

antagonist with vasoactive properties in addition to its effect

on oxidative metabolism and rheological properties on the red

blood cell and platelet.41 Although not approved in the United

States, it is currently used in Europe for the treatment of

claudication. In a patient-level meta-analysis, naftidrofuryl

improved symptomatic claudication without any serious ad-

verse events.42

Medical Treatment of the PatientUndergoing Revascularization

Antiplatelet therapy has good evidence for the prevention of

graft occlusion after peripheral vascular surgical procedures.

In the Antithrombotic Trialists’ Collaboration meta-analysis,

3000 patients with peripheral artery procedures had a 16%

graft occlusion rate on antiplatelet therapy in comparison

with 25% in the control group (P0.00001).43 Aspirin with

or without other antiplatelet therapy was associated with a

significantly lower risk of graft occlusion.44 Ticlopidine has

also been shown to promote vein graft patency without any

difference in cardiovascular events.45 Dual-antiplatelet ther-

apy with aspirin plus clopidogrel versus aspirin alone was

tested in the clopidogrel and acetylsalicylic acid in bypasssurgery for peripheral arterial disease (CASPAR) trial.46

Berger and Hiatt Medical Therapy in Peripheral Artery Disease 493




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There was no significant difference in the primary end point

(graft occlusion, amputation, or death) between groups. In a

subgroup analysis, clopidogrel plus aspirin was better than

aspirin alone among patients who received prosthetic grafts.

As expected, bleeding was more common in the dual-antiplatelet

therapy group.47

Anticoagulation has also been recommended as an adju-

vant to maintain surgical graft patency.47 The use of heparin

anticoagulation in the immediate postoperative period, par-

ticularly low-molecular-weight heparin, may improve the

patency of infrainguinal bypass grafts (vein and prosthetic),

but has also been associated with increased bleeding.48,49 The

role of long-term oral anticoagulation is more controversial.

In one trial of patients undergoing infrainguinal bypass

surgery (including the use of vein, prosthetic material, and

endarterectomy), long-term warfarin was associated with an

increased bleeding risk but no benefit in patency or survival.50

In contrast, another study performed in a similar population

demonstrated that oral anticoagulation improved graft pa-

tency, limb salvage, and survival.51

Several trials have compared the benefits of anticoagula-

tion versus antiplatelet therapy. Among patients treated with

infrainguinal bypass procedures (predominantly using pros-

thetic material), randomization to low-molecular-weight hep-

arin versus aspirin and dipyridamole was associated with

better graft patency, especially in the patients treated for

critical limb ischemia.52 The Dutch Bypass Oral Anticoagu-

lants or Aspirin study evaluated 2690 patients undergoing

infrainguinal bypass.53 Half the patients were treated for

claudication and the other half were treated for critical limb

ischemia with a fairly even distribution of vein versus

prosthetic material. The aspirin dose was 80 mg/d, and, inpatients randomly assigned to anticoagulation, the interna-

tional normalized ratio was maintained at 3.0 to 4.5. The

primary end point of patency was equal between groups after

21 months follow-up. In subgroup analysis, anticoagulation

maintained vein graft patency better than aspirin but at a

higher risk of bleeding complications. In contrast, aspirin

maintained prosthetic graft patency better than anticoagula-

tion. Although these results suggest that patients receiving

vein grafts should be preferentially treated with warfarin and

those with prosthetic material with aspirin, adequately pow-

ered studies are needed to determine the optimal antithrom-

botic and antiplatelet strategy following vascular surgery.

In the context of promoting patency after a revasculariza-

tion procedure, antiplatelet and antithrombotic therapy have a

clear role, but the data are somewhat dated. In terms of

selection between type of therapy, aspirin may be favored for

prosthetic grafts and anticoagulation for vein grafts or for

higher-risk patients for occlusion.44 Future trials are needed.

