Preventive Aspects in Peripheral Artery Disease

Abstract
The prevalence of peripheral artery disease is steadily increasing and is associated with significant morbidity, including a significant percentage of amputations. Peripheral artery disease often goes undiagnosed, making its prevention increasingly important. Patients with peripheral arterial disease are at increased risk of adverse cardiovascular outcomes which makes prevention even more important. Several risk factors have been identified in the pathophysiology of peripheral artery disease which should be modified to decrease risk. Smoking, hyperlipidemia, hypertension, and diabetes are among proven risk factors for the development of peripheral artery disease, thus smoking cessation, lipid control, blood pressure control, and glucose control have been tried and shown to be effective in preventing the morbidity associated with this disease. Pharmacologic agents such as aspirin and clopidogrel alone or in combination have been shown to be effective, though risk of bleeding might be increased with the combination. Anticoagulation use is recommended only for acute embolic cases. Other treatment modalities that have been tried or are under investigation are estrogen replacement, naftidrofuryl, pentoxifylline, hyperbaric oxygen, therapeutic angiogenesis, and advanced glycation inhibitors. The treatment for concomitant vascular diseases does not change in the presence of peripheral artery disease, but aggressive management of risk factors should be undertaken in such cases.

Introduction
Peripheral artery disease (PAD), particularly its manifestation in the lower extremity, is often seen in outpatient clinics. PAD is associated with a number of implications for the patient. The patient suffers from pain and disabling symptoms in the limb, and the disease can also lead to many long-term effects on cardiovascular mortality. Prevention of PAD can be a major step in improving quality of life and decreasing overall morbidity and mortality. Recent studies show that both primary and secondary prevention have excellent long-term benefits for the patient. In this article, we review such studies and discuss the means for achieving primary and secondary prevention of PAD.

Most studies estimate that PAD affects approximately 8–10 million people in the USA [Weitz et al. 1996; Criqui, 2001]. According to a more recent estimate by the SAGE group, the current prevalence of PAD in the USA is about 18 million, with this number estimated to reach 21 million by 2010 [SAGE Group, 2010]. This increase is mostly attributable to better diagnostic modalities, increased awareness, and the populations studied [Stoffers et al. 1996]. PAD remains largely undiagnosed, leading to grave consequences on patient health and the economy. For example, critical limb ischemia, one of the most severe sequelae of PAD, is estimated to effect nearly 3 million people [SAGE Group, 2010]. Patients are also at increased risk for developing cardiovascular complications which may result in mortality. Between 40% and 60% of patients with PAD will have some degree of coronary and cerebrovascular disease [Criqui et al. 1992; Newman et al.1993; Vogt et al. 1993; Ness and Aronow, 1999]. An Ankle-Brachial Index (ABI) of less than 0.9 is a risk factor for all-cause and cardiovascular mortality [McKenna et al. 1991; McDermott et al. 1994; CAPRIE Steering Committee, 1996; Wild et al. 2006]. An ABI of less than 0.4 is associated with severe reduction in patient survival [Howell et al. 1989]. In a recent study, it was reported that the participants who had ABI screenings that included arterial waveform analysis had a 78% rate of PAD diagnosis, whereas only 13% of the participants who did not elect ABI screening were diagnosed with PAD based on their symptoms and physical exam [Stephens et al. 2011]. This underscores the importance for primary care physicians to use ABI as a screening tool for PAD.

Atherosclerosis Progression and Regression
Atherosclerosis plays a major role in PAD and can allow for the prediction of PAD development and severity. Extent of atherosclerosis can also explain the various direct and indirect complications of the disease [Norgren et al. 2007]. Most of the known risk factors for atherosclerosis have also been implicated in the progression of PAD [Criqui et al. 1992; Vogt et al. 1993; Meijeret al. 2000]. Studies have demonstrated that management of atherosclerotic risk factors can lead to prevention of PAD or decrease its severity. Reduction of plaque size, and even complete plaque resolution, is now possible with various interventions.

Definitions
Primary prevention is defined as prevention of initial disease development. Once a disease has developed, diagnosing and treating it at an early asymptomatic stage can prevent further morbidity and this is called secondary prevention. Tertiary prevention is the strategy aimed at preventing, arresting, or delaying the progression of the disease, and also preventing its complications. Gofrit and colleagues defined quaternary prevention as the set of health activities that try to minimize the use of unnecessary interventions in the health system [Gofrit et al.2000]. This review discusses primary and secondary prevention of PAD.

