Intermittent claudication: An overview

Atherosclerosis 187 (2006) 221–237

Review

Intermittent claudication: An overview Ashwinkumar V. Meru ∗ , Shivani Mittra, Baskaran Thyagarajan, Anita Chugh New Drug Discovery Research, Department of Pharmacology, Ranbaxy Laboratories Limited, R&D, Plot 20, Sector 18, Udyog Vihar Industrial Area, Gurgaon 122001, Haryana, India Received 2 May 2005; received in revised form 26 October 2005; accepted 20 November 2005 Available online 28 December 2005

Abstract Intermittent claudication (IC) is defined by leg muscle pain, cramping and fatigue brought on by ambulation/exercise; relieved on rest; and caused by inadequate blood supply and is the primary symptom of peripheral arterial disease (PAD). PAD has a detrimental effect on the quality of life. PAD is a debilitating atherosclerotic disease of the lower limbs and is associated with an increased risk of cardiovascular morbidity and mortality. IC is an extremely important marker of atheroma. Up to 60% patients with IC have significant underlying coronary and/or carotid disease and 40% of all patients suffering from IC die or suffer a stroke within 5 years of presentation. The therapeutic intervention of IC essentially aims at providing symptomatic relief and reducing the systemic cardiovascular complications. Although exercise therapy is one of the most efficacious conservative treatments for claudication, the pharmacotherapeutic goals can be best achieved through an increase in the walking capacity to improve quality of life and a decrease in rates of amputation. In the development of treatment for IC, an aggressive non-pharmacological intervention and pharmacological treatment of the risk factors associated with IC are considered. In the next 2 years, the results of major trials of drugs that stabilize and regress atherosclerosis such as statins and angiotensin converting enzyme inhibitors, and anti-platelet agents, recombinant growth factors and immune modulators will be available for IC. Levocarnitine (l-carnitine) and a derivative, propionyl levocarnitine, are emerging agents that increase the pain-free walking and improve the quality of life in IC patients by working at the metabolism and exercise performance of ischemic muscles. This article provides a comprehensive review of the pathophysiology involved, diagnosis of IC and existing and emerging pharmacotherapies with rationale for their use in its treatment. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Intermittent claudication; Peripheral arterial disease; Pathophysiology; Risk factors; Pharmacotherapy

Contents 1. 2. 3. 4. 5. 6.

∗

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk factors for intermittent claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of “IC” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology/prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Existing pharmacotherapy for intermittent claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1. Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. Pentoxifylline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.3. Cilostazol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.4. Buflomedil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.5. Naftidrofuryl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +91 124 5195277; fax: +91 124 2343545. E-mail addresses: [email protected], [email protected] (A.V. Meru).

0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.11.027

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6.2.

7.

Emerging agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Levocarnitine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Policosanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.3. Arginine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.4. Sulodexide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.5. Prostaglandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.6. Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.7. Angiotensin converting enzyme (ACE) inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.8. Thromboxane receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.9. G. biloba . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.10. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.11. Therapeutic angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The word claudication is derived from the Latin word ‘claudicare’, meaning ‘to limp’, and is associated with the Roman emperor Claudius, who is said to have walked with one. Other common names for the condition are ‘hardening of the arteries’, ‘angina of the legs’ and ‘peripheral arterial occlusive disease’ [1,2]. Intermittent claudication (IC) is a cardinal symptom of lower-extremity peripheral arterial disease (PAD). With both asymptomatic and symptomatic PAD representing an independent risk factor for cardiovascular morbidity and mortality, there has been resurgence in epidemiological and clinical interest in PAD. Around 12 million people in the US alone have PAD, and as the world population is aging, the incidence of PAD is expected to rise. IC results from a condition “peripheral arteriosclerotic vascular disease” commonly known as atherosclerosis, a disease process that affects the coronary, cerebral and peripheral arterial circulation and is associated with significant limitation in function because of limb ischemia [2,3]. Atherosclerotic artery disease is global and typically involves multiple vascular territories in the same patient, including coronary and non-coronary circulations. There are now compelling indications that renal artery disease causing renal insufficiency in hypertension, carotid artery stenosis in precoronary bypass patients, subclavian artery disease causing myocardial ischemia and aortoilialfemoral artery obstruction causing IC are different manifestations of atherosclerosis with a common aetiopathogenesis and so regardless of the vascular territory affected, the therapeutic goals for all should be the same [4]. Atherosclerosis in the peripheral arteries of legs leads to an inadequate blood supply due to narrowing or hardening of the arteries. During exercise, increased oxygen demand leads muscles to operate anaerobically, producing lactic acid and other metabolites, which further lead to leg pain, aching, cramping or numbness in the calf, buttock, hip, thigh or arch

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of the foot. Lactic acid and other metabolites get washed away on rest but the condition reiterates on further exercising [5]. Calf muscle pain is the most common symptom, manifested usually due to diseased superficial femoral artery [6]. It arises when blood flow is insufficient to meet the metabolic demands of leg muscles in ambulating patients. This restriction can profoundly disrupt daily activities and requires treatment with pharmacological agents. However, though the patients’ and physicians’ attention is often focused on resolution of claudication symptoms, a more accurate risk assessment implicates the heart even more than the leg. The menace of limb threat in patients is low [7–9] when compared to the considerable inherent predisposition towards cardiovascular morbidity and mortality [10–12]. This has led to an international consensus of treating PAD as a coronary artery disease (CAD) equivalent. The American Heart Association (AHA) and the National Cholesterol Education Program, USA (NCEP), now recommend identical atherosclerotic risk reduction strategies for both CAD and PAD patients [13]. The treatment options for IC vary according to the degree of disease and co-morbidity of the patient. The best medical therapy (BMT) for IC comprising risk factor modification and drug therapy [3], that is the mainstay of treatment for PAD patients, has till now only four drugs on its panel. These are pentoxifylline, cilostazole, naftidrofuryl and buflomedil. Of these, the US FDA has approved only two drugs for the management of intermittent claudication: pentoxifylline and cilostazol, of which cilostazol is clinically more effective. The approval process of these agents primarily included evaluation of walking distance on a treadmill to determine if the pain-free and/or the maximum walking distance improved with the active compound. Many new agents such as levocarnitine [14] are emerging, including some clinically validated natural agents such as Ginkgo biloba and policosanol [15,16]. Novel approaches including angiogenesis mediated by growth factors are currently under extensive investigation [17].

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Rutherford categories

Fontaine’s classification Stage I Stage II

Asymptomatic arteriopathy Exercise-induced ischemia

Stage IIa

Intermittent claudication, pain during walking Relief of symptoms when standing Compensated disease: walking distance > 100 m

Stage IIb Stage III Stage IIIa Stage IIIb Stage IV Stage IVa Stage IVb

Decompensated disease: walking distance < 100 m Ischemia-driven symptoms at rest Ankle Pressure Index ≥ 50 mmHg Ankle Pressure Index < 50 mmHg Trophic ulcers and gangrene Limited gangrene Extensive gangrene

Recent reviews on IC primarily focus on the symptoms/diagnosis of IC or summarize available medical treatments and their comparative effects. Through this review we try to bring forth viewpoints encompassing the current understanding of pharmacological interventions that can be further developed for the still elusive ‘magic bullet’ treatment of IC.

