Peripheral arterial disease has traditionally been considered a less serious manifestation of systemic atherosclerosis than coronary or cerebral vascular disease. Consequently, there has been a relative lack of emphasis on aggressive medical management of risk factors for peripheral arterial disease. However, evidence has emerged over the last two decades demonstrating that the prognosis for patients with symptomatic peripheral arterial disease is extremely poor. Furthermore, the functional impairment suffered by patients with intermittent claudication is comparable to that of patients with disabling symptoms from coronary artery disease. Finally, there is substantial overlap in risk factors and pathophysiological mechanisms between atherosclerotic diseases in the different arterial beds. The sum of these observations has led to a recent paradigm shift and an increased focus on aggressive reduction of cardiovascular risk in patients with peripheral arterial disease.
Peripheral artery disease is a common yet often underdiagnosed medical condition. Although it predominantly affects older adults, it is also increasingly encountered in the middle-aged population and in people with diabetes. In many cases, it leads to impaired functional status and reduced quality of life. Only a minority of patients with peripheral arterial disease experience limb symptoms, with an even smaller minority experiencing critical limb ischemia. However, patients with intermittent claudication are important to identify because these individuals have a higher risk of cardiovascular morbidity and mortality. The presence of peripheral arterial disease heralds a marked increase in the risk of heart attack and stroke.
Pharmacological Treatment Options
It is essential to aggressively reduce cardiovascular risk factors in patients with PAD. Dyslipidemia is an important and potentially modifiable risk factor for the development and progression of PAD. Epidemiologic outcomes data and subgroup analyses of large-scale clinical trials have established the benefit of statin therapy in preventing cardiovascular events in both primary and secondary prevention populations. Although the evidence is not as strong, it is reasonable to set a target LDL cholesterol goal of <100 mg/dL and use statins for primary and secondary prevention in patients with PAD. High-dose statin is considered reasonable in patients with PAD for the secondary prevention of myocardial infarction and stroke. There is no clear data for the benefit of lipid lowering with agents other than statins in patients with PAD. Angiotensin-converting enzyme inhibitors (ACE-I) have been shown to reduce cardiovascular events in patients with PAD. The HOPE trial showed that ramipril reduced cardiovascular events in patients with PAD and established the benefit of ACE-I in patients with a variety of cardiovascular risk factors. Despite these findings, ACE-I are often underutilized in patients with PAD.
Antiplatelet therapy is considered the mainstay of pharmacologic treatment. Aspirin has been shown to be effective in reducing cardiovascular events in many patient populations and continues to be the most commonly used antiplatelet agent. Ticlopidine and clopidogrel have been shown to be more effective than aspirin in reducing cardiovascular events in patients with PAD. Limited data suggests that cilostazol is more effective than aspirin in preventing restenosis following peripheral angioplasty, but it has not been shown to be more effective in preventing cardiovascular events in patients with PAD. Ticlopidine and cilostazol have both been shown to increase walking distance in patients with PAD. Combinations of antiplatelet agents are often used in patients with recent cardiovascular events or those at high risk of cardiovascular events, but increase the risk of bleeding and therefore must be used with caution.
Antiplatelet Therapy
The benefit of combined antiplatelet therapy with aspirin and clopidogrel was investigated by the CAPRIE trial, which showed that this produced a further 8.7% reduction in the risk of ischemic events compared to aspirin alone, but was associated with increased incidence of moderate bleeding. Simulation studies from this trial suggest that the absolute benefits of clopidogrel therapy are greater in patients with MI or cerebrovascular disease, and lower in patients with PAD. Hence physicians should consider the individual patient’s risk of ischemic events and their risk of bleeding from clopidogrel therapy when deciding to use this agent.
A recent meta-analysis of 16 secondary prevention trials involving over 55,000 patients estimated that the use of antiplatelet therapy (mostly aspirin) produced a 22% reduction in serious vascular events, a 25% reduction in non-fatal MI, and a 24% reduction in stroke. The absolute benefits in each case varied according to the risk of these events but the relative risk reduction was similar. Hence it is clearly evident that antiplatelet therapy can significantly reduce the incidence of major vascular events and is thus a fundamental treatment for those with PAD and increased cardiovascular risk.
The Prevention of Atherothrombotic Events Following Ischaemic Vascular Events (PAVE) trial was a randomised, double-blind study comparing the effect of aspirin on vascular events. This trial showed that daily aspirin doses above 100mg did not reduce the incidence of MI, stroke or vascular death compared to doses of 100mg or less, but were associated with increased risk of major or life-threatening haemorrhage. Hence lower doses of aspirin are indicated for prevention of vascular events.
The philosophy of antiplatelet therapy is to target the thrombotic component of disease which, theoretically, can eventually cause complete occlusion of a vessel. Aspirin is the most widely used agent for prevention of arterial thrombosis. By blocking the cyclo-oxygenase enzyme in platelets, aspirin inhibits the production of thromboxane A2, an inducer of platelet aggregation and vasoconstriction.