Risk Factors and Their Management
A multitude of risk factors, both modifiable and nonmodifiable, play a role in the pathophysiology of PAD (Table 1). Nonmodifiable risk factors include being male, age greater than 50 years, being African American, and having a family history of vascular disease [Hirsch et al. 2001; Kullo et al. 2003; Selvin and Erlinger, 2004].

Smoking
Cigarette smoking is the leading cause in the development and progression of PAD [Willigendael et al. 2004; Norgren et al. 2007]. The diagnosis of PAD can be made about 10 years earlier in smokers compared with nonsmokers [Fowkes et al. 1992; Norgrenet al. 2007]. Thus, smoking cessation has been found to lead to a decrease in the incidence of PAD [Dagenais et al. 1991; Ingolfsson et al. 1994]. This association is even more pronounced in patients already suffering from intermittent claudication. Continued smoking has been shown to increase the symptoms of intermittent claudication and leads to an increase in the need for surgical intervention [Jonason and Ringqvist, 1985; Hirsch et al.1997]. For those who undergo surgical intervention, vessel patency rates and overall survival are lower in smokers compared with nonsmokers [Ameli et al. 1989]. Whether or not this extends to those who undergo a catheter-based strategy is still under debate [Kastrati et al. 1997; Schillinger et al. 2004]. The benefits of smoking cessation can be seen shortly after cessation, particularly in respect to cardiovascular morbidity and mortality [Rosenberg et al. 1990; Dagenais et al. 1991; Ingolfssonet al. 1994].

Nicotine replacement therapy (NRT) has proven to be fairly effective in smoking cessation. A meta-analysis carried out by Cochrane shows that NRT is successful and safe in all patients and that it should be among the initial methods employed by patients [Silagy et al. 1994]. Bupropion in combination with NRT has been shown to provide additional advantage [Hurt et al. 1997; Hall et al. 2002; Tonstad et al. 2003]. A new therapeutic agent, varenicline, has been shown to be superior to NRT and bupropion [Jorenby et al. 2006; Wu et al. 2006]. Initial concerns of increased incidence of depression associated with varenicline use were dampened by a recent study that failed to find an increased risk of depression in patients treated with varenicline [Gunnell et al. 2009]. Combined treatment with varenicline and NRT has also been shown to be safe and effective [Ebbert et al. 2009]. Recently, safety concerns for varenicline have come up and a meta-analysis has reported increased adverse cardiovascular events for varenicline compared with placebo [Singhet al. 2011].

In spite of the aforementioned, the role of psychological support cannot be disregarded. Thorough psychological counseling helps motivate patients to quit and continue remittance [Hall et al. 2002]. Phone quit-lines [Stead et al. 2006] and Nicotine Anonymous [Green et al. 2003] are also considered to be very effective. Physician advice and the number of counseling sessions can have an influence on the cessation program [Hall et al. 2002]. Smokeless tobacco [Bolinder et al. 1994] and electronic cigarettes [Eissenberg, 2010] have no benefits and have even been reported to have adverse effects. Self-help books and computerized programs like Quit Meters have some drawbacks and require more research and improvements [Nakajima et al. 2008]. Acupuncture therapy and electrostimulation have also been reported to help in smoking cessation. Though in a systematic review, White and colleagues concluded that there was no consistent evidence that these are effective, though the authors advocated that further research be done due to a lack of bias-free evidence [White et al. 2011].

Smoking cessation is one of the most cost-effective interventions in prevention of adverse cardiovascular events [Norgren et al. 2007].

Hyperlipidemia
There is clear evidence that dyslipidemia can cause and increase the severity of PAD [Vogt et al. 1993; Meijer et al. 2000]. Incidence of new onset intermittent claudication was shown to be significantly lower in patients with coronary disease who were on simvastatin [Terje et al. 1998]. High levels of low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), triglycerides, and total cholesterol are positive risk factors for PAD [Vogt et al. 1993; Meijer et al. 2000]. High levels of high-density lipoprotein (HDL) and apolipoprotein A-1 are both known to decrease the progression of atheromas [Norgren et al. 2007]. The ratio of total cholesterol to HDL fraction has been shown to be the best predictor of PAD development [Ridker et al. 2001]. Apolipoprotein (Apo)-E [Rouis et al. 1999] has also been shown in several animal studies to decrease the risk of atherosclerosis and requires further research to detect its risks and benefits in humans. Recently, Gary and colleagues have shown that an increased level of Apo-B, a constituent of all atherogenic lipoproteins, is associated with increased rate of stent restenosis [Gary et al. 2010]. Target LDL levels are less than 2.59 mmol/liter (100 mg/dl) in asymptomatic patients with PAD without other clinical evidence of cardiovascular disease and less than 1.81 mmol/liter (70 mg/dl) in patients with concomitant disease in other arterial beds [Norgren et al. 2007].

