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10
international Heart and Vascular Disease Journal Volume 3, Number 5, March 2015
Journal of the Cardioprogress Foundation
LEADING ARTICLE
Treatment of lower extremity
peripheral arterial disease
Aronow W.S.*
Cardiology Division, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA Author:
Wilbert S. Aronow, MD, FACC, FAHA, Professor of Medicine, Cardiology Division, New York Medical College, USA
Abstract
Patients with lower extremity peripheral arterial disease (PAD) are at increased risk for all-cause mortality, cardiovascular mortality, and mortality from coronary artery disease (CAD). Smoking should be stopped and hypertension, dyslipidaemia, diabetes mellitus, and hypothyroidism treated. Statins reduce the incidence of intermittent claudication and improve exercise duration until the onset of intermittent claudication in patients with PAD and hypercholesterolaemia. Patients with PAD should be treated with high-dose statins which include atorvastatin 40 mg to 80 mg daily or rosuvastatin 20 to 40 mg daily. Antiplatelet drugs such as aspirin or clopi-dogrel, angiotensin-converting enzyme inhibitors, and statins should be given to patients with PAD unless contraindicated. Beta-blockers should be given if CAD, especially prior myocardial infarction (MI), is present unless contraindicated. Vorapaxar is an antiplatelet drug which reduces acute limb ischaemia and peripheral revascularization in patients with PAD but is contraindicated if there is a history of stroke, transient ischaemic attack, or bleeding in the head. Cilostazol improves exercise time until intermittent claudication. Exercise rehabilitation programmes should be used. Indications for lower extremity percutaneous transluminal angioplasty or bypass surgery are 1) incapacitating claudication in patients interfering with work or lifestyle; 2) limb salvage in patients with limb-threatening ischaemia as manifested by rest pain, non-healing ulcers, and/or infection or gangrene; and 3) vasculogenic impotence.
Keywords
Peripheral arterial disease; intermittent claudication; exercise rehabilitation; revascularization; aspirin; statins
* Corresponding author. Tel: +19144 935311. Fax: +19142 356274. E-mail: wsaronow@aol.com
Introduction
Peripheral arterial disease (PAD) is chronic arterial occlusive disease of the lower extremities caused by atherosclerosis. PAD may cause intermittent claudication which is pain or weakness with walking that is relieved with rest. The Rutherford classification of PAD includes 7 stages [1]. PAD is classified as stage 0 if the person is asymptomatic, stage 1 if mild intermittent claudication is present, stage 2 if moderate intermittent claudication is present, stage 3 if severe intermittent claudication is present, stage 4 if isch-aemic rest pain is present, stage 5 if the person has minor tissue loss, and stage 6 if the person has ulceration or gangrene.
If the arterial flow to the lower extremities cannot meet the needs of resting tissue metabolism, critical lower extremity ischaemia occurs with pain at rest or tissue loss. Critical ischaemia causes rest pain in the toes or foot with progression to ulceration or gangrene. Chronic arterial insufficiency ulcers commonly develop at the ankle, heel, or leg. Mummified, dry, black toes or devitalized soft tissue covered by a crust is gangrene caused by ischaemic infarction. Suppuration often develops with time, and dry gangrene changes to wet gangrene.
Risk factors
The prevalence of PAD increases with age. Modifiable risk factors that predispose to PAD include cigarette smoking [2-13], diabetes mellitus [2-12,14], hypertension [2-4,9-12,15,16], dyslipidaemia [2-5,712,14,17-19], obesity [20], the metabolic syndrome in women [21], and hypothyroidism [22]. These risk factors contribute to the development of PAD and to the increased risk for all-cause mortality, cardiovascular mortality, and cardiovascular events associated with PAD.
Coexistence of other atherosclerotic disorders
PAD coexists with other atherosclerotic disorders [4,12,23-28,29]. In a study of 1,886 men and women, 270 of 468 patients (58%) with PAD had coexistent CAD and 159 of 468 patients (34%) with PAD had prior ischaemic stroke [23]. In a study of 1,802 men and women, 161 of 236 patients (68%) with PAD had coexistent CAD and 100 of 236 patients (42%) with PAD had coexistent prior ischaemic stroke [24]. In 1,006 men and women, if PAD was present, 63% had coexistent CAD, and 43% had prior ischaemic stroke [4]. In 273 patients with CAD, the lower the ankle-brachial index (ABI), the higher the prevalence of 3-vessel or
4-vessel CAD [28]. Patients with PAD and CAD have more extensive and calcified coronary atherosclerosis, constrictive arterial remodelling, and greater disease progression [30]. Patients with PAD also have a higher prevalence of left ventricular systolic dysfunction than patients without PAD [31].