Lipid-Lowering Agents
The mechanism for statins is through HMG-CoA reductase inhibitors, which is the rate-limiting step in cholesterol synthesis. It also serves as a pivotal point for intracellular signals, whereby its inhibition is shown to exert vascular effects beyond LDL-C lowering. This includes plaque stabilization, improvement in endothelial function, and reduction in inflammation. A recently updated Cochrane review in 2013 analyzing data for patients with PAD has demonstrated a reduction in cardiovascular events and improved walking distance, however, with the limitations of few randomized trials and a small number of participants. These findings are also consistent with a sub-analysis from the Heart Protection Study, which demonstrates a reduction in major vascular events and revascularization in high-risk patients with various established atherosclerotic diseases. An interesting development has been the use of ezetimibe, which is a cholesterol absorption inhibitor. It serves as a complementary agent for further LDL-C lowering while being relatively well tolerated.
Lipid-lowering agents, namely statins, have become a staple in the management of patients with coronary artery disease, as well as patients with risk factors for coronary artery disease. This is primarily a result of the substantial evidence accumulated through large, randomized trials which support their use. Clinical trials such as the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, as well as the Scandinavian Simvastatin Survival Study (4S), have demonstrated a significant reduction in cardiovascular events, as well as an increase in long-term survival for patients with known coronary artery disease. These trials have paved the way for further research into the use of statins for other cardiovascular disease entities and their role in primary prevention.
Antihypertensive Medications
Antihypertensive medications are an essential therapy for hypertensive patients with peripheral arterial disease (PAD). Approximately three-fourths of hypertensive patients with PAD have blood pressure readings above 140/90 mm Hg. In Stage I of the thiazide-type diuretics are recommended for most patients with hypertension, including those with PAD. Low doses of chlorthalidone have been shown to reduce the progression of established claudication and to reduce the overall cardiovascular event rate in patients with PAD. Standard doses of antihypertensive medications may slow progression of claudication, but are likely to have a greater effect on preventing MI, stroke and cardiovascular related death. In the absence of comorbid indications, beta blockers and ACE inhibitors are considered first-choice medications for patients with concomitant PAD and coronary artery disease due to their cardiovascular protective effects. High dose beta blockers (three times daily) will be needed for many patients to prevent an adverse effect on claudication.
Vasodilators
Vasodilator therapy attempts to directly increase peripheral blood flow, and this has the potential to cause harm if underlying stenotic lesions compromise critical perfusion to end organs such as the brain, heart, and kidney. This is a particular concern with the use of oral and parenteral vasodilators, and studies of treatment for claudication with cilostazol and pentoxifylline have largely avoided adverse effects by routinely excluding subjects with coexistent cardiovascular diseases.
Vasodilator therapy represents a logical approach to the treatment of PAD. The benefit of vasodilator agents for those with claudication is based on the premise that increasing blood flow to ischemic muscle will improve function and limb status. It is generally agreed that vasodilators have little influence over the natural history of atherosclerosis, but they may ameliorate symptoms associated with luminal stenoses. The most widely used vasodilator is probably niacin, which has weak but consistent evidence of benefit for relief of claudication. Inositol nicotinate is a preferable formulation to nicotinic acid because it does not cause flushing. The quofen and clonidine in the treatment of intermittent claudication in a double-blind placebo-controlled trial showed no significant change in walking distance or ankle-brachial pressure indices, but a significant decrease in blood pressure, which required cessation of the study drug in 56% of patients.
Novel Approaches in Pharmacotherapy
Gene therapy is the thought that healthy genes can be put into cells that contain unhealthy genes. The new healthy genes will take over the old unhealthy genes. This is done by using a catheter with a small balloon on the end of it to insert the gene into the blood vessel. As the balloon inflates and deflates, pores are created in the cells and the gene is pushed into the artery. The catheter also releases a drug that will help the new healthy gene get into the cell and work its way through the blood vessel. Results from the first gene therapy experiment for peripheral artery disease in humans will be available in the near future. This experiment involves injecting a gene called vascular endothelial growth factor (VEGF) into the leg muscles of patients with a form of peripheral artery disease called critical limb ischemia. VEGF, a substance that stimulates the formation of new blood vessels, has shown promise for improving circulation in animal experiments. In this study, eleven medical centers in the US and Canada seek to determine whether one injection of VEGF can help alleviate pain and improve wound healing in patients with critical limb ischemia. Studies on gene therapy continue. Though it is a new technology and still has a long way to go, it can prove to be beneficial in the near future.
Gene Therapy
Gene therapy is administered to the patient through the use of viral vectors or non-viral vectors. The viral vectors are particularly efficient at delivering genes to the target cells; however, there are safety concerns, and they are tightly regulated. Several types of viral vectors have been investigated. In 2000, Vale and colleagues undertook the first human trial of gene therapy for PAD. They administered naked plasmid DNA encoding for Vascular Endothelial Growth Factor (VEGF) to six subjects with limb-threatening ischemia. Although the study showed that the method was safe and feasible, the growth factor was not produced in sufficient quantities to induce therapeutic angiogenesis. A subsequent study used an adenovirus vector encoding VEGF in 30 patients, which proved to be more effective.