Lifestyle modifications should be attempted before pharmacologic intervention [Norgren et al. 2007]. Patients should be advised to adopt a low-fat diet and maintain a regular exercise regimen. Once these have proven to be unsustainable for patients, pharmacologic treatment may be initiated. Statins have been shown to have anti-inflammatory effects and decrease plaque size, and should be the primary drugs of choice [Heart Protection Study Collaborative Group, 2002; Nissen et al. 2006]. Simvastatin and pravastatin are both statins that have been thoroughly studied in this setting. In patients with PAD, statins have been shown to increase pain-free walking time, a finding that may be independent of the cholesterol-lowering action of statins [Mohleret al. 2003]. Fibrates can be given to people who are intolerant to statins as they help lower triglyceride levels and increase HDL levels. Some studies show that they even improve insulin resistance [Samuel et al. 2009; Jun et al. 2010]. Niacin has also been shown to decrease LDL, VLDL, triglycerides, and total cholesterol, while simultaneously increasing HDL [Elam et al. 2000]. It may also lead to lower levels of Apo-A [Jin et al.1997]. Niacin has recently been found to be superior to ezetemibe when used in combination with statins [Villines et al. 2010]. The adverse effects of niacin, particularly skin flushing, are usually preventable by pretreatment with aspirin [Cefali et al. 2007]. Laropripant, used in Europe to decrease niacin-induced flushing, failed to received US Food and Drug Administration approval in this role but additional data about its efficacy may impact this decision [Hughes, 2008; Paolini et al. 2008].

Bile acid sequestrants are not frequently used in the current era of statins. However, they may still be beneficial in some patients due to their lack of systemic toxicity [Insull, 2006] and can be combined with statins instead of fibrates if there is a risk of rhabdomyolysis with the latter. Ezetemibe, which works by decreasing cholesterol absorption in the gut, has not been shown to improve clinical outcomes. In some studies, it has been even been shown to worsen the outcome and hence is recommended only as a last resort [John et al. 2005; Mitka, 2008]. Cholesterol enzyme transfer protein inhibitors [Davidson et al. 2006] and squalene synthase inhibitors [Davidson, 2007] are currently being investigated for their role in lowering lipid levels and other potential benefits.

Hypertension
Hypertension is an independent risk factor for PAD and can increase PAD risk threefold [Murabito et al.1997]. Isolated systolic hypertension is associated with increased arterial stiffness and progression of atherosclerosis. Even a small reduction in blood pressure can lead to a 16%, 30%, and 40% decrease in the incidence of coronary heart disease, stroke, and overall mortality, respectively [Neal et al. 2000]. Some studies have shown that the use of certain antihypertensives can even be beneficial in patients who are normotensive with prior history of vascular events, such as stroke, for prevention of adverse vascular events [PROGRESS Collaborative Group, 2001]. The target blood pressure is less than 140/90 mmHg except for patients with diabetes or renal insufficiency in whom target blood pressure should be less than 130/80 mmHg [Norgren et al. 2007].

According to Joint National Committee VII (JNC VII) and European guidelines [Chobanian et al. 2003; European Society of Hypertension–European Society of Cardiology, 2003] thiazides and angiotensin-converting enzyme (ACE) inhibitors should be considered as first-line drugs. These drugs have various beneficial effects in patients with PAD. Thiazides are especiallybeneficial in the treatment of isolated systolic hypertension seen in older people [Ott et al. 2003]. However, low doses are beneficial only in mild to moderate hypertension and when renal function is normal. They can cause glucose intolerance or worsening of glycemic control and hence ACE inhibitors should be used in patients with diabetics. ACE inhibitors have been shown to decrease the risk of diabetic nephropathy and mortality associated with congestive heart failure [Yusuf et al. 2000; PROGRESS Collaborative Group, 2001; Lewis et al. 2001]. ACE inhibitors may even decrease the incidence of arrhythmias and sudden death by increasing parasympathetic activity [Ajayiet al. 1985]. PAD patients gain even more benefit than those without PAD as shown by subgroup analysis [Yusuf et al. 2000; Ostergren et al. 2004]. Patients on ACE inhibitors have also been shown to have a decreased need for revascularization procedures [Yusuf et al. 2000]. Monotherapy should always be tried initially, with dual or triple therapy tried only if monotherapy fails to adequately achieve the desired results. Cost effectiveness of ACE inhibitors also makes them of particular use [Lamy et al. 2003].