2. Diagnosis The diagnosis of intermittent claudication is quite subjective. The symptoms generally seen in intermittent claudication are 90–100% stenosis and occlusion of superficial femoral artery, bilateral iliac arteries, bilateral superficial femoral–popliteal artery, branch of right iliac artery and left iliac artery region. Calf claudication is more commonly due to the disease in femoral arteries and less commonly due to disease in popliteal or proximal tibial or peroneal arteries; hip/thigh/buttock claudication is due to aortoiliac disease [5]. Despite its significant impact on life expectancy, functional status and quality of life, approximately 75% of patients with intermittent claudication are undiagnosed. Therefore, it is essential that physicians be proactive in identifying this potential “time bomb” in their patients. Recognition is crucial as intermittent claudication is a marker for more serious vascular events. Diagnosis, however, may be challenging. Treatment of PAD is usually evaluated in terms of clinical parameters such as Rutherford classification, anklebrachial pressure index (ABPI) and walking distance [18]. In clinical terms, PAD is divided into Fontaine’s four stages [1] as given above. A new classification has recently been proposed by Rutherford et al. [19] It comprises six clinical categories, and its use is recommended by the TransAtlantic Inter-Society Consensus (TASC) Working Group for the diagnosis and assessment of the progression of PAD [18–21]. It is very necessary to diagnose and treat patients with intermittent claudication, as the symptoms worsen in 25% of patients and approximately 5% will require amputation within 5 years and around 5–10% will have critical limb ischemia, risk of limb loss and increased risk of mortality, primarily due to cardiovascular causes [5] (Table 1).

Category

Clinical description

0 1 2 3 4 5 6

Asymptomatic Mild claudication Moderate claudication Severe claudication Ischemic rest pain Minor tissue loss Major tissue loss

The diagnosis of intermittent claudication patient starts with an appropriate history taking. IC must be differentiated on the basis of its origin. In the calf region, it can be a venous occlusion, chronic compartment syndrome, nerve root compression, Baker’s cyst (which is a tight bursting pain/dull ache that worsens on standing and resolves with leg elevation). In all these conditions a change in position relieves pain. In case of hip/thigh/buttock it can be arthritis where it can be a persistent pain, brought on by variable amounts of exercise. It should be differentiated from the spinal cord compression, which can be presented with a history of back pain, the symptoms worsening on standing and getting relieved by change in position. In case of foot region it can be either arthritis or Buerger disease (thromboangitis obliterans) [22]. Ankle-brachial pressure index is an effective screening tool for PAD [23]. An “ABPI” can be calculated by dividing the ankle systolic pressure measured with a blood pressure at the malleolar level by the higher of the two brachial pressures [24]. Doppler evaluation and calculation of the AnkleBrachial Index (ABI) follows the physical examination. The brachial, posterior tibial and dorsalis pedis pressures are measured using an appropriately sized blood pressure cuff placed on the arms and above the ankles (Fig. 1). Using a handheld continuous-wave Doppler probe, the systolic pressure in each artery is determined when flow resumes after gradual cuff deflation. A diminished ABI (<0.9) is a definite sign of PAD. Values < 0.90 are thought to represent >50% vessel stenosis and, independent of presence or absence of symptoms, serve as a marker for systemic atherosclerosis. ABI values > 1.25 are considered falsely elevated, most commonly due to vessel wall rigidity caused by medial calcinosis associated with diabetes. This rigidity may be so severe that pressures cannot be obtained in which case the result is recorded as non-compressible. Other non-invasive diagnostic tests like segmental blood pressure (SBP), pulse volume Table 1 Progression of intermittent claudication (5%) for a population > 65 years Peripheral vascular outcomes 5–10% have critical limb ischemia Worsening claudication 16% Lower extremity bypass surgery 7% Major amputation 5% within 5 years Other cardiovascular morbidity/total mortality Non-fatal cardiovascular event (MI/stoke, 5 year rate 20%) 5 year mortality 30% (cardiovascular events 75%)

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Fig. 1. Ankle-brachial pressure measurement. ABPI: ankle-brachial pressure index. Inset describes the clinical classification of peripheral arterial disease.

recording, exercise stress testing, reactive hyperemia and CW Doppler and duplex ultrasound are also useful [25–27]. In a recent Swiss Atherosclerotic Survey, the suitability of ABI measurement in routine practice to identify patients at atherothrombotic risk was investigated [27] by subjecting all patients, in a field survey carried out for 5 days, to this test. The ABI measurements identified 2.7% asymptomatic patients of PAD (ABI < 0.9) in addition to the 3.7% symptomatic patients. Ninety-four percent of the participating doctors recommended the use of ABI to be incorporated into the diagnostic routine of patients presenting with risk factors. ABI measurement can be an easy to use, non-invasive and reliable method to identify patients at risk of future atherothrombotic events [13].

3. Risk factors for intermittent claudication Diabetes mellitus and smoking [28–30] are the major risk factors for PAD. Others noted in cohort studies include

advanced age, male sex, arterial hypertension and hyperlipidemia [31–34] and the so-called metabolic syndrome, a cluster of medical conditions that may include these risk factors plus abdominal obesity, hypertriglyceridemia and insulin resistance [35]. Emerging predictors of PAD include elevated levels of high-sensitivity C-reactive protein (hs-CRP) and total homocysteine (tHcy) [36]. High-sensitivity C-reactive protein is a marker of inflammation that predicts incident myocardial infarction, stroke, peripheral arterial disease and sudden cardiac death among healthy individuals with no history of cardiovascular disease [37]. It has been recently observed that presence of even mildly elevated plasma Hcy is reported to increase dramatically the thrombotic risk in patients of IC presumably by altering the platelet activity. Sixty-three percent of patients with IC were found to be mildly hyperhomocysteinemic in a recent study [38]. Serum total 8-iso-PFG2␣ is emerging as a new and independent predictor for PAD, CAD and myocardial ischemia [39]. In the atherosclerotic process lipids are the first line of radical attack and isoprotanes are the stable end products of lipid

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peroxidation [40]. F2 -isoprotanes, including 8-iso-PFG2␣, have been suggested as indicators of oxidative stress and quantification of 8-iso-PFG2␣ is considered the most accurate method of measuring oxidant stress in humans [39,41]. Since there is evidence of extensive endothelial cell damage in atherosclerosis, increased levels of plasma von Willebrand factor (vWF) can be an independent risk factor for the progression of atherosclerosis in claudicants [42].

