Peripheral Arterial Disease: Novel Therapeutic Approaches


Overview of Peripheral Arterial Disease (PAD)

Peripheral arterial disease (PAD) is most frequently seen in the older patient, often in association with diabetes and is related to acute or chronic reduction in blood flow to the legs. The prevalence of PAD is difficult to measure because many of the early symptoms go unnoticed by patients and are considered a normal part of aging. In general, PAD is the result of a constriction or blockage of arteries in the legs. Chronic PAD is estimated to affect 15% of people over 70 years of age and up to 20% of people over 80 years of age. The onset of PAD is rare in women before 50 years of age and subsequent rates increase with age. Smoking is the strongest known risk factor across the world for the development of PAD with risk being two to four times that of nonsmokers. The smoking and rates of various vascular events in people with PAD are higher in developing Asian countries compared to North America, one would expect that global rates of PAD and its associated diseases will increase substantially given the strong correlation between smoking and PAD. Diabetes is the second most significant risk factor and is the leading cause of PAD in the developed and developing countries. Randomized controlled trials and observational data have shown that the control of lipids and blood pressure, and lifestyle changes can prevent and slow the progression of PAD. High saturated fat intake, high homocysteine levels and the metabolic syndrome have been indicated as potential risk factors for PAD but their independent association is yet to be established.

Prevalence and Risk Factors

The disease is greater in men compared to women. The prevalence of symptomatic PAD is greater in adults over 50 years of age, with estimates as high as 15% in adults over the age of 70. The higher the age, the greater the incidence of this disease is. In women, the prevalence is also estimated to be frequent in the above 50 age group, although there is lesser prevalence compared to men. This is explained by the fact that the female hormone, estrogen, may delay the development of atherosclerotic disease. Also, women who have PAD appear to have a more benign course than men with similar disease severity.

Our second part is about the prevalence of this health problem and what leads to its occurrence. The incidence of this disease increases with age. About 50% of the patients are known to be about 65-75 years. Many of the patients will have multiple risk factors and coexisting cardiovascular disease. The main and important risk factor is cigarette smoking. Smoking increases the risk of getting PAD and has been shown to increase the progression of this disease. The risk is directly proportional to the number of cigarettes smoked. Patients with cardiovascular disease who smoke are urged to quit in order to control and prevent the progression of this disease. Diabetes mellitus patients with PAD have a higher risk of morbidity. They also have a poor prognosis due to a higher rate of coronary and cerebrovascular disease. The disease in this group of patients also progresses faster and the re-occlusion rate post-intervention is also higher. This is due to their coexisting microvascular disease.

Current Treatment Options

Current treatment options for patients with PAD can be discussed in terms of relief of symptoms, halting disease progression, and prevention of vascular events. Managing cardiovascular risk factors is important in all patients, particularly in the elderly and in those with intermittent claudication. In addition to improving symptoms, aggressive management of risk factors is likely to improve the life expectancy of patients with PAD. Control of hypertension and diabetes is of proven benefit. Blood pressure reduction in those with hypertension, using ACE inhibitors, is of benefit in all patients with PAD. Statins reduce cardiovascular morbidity and mortality in patients with, or at risk of, cardiovascular disease, including those with intermittent claudication. Antiplatelet therapy and anticoagulation are also discussed in the context of relief of symptoms and prevention of vascular events. There is good trial evidence to support the use of antiplatelet therapy with aspirin in patients with symptomatic lower extremity PAD for the prevention of myocardial infarction, stroke, and vascular death. Clopidogrel appears to be more effective than aspirin in the prevention of vascular events in patients with established cardiovascular disease and normal lipid levels. The CURE trial also included a subgroup with PAD and showed benefit with combined aspirin and clopidogrel, although the risk of bleeding was increased. Further trials are needed to define the most appropriate antiplatelet regimen. High-intensity warfarin anticoagulation with a target INR of 3-4 is more effective than aspirin in the prevention of vascular events but carries a higher risk of bleeding. It may be considered in patients with PAD who have comorbid conditions that predispose to thrombosis, such as atrial fibrillation, or those with atherothrombotic disease of other vascular beds.

Novel Therapeutic Approaches for PAD

The today has investigation will evaluate gene angiogenesis with respect to its safety and effects on clinical endpoints in developing patients with that’s limb ischemia. This research has the potential to provide meaningful treatment options for those with PAD at all levels of disease severity.