Novel TherapiesTherapeutic angiogenesis is a promising investigational strat-

egy for the treatment of patients with claudication and

chronic leg ischemia (CLI). It is an application of biotech-

nology to stimulate new vessel formation via local adminis-

tration of proangiogenic growth factors delivered as recom-binant protein or by gene therapy, or by implantation of

endothelial or other progenitor cells that will synthesize

multiple angiogenic cytokines.

Gene TherapyGene therapy involves transfer of genetic material into cells

to modify their genetic expression to produce a clinically

useful effect on angiogenesis, capillary generation, and col-

lateral formation. Clinical trials have sought to establish the

role for therapeutic angiogenesis by use of gene transfer with

proangiogenic factors mediated by plasmids or viral vectors

in patients with PAD, although results have been inconsistent

(Table 2). These proangiogenic factors include vascular

endothelial growth factor (VEGF), fibroblast growth factor

(FGF), hypoxia-inducible factor (HIF)-1, and hepatocyte

growth factor (HGF).

In a meta-analysis evaluating the efficacy and safety of

different gene therapies, recombinant protein and cellular-

based treatment approaches in patients with PAD, therapeutic

angiogenesis was associated with a modest, albeit significant

clinical improvement in peak walking time, ulcer healing, restpain relief, and limb salvage versus placebo in subjects with

PAD (odds ratio 1.44, 95% CI 1.03–2.00).62 The improve-

ment was most impressive in subjects with CLI. There was

also a 30% increase in the odds of the adverse events of

edema, hypotension, and proteinuria. No significant differ-

ence was detected for the endpoints of mortality, malignancy,

or retinopathy.

Vascular Endothelial Growth FactorVascular endothelial growth factor is expressed under hy-

poxic conditions and is a potent regulator of endothelial cell

migration, proliferation, repair, and survival.63 In previous

studies involving animal studies, VEGF gene transfer inducedrapid production of nitric oxide and prostacyclin from endo-

thelium causing a vasculoprotective effect.64,65 In a hindlimb

ischemia animal model, VEGF was demonstrated to induce

angiogenesis and arteriogenesis.66,67 Initial uncontrolled clin-

ical trials have suggested promising therapeutic effects with

naked VEGF plasmid gene transfer.68,69 In a comparison of

intra-arterial infusion of adenoviral VEGF165, plasmid lipo-

some VEGF165, or Ringers lactate placebo, Makinen et al70

noted that both VEGF165 treatments appeared safe and were

associated with significant increases in vascularity.

In a phase I trial, Baumgartner and colleagues70 found that

intramuscular injection achieves overexpression of VEGF

sufficient to induce therapeutic angiogenesis in selected

patients with CLI.

In the Regional Angiogenesis with VEGF (RAVE) trial, a

single intramuscular adenoviral delivery of VEGF121 in

patients with unilateral exercise-limiting claudication failed

to achieve its primary end point of change in treadmill peak

walking time.54 There was no difference in any of the

secondary end points, and VEGF121 was associated with a

dose-dependent increase in peripheral edema. Reasons for the

lack of efficacy could be the population selected (patients

with bilateral PAD were excluded), the duration of expression

of the VEGF121 transgene by use of the adenoviral approach

may be insufficient to induce a phenotypic response, and thesingle injection may be insufficient.71 It is possible that





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importance of performing large phase III trials in this new

area of gene therapeutics.

In the setting of claudication, Lederman and colleagues57

performed the Therapeutic Angiogenesis with FGF-2 for

Intermittent Claudication (TRAFFIC) phase II trial testing the

efficacy and safety of intra-arterial FGF-2 protein in 190

patients with moderate-to-severe intermittent claudication.

Intra-arterial FGF-2 protein resulted in a significant increase

in peak walking time at 90 days. No follow-up study has been

performed.