Once considered contraindicated for use in patients with PAD due to fear of worsening of claudication symptoms, β blockers are now considered safe for use [Radack and Deck, 1991]. Patients with coronary disease may gain additional benefits in the form of decreased cardiovascular morbidity and mortality with β blockade [Norgren et al. 2007]. β Blockers should be given perioperatively to patients with PAD undergoing vascular surgeries to decrease risk of adverse cardiovascular events during, and after, surgery if there are no contraindications [Poldermans et al. 1999, 2001].

Thus, all at-risk or diagnosed patients with PAD and hypertension should be initially started on thiazides or ACE inhibitors. Other therapies may be considered in special circumstances [Chobanian et al. 2003]. Newer modalities for hypertension like coenzyme Q [Rosenfeldt et al. 2007] and blood pressure vaccine [Alain et al.2008] are still under research and have shown some promise in lowering blood pressure.

Diabetes Mellitus
Patients with diabetes mellitus have a nearly fourfold greater risk of developing PAD than those without diabetes mellitus [Kannel et al. 1970].

Claudication has been shown to have doubled the prevalence in diabetics. There is approximately a 26% increased risk of PAD and a 28% increased risk of death for every 1% increase in HbA1C level in diabetics. This finding is independent of age, blood pressure, cholesterol, and smoking status [Selvin and Erlinger, 2004]. PAD in patients with diabetes is also less amenable to revascularization, being associated with lower patency rates post revascularization [Bypass Angioplasty Revascularization Investigation Investigators, 1996]. Due to increased risk of infections and neuropathy, patients with diabetes are more prone to complications in PAD and experience higher amputation rates than those without diabetes [Donnelly et al.2000; Centers for Disease Control and Prevention, 2001; Johannesson et al. 2009]. Even insulin resistance in the absence of diabetes increases the risk of PAD by 40–50% [Muntner et al. 2005].

For this reason, the American Diabetes Association recommends monitoring ABI once every 5 years in patients with diabetes. Additionally, all those with diabetes and ulcers should be checked for PAD [American Diabetes Association, 2010]. Though some studies have failed to show a risk reduction for PAD with strict glycemic control [Diabetes Control and Complications Trial, 1995; UK Prospective Diabetes Study (UKPDS) Group, 1998] its effects are clear in secondary prevention confirmed by lower rates of coronary and cerebrovascular events [Dormandy et al. 2005]. Additional studies are still needed to investigate this association.

The goals for treatment are HbA1C levels less than 7%, or even less than 6%, but only if it can be achieved while ensuring that there are no hypoglycemic episodes [Norgren et al. 2007]. All patients with diabetes should be supervised by a registered dietician for a medical nutrition therapy [American Diabetes Association, 2010]. Lifestyle modifications take precedence over all other therapies. If they fail to control glucose levels, drug therapy should be started. The therapy should be tailored to an individual’s needs and other comorbidities. All patients with diabetes should have annual lower extremity examinations to monitor for ulcers, which are early signs of PAD. All patients should be counseled thoroughly about adequate foot care [American Diabetes Association, 2010]. Strict blood pressure control must also be stressed to patients with diabetes [Hansson et al. 1998].

Lifestyle Modification
Lifestyle modifications remain the most cost-effective interventions for the prevention of complications and sequelae in patients with PAD. These include cessation of smoking [Hobbs and Bradbury, 2003], diet changes [Merchant et al. 2003; Khan et al. 2005] and exercise [Lowensteyn et al. 2000]. Even modest weight reduction has been shown to be beneficial in improving insulin resistance, dyslipidemia, and hypertension control [Klein et al. 2004], factors frequently seen in patients with PAD.