One of the most favored gene therapy methods for therapeutic angiogenesis in PAD is delivering pro-angiogenic genes to increase growth factor expression in a patient’s own ischemic tissue. This is popular because it can potentially stimulate sustained growth factor expression that is required to drive new vessel growth from a single application of therapeutic agent. There is also optimism that this method will be effective and safe, based on what has been learned from protein-based methods. Gene angiogenesis will require sustained and overexpression of growth factor to be dependably efficacious in stimulating new vessel growth in a patient’s ischemic limb. This technique has been tested with a variety of growth factors and cytokines with promising results in preclinical models and early-stage clinical trials.

Although a variety of growth factors and cytokines have been shown to have angiogenic properties in animal studies, only a select few have been tested in human clinical trials with mixed results. Steps toward gene therapy Many of the early studies investigated direct protein delivery via recombinant protein injection or protein overexpression using a variety of viral and nonviral gene transfer methods. There are several consensus points from early-stage PAD gene therapy trials. First, recurrent pro-angiogenic protein delivery has not been effective in stimulating a sustained and clinically meaningful change in blood vessel growth in ischemic tissue. And secondly, protein overexpression by in vivo gene transfer has been shown to be safe; however, its success has been insufficient for many investigational angiogenesis therapy products to lead to a phase I trial. This has led to refocusing of efforts from protein-based to gene-based therapy.

The promise of angiogenesis therapy began with the laboratory research that laid a cornerstone of principles for therapeutic angiogenesis in the late 1980s and early 1990s. Therapeutic angiogenesis, the stimulation of growth of new blood vessels from preexisting ones in organ or tissue with inadequate blood supply, is a strategy that could potentially change the treatment of PAD. Conventional revascularization techniques such as bypass surgery and angioplasty depend on the presence of viable conduit vessels to be effective. No option currently exists for patients who are not candidates for these procedures, a population that includes a significant number of those with critical limb ischemia. There is also a need for additional approaches that can be used as an adjunct to conventional revascularization therapies, especially for those with diffuse multilevel disease that is not amenable to surgical or catheter-based approaches. Therapeutic angiogenesis could address all of these issues. It could also potentially provide a more durable and minimally invasive alternative to conventional revascularization techniques for the treatment of claudication if new vessel growth could be sustained with a single treatment that would result in a long-lasting improvement in blood flow to the affected limb.

Peripheral artery disease (PAD) is almost always a result of atherosclerosis. The manifestations of PAD can be a formidable challenge to the clinician. Although considerable advances have been made in medical, surgical, and endovascular therapies for those with intermittent claudication, the apparent limitations of current therapy for those with critical limb ischemia are largely because of a paucity of effective therapy that selectively stimulates blood vessel growth.

Gene Therapy

Gene therapy is the method of transferring genetic information into a patient’s cells and tissues as a therapeutic intervention. The potential for gene therapy to provide effective, long-lasting therapies for PAD is reflected by the fact that many of the causative events in peripheral atherogenesis are now known. Genes that are potential targets for therapeutic intervention in PAD include those that determine the production of vasoactive molecules, genes that impact lipid and lipoprotein metabolism, and haemostatic genes. Many animal studies have demonstrated the potential for gene therapy to be an effective treatment for PAD. The transfection of genes encoding for vasoactive molecules such as nitric oxide synthase and VEGF has been shown to increase angiogenesis and blood flow in models of hindlimb ischaemia. Similarly, the overexpression of EDRF, which is a potent vasodilator, has been shown to increase vasodilation, blood flow, and angiogenesis in ischaemic limbs. An exciting recent development is the potential for gene editing with CRISPR/Cas9 to correct genetic mutations related to PAD, although this is still very much at the experimental stage. Although these studies are promising, the translation of gene therapy from animal experiments to clinical trials has been slow. Issues over safety, durability of the therapeutic effect, and the perceived lack of commercial interest in developing gene therapies for PAD have all been barriers to progression. However, the increasing understanding of the genetic basis of PAD and developments in gene editing techniques mean that gene therapy remains a very promising treatment for the future.