Hypoxia Inducible Factor-1The transcription factor HIF-1 is important in vascular

hemostasis; HIF-1 regulates the expression of specific genes

involved in the response to hypoxia and wound healing.74

Because HIF-1 involves both physiological and pathologi-

cal angiogenesis, strategies that target this factor have been

tested in the setting of PAD. In a phase I dose escalation

study, HIF-1 delivered intramuscularly with an adenoviral

vector was safe out to 1-year.75

There were data to suggestthat certain subjects had amelioration of rest pain symptoms

and complete ulcer healing. In a larger study (WALK) to

assess the transcription factor HIF-1 , results demonstrated

no benefit in the primary end point.71

Hepatocyte Growth FactorHepatocyte growth factor stimulates the growth of endothe-

lial cells and promotes angiogenesis.76 HGF is able to induce

robust collateral formation in preliminary studies.77 Subse-

quently, a randomized trial was performed to assess the safety

and potential efficacy of intramuscular injections of HGF

plasmids in 104 patients with CLI.78 There was no safety

concern attributed to the HGF therapy. Seventy-three patientswere available for the efficacy component; the highest-dose–

treated group had a significant increase in transcutaneous

partial pressure of oxygen at 6 months, which was signifi-

cantly greater than in the placebo group. There was no

difference between groups in the ABI, toe-brachial index,

pain relief, wound healing, or major amputation. In a recent

phase I/IIa study, Morishita and colleagues79 evaluated the

safety and potential efficacy of intramuscular injection of

plasmid HGF in patients with CLI. No serious adverse events

were noted. In a nonrandomized comparison, patients had an

improvement in ABI, toe-brachial index, rest pain, and ulcer

size at 6 months. There was no difference in transcutaneous

partial pressure of oxygen. Larger studies are needed to

determine the efficacy and safety profile of HGF.

Developmentally Regulated Endothelial LocusDevelopmentally Regulated Endothelial Locus (Del-1) is an

extracellular matrix protein that accumulates around angio-

genic blood vessels and promotes angiogenesis even in the

absence of exogenous growth factors.80 The Del-1 for Ther-

apeutic Angiogenesis (DELTA) trial randomly assigned 105

PAD patients with claudication to intramuscular injections of

Del-1 plasmid with poloxamer 188 (to enhance transfection)

or poloxamer 188 alone.56 No significant safety issues were

associated with Del-1. Peak treadmill walking time improvedsignificantly in both groups without any incremental benefit

in the Del-1 group. Although ABI, claudication onset time,

and quality of life improved in both groups, no difference

emerged between Del-1 and the control group. The improve-

ment of outcomes in both groups observed in this study

underscores the substantial placebo effect and the importance

of having a placebo group.

Advancement of gene therapy from the safety-and-feasibilitystage to routine clinical use will require carefully designed,

adequately powered, large-scale, randomized, controlled phase

III trials that incorporate end points that address methodological

improvements, long-term safety, and clinically important end

points.

Cell TherapyAnother potential novel treatment modality for PAD patients

with claudication and chronic ischemia is the stimulation of

angiogenesis with cell therapy. Endothelial progenitor cells

are important mediators in postnatal neovascularization after

mobilization from the bone marrow.81,82 Numerous studies

have demonstrated that, in the setting of both hindlimb and

coronary ischemia models, endothelial progenitor cells can be

harvested, expanded ex vivo, and delivered to augment capillary

density, perfusion, and organ function.83 Bone marrow–derived

mononuclear cell implantation stimulates the production of

endothelial progenitor cells and increases collateral vessel

formation in both ischemic limb models and patients with

limb ischemia.84,85 Implantation of bone marrow mononu-

clear cells (versus peripheral blood mononuclear cells) im-

proved the ABI, transcutaneous oxygen pressure, rest pain,

and pain-free treadmill walking time at 4 and 24 weeks after

injection.85 In a follow-up study, Higashi and colleagues86

demonstrated that bone marrow mononuclear cells improvedendothelium-dependent vasodilation in patients with limb

ischemia in addition to an effect on ischemic symptoms and

findings of angiography. Several international phase II trials

are underway to assess the benefit/safety profile of cell therapy

in patients with PAD.

