The peripheral arterial disease (PAD) is one of the most common and the most important manifestation of systemic atherosclerosis. The disease progresses with aging regardless from gender (1, 2). After the age of 40 years, there is two- to three-fold increase in risk of PAD development in each decade. PAD is closely related to coexistence of risk factors for the atherosclerosis development: smoking, diabetes mellitus, hyperlipidemia and hypertension (2-4).

While PAD develops, risk of vascular and ischemic complications associated with myocardium, and CNS increases, as well as risk of other vascular death (5). It is estimated that in patients with PAD, comparing to the remaining population of the patients, there is three-fold increase in risk of any vascular death, and six-fold increase in risk of cardiac death (6). In this case, gender does not matter, and risk is still high despite absence of the ischemic heart disease in the past (7, 8). It has been proven that together with increasing intensity of the peripheral arterial disease measured by the ankle-brachial index, risk of myocardial ischemia, ischemic stroke, and other vascular death, proportionally increases as well (9, 10). The main purpose of pharmacological treatment is an aggressive modification of risk factors, which is extremely important in inhibiting development of the peripheral arterial disease, as well as in lowering risk of other vascular complications. Introduction of antiplatelet therapy together with ACE inhibitors provides significant benefits in reducing occurrence of undesirable cardiovascular events.

The most common manifestation of the peripheral arterial disease is the intermittent claudication. Conservative treatment includes smoking cessation at the beginning, and then supervised exercises and pharmacological therapy in order to stop progress of the disease as well as reduce risk of occurrence of the vascular events. The patients with critical peripheral arterial disease require surgical treatment in order to supply the limb with blood, which provides optimum conditions for treatment of the ischemic lesions. In such cases, pharmacological therapy is an adjunctive therapy for the first-line surgical treatment.

Very important in the group of patients undergoing surgical treatment is to prevent myocardial ischemia during perioperative course and to provide long-term protection from coagulation in the vascular graft. In order to achieve these goals, beta-blockers and acetylsalicylic acid should be administered in the perioperative course.

This article presents review of current recommendations regarding conservative therapy of the peripheral arterial disease, which purpose is to modify risk factors for cardiovascular complications and to increase walking distance. Conservative treatment should also include prevention of the disease progress, treatment of coexisting diseases, improvement in the limb blood supply, prevention of necrotic lesions, and treatment of skin lesions.

As it was mentioned before, the patients with PAD constitute the group of patients with significantly increased risk of the cardiovascular event occurrence. It should be taken into consideration that majority of these patients have no symptoms of the peripheral arterial disease, and half of them have not yet experienced the cardiovascular event. Medical history and preliminary clinical examination may result in underestimation of the actual number of patients with PAD. Cirkulation 2001’ published the article presenting positive correlation between coexisting PAD and the ankle-brachial index ABI ≤ 0.9 (11). Based on the article of A. Hirsch published in JAMA 2003’ (12), ABI measurement was recommended in all symptomatic patients, in all patients in the age of 60-69 years with coexisting risk factors for the cardiovascular disease, and in all patients in the age of over 70 years.

The article listed recommendations of Trans-Atlantic Inter-Society Consensus – its second edition (TASC II) (13), regarding diagnostics and treatment of the peripheral arterial disease. The article is a result of cooperation among fourteen scientific societies from Europe and North America involved in problems regarding vascular diseases.

The patients with PAD are frequently burdened with many risk factors for cardiovascular complications. Many broad-spectrum studies confirmed basic role of their modification.

Smoking cigarettes is associated with significant increase in risk of vascular complications and development of chronic ischemia of lower limbs at the background of atherosclerosis (14). Number of smoked cigarettes per year significantly correlates with increased risk of amputation, occlusion of the vascular graft, and death (15). In addition, during exercises on a treadmill, the smoking patients with PAD reported significantly less intensive pain in shanks than non-smoking patients (16). Therefore, smoking cessation is a significant factor for reducing cardiovascular complications, however, it has to be combined with formal program of nicotine replacement therapy (17) and administration of an antidepressant drug – bupropion (18). Introducing such regimen allows achieving 22% cessation rate within five years and if it is compared with 5% cessation rate achieved in patients with standard treatment, it becomes obvious how important is to apply aforementioned recommendations. The patients have to be informed about purpose of smoking cessation, which is not used in order to increase walking distance, but in order to significantly reduce risk factors for vascular and ischemic episodes. No broad-spectrum study explicitly proved that smoking cessation is associated with significant increase in walking distance (19, 20). The patients have to be aware of this fact in order to prevent losing effort put in therapy, if the patient is discouraged by noticing no increase in walking distance.