Stem Cell Therapy

The use of stem cell therapy as a novel therapeutic approach for PAD is being heavily investigated in both preclinical studies and early clinical trials. One of the main reasons stem cell therapy is considered an attractive option as a treatment for PAD is due to the poor prognosis for patients resulting from the prevalence of co-morbid conditions which make both surgical and endovascular revascularization therapies high-risk treatment options. Bone marrow mononuclear cell (BM-MNC) therapy has a wealth of clinical evidence in the treatment of myocardial ischemia and has thus led to an explosion of research aimed at using similar treatment for peripheral arterial disease. The PROVASA trial was a randomized double-blind placebo-controlled clinical trial comparing the use of BM-MNC therapy versus placebo in patients with critical limb ischemia which showed that the treatment was well tolerated and associated with significant improvement in amputation-free survival and wound healing. Similar studies have since shown the safety and efficacy of BM-MNC therapy in patients with critical limb ischemia or severe claudication.

Pharmacological Interventions

Deferoxamine is an iron chelator that up-regulates the transcription of hypoxia-inducible factor-1 (HIF-1) and promotes angiogenesis. HIF-1 is a transcription factor that is activated in response to hypoxia and controls the expression of genes that are essential for the formation of new blood vessels. It is degraded in normoxic conditions in a process involving prolyl hydroxylase and an iron-dependent step. Depletion of iron prevents prolyl hydroxylase from acting, leading to increased levels of HIF-1. Deferoxamine has been shown to up-regulate HIF-1 and VEGF in both animal and human studies. An alternative to deferoxamine is gene therapy with HIF-1 and VEGF. An HVJ-liposome with a plasmid including HIF-1 and VEGF was intramuscularly injected into patients with CLI. Although it was safe, there were no significant effects on the primary endpoints in this small-scale trial. HGF is a multifunctional growth factor that promotes growth, motility, and morphogenesis of various cells and has a positive angiogenic action. It also up-regulates several angiogenic growth factors such as VEGF and has anti-apoptotic effects on endothelial cells. A phase I and II study were conducted in Japan which involved injecting naked HGF plasmid into the muscles of patients with CLI. Although it was safe and there was an improvement in the ABI and some angiogenic factors, there were no improvements in the clinical symptoms of CLI.

Medical therapy is the cornerstone for the treatment of patients with symptomatic PAD. It should be noted that aggressive control of risk factors is essential for all patients with PAD. This includes smoking cessation, lowering of blood pressure, and aggressive cholesterol reduction. The Antiplatelet Clopidogrel Trials to Reduce Atherothrombotic Events (CHARISMA) showed that clopidogrel was not significantly better than aspirin for the primary endpoint in PAD patients. However, the warfarin and clopidogrel combination appeared to have a beneficial effect for the secondary endpoints in PAD patients. The combination of clopidogrel and aspirin will be tested in the ongoing Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial. The management of PAD patients often requires a multi-faceted approach. Claudication and rest pain can often be managed with cilostazol, a specific PDE III inhibitor, which leads to increased cAMP levels and subsequent vasodilation and inhibition of platelet aggregation. Surgical or catheter-based revascularization is often not possible in patients with CLI due to high surgical risk and co-morbidities. These ‘no-option’ CLI patients can often be managed with prostanoids, which are potent vasodilators and inhibitors of platelet aggregation. Although the best known is iloprost, which is administered intravenously, it should be noted that prostanoids such as alprostadil are also effective and can be given orally. The BEST trial showed that beraprost, a stable oral prostacyclin analog, significantly increased pain-free walking distance compared to placebo. Simulation of angiogenesis is a novel alternative or adjunctive strategy in PAD. Revascularization involves distending the lumen through angioplasty and placing a scaffold, the stent, to maintain patency.

Non-Invasive Treatments

The patients with peripheral arterial disease who are considered poor candidates for revascularization procedures necessitate a trial of non-invasive treatment. There are several medications and mechanical treatments that can help symptoms and might improve an individual’s ability to walk. Supervised exercise, cilostazol, and pentoxifylline have been shown to improve walking distance in selected patients. The benefit of antiplatelet therapy in PAD patients is well established, therefore it is a reasonable addition or initial therapy for claudication. Although cholesterol lowering drugs do not improve symptoms of intermittent claudication, they are indicated for claudicants with hyperlipidemia for the prevention of cardiovascular events. To date, there are no pharmaceutical agents that have been shown to significantly alter the natural history of atherosclerotic disease in the peripheral arteries. The recently reported negative results of the “IELFT Study” which tested the hypothesis that aggressive low-density lipoprotein cholesterol lowering with the ileofemoral stent would reduce cardiovascular events and ultimately improve limb outcomes in patients with lower extremity peripheral arterial disease, offers a cautionary tale that proposed mechanism based interventions can have unexpected outcomes.