Cardiovascular mortality and morbidity
Patients with PAD are at increased risk for all-cause mortality, cardiovascular mortality, and cardiovascular events [7,32-39]. At 10-year follow-up of 565 men and women, PAD significantly increased the risk of all-cause mortality (relative risk = 3.1), of mortality from cardiovascular disease (relative risk = 5.9), and of mortality from CAD (relative risk = 6.6) [32]. At 4-year follow-up of 1,492 women, an ABI of 0.9 or less was associated with a relative risk of 3.1 for all-cause mortality after adjustment for age, smoking, and other risk factors [34]. At 7.5-year follow-up of patients in the Cardiovascular Health study in a propensity-matched study of community dwelling older adults, matched hazard ratios for PAD for all-cause mortality, incident heart failure, and symptomatic PAD were 1.57, 1.32, and 3.92, respectively [37]. In a well-balanced propensity-matched population of 2,689 patients with advanced chronic systolic heart failure, during 4.1 years of follow-up, PAD was significantly associated with increased mortality and hospitalization [38].
At 33-month follow-up of 414 patients with PAD and at 48-month follow-up of 89 patients without PAD followed in a vascular surgery clinic, the incidence of death, new stroke/transient ischaemic attack, new MI, new coronary revascularization, new carotid end-arterectomy, or new PAD revascularization was significantly higher in patients with PAD (63%) than in patients without PAD (24%) [39]. PAD was a significant independent risk factor for all-cause mortality with a hazard ratio of 2.2.
Risk factor modification
Smoking cessation
Continuing smoking increases the risk of amputation in patients with intermittent claudication [40]. Patency in lower extremity bypass grafts is also worse in smokers than in non-smokers [41]. Smoking cessation reduces the progression of PAD to critical leg ischaemia and reduces the risk of MI and death from vascular causes [42]. Smoking cessation programmes should be strongly encouraged in persons with PAD (Table 1). Patients should be assisted with counselling and developing a plan for quitting that
may include pharmacotherapy and/or referral to a smoking cessation programme [43,44].
Approaches to smoking cessation include use of nicotine patches or nicotine polacrilex gum, which are available over the counter [45]. If this therapy is unsuccessful, nicotine nasal spray or treatment with the antidepressant bupropion should be considered [45,46]. A nicotine inhaler may also be used [47]. The dosage and duration of treatment of each of these pharmacotherapies are discussed in detail elsewhere [47]. Varenicline is also effective for smoking cessation [48]. Concomitant behavioural therapy may also be needed [49]. Repeated physician advice is very important in the treatment of smoking addiction.
Treatment of hypertension
Hypertension should be adequately controlled to decrease cardiovascular mortality and morbidity in patients with PAD [16,50] (Table 1). The blood pressure should be reduced to less than 140/90 mmHg [16]. In the Heart Outcomes Prevention Evaluation (HOPE) Study, 1,715 patents had symptomatic PAD, and 2,118 persons had asymptomatic PAD with an ABI less than 0.9 [50]. In the HOPE study, compared with placebo, ramipril 10 mg daily significantly reduced cardiovascular events by 25% in patients with symptomatic PAD [50]. In this study, ramipril reduced the absolute incidence of cardiovascular events by 5.9% in patients with asymptomatic PAD and by 2.3% in patients with a normal ABI [50].
Treatment of diabetes mellitus Patients with diabetes mellitus and PAD and no CAD have a 1.5 times higher incidence of new coronary events than non-diabetics with PAD and prior MI [51]. The higher the haemoglobin A1c levels in patients with diabetes mellitus and PAD, the higher the prevalence of severe PAD [52]. Diabetes mellitus should be treated with the haemoglobin A1c level decreased to less than 7% to decrease the incidence of MI [53] (Table 1). The blood pressure should be reduced to less than 140/90 mmHg in diabetics with PAD [16] Diabetics with PAD should also be treated with highdose statins which include atorvastatin 40 mg to 80 mg daily or rosuvastatin 20 to 40 mg daily [54].