Independent risk factors for the lower limbs atherosclerosis include elevated level of total cholesterol, low-density lipoprotein (LDL) and triglycerides (TG) (21). Factor that is protective for the development of PAD is elevated high-density lipoprotein (HDL) (22). Current recommendations for the management of lipid disorders in patients with PAD are to achieve LDL level in serum < 100 mg/dL, however, in patients with PAD and other vascular disease (e.g. coronary heart disease), concentration of LDL in serum should be at the level of < 70 mg/dL. Administration of statins is the main method for lowering level of LDL and reducing risk of the cardiovascular episode. Fibrates are recommended in order to lower concentration of triglycerides. Data coming from broad-spectrum, randomized study including population of over 20 thousand patients – Heart Protection Study (HPS), emphasizes the role of lowering LDL concentration in order to reduce undesired cardiovascular events. Use of simvastatin (40 mg/day) over the period of five years was associated with a 12% reduction in total mortality, 17% reduction in vascular mortality, 24% reduction in undesired vascular events and 27% reduction in all strokes (23). Moreover, HPS study revealed that long-term therapy with statins was associated with reduction in incidence of myocardial ischemia, stroke, and vascular death in patients with PAD.

Hypertension is the next independent factor associated with a two- to three-fold increased risk of the lower limbs ischemia at the background of atherosclerosis (24). It is recommended to maintain the blood pressure in patients with atherosclerotic process at the level of 130/85 mm Hg (25). Beta-blockers are not contraindicated in therapy of the peripheral artery disease, as it was claimed in previous papers. Currently, it is believed that the patients qualified for surgical treatment of the peripheral artery disease should take beta-blockers due to their cardioprotective action in this group of patients (26). HOPE (Heart Outcomes Prevention Evaluation) study conducted on over four thousand of subjects proved positive effect of using ACE inhibitors on reduction of hypertension in the group of patients with PAD (27). Therefore, it is recommended to use ACE inhibitors in the group of patients with PAD and hypertension, who are at high risk of cardiovascular complications.

In diabetes mellitus, there is approximately three-fold increase in risk of PAD and approximately five-fold increase in risk of intermittent claudication (28). Risk of other complications, such as peripheral neuropathies or skin infections leading to non healing ulcerations, is also a few times higher within the course of diabetes mellitus. Several studies of both type 1 and type 2 diabetes mellitus have shown that aggressive blood-glucose lowering can prevent microvascular complications, particularly retinopathy. However, explicit positive effect of blood-glucose lowering on reduction of cardiovascular events and PAD development has not been proven (29). The current American Diabetes mellitus Association guidance recommends hemoglobin A1C level of 7%, however, it is unclear whether achieving this goal will effectively reduce PAD development.

An elevated serum homocysteine level is an independent risk factor for PAD (30). However, no positive effect of using supplements with vitamin B on reduction of cardiovascular events has been proven.

Hypercoagulation is the most common cause of venous thrombosis, which has been proven in numerous studies (31). Pathologies associated with coagulation in patients with PAD have been evaluated in not many studies, which provided evidence of coexisting elevated concentration of platelet activation markers and PAD (32).

Acetylsalicylic acid (ASA) is a well-recognized antiplatelet drug that has clear benefits in patients with cardiovascular diseases. Antithrombotic Trialists’ Collaboration study proved efficacy of this drug in patients with ischemic heart disease (33). This study also proved that low doses of ASA (75-160 mg daily) are safe for the gastrointestinal tract. Thus, current recommendations would strongly favor the use of low doses of ASA in patients with cardiovascular diseases. Antiplatelet drugs are clearly indicated in the overall management of PAD, although the efficacy of ASA is shown only when PAD and cardiovascular disease coexist (34).

The thienopyridines are a class of antiplatelet agents that have been studied in terms of treatment of the peripheral artery disease. Despite benefits of administration of these drugs in patients with the peripheral artery disease, which are resulted from reduction in myocardial infarction, stroke and vascular death, its use is not recommended due to risk of side effects (neutropenia, thrombocytopenia) (35). As opposed to ticlopidine, clopidogrel was shown to be highly effective in reducing risk of vascular and ischemic episode in patients with PAD, with acceptable frequency of side effects. It was proven in Clopidogrel versus Aspirin in the Prevention of Recurrent Ischemic Events study (36, 37). In recent publications regarding patients with the acute coronary syndromes, it is suggested that combined therapy with ASA and clopidogrel is more effective than monotherapy with ASA, however it is associated with higher risk of bleeding (38). The last conducted study regarding this issue did not demonstrate general benefits resulted from combined therapy (ASA and clopidogrel) that are superior to monotherapy with ASA in preventing myocardial infarctions, strokes or vascular death (39). Therefore, combined therapy in patients with PAD is not recommended. If clopidogrel is considered, it should be used in monotherapy.