Advancements in PAD Research

In the past 20 years, the NIH has funded analyses to understand the trends within the funding for various diseases. In 2001, Murphy et al. found that NIH funding for PAD was at $245 million. Cardiovascular diseases, as a whole, had increased by 107% from 1992. During this same period, NIH funding for PAD has only increased by 31%. This trend is disturbing since PAD continues to represent a growing public health risk and the economic burden of PAD is expected to rise due to projected increases in the prevalence of disease. In addition, the percentage of NIH funding for PAD continues to decline. In 2008, Murphy et al. found that the 2006 NIH funding for PAD was only 0.65% of the total funding allocated for the 11 cardiovascular diseases defined by the American Heart Association. This trend in funding is disproportionate to the impact that PAD has on healthcare and marks an ongoing disparity between NIH funding for PAD and other cardiovascular diseases. Obtaining funding for PAD research has been challenging, and investigators in the PAD field will need to engage new research strategies that provide the scientific evidence required to increase NIH support for PAD research. Although funding has been limited, advancements in PAD research have been steadily increasing and show tremendous potential for significant improvements in patient care. Learning from the mistakes and missed opportunities in previous PAD research, it is essential to integrate proposed mechanisms of research support with the latest advancements in PAD research. By doing so, we can bridge the gap between new discoveries in PAD and transition these findings into beneficial applications for patient care. With the rising prevalence and economic burden of PAD, obtaining new discoveries and a steady flow of funding in PAD research has become increasingly important to prevent further stagnation of public health and continued advances in patient care.

Emerging Technologies

High hopes for stem cell and gene therapy will be tested by the future FRACTAL trial. This will be an international, multicenter, randomized controlled trial comparing standard best medical care to the combination of leg angioplasty and injections of bone marrow cells containing a concentrated amount of the growth factor granulocyte-colony stimulating factor.

Stem cell therapy has also shown potential in the induction of therapeutic angiogenesis. Stem cells may also be used to create a “biological bypass graft” in which autologous or allogeneic cells are fashioned into a conduit for blood flow by tissue engineering in a bioreactor. Although this method is still in its early stages and only seen in animal models, it holds promise as an alternative to surgical bypass.

Gene therapy involves the introduction of genetic material into cells to fight or prevent disease. This strategy is being explored for PAD treatment by targeting growth factor genes, which encourage the formation of new blood vessels. A recent systematic review of gene therapy for PAD showed that it was superior to medical treatment for inducing ulcer healing and improving symptoms of intermittent claudication. However, the studies reviewed were small and at moderate to high risk of bias, demonstrating the need for more research in this area.

Emerging technologies provide alternative methods for the treatment of PAD by focusing on PAD-related ischemia. One of the most exciting prospects for treating limb ischemia is the use of gene therapy and stem cell therapy. Both methods have shown promise in the laboratory, and early phase clinical trials have yielded some encouraging results.

Targeted Drug Delivery Systems

Some drug delivery systems may lack the ability to direct drugs to specific areas within the vessel wall, but the concept for local therapy is still promising. One such drug with direct ACE inhibitory effects, DDPM-53, was delivered to the adventitia of rabbit aorta using a special catheter delivery system. This drug was particularly effective after balloon injury and significantly reduced neointimal formation compared with local delivery of other ACE inhibitors to the media and systemic oral delivery of the drug. Hormone and antioxidant therapies have also been more effective when delivery to the arterial wall has been local. These include estradiol therapy delivered to the media in OVX monkeys and a novel antioxidant from green tea catechins delivered to the adventitia in animal models of restenosis.

Today, advances in angioplasty and stenting are approaching the point where it appears we may have devices and techniques that are able to avoid the recurrent restenosis seen in previous experiences over the past 20 years. The concept that has evolved revolves around the development of drug-eluting stents and other platforms for local drug delivery to the arterial wall. Some of the advances are relatively simple in concept, such as the use of porous balloon catheters where the balloon has holes in it through which the drug is absorbed and then released in a local fashion. More complicated methods are being developed, such as catheters that can strip endothelial cells from the vessel wall and create temporary holes in the elastic membrane, allowing for gene and drug delivery to the medial smooth muscle cells and the adventitial fibroblasts. These later methods are still in development phases, and it is unclear as yet to what extent they will be used in clinical practice.