4. Pathophysiology of “IC” Understanding the pathophysiology of intermittent claudication is pertinent to the development of novel therapeutic agents to treat the condition. Initial symptoms of exertional limb ischemia relate to a decrease in blood flow from proximal arterial atherosclerotic stenoses. Blood flow regulation is governed by Poiseuille’s law: Pr 4 VL where F is the flow, P the pressure, r the radius of the vessel, V the viscosity and L is the length of the vessel. At rest, the blood supply meets the tissue needs, but with exercise, a supply/demand mismatch occurs that presents as exertional pain that is relieved by rest. As is evident from above that the flow of blood is directly proportional to the fourth power of the radius of the vessel, pathogenesis of IC/PAD may be best considered through a study of atherogenesis in general. PAD is an important manifestation of systemic atherosclerosis, which is a diffuse process that starts early and progresses asymptomatically with age [43]. Atherosclerosis being a multi-territory arterial disease within the same patient manifests itself as coronary artery disease, peripheral arterial disease, cerebrovascular disease (CVD) and renal artery disease (RAD) [4]. Endothelial dysfunction is the earliest pathological process leading to atherothrombosis. The loss of adequate vascular function and endothelial damage are important in the pathogenesis of atherosclerosis and thus peripheral artery disease [42,44]. Disruption of the endothelium and exposure of the blood constituents to a thrombogenic surface may in part account for the triad of the prothrombotic or hypercoagulable state seen in atherosclerosis, i.e. abnormally turbulent blood flow, pro-thrombotic blood constituents (e.g. platelets and clotting factors) and abnormalities in endothelial physiology [45]. Endothelial damage can be assessed by measurement of plasma von Willebrand factor and by changes in endothelial cell responses to altered blood flow (e.g. flow-mediated dilatation) [42,45,46]. More recently developed index of endothelial damage is the quantification of immunologically defined circulating endothelial cells (CECs) [47]. Resting levels of vWF were found to be higher in patients with peripheral vascular disease that further increased on claudication after treadmill exercise [48] possibly because of the endothelial damage induced by ischemia–reperfusion injury [49,50].

F=

225

Endothelial cells produce cytokines, express adhesion molecules such as ICAM-1, VCAM and selectin and assist deposition of leucocytes on the endothelium [51]. Damage to the endothelium and exposure of subendothelial components, notably collagen and vWF, result in adherence of platelets to vessel wall and their subsequent activation [42,52]. At this point of time, the process is reversible with locally released nitric oxide (NO) assuming an anti-inflammatory and vasodilatory role. On migration of leucocytes into the intima, lipid accumulation takes place making the process of atherosclerosis recognizable by the appearance of a fatty streak that over time with the accumulation of more foam cells gets converted into a plaque. The plaque becomes increasingly more fibrous and lipid laden and is separated from the blood by a fibrous cap. If the fibrous cap is disrupted, the ‘uncomplicated’ ‘stable’ plaque gets converted into an ‘unstable’ plaque by exposure of subintimal thrombogenic, proaggregatory substances, such as tissue factor, to the blood stream thereby initiating the coagulation cascade [52]. Exposed subintimal collagen interacts with glycoprotein Ia/IIa and vWF with glycoprotein Ib/IX complex on the platelets resulting in adhesion of platelets to subendothelial matrix. The binding generates an intracellular signal activating glycoprotein IIb/IIa receptor and this surface integrin receptor within the platelet membranes undergoes a change in shape on activation expressing a high affinity binding site for fibrinogen [53]. Along with concomitant release and action of 5-HT, ADP and TXA2 this leads to a complex formation of a matrix of platelets and fibrinogen molecules. The platelet plug formed thus progresses in two ways, if firmly attached to the vessel wall it grows till it completely obstructs the lumen or else, the rapid arterial flow detaches it and the platelet rich emboli flows into the peripheral vessels to cause intermittent claudication. The ‘unstable’ high-risk plaques of the lower extremeties are very stenotic and fibrotic [54]. In PAD, flow limiting plaque stenosis and hyperthrombogenicity are major contributors towards acute ischemic syndrome leading to IC and critical leg ischemia, under severe conditions. Whether a lesion is flow limiting depends on both the degree of stenosis and flow velocities. Flow velocity at rest has been measured as low as 20 cm/s in the femoral artery. At these rates, a diameter reduction of >90% would be required for a lesion to be considered hemodynamically significant. Metabolic requirements in the distal tissues of an exercising, active individual are higher, and femoral artery velocities might need to increase up to 150 cm/s. At this pace, a stenosis of even 50% can cause a significant pressure and flow gradient leading to inadequate oxygen delivery. Moreover, high shear stress in exercising/ambulatory patients may lead to local platelet thrombosis. Shear force which is directly proportional to flow velocity and inversely to the fourth power of the radius of the vessel becomes very high at sites of stenosis induced by atherosclerotic plaques. Shear-induced platelet aggregation is initiated by binding of soluble vWF to platelet glycoprotein Ib [51,53] which triggers intracellular signaling leading to

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platelet activation and binding of fibrinogen to glycoprotein IIb/IIIa and subsequent platelet aggregation. The importance of role of platelets in the progression of peripheral occlusive disease has been demonstrated in a double-blind controlled trial of 300 patients with PAD [55]. Platelets are also known to have a central role in the development of restenosis and reocclusion in PAD patients undergoing peripheral percutaneous transluminal angioplasty (PTA). Platelet adhesion is the first mechanical event that occurs after endothelial denudation induced by angioplasty. Initial success rates of PTA are >90% but subsequent failure rates remain high. The 4-year primary patency rate following PTA for aortoiliac occlusive disease in a meta-analysis has been reported to be 65% for stenoses and 54% for occlusions. For femoropopliteal disease the patency rate 4 years after angioplasty is 52%. Early failure is due to occlusion following thrombosis and spasm and delayed failure occurs as a result of restenosis secondary to intimal hyperplasia. Both processes are believed to be platelet-dependent [56]. The active patient with mild IC typically has singlesegment disease often associated with collateral formation. On the other hand, severe claudication and chronic critical limb ischemia commonly implies a multilevel disease. The primary sites of the involvement of this disease are femoral and popliteal arteries; tibial and peroneal arteries; aorta and iliac arteries that get affected by 80–90, 40–50 and 30%, respectively [31,57] (Fig. 2).

5. Epidemiology/prevalence Intermittent claudication is indicative of systemic atherosclerosis and has been used as a marker for PAD in epidemiological studies to approximate the frequency and severity of lower extremity PAD in a particular patient population. The estimate is dependent on demographic factors of the specific population under study, including age, sex and geographic area and also in the methods used to determine the frequency of IC [58]. IC is a relatively common condition, the frequency of which increases dramatically with age and significantly higher rates of occurrence are seen in older adults. The prevalence of intermittent claudication among people aged 45–54 years is 0.6% and 55–74 years is 4.6%. Eighteen percent population over 70 years of age have intermittent claudication, with smokers and diabetics at higher rate of 50–75%, and the amputation risk is approximately 1% a year. Intermittent claudication is more common among men than women and among individuals with other manifestations of atherosclerosis [10,59]. For some, claudication pain is no more than an inconvenience, whereas for others it may lead to significant limitations on their usual lifestyle and even social isolation and unemployment. The incidence of IC has reportedly declined since 1950 but mortality still remains high and unchanged [60]. Examination of long-term trends for IC in the community needs