At the beginning, treatment should include introduction of physical exercises, and in some patients, pharmacotherapy. Purpose of modification of risk factors and antiplatelet therapy is to reduce risk of cardiovascular episodes. If the patient does not respond to used conservative treatment, surgical treatment should be considered.

Conducting supervised exercises is the most effective, conservative therapy of intermittent claudication (40). Physical exercises 3 times a week are recommended. At the beginning, exercises should take 30 minutes, however, over the time, an exercise session should be prolonged to one hour. During exercises on a treadmill, its slope and its speed should be set in such manner that pain would occur within 3-5 minutes. Pain intensity should remain at moderate level. If the patient stops at the moment of pain occurrence, response to workout would be less effective. Workout should be repeated three times a week over at least three months.

All patients with intermittent claudication should receive suitable treatment and directions in order to modify risk factors for vascular diseases. However, radical improvement cannot be expected during conservative treatment. Despite promotion of many drugs, only small percentage of them reveal proven clinical effect. Therapeutic effect of physical exercises, which cannot be replaced by any pharmacological product, is still underestimated.

Formerly used vasodilator agents do not reveal documented therapeutic effect (41). In 1984, pentoxifylline was approved for treatment of intermittent claudication. However, the most recent clinical studies showed that in treatment of intermittent claudication this drug is not more effective than placebo (42).

Cilostazol is the only drug with proven clinical effect in intermittent claudication, however, lack of marketing authorization of this drug in Poland makes its use impossible. Its vasodilating, metabolic, and antiplatelet action is based on phosphodiesterase type 3 inhibition (43). Four clinical trials with enrolled over 1500 patients taking 100 mg of cilostazol twice daily showed obvious benefits resulted from administration of this drug comparing to placebo (statistically significant increase in walking distance) (44). The studies comparing cilostazol and pentoxifylline showed that cilostazol is more effective (45). Use of cilostazol is contraindicated in patients, whose peripheral arterial disease is accompanied by heart failure (46). However, despite recent reports denying negative effect of cilostazol in this group of patients, it is still recommended to avoid therapy with this drug in patients with circulatory failure.

Acetylsalicylic acid and other antiplatelet drugs are important elements of long-term therapy of patients with PAD, which are used in order to reduce risk of cardiovascular events. However, no study demonstrated beneficial effect of antiplatelet or antithrombotic therapy in treatment of intermittent claudication (47).

Prostaglandins were evaluated in a few studies, however, there was no explicit evidence of benefits resulted from use of these drugs in treatment of intermittent claudication (48). Furthermore, other treatments formerly used in vascular diseases: buflomedil, vitamin E, chelation therapy, omega-3 fatty acids, and ginko biloba turned out to show no proven clinical effect (49).

Since 1990s, the reports have been published on possible use of gene therapy in patients with the peripheral arterial disease (50). The studies focus on using multi-gene therapy in order to induce activity of angiogenic cytokines as well as other factors with basic significance in angiogenesis process, such as nitric oxide synthesis or angiopoietin. In recent years, scientists are also interested in other angiogenic growth factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). After intra-arterial administration of bFGF protein in patients with intermittent claudication, improvement occurred in form of increase in walking distance. The newest method of administration of angiogenic factors is gene therapy using viral vector in intramuscular injections. At the beginning, this method seemed to be very promising, however broad-spectrum clinical studies conducted on large group of patients showed no expected efficacy of treatment with VEGF (51). Therefore, it is necessary to conduct more studies on use of angiogenic growth factors in therapy of the peripheral arterial disease.

There is much evidence that chronic use of antiplatelet drugs, especially acetylsalicylic acid, contribute to reduction in vascular adverse events and prolonging patency of vascular grafts. Meta-analysis Antithrombotic Trialists’ Collaboration showed that among 3000 patients after peripheral grafting surgery, who were taking acetylsalicylic acid, there was 16% of the graft occlusions comparing to 25% in the group taking placebo. Low doses of acetylsalicylic acid (50-100 mg) revealed similar efficacy as high doses (900-1000 mg) (52).

Justification for use of anticoagulant therapy in form of low molecular weight heparin administration following vascular surgeries in order to prolong the period of the graft patency was evaluated in many clinical trials. It was proven that prolonged use of low molecular weight heparin may positively influence long-term patency of the graft, but it is associated with increased postoperative bleeding (53).

Therapy with oral anticoagulant agents is more controversial. A few studies on therapy with warfarin used in patients after vascular grafting located below the inguinal ligament (venous grafts, prosthetic blood vessels and endarterectomy surgery) did not prove superiority of this treatment method over antiplatelet therapy resulted in prolonged period of patency of the graft or the vessel. In addition, use of warfarin was associated with increased risk of postoperative bleeding (54).