Treatment of dyslipidaemia
Treatment of dyslipidaemia with statins has been documented to reduce the incidence of mortality, cardiovascular events, and stroke in patients with PAD [18,19,54-57]. At 5-year follow-up of 4,444 men and women with CAD and hypercholesterolaemia in the
Scandinavian Simvastatin Survival Study, compared with placebo, simvastatin significantly decreased the incidence of intermittent claudication by 38% [55]. In a study of 264 men and 396 women with symptomatic PAD and a serum low-density lipoprotein (LDL) cholesterol of 125 mg/dL or higher, 318 of 660 patients (48%) were treated with a statin and 342 of 660 patients (52%) with no lipid-lowering drug [57]. At 39-month follow-up, treatment with statins caused a significant independent reduction in the incidence of new coronary events of 58%, of 52% in persons with prior MI, and of 59% in persons with no prior MI [57].
In the Heart Protection Study, 6,748 of the 20,536 patients (33%) had PAD [55]. At 5-year follow-up, treatment with simvastatin 40 mg daily caused a significant 19% relative reduction and a 6.3% absolute reduction in major cardiovascular events independent of age, gender, or serum lipids levels [55]. These data favour administration of statins to patients with PAD regardless of serum lipids levels.
Patients with PAD should be treated with high-dose statins to reduce cardiovascular mortality and morbidity and progression of PAD [54-57] and to improve exercise time until intermittent claudication [58-60] (Table 1). Statins also reduce perioperative MI and mortality [61,62] and 2-year mortality [62] in patients undergoing non-cardiac vascular surgery.
Other lipid-lowering drugs do not reduce cardiovascular events and mortality in patients with atherosclerotic vascular disease treated with statins [54]. Fenofibrate or fish oils may be used to treat patients with serum triglycerides greater than 500 mg/dL to prevent pancreatitis [54]. Niacin should especially not be administered because it does not reduce cardiovascular events and is associated with serious adverse events [63,64].
Increased plasma homocysteine
Increased plasma homocysteine level is a risk factor for PAD [65-68]. Lowering of increased plasma homocysteine levels can be achieved by a combination of folic acid, vitamin B6, and vitamin B12. However, double-blind, randomized, placebo-controlled data have not shown that reduction of increased plasma homocysteine levels will reduce coronary events and slow progression of PAD.
Hypothyroidism
Hypothyroidism is a risk factor for PAD [22]. However, there is no evidence showing that treatment with l-thyroxine will reduce the development of PAD or improve symptoms in patients with PAD.
Antiplatelet drugs
Antiplatelet drugs that have been demonstrated to decrease the incidence of vascular death, non-fatal MI, and non-fatal stroke in persons with PAD are aspirin, ticlodipine, and clopidogrel [69]. Aspirin plus dipyridamole has not been shown to be more efficacious than aspirin alone in the treatment of patients with PAD [69]. Oral platelet glycoprotein IIb/IIIa inhibitors have been shown to increase mortality in treating patients with CAD and have not been investigated in treating patients with PAD [70]. Adverse hemato-logic effects associated with ticlodipine limit the use of this drug in the management of PAD [71].
Thromboxane A2 induces platelet aggregation and vasoconstriction. Aspirin decreases the aggregation of platelets exposed to thrombogenic stimuli by inhibiting the cyclooxygenase enzyme reaction within the platelet and thereby blocking the conversion of arachidonic acid to thromboxane A2 [72]. Clopidogrel is a thienopyridine derivative that inhibits platelet aggregation by inhibiting the binding of adenosine 5'-di-phosphate to its platelet receptor [73].
The Antithrombotic Trialists' Collaboration Group (ATCG) reported a meta-analysis of 26 randomized studies of 6,263 patients with intermittent claudication due to PAD [69]. At follow-up, the incidence of vascular death, non-fatal MI, and non-fatal stroke was 6.4% in patients randomized to antiplatelet drugs versus 7.9% in the control group, a significant reduction of 23% caused by antiplatelet therapy with significant reductions for all subgroups.
The ATCG reported a meta-analysis of 12 randomized studies of 2,497 patients with PAD undergoing peripheral arterial grafting [69]. At follow-up, the incidence of vascular death, non-fatal MI, and non-fatal stroke was 5.4% in patients randomized to antiplatelet drugs versus 6.5% in the control group, a significant reduction of 22% caused by antiplatelet therapy.