more focused long-term monitoring. Causes of intermittent claudication include atherosclerosis, thromboembolism, thromboangitis obliterans (Buerger’s disease), arteritis due to systemic lupus erythematosus, fibrosis and developmental anomalies such as coarctation, persistent sciatic artery, popliteal entrapment, cystic adventitial disease and trauma [61]. Intermittent claudication, myocardial infarction and angina pectoris share many epidemiological and biological features. Yet few large cohort studies describing the prevalence, incidence and risk factors for intermittent claudication have been done. A recent study evaluating the prevalent and incident cases of intermittent claudication was defined by the London School of Hygiene Cardiovascular Disease Questionnaire, and all cardiovascular disease risk factor evaluations were standardized. The risk factors for intermittent claudication were a blend of those relating to myocardial infarction (smoking, cholesterol, diabetes, but not hypertension) and others relating to angina pectoris (stress and coping variables). There are now enough studies to support the fact that preventing or modifying these factors will prove effective in altering the natural history and clinical outcomes of peripheral vascular disease as shown in other forms of atherosclerosis [30]. The prevalence of cerebrovascular disease in intermittent claudication patients is about 25–50%. The mortality in peripheral artery disease as a result of cardiovascular events is about 80%, of which about 40–63% of deaths are the result of coronary artery disease, and 8% the result of other cardiovascular events, such as ruptured aneurysms [5,62]. Only 10% of patients with lower extremity ischemia have normal coronary arteries as evaluated by cardiac catheterization. Furthermore, the presence of PAD, even in the absence of CAD, confers the same relative risk of death from a cardiovascular event as in patients with a previous event [13]. Recent studies indicate that patients of PAD should be considered for secondary prevention strategies comparable to those for patients with a previous myocardial infarction and identical atherosclerotic risk reduction strategies are recommended for both CAD and PAD [13,63,64]. In a recent study patients from two large medical offices serving 92,940 patients were administratively screened for PAD as defined by: (1) an International Classification of Diseases 9th revision code for claudication or PAD (443.9), (2) a previous peripheral revascularization procedure, (3) a prescription for either pentoxifylline or cilostazol, (4) an ABI evaluation or full non-invasive arterial study or (5) confirmation by a vascular surgeon. A total of 2839 patients had PAD; exclusion of 1106 with accompanying CAD left a cohort of 1733 patients. In these patients fasting lipid profiles had been evaluated only in 62.6% patients. Fifty-six percent had LDL of >100 mg/dL; 21% had >130 mg/dL. Only 33.1% were on ␤-blockers, 28.9% on angiotensin converting enzyme inhibitors and 31.3% on statins [13]. It was interesting to note that IC symptoms significantly improved in the subgroup of patients on statins. The improvement in leg

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Fig. 2. Primary sites for “IC” presentation: (a) anterior view and (b) posterior view. Primary sites of involvement of “IC”. Femoral and popliteal arteries: 80–90%. Tibial and peroneal arteries: 40–50%. Aorta and iliac arteries: 30%. Adapted with permission from Harrison’s Principle of Internal Medicine.

functioning was independent of the change in cholesterol levels suggesting some undefined non-cholesterol lowering property of statins [13]. Results from these largest and most detailed data on PAD patients reveal that PAD patients are grossly under-treated and fall short of the internationally

established goals for secondary prevention (Table 2). The physician’s major attention gets focused on treating symptoms of IC. It is striking that this group could benefit so greatly with just a little more improved public and physicians’ awareness.

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Table 2 Standards for atherosclerotic risk factor control in patients with PAD Risk factor

AHA/ACC goal

␤-Blockers ACE inhibitors Lipid management Diabetes management

100% of patients 100% of patients LDL < 100 mg/dL Hemoglobin A1c < 7.0%

Blood pressure

Systolic: <130 mmHg Diastolic: <80 mmHg

Smoking Anti-platelet agents

Complete cessation 100% of patients

PAD, peripheral arterial disease; ACE, angiotensin converting enzyme; LDL, low-density lipoprotein. Adapted from the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease.

6. Pharmacotherapy 6.1. Existing pharmacotherapy for intermittent claudication Pharmacological treatment for intermittent claudication is a management option [36]. Although endovascular therapy has revolutionized the management of patients with peripheral arterial disease, non-interventional regimens, such as structured exercise therapy, atherosclerotic risk factor modification and pharmacotherapy, are effective in patients suffering from mild-to-moderate PAD and intermittent claudication (Fig. 3). The Trans-Atlantic Inter-Society Consensus has issued certain recommendations and guidelines for PAD/IC therapy. The report does not endorse any particular pharmacological therapy over and above the exercise programs but places it at best as an adjunctive therapy [65]. According to it, valid clinical trials of IC therapy must be parallel group, double blind and randomized. As the symptom being targeted is difficulty in walking, pain-free walking distance (PFWD; initial claudication distance), i.e. the distance walked on an inclined treadmill when the claudication symptoms are first felt, and

Fig. 3. Interventions for peripheral arterial disease.

maximum walking distance (MWD; absolute claudication distance), i.e. the distance at which the pain is severe enough for a patient to stop, have to be recorded. Since MWD is more reproducible it is generally taken as the primary endpoint [66]. The best medical therapy for IC comprising risk factor modification and drug therapy, that is the mainstay of treatment for PAD patients, has till now only four drugs on its panel. These are pentoxifylline, cilostazole, naftidrofuryl and buflomedil. Of these, only pentoxifylline and cilostazole have been approved by the US FDA [67]. Naftidrofuryl and buflomedil, however, have been in the European market for scores of years. 6.1.1. Aspirin Although there has been a paucity of studies directly addressing the effects of aspirin on IC symptoms, aspirin reduces the risk of adverse cardiovascular events including cardiac death in patients with peripheral arteriosclerosis, and is the overwhelming anti-platelet drug of choice in patients with vascular disease of any origin, which includes stroke, myocardial infarction, peripheral vascular disease (PVD) and angina [68]. The significance of aspirin in PAD is due to its antithrombotic potential [69]. The ISIS-2 study reports that the effect of aspirin in acute myocardial infarction was comparable to the effect of streptokinase [70]. A recent meta-analysis by the Antithrombotic Trailists Collaboration included results from 287 randomized trials involving 135,000 high-risk patients on anti-platelet regimen, of which 9500 patients were diagnosed with PAD including a cohort of 6000 patients with IC [71]. The results suggested the use of aspirin in diabetes, PAD, carotid disease and renal disease and also that the low doses of aspirin (75–100 mg/day) were as effective as higher doses [71]. However, a drawback with aspirin is that aspirin, even in relatively low doses (<325 mg/day), has been associated with gastrointestinal intolerance [72]. Aspirin plus dipyridamole have been reported to delay angiographic progression of PAD [73]. A recent Cochrane overview report states that aspirin 50–300 mg/day started prior to femoropopliteal endovascular treatment can cause a 66% reduction of recurrent obstruction at 12 months [74]. Clopidogrel was also considered as an alternative but enough data were lacking [74]. In a metaanalysis of 11 trials involving over 2000 patients, the use of anti-platelet agents has been associated with a reduced risk of vascular graft occlusion from 24 to 16% (Antiplatelet Trialists’ Collaboration) implicating the use of these agents in prevention of restenosis after peripheral revascularization interventions [69]. The thienopyridines, ticlopidine and clopidogrel, have also demonstrated efficacy in patients with PAD [75]. In CAPRIE trial, clopidogrel (75 mg once daily) or aspirin (325 mg/day) given to a large subgroup of PAD patients (n = 6452) showed a significant relative risk reduction of up to 23.8% [76]. A recent study suggests cost-effectiveness of clopidogrel in PAD patients as compared to ticlopidine,

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and also shows a significant gain in quality-adjusted life expectancy [77]. The ongoing CHARISMA trial will evaluate the efficacy of clopidogrel plus aspirin versus aspirin in a PAD subgroup [78,79]. Results from another clopidogrel trial, CAMPER, on post-angioplasty restenosis in PAD patients are awaited in 2006 after a 30 month follow up [52]. Vigilance needs to be exercised with clopidogrel regarding precipitation of thrombotic thrombocytopenic purpura (TTP) on its use; however, the incidence of TTP with ticlopidine is much higher (2.3% patients) [80–82]. Though a number of trials on ticlopidine have shown beneficial effect in PAD/IC, its use is limited due to its association with neutropenia and TTP [83].