Biomarkers for Early Detection

The MMPs are a family of enzymes that have been implicated in the pathogenesis of many cardiovascular diseases. Work by our group has identified elevated circulating levels of MMP-9 to be associated with prevalent PAD and to be an independent predictor of cardiovascular events in PAD patients. This work was the stimulus for a large scale prospective study aimed at identifying novel risk factors for PAD progression and cardiovascular events in PAD. An understanding of the enzymes involved in ECM remodeling in PAD and their associated TIMP inhibitors may identify new targets for therapy and lead to markers of disease activity in PAD.

Currently, the clinical diagnosis of PAD is based on non-specific indicators such as intermittent claudication. There is recognition of the need for more sensitive ways to identify patients in the early stages of the disease. Confirmatory tests such as ABI and angiography are impractical for large scale screening. There is much interest in identifying biomarkers in the blood or urine of patients that may be indicative of early stages of PAD. Several studies have found an association between high sensitivity CRP and PAI-1 levels and prevalent PAD. Other possible biomarkers identified include homocysteine, reactive oxygen species and cytokines. Most of these studies are small scale and the identified biomarkers will require validation in large scale clinical studies. Others are assessing genetic markers for PAD. The identification of validated markers for early PAD would greatly facilitate large scale screening of high risk patients and allow earlier treatment which may alter the course of the disease.

Personalized Medicine Approaches

With the advent of the Human Genome Project in 2003, the science of genetics has advanced at a rapid pace. The ability to identify specific genetic variations has led to a new era in medicine, one that targets an individual’s specific ailment. With 20 to 30% of cases of intermittent claudication being unresponsive to conventional treatments, and no medical treatments available for advanced stages of PAD, the implementation of personalized medicine may yield more significant findings than those in the past. The availability of genome data enables the identification of genetic variations that predispose individuals to certain diseases, alter the course of disease and its severity, as well as the individual’s response to specific medications. This information may be used to determine those who are at greater risk for PAD and its complications and may also bring insight into the often slow progression of the disease. Those at greater risk with genetic predispositions to more rapid disease progression, or individuals who are more likely to develop severe forms of PAD, may be identified as candidates for more aggressive treatments. Alternative therapies may be available for those who have specific response-altering genetic variations. An example of this would be the use of specific drugs that alter lipid metabolism for the prevention of atherosclerosis in those who have genetic variations that cause adverse effects from standard cholesterol-lowering medications. With a greater understanding of the mechanisms underlying PAD, a wide array of genetic variations has the potential to be identified. The information gained from such discoveries can be organized into a comprehensive database detailing numerous genetic variations and their correlation with PAD. This information can then be used to develop a tool for risk assessment and prediction of disease outcome. These benefits would greatly aid in the prevention of PAD, as the identification of risk factors specific to individuals may lead to the implementation of preventative measures in those who are at greatest risk, prior to the development of any symptoms.

Future Directions and Challenges

Finally, it is likely that new PAD treatments may be held to higher safety and efficacy standards than older treatments that are currently in practice. As such, it may become increasingly difficult for new therapies to prove superiority over placebo or active comparators or to justify their cost. These issues will require creative solutions and close collaboration between academia, industry, and regulatory agencies.

Second, the potential number of treatments for PAD may be too great for all to be tested in large randomized clinical trials or to be practical given modern healthcare economics. This reality may require better coordination between basic science and clinical research and early phase trials that are designed to efficiently screen promising new therapies.

First, it is likely that patients with PAD are a heterogeneous group with regard to the location, type, and severity of disease. An approach that is effective for one patient with intermittent claudication may not work for another with multi-level aorto-iliac and infra-inguinal stenoses and isolated systolic hypertension. Therefore, a major goal will be to match the right patient with the right treatment in a cost-effective manner. This will require not only the ability to identify patients who are most likely to benefit from specific treatments but also a better understanding of the natural history of PAD and improved classification systems.

Growing evidence regarding the cellular and molecular basis of PAD will lead to the design of new and more effective treatments in the future. It is likely that a variety of different therapies will be employed, ranging from those designed to prevent the development of atherosclerosis in at-risk individuals, to those aimed at halting the progression of the disease, to those intended to interrupt the sequelae of chronic critical limb ischemia. Regenerative medicine strategies are also likely to become increasingly important as a means of restoring perfusion and function in ischemic limbs. This diverse array of potential treatments offers great promise, but also presents a number of challenges.