The ATCG also reported a meta-analysis of 4 randomized studies of 946 patients with PAD undergoing peripheral angioplasty [69]. At follow-up, the incidence of vascular death, non-fatal MI, and non-fatal stroke was 2.5% in patients randomized to antiplatelet drugs versus 3.6% in the control group, a significant reduction of 29% caused by antiplatelet therapy.
If one combines the 42 randomized studies of 9,706 patients with intermittent claudication, peripheral arterial grafting, or peripheral angioplasty, the incidence of vascular death, non-fatal MI, and non-fatal stroke at follow-up was significantly decreased 23% by antiplatelet drugs, with similar benefits among patients with intermittent claudication, those having pe-
ripheral arterial grafting, and those having peripheral angioplasty [69]. These data favour treatment with aspirin in men and women with PAD [69] (Table 1).
Aspirin
In high-risk patients, the incidences of vascular death, non-fatal MI, and non-fatal stroke were 19% with an aspirin dose of 500 to 1500 mg daily, 26% with an aspirin dose of 160 to 325 mg daily, 32% with an aspirin dose of 75 to 150 mg daily, and 13% with an aspirin dose of less than 75 mg daily [69]. Since aspirin doses greater than 150 mg daily do not reduce vascular death, non-fatal MI, and non-fatal stroke more than does an aspirin dose of 75 to 150 mg daily and cause more gastrointestinal bleeding than the lower doses, this author prefers an aspirin dose of 81 mg daily in treating patients with atherosclerotic vascular disease.
Clopidogrel
In the Clopidogrel versus Aspirin in Patients at Risk for Ischaemic Events (CAPRIE) trial, 5,795 patients with PAD were randomized to clopidogrel 75 mg daily and 5,797 patients with PAD were randomized to aspirin 325 mg daily [74]. At 1.9-year follow-up, the annual incidence of vascular death, non-fatal MI, and non-fatal stroke was 3.7% in patients randomized to clopidogrel versus 4.9% in persons randomized to aspirin, a 24% significant decrease with the use of clopidogrel [74].
On the basis of the available data, it is reasonable to treat patients with PAD with either aspirin or clopidogrel. Aspirin 75 to 325 mg daily or clopidogrel 76 mg daily are recommended by the 2011 updated American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines to reduce the risk of MI, stroke, or vascular death in patients with PAD [43,75]. These guidelines recommend the use of aspirin or clopidogrel in patients with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or critical limb ischaemia, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischaemia, with a class I indication [43,75]. These guidelines also recommend the use of aspirin or clopidogrel to reduce the risk of MI, or vascular death in asymptomatic patients with a n ABI less than or equal to 0.90 with a class IIa indication [43,75].
Vorapaxar
Vorapaxar is a protease-activated receptor-1 antagonist. Of 26,449 patients with atherosclerotic vascular disease randomized to vorapaxar or placebo, 3,787
patients had PAD [76]. At 2.5-year follow-up, patients with PAD randomized to vorapaxar had a 6% insignificant reduction in MI, stroke or cardiovascular death, a significant 42% reduction in hospitalization for acute limb ischaemia from 3.9% to 2.3% (P=0.006), a significant 16% reduction in peripheral artery revascularization from 22.2% to 18.4% (P=0.017), and a significant 62% increase in bleeding from 4.5% to 7.2% (P=0.001) [76]. Vorapaxar has recently been approved by the US Food and Drug Administration to treat patients with PAD receiving aspirin or clopidogrel to reduce the need for peripheral artery revascularization. This drug should not be used in patients with a history of stroke or transient ischaemic attack or bleeding in the head.
Oral anticoagulants
In the Dutch Bypass Oral Anticoagulants or Aspirin Study, 2,690 patients were randomized after in-frainguinal bypass surgery to aspirin 80 mg daily or to oral anticoagulation with phenprocoumon or acenocoumarol to maintain an INR of 3.0-4.5 [77]. At 21-month follow-up, there was no significant difference between the two treatments in the primary outcome of infrainguinal graft occlusion. There was no significant difference between the two treatments in the secondary outcomes of MI, stroke, amputation, or vascular death. However, persons treated with oral anticoagulant therapy had 1.96 times more major bleeding episodes than persons treated with oral aspirin [77]. The ACCF/AHA guidelines state that oral anticoagulant therapy with warfarin should not be given to reduce the risk of adverse cardiovascular ischaemic events in persons with atherosclerotic lower extremity PAD (class III indication with no benefit) [43,75].