Clinical trials of pentoxyfylline in IC, however, have not consistently demonstrated statistical significance over the placebo group regarding an increase in MWD [92]. Though positive outcomes have been observed in a meta-analysis of 11 randomized, placebo-controlled, double-blind trials evaluating 612 patients, wherein a statistically significant mean improvement in MWD of 48.4 m was observed [93], lacklustre clinical data and critical reviews of available data have left many clinicians skeptical about pentoxifylline’s efficacy [94]. The adverse reactions of pentoxifylline include dizziness, headache, dyspepsia, nausea and vomiting. It is contraindicated in patients hypersensitive to xanthines and patients with cirrhosis receive a quarter dose [95].

6.1.2. Pentoxifylline Pentoxifylline, a hemorheologic agent (methylxanthine derivative), was approved in 1984 for treatment of intermittent claudication. Though there is a poor understanding of how pentoxifylline relieves symptoms of IC, it is thought to improve the deformability of red and white cells, lower plasma fibrinogen concentrations, platelet adhesiveness, whole blood viscosity and plasma hypercoagualibility [84–87]. The mechanism by which pentoxifylline works is not well known, but appears to be related to erythrocyte adenosine triphosphate (ATP) concentrations and the phosphorylation of erythrocyte membrane proteins, both mechanisms resulting in an improvement in erythrocyte flexibility [88]. Some recent studies have implicated that there is more to pentoxifylline than what meets the eye. Infiltration and accumulation of monocytes in the subendothelial space of the arterial wall is a prominent pathobiological feature in early atherogenesis, wherein chemokines are thought to play a key role. Among these, the cytokine-induced CCL2/monocyte chemoattractant protein-1 (MCP-1) is important for its ability to promote migration of monocytes harboring its receptor, chemokine receptor 2 (CCR2). A growing body of evidence indicates that local overexpression of CCL2/MCP-1 by infiltrating monocytes or vascular cells induces accumulation of monocytes/macrophages and formation of atherosclerotic lesion, which seems to synergize with hypercholesterolemia. TNF-␣ has been shown to induce CCL2/MCP-1 expression via activation of the NF-␬B signals and the p42/44 MAPK pathways. Pentoxifylline, by virtue of its PDE III inhibition, potently suppresses TNF-␣-induced CCL2/MCP1 production and the signaling pathways upstream to it. In view of the critical role of CCL2/MCP-1 in atherogenesis, the ability of pentoxifylline to antagonize cytokineinduced CCL2/MCP-1 expression may have implications in the prevention, treatment and regression of atherosclerotic vascular disorders [89,90]. Short-term treatment by pentoxifylline is also observed to completely prevent tissue factor (TF)-induced upregulation of platelet-derived growth factor (PDGF) that occurs through the activation of MAPK pathway and may be important in circumstances where smooth muscle cell proliferation is observed, such as atherosclerotic vascular events [91].

6.1.3. Cilostazol Cilostazol, a potent, reversible and specific inhibitor of human cyclic nucleotide phosphodiesterase III (PDE III), and a platelet anti-aggregant was launched in 1988 and was the second drug to gain FDA approval for treatment and management of IC. Cilostazol and several of its metabolites inhibit phosphodiesterase activity and suppress cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation in vessels compromised with atherosclerotic plaques [96]. Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine and shear stress [97]. Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries [97]. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake thereby augmenting anti-platelet and vasodilatory effects of the drug [98]. Cilostazol increases blood flow in ischemic regions in patients with chronic arterial occlusion. It is equally well tolerated and efficacious in patients with cerebrovascular and peripheral vascular diseases. A favorable effect of cilostazol is seen on lipid metabolism in patients with hypertriglyceridemia and this is attributed to the effects of suppression of VLDL synthesis in liver [99]. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in triglycerides by 29.3 mg/dL (15%) and an increase in HDL-cholesterol by 4.0 mg/dL (∼ =10%) [97]. Cilostazol significantly reduces atherogenic remnant lipoprotein concentrations in patients with IC and the lipid-modifying effects of cilostazol are thought to be due to the activation of lipoprotein lipase, which improves the metabolism of triglyceride rich lipoproteins [99]. Another possibility of the lipid modifying effect may be the inhibition of cholesteryl ester transfer protein (CETP) activity by cilostazol [99]. The results of seven phase III trials show that patients receiving 100 mg cilostazol twice daily experience statistically significant improvements in symptoms of IC as compared to placebo. In three key trials, primary analysis shows

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that the maximum distance that patients can walk improves by 21, 29 and 31%, corresponding to increased ambulatory distances of 58.6, 51.6 and 106.3 m, respectively. In addition to improving functional status and quality of life, cilostazol has been shown to be superior in improving walking ability compared to pentoxifylline. The adverse effects that occur such as headache, diarrhoea, abnormal stools, palpitations and dizziness appear to be dose related [100]. The incidence of adverse events is significantly greater, headache (28–41% versus 9–15%), loose stools (15–19% versus 3–5%), diarrhoea (12–13% versus 4–7%), dizziness (13% versus 5%) and palpitations (11–17% versus 0–1%) when compared with pentoxifylline [101]. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III and as several drugs with this pharmacological effect have caused decreased survival compared to placebo in patients with class III–IV congestive heart failure, cilostazol is contraindicated in patients with congestive heart failure of any severity [97]. Since cilostazol is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when it is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole [97]. 6.1.4. Buflomedil Buflomedil is a vasodilator with ␣1 and ␣2 adrenolytic action claimed to have beneficial effects on microcirculation [102]. Both ␣1 - and ␣2 -adrenoceptors are implicated in vascular constriction and ␣1 -adrenoceptors are also observed to mediate long lasting trophic responses by stimulating smooth muscle proliferation in blood vessels [103]. Recent evidence indicates that norepinephrine directly induces proliferation, hypertrophy and migration of VSMCs in vasculature. Thus, in addition to biomechanical forces and paracrine growth factors, certain G protein-coupled receptor agonists, such as angiotensin and norepinephrine, are also now known to exert trophic actions contributing towards pathological growth [103]. Buflomedil seems to improve nutritional blood flow in ischemic tissue of patients with peripheral and/or cerebral vascular disease by a combination of pharmacological effects: inhibition of ␣-adrenoceptors, inhibition of platelet aggregation, improved erythrocyte deformability, non-specific and weak calcium antagonistic effects, and oxygen sparing activity [104]. Buflomedil is observed to improvise impaired vascular microcirculation by specifically increasing arterial perfusion with minimal effects on central hemodynamics [104]. Buflomedil, 600 mg orally b.i.d., has been observed to produce pulsed increases in plasma adenosine levels [105]. Adenosine is implicated as the mediator of pharmacological preconditioning of ischemic tissues [106]. Besides its vasodilating properties, adenosine possesses antiplatelet and anti-neutrophil activities and provides cytoprotection. The adenosine increase that follows the administration of drugs, such as buflomedil and propionylcarnitine, opens new perspectives in the management of leg ischemia.