Potential Benefits and Limitations of Novel Therapies

Comparative effectiveness studies are now increasingly used to address similar questions in medical practice. The methodological approaches used in these studies may be useful in comparing the relative benefits of symptomatic therapy in patients with intermittent claudication. Because of the large number of patients with PAD and the substantial costs associated with their care, novel therapies for PAD face increasing scrutiny from third-party payers. Economic analyses can help to identify the most cost-effective therapies and the patient populations in which they should be targeted. These analyses can also provide insight into potential limitations to care resulting from reimbursement policies. High-quality evidence on the benefits of new therapies is necessary to ensure optimal care for patients with PAD. It is our responsibility as researchers and clinicians to make certain that this evidence is generated.

New treatments require new strategies. Unfortunately, our lack of understanding of the natural history of PAD and of meaningful clinical endpoints to evaluate new therapies severely limits our ability to compare the relative benefits of individual therapies. Placebo-controlled trials provide the highest level of evidence for determining the efficacy of a new therapy, but they may be difficult to justify for evaluating symptomatic therapies in patients with advanced PAD. There is a compelling need to elucidate what therapies are most effective at altering the natural history of PAD and preventing limb loss. A careful assessment of alternative study designs that can provide valid comparisons of various therapies is also needed.

Regulatory Considerations

Although the study was successful, the costs associated with meeting such endpoints can be off-putting to device manufacturers considering new technologies. Finally, any novel therapies which are intended to compete with existing ones must take into account the pace of medical progress and changes in clinical practice. This could further increase the research and development timelines and costs for future PAD therapies.

As such, demonstrating a clear benefit over placebo or current standard therapy can be difficult and costly. Given the attrition rates of drugs and devices moving through the development pipeline, meeting these endpoints can be a formidable task. In the case of cilostazol, it took 13 years from the drug being first synthesized to passage of the aforementioned trial, and longer still to obtain FDA approval for intermittent claudication indication in 2011! Similar to drug therapies, device approval for PAD is also determined by demonstration of safety and efficacy. The pivotal study for example, randomized 124 patients to angioplasty vs stenting for iliac artery lesions and had three co-primary endpoints which included objective measures of lesion success and patency at 9-months.

Demonstrating improved clinical outcomes and reduced cardiovascular events often requires large and lengthy phase III trials. Recent examples include the negative studies; both aimed at improving cardiovascular and limb outcomes with cilostazol and clopidogrel respectively, yet neither demonstrated benefit over existing therapies. A further limitation is that the successful revascularization of limb ischemia is an increasingly common endpoint in trials of therapeutic angiogenesis and stem cell therapies. While endovascular and surgical revascularization procedures are relatively low risk compared with major amputation, they are technically demanding and are associated with significant placebo rates in blinded trials.

As patients with PAD present with a wide spectrum of symptoms and functional limitations, the potential for novel therapies to improve outcomes is enormous. However, regulatory approval for new drug and device therapies for PAD is at present complex, costly and time-consuming. In the US, for example, approval of new drug therapies for symptomatic PAD (including intermittent claudication and CLI) is contingent upon improvement in functional status and limb outcomes. The latter is commonly determined by time to claudication or pain-free walking, treadmill testing, ankle-brachial index and more recently, contrast-enhanced magnetic resonance angiography.

Patient Perspectives and Quality of Life

One of the great limitations of existing therapies for PAD is the fact that major advances in the treatment of claudication and critical limb ischemia have culminated in minimal improvement in patients’ QOL. These patients suffer both physically and mentally. They not only have limitations in their physical functioning, but they may also have social, emotional, and vocational problems. The SF-36 is a simple questionnaire that is widely used to assess quality of life. It has been used in many studies of PAD patients and has often confirmed that they have significantly impaired quality of life, especially in the physical domains. This impaired quality of life is similar to that of patients with other chronic diseases such as COPD, congestive cardiac failure, and angina. The only randomized trial of atherosclerotic disease therapy to use clinical events and quality of life as co-primary endpoints was the CORAL study of renal artery stenting. Quality of life was assessed by the SF-12 and was found to be markedly impaired in the renal artery stenosis patients but did not improve significantly in those that underwent stenting compared to those who were treated with medication. This illustrates the fact that despite high patient expectations, treatment to improve quality of life in PAD has often been unsuccessful. Although it is hoped that the novel therapies discussed in this article will ultimately improve quality of life by preventing complications of PAD, improving symptoms and increasing functional capacity, it is essential that they are actually assessed using established methodology to ensure that this is the case. Measures of quality of life are subjective and therefore it is important that they are always used in conjunction with objective endpoints such as functional capacity and symptom assessment.

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