Gene therapy involves the delivery of DNA which encodes therapeutic genes to the patient’s cells that can result in the expression of a functional or therapeutic protein. Therapeutic angiogenesis is a treatment strategy that has ignited widespread interest in the scientific community. It involves the administration of growth factors to stimulate the growth of new blood vessels from pre-existing collateral vessels. It has been shown to be an effective treatment for coronary artery disease and peripheral arterial disease. This has led researchers to investigate the potential of gene therapy as a means of inducing therapeutic angiogenesis. Over the past thirty years, significant progress has been made in the clinical application of gene therapy to cardiovascular diseases, and it is now well established as a potential treatment strategy. Pre-clinical studies investigating the efficacy of gene therapy for the treatment of PAD have shown promising results.
Stem Cell Therapy
There exists one ongoing and several planned trials of cell transplantation therapy in the United States and elsewhere. Although evidence of safety will take several years to accumulate, the evidence of preliminary efficacy may also become apparent in this time. Observational research quantifying long-term survival and morbidity in patients with peripheral arterial disease has demonstrated a benefit in cardiovascular outcomes amongst those receiving revascularization therapy. With these data in mind, there are tremendous potential cost savings to healthcare systems worldwide if cell transplantation therapy can lessen the need for expensive and complication-prone revascularization and amputation.
Kawamoto and Asahara presented the first of these trials at the American Heart Association in 2006. They intramuscularly injected bone marrow mononuclear cells (BM-MNC) and bone marrow mesenchymal cells (BM-MSC) in patients with limb ischemia from peripheral arterial disease. The primary end point of the trial was safety through 6 months, with several secondary end points including reduction in amputation and improvement in rest pain and ankle brachial index.
Stem cells have an enormous potential in the treatment of vascular disease. Early work has demonstrated their capability in vivo to differentiate into endothelial and smooth muscle cells, the primary cellular components of blood vessels. In a rabbit model of hindlimb ischemia, adipose-derived stem cells appeared to enhance perfusion and angiogenesis over a 40-day period. Based largely on these preclinical studies, several early phase clinical trials have been initiated.
Targeted Drug Delivery Systems
Fresh insights are required to adequately deliver drugs and therapeutic substances at the cellular or subcellular levels to effectively treat PAD. Conventional drug treatments for PAD with systemic delivery have been far from successful. Cilostazol and pentoxifylline are two examples of drugs that have not shown consistent clinical efficacy in improving maximum walking distance or promoting limb salvage in patients with PAD. Cilostazol is a phosphodiesterase inhibitor which inhibits platelet aggregation and has vasodilatory properties. Pentoxifylline has activity as a nonspecific phosphodiesterase inhibitor and increases red cell flexibility and decreases fibrinogen binding to red cells. Both of these drugs have a primary action on platelets and should, in theory, effect a reduction in cardiovascular events in PAD patients, although the positive effects seen with these drugs are minimal at best. Cilostazol is also associated with an increased risk of bleeding events and thus therapy is often not recommended. This example illustrates the need for targeted drug delivery systems in PAD, as it is likely that these drugs would prove more effective at reducing limb claudication symptoms and promoting limb salvage with local delivery to limb tissues. Cilostazol, in particular, is an ideal candidate for local delivery due to its many antiplatelet and vasodilatory properties, but due to its systemic administration with similar dosing to that of antiplatelet therapies, its full potential has not been realized.
Future Directions and Conclusion
Lastly, surgery and catheter interventions for both intermittent claudication and critical limb ischaemia are continuing to evolve. Endovascular procedures have become increasingly popular for revascularisation due to the minimally invasive methods and rapid patient recovery times. Evidence based trials comparing newer and older surgical and catheter techniques are required to ensure these prove successful for the long-term and there are no detrimental effects. Any comparison between surgical and medical interventions requires an effective and safe perioperative pharmacological regimen for antiplatelet, anticoagulation or lipid-lowering therapy. All these methods will require testing against standard care or current drugs so future pharmacotherapy research remains vital.
It is also important to address the high prevalence of PAD in patients with other cardiovascular and cerebrovascular disease. Studies in these patients often test medications that prove successful in CAD or cerebrovascular disease, on PAD patients though drug effects on limb and ankle brachial blood flow pressures are often minimal. This has previously led to under-treatment of PAD patients. Therefore it is important to see research into drugs specifically for PAD.
The clearest opportunities lie in new drugs and methodologies targeting lipids and lipoproteins. These have proved successful in the treatment of CAD and with the continuing growth in PAD patient numbers, future research in this area would be highly beneficial.
The goal of future direction in the treatment of PAD is how can we improve on what we have. It is not feasible to think new drugs are going to outperform current antiplatelet agents, nor practical to test all future drugs against placebo.