Angiotensin-converting enzyme inhibitors
Data from the HOPE Study showed that ramipril 10 mg daily significantly decreased cardiovascular events in patients with symptomatic PAD and in patients with asymptomatic PAD [50]. Angiotensin-converting enzyme inhibitors as well as statins also have many pleiotropic effects to account for their vascular protective properties beyond their primary mode of action including inhibition of cellular proliferation, restoration of endothelial activity, inhibition of platelet reactivity, and an antioxidant potential [78]. The ACC/AHA guidelines recommend treating patients with PAD with angiotensin-converting enzyme inhibitors unless there are contraindications to the use of these drugs to reduce cardiovascular mortality and morbidity [43,75,79] (Table 1).
Table 1. Medical treatment of peripheral arterial disease
1 Smoking cessation programme
2 Treatment of hypertension with blood pressure reduced to less than 140/90 mmHg
3 Control diabetes mellitus with the haemoglobin A1c level reduced to less than 7%
4 Treat dyslipidaemia with high-dose statins
5 Antiplatelet drug therapy with aspirin or clopidogrel to reduce MI, stroke, or cardiovascular death with addition of vorapaxar considered to reduce peripheral artery revascularization
6 Treatment with an angiotensin-converting enzyme inhibitor
7 Treatment with beta-blockers in patients with CAD in the absence of contraindications to these drugs
8 Use of high-dose statins to reduce cardiovascular events and mortality and progression of PAD and to improve exercise time until intermittent claudication
9 Treatment with cilostazol in patients with intermittent claudication
10 Exercise rehabilitation programme
11 Foot care
Beta-blockers
Patients with PAD are at increased risk for developing new coronary events [7,32-39]. Many physicians have been reluctant to use beta-blockers in patients with PAD because of concerns that beta-blockers will aggravate intermittent claudication. However, a metaanalysis of 11 randomized controlled studies found that beta-blockers do not adversely effect walking capacity or the symptoms of intermittent claudication in patients with mild-to-moderate PAD [80].
An observational study was performed in 575 men and women with symptomatic PAD and prior MI [81]. Of the 575 patients, 85 patients (15%) had contraindications to the use of beta-blockers. Of the 490 patients without contraindications to the use of beta-blockers, 257 patients (52%) were treated with beta-blockers. Adverse effects causing cessation of beta-blockers occurred in 31 of the 257 patients (12%). At 32-month follow-up, use of beta-blockers caused a 53% significant independent decrease in the incidence of new coronary events in patients with PAD and prior MI [81]. In a vascular surgery clinic, 301 of 364 patients (83%) with PAD and CAD were treated with beta-blockers [82]. Beta-blockers should be used to treat CAD in patients with PAD in the absence of contraindications to these drugs (Table 1). The ACC/AHA guidelines state that beta-blockers are not contrain-dicated in treating patients with PAD [43,75,79].
Statins
On the basis of data from the Heart Protection Study, patients with PAD should be treated with statins regardless of age, gender, or initial serum lipids levels [56] (Table 1). Patients with PAD should be treated
with high-dose statins to reduce cardiovascular mortality and morbidity and progression of PAD [54-57] and to improve exercise time until intermittent claudication [58-60] (Table 1). Statins also reduce perioperative MI and mortality [61,62] and 2-year mortality [62] in patients undergoing non-cardiac vascular surgery.
In a study of 69 patients with intermittent claudication, a mean ABI of 0.63, and a serum LDL cholesterol of 125 mg/dL or higher, 3 of 34 patients (9%) treated with simvastatin and 6 of 35 patients (17%) treated with placebo died before the 1-year study was completed [58]. Compared with placebo, simvastatin significantly increased the treadmill exercise time until the onset of intermittent claudication by 24% at 6 months and by 42% at 1 year after therapy. In a study of 354 patients with intermittent claudication and hypercholesterolemia, at 1-year follow-up, compared with placebo, atorvastatin 80 mg daily significantly improved pain-free treadmill walking distance by 40% and significantly improved community-based physical activity [59]. In a study of 86 patients with intermittent claudication and hypercholesterolae-mia, at 6-month follow-up, compared with placebo, simvastatin 40 mg daily significantly improved pain-free walking distance and total walking distance on a treadmill, significantly improved the mean ABI at rest and after exercise, and significantly improved symptoms of claudication [60].