In fact, a new concept is arising of an ischemic (exercisedependent) or pharmacological preconditioning (adenosinedependent) for the treatment of patients with claudication [106]. Therapeutic trials with buflomedil in patients with peripheral vascular diseases have shown that it increases walking distances in those with intermittent claudication and heals trophic lesions and reduces rest pain in many patients with more severe vasculopathies. It has been in market for >10 years. A meta-analysis of 744 patients receiving buflomedil in 10 randomized controlled trials found a moderate effect of buflomedil with an average PFWD improvement of 60% as compared to placebo. Adverse effects include GIT symptoms, headache, dizziness, syncope, erythema and pruritis [102]. On the whole, as of now, there is a lack of evidence for the clinical efficacy of buflomedil in IC and a few well-designed long-term studies are needed to fully define its overall place in therapy. 6.1.5. Naftidrofuryl Naftidrofuryl has been available for treatment of claudication in Europe for over 20 years. Naftifrofuryl, a 5HT2 receptor antagonist, ameliorates symptoms of PAD through vasodilation and improved aerobic metabolism [107]. Serotonin (5HT) induces shape change and aggregation of platelets, vasoconstriction and increase of vascular permeability and cell proliferation, after release from the site of vascular injury and 5HT2A receptor is implicated in these pathophysiological effects. Though 5-HT, through 5-HT2A , produces vasoconstriction in human vasculature, the direct effect can be called minor. The major role of 5-HT in the vasculature comes into play in pathophysiological conditions in causing platelet aggregation. If the endothelium is intact the 5-HT released from the platelets causes vasodilation; however, if atherosclerosis prevails, 5-HT causes vasoconstriction and impairs blood flow further. Naftidrofuryl, being a selective inhibitor of the 5-HT2 receptor expressed on human endothelial cells, has been used over the years to cope with cerebral or peripheral ischemic accidents; however, no clear mechanism of action of this molecule has been highlighted to explain its vascular effects. Involvement of nitric oxide has been recently observed to account for the effects of naftidrofuryl, for its potent inhibition of TNF-␣-triggered increase of intercellular adhesion molecule1 (ICAM-1) expression as well as stress fiber formation in human umbilical vein endothelial cells (HUVEC) [108]. Moreover, it has been observed to induce expression of type II nitric oxide synthase (NOS II) messenger and protein, leading to a noticeable increase in nitric oxide synthesis that gets attenuated with specific NOS II inhibitor 1400W. As the biology of nitric oxide accounts for the strong inhibition of platelet aggregation this highlights a novel NOS II-dependent mechanism of action for naftidrofuryl [108]. Naftidrofuryl also reduces hypercholesterolaemia-induced intimal proliferation [109]. It has also shown inhibitory effect on prejunctional adrenergic neurotransmission and

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non-selective inhibition of smooth muscle contractile processes [110]. Early clinical trials show an increase in mean PFWD with no increase in MWD with naftidrofuryl when compared with placebo [111]. A subsequent randomized, placebo-controlled study of 181 patients showed a 92% improvement in PFWD and 83% improvement in MWD at 6 months as compared to 17 and 14% in the placebo group. In addition to improving the PFWD and MWD, patients taking naftidrofuryl show an improved quality of daily life [108,112]. Available data also provide some evidence of efficacy of the drug in the treatment of ischemic rest pain and vascular ulceration [109]. Adverse reactions of naftidrofuryl include headache, dizziness, insomnia and hepatitis. Therapy is contraindicated in patients with hyperoxaluria or kidney stones. Sarpogrelate, another 5-HT2 antagonist, that acts as an oral platelet anti-aggregant is in phase II trials for IC and phase III for cerebral infarction. Sarpogrelate has been observed to reverse the progression of atherosclerosis in preclinical models presumably through an upregulation of eNOS [113]. In clinical trials sarpogrelate exhibits similar efficacy to that of other drugs of its class but has a superior side effect profile [114]. Sarpogrelate has been introduced as a therapeutic agent for the treatment of ischemic diseases associated with thrombosis as it has been observed to inhibit thrombus formation, lower platelet aggregation and inhibit serotonin-induced coronary artery spasm and contraction as well as vascular smooth muscle cell proliferation. Though these pathophysiological effects are said to be mediated by 5-HT2A receptors, based on radio-ligand binding and functional studies, it has been shown that sarpogrelate exhibits specificity towards both 5-HT2A and 5-HT2C receptors, with a profile similar to ketanserin [115]. 6.2. Emerging agents 6.2.1. Levocarnitine Several new agents are under various phases of development and are showing benefit in IC. There are some exciting new approaches to the treatment of IC, including levocarnitine and propionyl-l-carnitine. Patients with PAD develop metabolic abnormalities in the skeletal muscles of the lower extremity. These abnormalities include impairment in ischemic muscle mitochondrial electron transport chain activity and accumulation of intermediates of oxidative metabolism (acylcarnitines). Patients with the greatest accumulation of muscle acylcarnitines have the most impaired exercise performance. Thus, claudication is not simply the result of reduced blood flow; alterations in skeletal muscle metabolism are also an integral part of its pathophysiology [14]. Levocarnitine (l-carnitine) and a derivative, propionyl levocarnitine, act on the leg muscle metabolism and are carrier molecules in the transport of long-chain fatty acids across the inner mitochondrial membrane, which provides substrates for energy production and improves the metabolism and exercise performance of ischemic muscles [116]. Sup-

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plementation with oral propionyl-l-carnitine increases availability of l-carnitine and, in addition to improving muscle metabolism, also improves vascular endothelial function [14,117]. Both these agents are proving to increase pain-free walking and the quality of life in IC patients. Propionyl levocarnitine appears to be the more effective of the two but is not yet available in the US. High doses of l-carnitine may cause body odor and gastrointestinal disturbances such as nausea, vomiting, diarrhoea and abdominal cramps [118]. 6.2.2. Policosanol It is a dietary supplement made of medium-chain alcohols extracted from sugarcane. Policosanol has shown favorable effects on intermittent claudication [119]. In both clinical and animal studies, policosanol has been shown to significantly reduce LDL, increase HDL, decrease platelet aggregation with, however, no effect on prostacyclin (PGI2 ) [120]. Two studies with policosanol have demonstrated positive results in patients with moderately severe intermittent claudication wherein 62 patients treated with 10 mg policosanol twice daily for 6 months, had their PFWD increased by 63.1%, and MWD by 65.1%, as compared to placebo. Policosanol also improved lower extremity symptoms of coldness and pain compared to placebo [16]. In post-marketing surveillance of 27,879 patients, the most significant adverse effects were weight loss (0.07%), polyuria (0.07%), insomnia (0.05%) or polyphagia (0.05%) [121]. 6.2.3. Arginine Due to arginine’s NO-stimulating effects, it has been used in the treatment of intermittent claudication and other cardiovascular complications [122]. Intravenous arginine injections significantly improved symptoms of intermittent claudication in a double-blind trial. Eight grams of arginine, infused twice daily for 3 weeks, improved pain-free walking distance by 230 ± 63% and the absolute walking distance by 155 ± 48% compared to no improvement with placebo [123]. 6.2.4. Sulodexide A glycosaminoglycan containing fast moving heparin and dermatan sulfate, it improves the walking ability of peripheral arterial obstructive disease patients to a significantly greater extent than placebo, with a concurrent significant decrease in fibrinogen activity [124]. Sulodexide is contraindicated in patients on heparin or oral anticoagulants. Some reported adverse effects include gastrointestinal intolerance and rare skin rashes [125]. 6.2.5. Prostaglandins These are naturally occurring lipids with vasodilating and anti-platelet activity [126]. Intravenous infusions of prostaglandins (PGs), PGE1 and PGI2 , have an established role in severe peripheral arterial disease. The recent introduction of longer lasting and/or oral forms of the PGs makes them more likely to be useful in the IC associated with less severe forms of the disease. Prostaglandins improve blood