Diet.
Diet changes should be made according to nutritional requirements and comorbidities. Consultation with a dietician can often be helpful for patients, particularly those with significant comorbidities. According to American Diabetes Association guidelines [American Diabetes Association, 2010], patients should commit to a diet low in carbohydrate and fat content. Saturated fat intake should be limited to less than 7% of total calorie intake with a reduction in trans fat. A daily dietary fiber intake of 14 g/1000 kcal and foods containing whole grains should also be encouraged [Merchant et al. 2003; American Diabetes Association, 2010]. Eating small portions of food more frequently during the day, rather than a few large meals, has also shown benefits. Alcohol intake should be limited to one and two drinks per day for women and men, respectively. Supplementation with vitamin C, vitamin E, and chromium has failed to show significant benefits and is not recommended. Patients with hypertension should reduce salt intake [Appel et al. 2001; Sacks et al. 2001].

Exercise.
People without symptoms of claudication should exercise for at least 150 min per week with heart rate being maintained at 50–70% of age-appropriate maximums. In the absence of contraindications, resistance training should be done at least three times a week [American Diabetes Association, 2010]. Patients with PAD should exercise three times a week to a level that brings on moderate claudication followed by rest [Hirsch et al. 2006]. Exercise regimens like treadmill walking are sufficient. Supervised exercise regimens have been proven to give better results and should be recommended to patients [Gardner and Poehlman, 1995; Hirsch et al. 2006; Norgren et al. 2007]. An exercise period of at least 3 months is usually required to demonstrate the benefits [Hirsch et al. 2006].

Hyperhomocysteinemia
The association of hyperhomocysteinemia with atherosclerosis is widely recognized [Boushey et al. 1995]. It might even be a stronger risk factor for PAD than for coronary artery disease (CAD), but the association has not been noted in all studies [Taylor et al. 1991; Ridker et al. 2001]. High levels of homocysteine have been seen in up to 30% of patients with PAD [Norgren et al. 2007] but studies have failed to show that lowering homocysteine levels decreases cardiovascular mortality. In fact, some studies have even reported adverse effects with vitamin or folate therapy aimed at decreasing homocysteine levels [Bonaa et al. 2006; Lonn et al.2006; VITATOPS Trial Study Group, 2010]. This occurrence may be due to increased plaque growth because of direct effects or gene methylation in the vascular cells [Rippel et al. 2007]. More research is needed to establish the role of lowering homocysteine levels, and until then, pharmacologic treatment with the aim of decreasing homocysteine levels to decrease cardiovascular morbidity and mortality should be avoided [Norgren et al. 2007].

Inflammation
Various studies have found that increased levels of inflammatory markers are associated with increased atherosclerosis and cardiovascular events. C-reactive protein (CRP), fibrinogen, complement component C5a, monocyte counts, and plasma tissue factors have all been demonstrated to be predictors of restenosis after revascularization [Ridker et al. 2001; Ray et al. 2007; Speidl et al. 2007]. Data from various studies, however, have been conflicting. Of all these inflammatory markers, CRP levels have been most consistently found to be an independent risk factor for PAD and restenosis [Ridker et al. 1998; Schillinger et al. 2003]. High-sensitivity CRP has also been shown to predict cardiovascular mortality in patients with PAD [Criquiet al. 2010; Urbonaviciene et al. 2011]. Statins have also been shown to reduce high-sensitivity CRP levels in patients with PAD [Aguilar et al. 2009]. Additionally, platelets form microthrombi and secrete cytokines responsible for increasing atheroma size and remodeling. Increased cytokines, adhesion molecules, and chemokines causing increased vascular smooth muscle proliferation are all central to the development of restenosis [Clowes et al. 1983; Rollins, 1997; Libby and Simon, 2001].

Antiplatelet Therapy
Aspirin. Aspirin or acetyl salicylic acid has been shown to cause a significant decrease in the progression of PAD. It has been studied extensively for its role in reduction of cardiovascular events and associated mortality and almost all the studies have proven its benefit. In patients with PAD and CAD or cerebrovascular disease, aspirin should be used in doses ranging from 75 to 325 mg [Clagett et al. 2004; Norgren et al. 2007]. Even in the absence of CAD or cerebrovascular disease, it offers protective effects. The benefit of even 150 mg of aspirin has been shown to be comparable to high-dose therapy and features lower incidence of gastrointestinal side effects like bleeding [Dutch TIA Trial Study Group, 1991]. Studies have shown the decreased need for revascularization procedures in patients with PAD who were on aspirin [Giansante et al.1990; Goldhaber et al. 1992]. After revascularization, aspirin use leads to decreased incidence of restenosis [Clagett et al. 2004]. Favorable effects on coagulation profile, ABI [Giansante et al. 1990] and angiographical progression [Hirsh et al. 1995] of the disease have been shown in patients taking aspirin. Aspirin has also been shown to inhibit the formation of advanced glycation end products (AGEs).