Statin use is also associated with superior leg functioning independent of cholesterol levels and other potential confounders [83]. The data suggest that non-cholesterol-lowering properties of statins may favourably influence functioning in persons with and without PAD [83].
Despite the data recommending use of statins, aspirin, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for secondary prevention in patients with PAD, millions of adults in the United States with PAD are not receiving these drugs [84]. Use of these drugs in patients with PAD and no other cardiovascular disease was associated with a 65% significant reduction in all-cause mortality [84]. Statins also are associated with reduced amputation rates in patients with PAD [85,86].
Drugs to increase walking distance
Chelation therapy has been demonstrated to be ineffective in the therapy of PAD [87], has a class III indication for treating PAD, and may have harmful effects [75]. Numerous drugs have been shown to be ineffective in improving walking distance in patients
with intermittent claudication [88,89]. Beraprost sodium, an orally active prostaglandin I2 analogue, was demonstrated to be no more effective than placebo in persons with intermittent claudication [90]. Oral vasodilator prostaglandins such as beraprost and iloprost have a class III indication for treating PAD [75]. Naftidrofuryl [91] and propionyl levocarnitine [92] have been reported to improve exercise walking distance in patients with intermittent claudication but have not been approved for use in the United States. Use of L-arginine, propionyl levocarnitine, and ginkgo biloba to improve walking distance is not established [75]. Use of vitamin E to treat intermittent claudication has a class III indication [75].
Two drugs, pentoxifylline and cilostazol, have been approved by the United States Food and Drug Administration for symptomatic treatment of intermittent claudication. However, many studies have found no consistent improvement with pentoxifylline in patients with intermittent claudication in comparison with placebo [93,94]. The clinical effectiveness of pentoxifyline to treat intermittent claudication is not established [75].
Cilostazol inhibits phosphodiesterase type 3, increasing intracellular concentration of cyclic adenosine monophosphate. Cilostazol suppresses platelet aggregation and also acts as a direct arterial vasodilator. Cilostazol has been documented in numerous trials to improve exercise capacity in patients with intermittent claudication [89,94-98], and in a dose of 100 mg twice daily, was shown to be superior to both placebo and pentoxifylline [97].
Cilostazol should be administered to patients with PAD to increase walking distance (Table 1) but should not be given to patients with PAD who also have heart failure. Other contraindications to the use of cilostazol include a creatinine clearance <25 mL/min, a known predisposition for bleeding, or coadministration of CYP3A4 or CYP2C19 inhibitors such as cimeti-dine, diltiazem, erythromycin, ketoconazole, lansoprazole, omeprazole, and HIV-1 protease inhibitors. The ACCF/AHA guidelines state cilostazol 100 mg orally 2 times daily is indicated to improve symptoms and increase walking distance in patients with intermittent claudication due to lower extremity PAD in the absence of heart failure with a class IA indication [75].
A randomized, placebo-controlled trial showed that in 212 patients with intermittent claudication due to PAD, 24-week treatment with ramipril caused a significant 75 second increase in mean pain-free walking time and a significant 255 second increase in maximum walking time [99]. Ramipril also signifi-
cantly improved the overall SF-36 median Physical Component Summary score by 8.2 [99]. Of 159 patients with intermittent claudication due to PAD, patients were randomized to 4 weeks of therapy with subcutaneous injections 3 times a week of granu-locyte-macrophage colony-stimulating factor (GM-CSF) or placebo. At 3-month follow-up, treadmill walking performance was not improved by GM-CSF [100].
Exercise rehabilitation
Exercise rehabilitation programmes have been demonstrated to increase walking distance in persons with intermittent claudication through improvements in peripheral circulation, walking economy, and cardiopulmonary function [101,102]. The optimal exercise programme for improving claudication pain distance in patients with PAD uses intermittent walking to near-maximal pain during a programme of at least 6 months [103]. Strength training is less effective than treadmill walking [104]. The ACC/AHA guidelines recommend a supervised exercise programme for patients with intermittent claudication [75] (Table 1).
Supervised exercise training is recommended for a minimum of 30-45 minutes in sessions performed at least 3 times per week for a minimum of 12 weeks [75] and preferably for 6 months or longer [103]. Among persons with PAD, self-directed walking exercise performed at least 3 times weekly is associated with significantly less functional decline during the subsequent year [105]. A home-based walking exercise programme significantly improved walking endurance, physical activity, and speed in patients with PAD and should be used in patients unwilling to participate in a supervised exercise training programme [106].