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flow by relaxing smooth muscles and also possess some anti-clotting activity. Early studies on prostaglandin E1 in an injectable form in intermittent claudication are promising. Beraprost, ecraprost, limaprost, some newly developed oral prostaglandins, are also showing promise in extending the limits of exercise with cardiovascular benefits. A phase III trial using a lipid emulsion of ecraprost is underway for the treatment of patients with severe peripheral arterial disease [127]. However, more research is required before their validated use in PAD. 6.2.6. Statins Drugs in current clinical use such as HMG-CoA reductase inhibitors (statins) that may also lower oxidative stress can be included in PAD treatment regimen. A number of clinical trials have shown that statins improve endothelial dysfunction in patients with coronary risk factors beyond what could be attributed to their impact on plasma lipids [128]. Statins not only lower the risk of vascular events, but they also improve the symptoms associated with PAD [129]. There is also evidence that statins reduce surgical mortality and improve graft patency and limb salvage [130]. The pleotropic effects of statins include increase in NO bioavailability, antioxidant properties, inhibition of inflammatory responses and stabilization and regression of atherosclerotic plaques [131–134]. Many epidemiological studies are revealing that the HDLcholesterol raising ability of statins also plays a role in bringing about regression of atherosclerosis [135]. Recent studies have demonstrated statins to be very effective as secondary preventive measures in patients with PAD but these continue to be underutilized [136,137]. 6.2.7. Angiotensin converting enzyme (ACE) inhibitors The proatherogenic effects of angiotensin-II, especially in the presence of hyperlipidemia, are well documented and ACE inhibitors have the potential to stabilize and regress atherogenic plaques [138]. The HOPE study, a doubleblind randomized study evaluating ramipril in 9297 patients, included a cohort of 4051 (44%) patients with PAD [139]. At a mean follow up of 4.5 years, ramipril significantly reduced the composite endpoint by 25% in PAD patients implicating that all patients with clinical evidence of PAD should be considered for ACE inhibition as a part of their BMT for PAD [140]. It is of interest that the biochemical mechanisms by which ACE inhibitors achieve their vascular protective effects are shared by statins, although it yet remains to be established whether this combination therapy will result in additive or synergistic vascular effects. 6.2.8. Thromboxane receptor antagonists If 8-iso-PFG2␣ emerges as a potential, independent risk factor for PAD, doors open for a host of drug classes that may be of therapeutic relevance in PAD. As 8-iso-PFG2␣ activates TXA2 receptors, TXA2 receptor antagonists, especially in combination with oral prostacyclin mimetics and NO-aspirin, can be a viable therapy [141]. SOD-mimetics,

thiols, xanthine oxidase and NADPH oxidase inhibitors are currently receiving much interest in developing strategies to reduce oxidative stress in atherosclerosis. 6.2.9. G. biloba The possibility that G. biloba may be effective for intermittent claudication is supported by its pharmacological actions, its active principals being flavonoides and terpene trilactones, comprising of bilobalide and ginkgolides [142]. The latter, in particular ginkgolide B, inhibits platelet activating factor [143]. Other actions include a decrease in eythrocyte aggregation and blood viscosity, as well as anti-ischemic effects through the increase of trancutaneous partial pressure of oxygen [142]. Extract from G. biloba, discovered in China in 1690 by Kaempfer, has vasoregulatory and blood thinning effects, and furthermore, recent in vitro experiments have suggested that the vasorelaxing effects of G. biloba extract are related to the release of nitric oxide which, in turn, may be influenced by the free radical-scavenging activity of the extract [142], preventing oxidative damage to membranes [118,144]. An analysis of eight studies reports its modest beneficial effect on pain-free walking in IC patients [125]. However, it should be noted that herbal remedies are not regulated and the standards not guaranteed. Moreover, herbals are also likely to have side effects contrary to popular belief although G. biloba extracts reported in the literature are relatively safe and most extensively researched upon [145]. Ginkgo has an increased risk of bleeding, in combination with warfarin or high-doses of Vitamin E. The most common adverse effect seen is gastrointestinal symptoms, dyspepsia, nausea, dermatitis and headache [116]. 6.2.10. Antioxidants Vitamin C (ascorbic acid), an important anti-oxidant, reduces free radical damage and atheroma formation in blood vessels [146,147] and may be useful in stopping the progress in atherosclerosis. In IC patients, Vitamin C may prevent the acute, systemic impairment in endothelial function induced by maximal exercise [148,149]. The beneficial effect of Vitamin E on intermittent claudication was suggested as early as in 1948, although at that time, the antioxidant properties of Vitamin E were unknown. Vitamin E improves tolerance to pain caused by ischemia in the leg muscles during exercise, thereby relieving the pain, through a variety of mechanisms including reduction of oxidative stress [150]. Randomized clinical trials of the effects of Vitamin E on intermittent claudication have concluded a positive effect [151] and its use has been recommended for IC. An epidemiological study has suggested the use of folic acid supplementation in IC subjects with hyperhomocysteinaemia that has been recently identified as an important risk factor for atherosclerotic vascular disease and also PAD [147]. 6.2.11. Therapeutic angiogenesis This is viewed as an adjunct to current surgical revascularization techniques rather than a treatment modality for