Thienopyridines. Thienopyridines include drugs such as clopidogrel, ticlopidine, and prasugrel. These have been of particular benefit in patients intolerant of aspirin. Though the overall advantages of clopidogrel over aspirin are modest [CAPRIE Steering Committee, 1996], clopidogrel has been shown to be effective in reducing risk of myocardial infarction, stroke, and death related to vascular diseases in patients with PAD [Clagett et al. 2004; Norgren et al. 2007]. Some studies report that clopidogrel may be superior to aspirin in controlling ischemic events [CAPRIE Steering Committee, 1996; Bhatt et al. 2000; Basili et al. 2010]. Higher cost and the risk of thrombocytopenia and leukopenia still leave aspirin as the preferred drug in patients with no contraindications [Gorelick et al. 1999; Clagett et al. 2004]. However, clopidogrel might be more cost effective in patients at very high risk of recurrent ischemic events [Ho et al. 2004]. Ticlopidine is not used frequently now [Clagett et al. 2004] due to associated risk of severe thrombocytopenia and neutropenia [Leonet al. 1998; Bhatt et al. 2002]. Prasugrel was approved by the FDA in 2009 for reduction of thrombotic events in patients with acute coronary events undergoing percutaneous coronary intervention. Though shown to be superior to clopidogrel when combined with aspirinin preventing adverse cardiovascular events, the increased risk of bleeding compared with clopidogrel is of concern [Wiviott et al. 2007a]. Itssustained and more efficacious platelet inhibition, compared with clopidogrel, may make it the agent of choice in the near future [Wiviott et al. 2007b]. However, its role in management of PAD needs to be studied more extensively.

Cilostazol . Cilostazol can be used as an adjunctive therapy in patients with PAD. However, it should never replace treatment with aspirin or clopidogrel [Clagett et al. 2004]. Cilostazol has not shown any benefit in reduction of cardiovascular morbidity or all-cause mortality [Craig, 2001]. Improvements in claudication symptoms and walking distance in patients with PAD are evident [Dawson et al. 1998; Regensteiner et al.2002; Thompson et al. 2002] lead to improved quality of life [Dawson et al. 1998; Regensteiner et al. 2002]. It has also been shown to have favorable effects on lipoprotein profile, particularly increasing HDL and reducing triglycerides [Elam et al. 1998]. Cilostazol can be safely given with other antiplatelets like aspirin and clopidogrel without any increased risk of bleeding [Douglas et al. 2003]. When given after an endoluminal revascularization process, it has been consistently shown to decrease the risk of restenosis [Ishii et al. 2008; Osamu et al. 2008; Soga et al. 2009]. Though its use in heart failure was discouraged because of its similarity to milrinone, which is contraindicated in heart failure [Packer et al. 1991], recent studies show that it might actually improve cardiac function by decreasing secondary remodeling [Sanganalmath et al. 2008]. It should be noted that though the drug has been approved by the FDA, it has not been approved for use in many countries in Europe.

Dipyridamole. Dipyridamole has been primarily used in prevention of stroke and transient ischemic attacks [ESPRIT Study Group, 2006]. Its role in PAD still needs investigation. Its use is limited mostly to combination therapy with aspirin [Hess et al. 1985; Clyne et al. 1987].

Picotamide. Picotamide is still in its early days of evaluation. It has been shown to be particularly effective in patients with PAD and diabetes [Balsano and Violi, 1993; Neri Serneri et al. 2004]. In a recent meta-analysis, there were trends for favorable outcome after picotamide therapy but statistical significance could not be demonstrated [Basili et al. 2010]. More data are required at present.

Combination Therapy. Although the use of aspirin in combination with clopidogrel has been shown to be superior to aspirin alone in patients with acute coronary syndromes [Yusuf et al. 2001], the recent Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Arterial Disease (CASPAR) trial found no evidence of increased benefit in patients with PAD [Jill et al. 2010]. Hence, its use is not recommended [Norgren et al.2007]. The CHARISMA trial concluded that the benefits of the combination were marginal while the risk of bleeding was significant [Bhatt et al. 2006].