In an animal model, intra-arterial infusion of granulocyte-

macrophage colony-stimulating factor (GM-CSF) stimulates

the development of arterial collateral blood vessels following

femoral artery occlusion.87 In a small study of 21 subjects

with extensive coronary artery disease not eligible for bypass

surgery, intracoronary injection of GM-CSF improved collat-

eral flow and led to a reduction in ST-segment changes andepisodes of angina.88 The STimulation of ARTeriogenesis

(START) study was the first placebo-controlled study in the

setting of moderate or severe claudication to investigate the

effect of GM-CSF on walking distance.60 Patients were

treated with placebo or subcutaneously applied GM-CSF (10

g/kg) for a period of 14 days. No major side effects were

observed; however, skin rash, muscle pain, and fever were

more common in the GM-CSF group. There was no differ-

ence in the primary end point (increase in maximum walking

distance) or secondary end point (ABI) either directly after

treatment or at 90 days of follow-up. Treatment with granu-

locyte colony-stimulating factor is another promising ap-proach in this setting.61





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AntimicrobialsObservational data provided the groundwork suggesting that

an infectious agent may be an important link between chronic

inflammation and PAD. In a small study, 20 subjects sero-

positive to Chlamydia pneumonia who received roxitrhomy-

cin (400 mg daily) had better walking distance and fewer

invasive revascularization procedures than 31 subjects seropos-itive for Chlamydia pneumonia who did not receive antibiotics.89

Several other small studies failed to demonstrate a benefit of

antimicrobial therapy in subjects with PAD.90,91 To better

understand the role of antimicrobials in PAD, Jaff and col-

leagues92 randomly assigned 283 PAD subjects with claudica-

tion to 25 mg rifalazil weekly for 8 weeks or matching placebo.

All subjects enrolled had Chlamydia pneumonia antibody titer

values 1:128. There was no benefit of rifalazil on the primary

or any secondary assessment measured.92 No difference in

cardiovascular events was noted, but the study was underpow-

ered to detect this difference. Combined with the plethora of

negative studies of antimicrobials in subjects with coronary

disease,93 there is little compelling reason to study this class of compounds in subjects with atherosclerotic disease.

Future DirectionsMedical management of PAD has gone through important

innovations over the past several decades with the widespread

use of exercise, antiplatelet therapy, and statin medications.

However, many of the recommendations for patients with

PAD were derived from subgroup analyses of trials per-

formed in populations with other atherosclerotic disease

manifestations. Even aspirin, a class I level of recommenda-

tion A therapy used in the treatment of PAD, has not been

demonstrated to decrease cardiovascular events in the settingof PAD. There are considerable gaps in knowledge regarding

the optimal treatment of PAD patients with claudication and

CLI in comparison with patients with atherosclerotic disease

in other territories. Current need for improvement in PAD

patient outcomes include (1) PAD-focused systemic therapies

designed to reduce the risk of ischemic events in the target

population, and (2) continued development of limb-specific

therapies, particularly in CLI.

ConclusionsDespite the paucity of PAD-specific limb and systemic thera-

pies, PAD patients are at very high risk for cardiovascularevents and impaired quality of life and should therefore be

treated aggressively. Until additional prospective, random-

ized trials are performed in this population, patients should be

treated with strategies based on current recommendations for

other manifestations of atherosclerotic disease. Current phar-

macological options include cilostazol for claudication but

little else to recommend as other claudication therapies or

medical approaches to CLI.

DisclosuresDr Hiatt has received grant support to his research institution (CPC

Clinical Research, a nonprofit affiliate of the University of Colorado)

from Sanofi-Aventis, AstraZeneca, Sigma Tau, and Aastrom. DrBerger has received grant support from AstraZeneca.

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KEY WORDS: angiogenesis antiplatelet therapy arteries treatment

vascular disease





11/11

Jeffrey S. Berger and William R. HiattMedical Therapy in Peripheral Artery Disease

Print ISSN: 0009-7322. Online ISSN: 1524-4539Copyright © 2012 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulationdoi: 10.1161/CIRCULATIONAHA.111.033886

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