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IC. Surgical and endovascular options, not covered in this review, offer greater degrees of improvement but also greater morbidity and hence are reserved as a last resort for severe claudication. Therapeutic angiogenesis too is reserved for such severe conditions as of now. The growth of new vessels from existing vascular structures can be achieved with direct administration of angiogenic growth factors, genes encoding these proteins, autologous bone marrow cells and several phase III trials are underway for the use of LFGF (FGF-2), VEGF, hepatocyte growth factor to promote formation of collateral vessels for treatment of severe myocardial or lower limb ischemia [152]. Raised endogenous level of plasma VEGF in patients of CAD and PAD has been reported as evidence of angiogenesis and is the compensatory response of the body to pathology by restoring blood flow to ischemic tissues [153]. Hence, administration of VEGF appears to hold significant promise in treating IC and seems to be the brightest option for IC in times to come; however, the form of treatment, dosing frequency and route of administration for maximum efficacy and safety profile are a concern. The adverse effects reported include increased risk of pathological angiogenesis, systemic effects such as hypotension, proteinuria and thrombocytopenia [154]. A multicenter, double-blind, placebo-controlled, phase II trial (TRAFFIC; therapeutic angiogenesis with FGF-2 for IC) has shown a significant improvement in MWD at day 90; however, the efficacy of the treatment was not maintained at day 180 [17]. A phase I trial administration of VEGF (adenoviral-mediated transfer and expression of vascular endothelial growth factor) has showed a 77% improvement in MWD but a phase II, doubleblind, placebo-controlled study designed to test the efficacy and safety of a single intramuscular delivery of AdVEGF121 (RAVE trial) involving 105 patients showed no improvement in Ankle-Brachial Index, claudication onset time and quality-of-life measures in comparison to placebo [155]. No major safety issues associated with AdVEGF121 were identified throughout 1 year of follow up except increased incidence of lower extremity edema, indicative of either a biological effect of the growth factor (enhanced permeability) or an inflammatory response to the virus itself. Design of the Del-1 for therapeutic angiogenesis trial (DELTA-1), a phase II multicenter, double-blind, placebo-controlled trial of VLTS-589, has been designed to assess the safety and efficacy of a plasmid-mediated approach to induce angiogenesis with angiomatrix protein developmentally regulated endothelial locus 1 (Del-1) [156]. DELTA-1 represents the largest plasmid-based gene transfer trial designed to test the efficacy of a Del-1 as a therapeutic approach in patients with IC caused by PAD.

7. Future trends Over the next 20 years, the total number of people affected by PAD/IC is expected to rise significantly due to the anticipated demographic changes. Current pharmacological inter-

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vention for IC, based on “antiartheriosclerosis”, “improvement of microvascular circulation”, “reduction of spasm” and “development of collateral vessels” aspects, is far from satisfactory. Effective medication for the relief of intermittent claudication is limited. The approach to manage intermittent claudication patients has changed considerably over the past decade, as the natural history, risk factors and co-morbidities are better understood and new viewpoints have emerged. CAD, stroke, transient ischemic attack (TIA) and PAD all are now envisaged as a single pathological entity that affects different vascular territories. A suggestive analogy being, TIA and IC can be considered as the unstable angina of the brain and lower limbs, respectively, and stroke and gangrene can be the myocardial infartion [52]. Current approaches for PAD/IC involve risk factor modification, exercise therapy, platelet inhibition and regression of atherosclerosis. Cilostazole is a recently approved therapeutic agent with proven effectiveness and clinical efficacy. Future research is likely to focus on agents that favorably alter the metabolic state of skeletal muscles such as l-arginine and propyl-l-carnitine. In the next 2 years, the results of major trials of drugs that stabilize and regress atherosclerosis such as statins and ACE inhibitors, and anti-platelet agents, recombinant growth factors and immune modulators will be available for IC [107]. The American Heart Association and the National Cholesterol Education Program, USA, have recommended identical atherosclerosis risk reduction strategies for both PAD and CAD patients. These recommendations include initiation of ␤-blockers and angiotensin converting enzyme inhibitors (ACEi’s) in all patients, use of statins to achieve a low-density lipoprotein (LDL) levels of less than 100 mg/dL, anti-platelet therapy and smoking cessation [13]. A new treatment paradigm for atherosclerosis is also fast emerging, namely medical therapies that rapidly mobilize cholesterol from existing atherosclerotic plaques and thereby reduce plaque burden, halt progression and/or induce regression of atherosclerosis. Regression of atherosclerosis might not improve maximal vasodilator capacity, but improves endothelium-dependent relaxation, decreases hypersensitivity of blood vessels and the susceptibility towards vasospasm [157]. In practice, this type of acute therapy, e.g. with recombinant apolipoprotein A-1, the main apoprotein component of HDL-cholesterol, might complement long-term maintenance therapies (e.g. statins and ACE inhibitors) in addition to newer modalities that stabilize and prevent the regrowth of atherosclerotic lesions [158]. Similar approaches with drugs that increase HDL-C through inhibition of cholesterol ester transfer protein, agonists of LXR/RXR receptors, drugs targeting the ABCA1 transporter, all are under extensive investigation [159]. The role of these in PAD/IC is yet to be established. The dismal performance and ineffectiveness of PAD drugs has provoked an international consensus that advices to allocate health resources for prevention and rehabilitation of IC rather than for re-imbursement of the existing PAD drugs with doubtful efficacy [160]. As understanding of

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atherothrombosis together with skeletal muscle functioning are clear key target areas to address PAD/IC, it is a pertinent thought as to why PAD/IC management is still elusive? In our view considerable strides have been made in the understanding of progression of atherosclerosis that offers to bring on the horizon the possibility of successful management of progression of IC; however, the potential for regression of atherosclerosis with acceptable efficacy–tolerability ratio has not yet emerged. A multifactorial and multidisciplinary approach emerges as a distinct need and emphasis is required to continue endeavors to find the effective pharmacotherapy. Moreover, it should be kept in mind that PAD still remains an esoteric disease and there is a significant lack of awareness of this condition leading to its under-diagnosis and undertreatment. Measures to promote awareness of treating PAD as an equivalent and not as a country cousin of CAD are needed. Since most PAD patients are asymptomatic and carry potentially significant morbidity and mortality risks, screening for PAD should be made a routine practice at the primary health care level [161]. Also, the roles of the cardiovascular specialists should be expanded to encompass panvascular disease treatment and prevention [162]. Acknowledgements We thank Mr. Venkatesh Babu and Mr. Rahul Singh, for the assistance in proof reading the manuscript. References [1] Bick C. Intermittent claudication. Nurs Stand 2003;17:45–52. [2] Duprez DA, De Buyzere ML, Hirsch AT. Developing pharmaceutical treatments for peripheral artery disease. Expert Opin Investig Drugs 2003;12:101–8. [3] Hiatt WR. Pharmacologic therapy for peripheral arterial disease and claudication. J Vasc Surg 2002;36:1283–91. [4] Lanzer P. Vascular multimorbidity in patients with a documented coronary artery disease. Z Kardiol 2003;8:650–9. [5] Schmieder FA. Intermittent claudication: magnitude of the problem, patient evaluation, and therapeutic strategies. Am J Cardiol 2001;87:3D–13D. [6] Murray S, editor. Vascular disease: nursing and management. London: Whurr Publishers; 2001. [7] Leng GC, Lee AJ, Fowkes FG, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996;25:1172–81. [8] Muluk SC, Muluk VS, Kelley ME, et al. Outcome events in patients with claudication: a 15-year study in 2777 patients. J Vasc Surg 2001;33:251–7 [discussion 57–8]. [9] Jelnes R, Gaardsting O, Hougaard Jensen K, et al. Fate in intermittent claudication: outcome and risk factors. Br Med J (Clin Res Ed) 1986;293:1137–40. [10] Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381–6. [11] Howell MA, Colgan MP, Seeger RW, Ramsey DE, Sumner DS. Relationship of severity of lower limb peripheral vascular disease to mortality and morbidity: a six-year follow-up study. J Vasc Surg 1989;9:691–6 [discussion 96–7].

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