Current Drug Targets - Cardiovascular & Hematological Disorders - Volume 4, Issue 3, 2004

Peripheral arterial disease is a common disease in adults and its complications take a great toll in terms of quality of life and treatment costs. As healthcare budgets have taken up more of the economy, and as employers and patients have become concerned about the escalating costs of healthcare, we have entered an era in which individual doctors must become concerned about the costs of a service relative to its benefits. The purpose of this article is to review the literature on the pharmacoeconomics of the diagnostic and therapeutic procedures for peripheral arterial disease. It emerges that peripheral arterial disease places a great burden on healthcare systems and on society as a whole. Some of these costs, including indirect and intangible costs (i.e. those related to lost productivity, and reduced quality of life, respectively) could be reduced if the condition were to be recognized and correctly treated at an early stage.

The term peripheral arterial disease (PAD) is often used to describe atherosclerosis involving the arteries supplying the lower extremities. Potentially modifiable factors that predispose to the development and progression of both symptomatic and asymptomatic PAD include smoking, diabetes mellitus, hyperlipidemia, and hypertension. Since the same risk factors for PAD predispose to the development of systemic atherosclerosis, identification of PAD increases the likelihood of coexistent coronary heart and cerebrovascular disease. Even after adjustment for risk factors, PAD appears to increase the risk for ischemic manifestations involving these other vascular territories with about a 2-fold increase in myocardial infarction and perhaps stroke. The most dramatic consequence of PAD is impaired survival with a 2- to 3-fold increased risk of 5- to 10-year mortality. While the adverse cardiovascular and cerebrovascular complications are highest for persons with more severe PAD, there is still a significant risk in persons with mild and even asymptomatic disease. The focus in the management of PAD should be on early diagnosis and efforts to reduce the risk of adverse events including risk factor modification and antiplatelet therapy.

The term critical limb ischemia refers to a condition characterized by chronic ischemic at-rest pain, ulcers, or gangrene in one or both legs attributable to objectively proven arterial occlusive disease. Critical limb ischemia implies chronicity and is to be distinguished from acute limb ischemia. Its incidence is approximately 500 to 1000 per million year, with the highest rates among older subjects, smokers and diabetics. The rate of primary amputation ranges from 10% to 40%, and was performed only when no graftable distal vessels were present, or in neurologically impaired or hopelessly nonambulatory patients. Contrarily, in some highly specialized and aggressive centres about 90% of patients with CLI had an attempted revascularization. Furthermore, patients with critical limb ischemia have an elevated risk of future myocardial infarction, stroke and vascular death, 3-fold higher than patients with intermittent claudication. Therefore, due to its negative impact on the quality of life and the poor prognosis both in terms of limb salvage and survival, critical limb ischemia is a critical public health issue.

Peripheral arterial disease is a major manifestation of systemic atherothrombosis that affects a large segment of the adult population. The major treatment goals for this population are to address the marked increase risk in cardiovascular events and then secondarily to treat the disability and reduced exercise tolerance. The primary goals for treating the limb symptoms of PAD are to improve functional capacity, exercise performance and qualify of life. Exercise training in a formal setting, revascularization with angioplasty and cilostazol all have proven efficacy. In addition, there is a major interest in developing new pharmacologic therapies for claudication. Prostaglandins have been utilized for critical leg ischemia for decades, but recent trials have not demonstrated any role for these drugs in treating claudication. Carnitine and its derivatives (propionyl-L-carnitine) have been shown to improve treadmill exercise performance and quality of life. These drugs also have an excellent safety profile. A final promising class of drugs is statins that not only reduce the increased risk of ischemic events but also appear to improve claudication symptoms.