Combination therapy with aspirin and dipyridamole has been shown to more effective than aspirin alone in delaying the progression of PAD and increasing the patency of grafts. This combination has been shown to have some benefit in patients with PAD in small trials [Hess et al. 1985; Clyne et al. 1987]. Larger trials are needed to further validate these results.

Triple therapy with aspirin, clopidogrel, and dipyridamole was studied for prevention of stroke, leading to high incidence of bleeding events [Sprigg et al. 2008]. Recently, a meta-analysis reported that triple therapy based on glycoprotein IIb/IIIa was more effective than aspirin-based dual therapy in reducing vascular events in patients with acute coronary syndromes, but had no beneficial effect and was associated with increase in transfusions and thrombocytopenia in patients undergoing elective percutaneous coronary intervention [Geeganage et al. 2010]. These combinations have not been studied in patients with PAD and should not be tried until more supportive data are available. Triple therapy with aspirin, clopidogrel, and cilostazol has been shown to be safe and effective in patients with PAD as discussed above [Douglas et al. 2003].

Anticoagulation
There are currently no recommendations to utilize anticoagulants for prevention of cardiovascular events in patients with PAD [Hirsch et al. 2006] or in those undergoing bypass [Clagett et al. 2004]. Compared with aspirin alone, their combination with aspirin is not more effective in preventing cardiovascular morbidity and mortality [Anand et al. 2007]. This combination may have some benefit in preventing graft occlusion in high-risk cases [Clagett et al. 2004; Norgren et al. 2007]. Anticoagulants might also have a better effect on patency after bypass surgeries [Dutch Bypass Oral Anticoagulants or Aspirin Study, 2000]. The use of anticoagulants should be limited to treatment of all patients with acute limb ischemia (ALI) and long-term prophylaxis when ALI occurs due to embolism [Norgren et al. 2007]. Anticoagulation should be started immediately for patients with ALI, but it must be kept in mind that they can increase the risk of bleeding if amputation has to be performed. Heparin should be followed by warfarin for 3–6 months or longer and there are no clear-cut guidelines on the duration of therapy [Norgren et al. 2007]. Atrial fibrillation has recently been shown to be independently associated with worse outcomes in patients with PAD [Winkel et al. 2010]. In patients with atrial fibrillation, anticoagulation with warfarin is clearly better than aspirin in preventing embolic lower limb ischemia and stroke [Stroke Prevention in Atrial Fibrillation II Study, 1994]. But the benefits should be compared with the risks of bleeding, especially in older people. This is especially important in the light of recent evidence which suggests that bleeding is independently associated with subsequent ischemic events [Van Hattum et al. 2009].

Some Other Drugs and Modalities
Estrogen Replacement Therapy . Although estrogen was previously thought to have cardioprotective benefits, studies have demonstrated that estrogen therapy is not recommended for management of PAD. It does not decrease the risk of PAD in patients with CAD [Hsia et al. 2000]. Also it has been noted that women on hormone replacement therapy may experience increased failure rates after revascularization or bypass procedures [Timaran et al. 2000]. This effect of PAD might be due to its effect on smooth muscle cell motility and matrix metalloproteinases [Oscar et al. 2009]. Recent evidence showing that estrogen might promote angiogenesis has again sparked interest in estrogen as a potential treatment option [Kyriakides et al. 2001; Ruifrok et al. 2009].

Pentoxifylline. Pentoxifylline was the first drug therapy approved for the treatment of claudication symptoms. It has only a small benefit over placebo for the improvement in walking distances [Girolami et al. 1999]. Cilostazol has been proven to be more effective and has virtually replaced pentoxifylline [Dawson et al.2000]. It can be used in people with severe claudication symptoms who have contraindications to cilostazol.

Naftidrofuryl. Naftidrofuryl is a 5-hydroxytryptamine-2 receptor which has been shown to be more effective than placebo for improvement of claudication symptoms [De Backer et al. 2009]. It has also been shown to improve cutaneous vasomotor symptoms of PAD in patients with diabetes [Tretjakovs et al. 2006].

Trans-sodium Crocetinate. Trans-sodium crocetinate (TSC) is a synthetic carotenoid designed to enhance the oxygenation of hypoxic tissues. Various models have shown the increased oxygen diffusivity to be the primary mechanism of action [Gainer, 2008; Manabe et al. 2010]. Mohler and colleagues reported that it was a safely tolerated drug at all doses and notable benefits were observed with higher doses in terms of peak walking time and patient perceived walking distance [Mohler et al. 2011].