Foot care
Patients with PAD must have proper foot care [75,107] (Table 1). They must wear properly fitted shoes. Careless nail clipping or injury from walking barefoot must be avoided. Feet should be washed daily and the skin kept moist with topical emollients to prevent cracks and fissures, which may have portals for bacterial infection. Fungal infection of the feet must be treated. Socks should be wool or other thick fabrics, and padding or shoe inserts may be used to prevent pressure sores. When a wound of the foot develops, specialized foot gear, including casts, boots, and ankle foot arthoses may be helpful in unweighting the affected area.
Lower extremity angioplasty and bypass surgery
Indications for lower extremity percutaneous transluminal angioplasty or bypass surgery are 1) incapacitating claudication in persons interfering with work or lifestyle; 2) limb salvage in persons with limb-threatening ischaemia as manifested by rest pain, non-healing ulcers, and/or infection or gangrene; and 3) vasculogenic impotence [108]. Percutaneous transluminal angioplasty can be performed if there is a skilled vascular interventionalist and the arterial disease is localized to a vessel segment less than 10 cm in length [108]. Compared to percutaneous transluminal angioplasty alone, stenting improves 3-year patency by 26%) [109]. After infrainguinal bypass surgery, oral anticoagulant therapy is preferable in persons with venous grafts, whereas aspirin is preferable in persons with non-venous grafts [77].
Percutaneous balloon angioplasty and/or stenting is indicated for short-segment stenoses, whereas multisegment disease and occlusions are most effectively treated with surgical revascularization [110]. Revascularization of PAD is discussed extensively elsewhere [75,107]. In patients presenting with severe limb ischaemia caused by infra-inguinal disease and who are suitable for either surgery or angioplasty, bypass surgery and balloon-angioplasty are associated with similar outcomes in terms of amputationfree survival [111]. Patients with intermittent claudication should be considered for revascularization to improve symptoms only in the absence of other disease that would limit exercise improvement such as angina pectoris, heart failure, chronic pulmonary disease, or orthopaedic limitations [75]. Endovascular intervention is not indicated as prophylactic therapy in an asymptomatic patient with lower extremity PAD (class III indication) [75]. Surgical intervention is not indicated to prevent progression to limb-threatening ischaemia in patients with intermittent claudication due to PAD (class III indication) [75].
However, 6-month outcomes from 111 patients with claudication due to aortoiliac PAD randomized to optimal medical therapy, optimal medical therapy plus supervised exercise, or optimal medical therapy plus stent revascularization showed that the greatest increase in treadmill walking performance occurred in the patients randomized to optimal medical therapy plus supervised exercise [112]. Cilostazol significantly reduced angiographic restenosis after endovascular therapy for femoropopliteal lesions with provisional nitinol stenting of femoropopliteal lesions in 200 patients [113].
Amputation
Non-randomized studies have shown that both immediate and long-term survival are higher in patients having revascularization rather than amputation for limb-threatening ischaemia [114,115]. However, amputation of lower extremities should be performed if tissue loss has progressed beyond the point of salvage, if surgery is too risky, if life expectancy is very low, or if functional limitations diminish the benefit of limb salvage [107].
Conclusion
In conclusion, patients with PAD are at increased risk for all-cause mortality, cardiovascular mortality, and mortality from CAD. Smoking should be stopped and hypertension, dyslipidaemia, diabetes mellitus, and hypothyroidism treated. Patients with PAD should be treated with atorvastatin 40 mg to 80 mg daily or rosuvastatin 20 to 40 mg daily. Antiplatelet drugs such as aspirin or clopidogrel and angiotensin-converting enzyme inhibitors should be given. Beta-blockers should be given if CAD, especially prior MI, is present unless contraindicated. Cilostazol improves exercise time until intermittent claudication. Exercise rehabilitation programmes should be used. Indications for lower extremity percutaneous transluminal angioplasty or bypass surgery are 1) incapacitating claudication in patients interfering with work or lifestyle; 2) limb salvage in patients with limb-threatening ischaemia as manifested by rest pain, non-healing ulcers, and/or infection or gangrene; and 3) vasculogenic impotence.
Conflict of interest: None declared
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