Peripheral arterial disease (PAD), when accompanied by claudication, is a disabling disease that affects 12 percent of the population of the United States (US). PAD is associated with increased mortality as well as decreased functional status and quality of life. Smoking cessation and treatment of diabetes are key aspects of risk factor modification for the PAD patient as well as controlling other cardiovascular risk factors. Typically, only the most severely diseased patients with PAD receive surgery for the indication of claudication and other therapeutic options are being sought. Exciting developments are taking place in the area of drug development for instance. The benefits of a supervised walking exercise program have been consistently demonstrated in persons with PAD and therefore, exercise rehabilitation constitutes an important form of therapy for these persons. Unfortunately, in the US, exercise rehabilitation is not always reimbursed which may lessen its utility presently. All therapies which are used to treat claudication should incorporate measures of functional status and quality of life in addition to treadmill walking in order to ascertain the benefit of a given treatment for patients with PAD.

Patients with threatening ischemia of the lower extremities constitute a steadily increasing patient population owing to the increasing age of the general population and the growing incidence of diabetes. The goals of treatment for patients with critical limb ischemia (CLI) are pain control, wound healing, limb salvage, improvement of quality of life and reduction of overall cardiovascular risk. A high proportion of patients with CLI have coexisting diseases, mainly cardiovascular and renal disorders. The purpose of this article is to summarize non-invasive treatment options in patients with CLI and to critically review the results of landmark investigations dealing with conservative therapy for chronic critical limb ischemia.

The two main causes of peripheral arterial occlusion (PAO) are embolism and thrombosis. Surgical treatment of acute limb ischemia, because of related complications, has a 30-day mortality rate of 15% to 25%. Intra-arterial thrombolysis for lower extremity ischemia is a well-accepted and frequently used technique. It may offer definitive treatment without the need for major surgery in a significant series of patients with acute occlusion of a native leg artery or a by-pass graft. Thrombolysis can offer several potential advantages when compared with surgical therapy. Thrombolytic agents include streptokinase (SK), urokinase (UK), pro-UK and recombinant tissue plasminogen activators (rt-PA-Alteplase and r-PA-Reteplase). All these agents induce a systemic fibrinolytic state. Three prospective randomized trials, ROCHESTER, STILE, and TOPAS, which compared thrombolytic therapy with traditional surgical revascularization for lower limb ischemia, have recently been published. They suggest that thrombolysis, as an initial therapy, reduces the risk of subsequent surgery and improves limb salvage for patients with PAO. Using this approach, the underlying lesions can be identified and treated by transluminal balloon angioplasty or stenting, or by elective surgical revascularization. However, severe bleeding is still a non rare complication of intra-arterial thrombolysis and the risk of intracranial hemorrhage is 1-2%.

Peripheral arterial disease (PAD) due to atherosclerosis, although frequently ignored in clinical practice, results in significant cardiovascular morbidity and mortality and may progress due to uncontrolled atherosclerotic risk factors. Although treatment of claudication symptoms is important for improved lifestyle, treatment of risk factors will prolong life. Smoking cessation, blood pressure control, lipid modification and strict control of diabetes mellitus will reduce the risk of both macro and micro vascular disease progression. Risk factor modification in conjunction with antiplatelet treatment results in decreased heart attack, stroke and peripheral vascular events in patients with PAD.

Antiplatelet therapy significantly reduces the incidence of vascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with peripheral arterial disease (PAD) and intermittent claudication, in patients undergoing peripheral grafting, in patients undergoing peripheral angioplasty, and in patients with carotid disease. Aspirin, aspirin plus dipyridamole, ticlodipine, and clopidogrel have been shown to be efficacious in the treatment of PAD. Data from the Clopidogrel versus Aspirin in Patients at Risk for Ischaemic Events (CAPRIE) trial demonstrated in 11,592 patients with PAD that patients randomized to clopidogrel 75 mg daily had a 24% significant (p=0.0028) reduction in vascular death, nonfatal myocardial infarction, and nonfatal stroke than patients randomized to aspirin 325 mg daily. These data favor the use of clopidogrel in patients with PAD.