Hyperbaric Oxygen Therapy. Treatment with hyperbaric oxygen therapy has been shown to result in rapid regression of atherosclerotic plaques in animals [Kudchodkar et al. 2000]. It has been shown to reduce the restenosis rate after coronary interventions [Mohsen et al. 2004]. Its application in CAD and later on in PAD is an area of future research.

Therapeutic Angiogenesis. Considerable interest has developed in this means of PAD prevention. Success has been shown with recombinant fibroblast growth factor and vascular endothelial growth factor (VEGF) in improvement of claudication and critical limb ischemia, respectively [Lederman et al. 2002; Shyu et al. 2003]. Polydeoxyribonucleotide, which stimulates VEGF production, has recently been shown to be a safe and effective approach in patients with PAD and diabetes with ulcers [Altavilla et al. 2009].

Prostaglandin E1. Prostaglandin E1 (PGE-1) has been shown to improve quality of life in patients with PAD [Matsuo and Shigematsu, 2010]. It exerts a peripheral vasodilation effect by increasing cyclic adenosine monophosphate, decreasing cellular calcium ions, and relaxing vascular smooth muscle; this may be further enhanced by improved walking. PGE-1 has also been reported to down-modulate soluble adhesion molecules involved in vascular inflammation and decrease the levels of monocyte chemoattractant protein [Gianetti et al. 2001; Matsui et al. 2003]. These are implicated in proatherogenic foam cell recruitment and formation. When compared with pentoxiphylline-buflomedil infusion, it was associated with significant improvements in pain-free walking distance and maximal walking distance [Milio et al. 2006].

Advanced Glycation End Products and Atherosclerosis. AGEs are formed when a sugar molecule binds to a protein or lipid molecule without enzymatic control. They have been implicated in development of atherosclerosis and vascular aging, leading to cardiovascular disease [Simm et al. 2007] and stroke [Zimmerman et al. 1995]. AGEs are thought to induce damage through a process called cross linking that causes intracellular damage and apoptosis [Shaikh and Nicholson, 2008]. This is currently under research and some drugs like aspirin [Bucala and Cerami, 1992], benfotiamine [Stirban et al. 2006] and carnosine [Guiotto et al. 2005] have been shown to inhibit this process, but their role in PAD management still seems to be only of research interest. Alagebrium, also an inhibitor, showed some promise during initial research but its further evaluation could not be continued due to financial issues and is now considered to be a failed drug [Bakris et al. 2004].
Peripheral Artery Disease Along With Other Diseases
There is high prevalence of CAD in patients with PAD [Criqui et al.1992; Vogt et al. 1993]. All patients with PAD should be considered to be at high risk for CAD and evaluated thoroughly. Patients with signs and symptoms of CAD should be managed according to current guidelines. Patients considered for vascular surgery should be evaluated for cardiac risks and need for coronary revascularization which should not be performed routinely [Eagle et al. 2002; Norgren et al. 2007]. The treatment of patients with PAD and cerebrovascular disease [Adams et al.2003] or renal disease [Plouin et al. 2003] should also be based on the current guidelines [Norgren et al. 2007]. Thus, the management of other diseases that may coexist with PAD does not change much with the presence or absence of PAD. All these patients should be evaluated properly and referred appropriately.

Financial Implications
The total annual costs of PAD in the USA are estimated to exceed $21 billion [Hirsch et al. 2008]. Complications after PAD treatment further increase this cost. Whether screening by ABI determination is cost effective is still controversial, but any clinical trial in this regard is unlikely as there is full agreement in favor of ABI use [Norgren et al. 2010]. Due to higher costs associated with disability, including loss of wages and impact on the family infrastructure, this area needs further deliberation. In a cost-effectiveness analysis, ACE inhibition was associated with the largest reduction in events leading to the highest gain in quality-adjusted life years and lowest mean cost [Sigvant et al.et al.2011]. The authors suggested that efforts should be made to identify patients with asymptomatic PAD and ACE inhibition considered for those identified.

Conclusion
The prevalence of PAD is increasing at an alarming rate. The associated morbidity and mortality call for greater emphasis on prevention and early treatment. Various risk factors contribute to the development of PAD and many of these are modifiable. In the light of growing evidence, recognizing and attempting primary and secondary prevention of this disease is of utmost importance.

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