In a few clinical trials, effects of anticoagulant therapy were compared with effects of antiplatelet treatment. One trial included patients after vascular grafting with prosthetic blood vessel placed below the inguinal ligament. After surgery, the patients were randomized for treatment with low molecular weight heparin or combined therapy with acetylsalicylic acid (300 mg daily) and thienopyridine. Using heparin was associated with prolonged period of graft patency. There was no difference between the groups in terms of incidence of postoperative bleeding, however, slightly higher number of deaths was recorded in the group taking low molecular weight heparin (55).

In one of the largest clinical study comparing therapy with oral anticoagulants to therapy with acetylsalicylic acid (Dutch Bypass Oral Anticoagulants or Aspirin Study) in patients after vascular grafting located below the inguinal ligament, the authors suggest using therapy with oral anticoagulants in patients after vascular grafting with the patient’s own vein, but in patients after vascular grafting with prosthetic blood vessel, better long-term effects were achieved in treatment with acetylsalicylic acid (56).

Many studies focus on combined therapy with oral anticoagulants and antiplatelet agents in patients with high risk of vascular complications. However, there is no evidence of definite superiority of combined therapy over therapy with acetylsalicylic acid alone, but simultaneous use of antiplatelet agents and oral anticoagulants is associated with higher risk of perioperative bleeding (57).

To recap, antiplatelet therapy is important treatment in patients after vascular surgery. It reduces risk of occlusions of the vessels or the vascular grafts as well as it has positive effect on lowering frequency of adverse events such as myocardial ischemia and cerebral infarction. However, previous clinical studies did not provide clear answer for the following question – which group of the drugs or what combination of the drugs is the best long-term adjuvant therapy for the patients after vascular surgery. The safest and the most carefully evaluated drug seems to be acetylsalicylic acid. Recently published articles expressed concern that patients undergoing intervention due to the peripheral arterial disease do not receive proper treatment related to atherosclerosis. As it was mentioned before, all patients should undergo treatment related to atherosclerotic process regardless of any actions, which are necessary in order to save the limb.

Patients undergoing surgery due to vascular diseases are at high risk of cardiovascular complications (58). There are many publications suggesting stratification of preoperative risk in these patients by detailed interview and physical examination as well as evaluation of myocardial performance using minimally invasive methods (59). Basic and the most typical risk factors for cardiovascular complications in surgical patients include: age > 70 years, ischemic heart disease, past episode of myocardial ischemia, heart failure, infarction (60). Patients with symptoms of coronary instability should be referred to the cardiologist in order to initiate suitable treatment. In patients with stable coronary disease, treatment should depend on intensity of symptoms. In majority of patients with symptoms of coronary heart disease, it would be necessary to perform coronary angiogram in order to establish suitable method of revascularization. Adequate therapy should be initiated in all patients. In patients with no high risk of cardiovascular complications, preventive coronary revascularization in preparation to vascular surgery usually should not be performed, however, in majority of patients, perioperative use of beta-adrenolytic drugs is associated with lower cardiovascular risk (61).

Significant percentage of patients with chronic ischemia, who are coming to doctor’s offices, are incorrectly diagnosed and treated. It happens that these patients are referred to the vascular surgeon with advanced ischemia of the limb, and in such condition possibilities of surgical treatment are limited. It is common that the patients with serious vascular problems do not receive adequate surgical assistance within the optimum time. Therefore, in order to prevent the disease development, therapy modifying risk factors for development of the atherosclerotic process should be initiated sufficiently early. The main elements of such management include smoking cessation, maintaining LDL cholesterol level below 100 mg/dL, maintaining blood pressure at <130/85 mm Hg and maintaining a hemoglobin A1c in diabetic patients at the level of < 7.0%. Recommended pharmacological treatment includes use of statins in order to reduce high level of LDL cholesterol, use of ACE inhibitors in order to treat hypertension and use of beta-blockers if not contraindicated. All patients should chronically use antiplatelet treatment. Besides reduction of risk factors for atherosclerosis, further treatment of the symptomatic patients with intermittent claudication includes introduction of supervised exercises. Cilostazol is the only drug approved for treatment of intermittent claudication; it is recommended to use one course of pharmacotherapy over at least three months in patients without contraindications, who are mentioned above. The patients, who underwent surgical treatment due to intermittent claudication or critical ischemia of the limb (surgery or angioplasty), have to take antiplatelet agents in order to prolong revascularization effect. Chronic use of acetylsalicylic acid is recommended. Multidrug therapy and its combinations are not approved in this population of patients.