Peripheral arterial disease (PAD) is an index of systemic atherosclerotic disease and is associated with a high incidence of atherothrombotic complications in coronary, cerebral and peripheral arteries. While antiplatelet agents have been extensively evaluated and shown to be effective in reducing the risk of ischemic vascular complications in PAD, few randomised controlled trials have compared the effects of antiplatelet agents with oral anticoagulants in PAD. Oral anticoagulants have been shown to be superior to aspirin only for the prevention of infrainguinal bypass occlusion of venous grafts in case the bypass is at high risk for occlusion. The effectiveness of oral anticoagulants in reducing vascular morbidity and mortality is still uncertain. However, the reduction of ischemic events by oral anticoagulants is associated with an increased risk of bleeding. As a result, oral anticoagulants have a limited role in patients with symptomatic PAD.

Atherosclerosis is the most common cause of peripheral arterial disease (PAD). Interventional procedures are the first treatments proposed for most PAD patients. Balloon angioplasty alone may offer good immediate results; however, has it been proposed that the addition of stents improves the procedural success of angioplasty and extends its application to more types of lesions. Isolated aortic lesions are relatively rare, and the indications for stent placement have not been established. Percutaneous transluminal recanalization of chronic iliac occlusions remains controversial. However, results of recent studies have been encouraging, with initial technical success rates greater than 90%, low complication rates, and good long-term results. About the use of stent in atherosclerotic lesions involving iliac arteries and upper region of femoral arteries, we think that it is feasible. Differently, for the lower region of the femoral artery and for the popliteal artery, the results on the use of stents are controversial. More difficult is the therapy of infrapopliteal arteries disease in which perhaps the best option is medical therapy. The Transatlantic Inter-Society Consensus Group summarized the results of femoropopliteal stenting as follows: in a comparison of 11 trials involving femoropopliteal artery stenting in 585 patients, the primary patency rate was 58% at 36 months. For percutaneous transluminal angioplasty, the patency rates were 51% at 36 months. Although the results are satisfactory in femoral lesions, especially in stenoses shorter than 10 cm, they are less favorable both in longer femoral lesions than in the popliteal artery, where the results were worst. Large clinical series after angioplasty of lower limb arteries have confirmed the clinical and economical impact of restenosis: its rate varies in a range between 30% and 50%. The restenosis after stent deployment is the result of neointima formation; therefore, the interest of investigators turned towards an agent to suppress neointimal growth and restenosis after stent deployment, as Sirolimus and/or Taxolo. The first multicenter, randomized study, evaluating the 6-month outcomes of drugeluting stent implantation in long-segment obstructions of the superficial femoral artery, was SMART trial, published in 2002. This is the first trial to show that controlled drug release is also feasible using a selfexpandable nitinol stent platform. The results at 6 months demonstrate inhibition of in-stent neointimal proliferation, reflecting a trend toward a reduction in late loss.

Peripheral arterial disease (PAD) is an important manifestation of systemic atherosclerosis that is characterized by obstruction of the arteries in the lower limbs. Experimental and epidemiological studies suggest a key role for oxidative stress in initiation and progression of the atherosclerotic process. The results of these studies provided a good basis for interventional trials with antioxidants, particularly with vitamin E, but the findings were conflicting. In this paper we review the observational and interventional studies with antioxidants, and ask whether vitamin supplementation should be recommended for PAD patients.

In the last decade, studies of the biological mechanisms underlying angiogenesis, i.e. the development of a new vasculature from pre-existing blood vessels, have suggested a new approach to peripheral obstructive artery disease based on the treatment of ischemic tissues with angiogenic growth factors. As demonstrated by experimental studies in animal models, a therapeutic effect can be reached as the newly formed vascular network, functioning as a biologic by-pass, restores a normal blood supply to the ischemic territories. New techniques of gene therapy proved effective in reaching sustained concentrations of angiogenic factors in the target tissues. This review concerns the pre-clinical background and the results of the early clinical trials of angiogenic gene therapy, which have shown the safety and feasibility of this new approach.