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Peripheral Arterial Disease

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1 Peripheral Arterial Disease
Slide Kit 2 Peripheral Arterial Disease Vascular disease in peripheral vessels, peripheral arterial disease (PAD), produces a variety of symptoms ranging from intermittent claudication to pain at rest. Patients with the most serious PAD have critical limb ischemia that produces pain at rest and threatens the viability of the limb by increasing the risk for gangrene and necrosis. PAD is a strong marker for cardiovascular disease. Over a 10-year period, PAD increases risk for death due to cardiovascular disease approximately 6-fold. KOIAA Pletaal Training Manual

2 Coexisting Vascular Diseases
Atherothrombosis is commonly found in more than one arterial bed. (CAPRIE study, n = 19,185) 70 CAD 68 60 PAD CVD CAD 7.4% 50 56 CVD 24.7% 29.9% 40 42 Coexistent Disease (%) 30 3.3% 32 28 20 26 3.8% 11.8% 10 19.2% Coexistent Stroke PAD Coexistent PAD Coexistent CAD Because PAD, CAD, and CVD are all manifestations of atherosclerosis, it is not surprising that the three conditions commonly occur together. At CAPRIE study entry approximately 26% of the patients had ischemic vascular disease in at least two vascular beds, demonstrating the generalized nature of atherothrombosis. 11.8% of patients had both coronary disease and PAD, 7.4% had both CAD and CVD, 3.8% had a combination of CVD and PAD, and 3.3% had disease of all three arterial beds. Over time this overlap will most probably increase (in the CAPRIE trial more than 2,000 patients experienced a major ischemic event over the mean 1.9 year follow-up, and many others developed other ischemic events such as transient ischemic attack and angina). Ness and Aronow evaluated the incidence and degree of overlap of CAD, CVD, and PAD in 1,802 elderly patients (aged  60 years) in an academic, hospital-based geriatric practice. The results demonstrated that two-thirds of patients had some manifestation of vascular disease and a significant degree of overlap of these conditions. For example, in patients with PAD, 42% of the patients had concomitant stroke, and 68% also had CAD. Lancet. 1996;348:1329–39 Ness J. et al. J Am Geriatr Soc. 1999;47: CVD: Cerebrovascular Disease, CAD: Coronary Arterial Disease, PAD: Peripheral Arterial Disease KOIAA Pletaal Training Manual

3 Long-Term observation of IC patients
Survival, myocardial infarction, surgical or percutaneous revascularization, and major amputation over 10 years of follow-up in patients initially presenting with intermittent claudication 100 80 60 40 20 Survival Myocardial infarction Patients (%) Intervention Amputation Time (years) Increased risk of myocardial infarction Increased risk of stroke PAD 4 X greater risk4 (includes only fatal MI and other CHD death) 2-3 X greater risk3 (includes TIA) Post MI 5-7 X greater risk1 (includes death) 3-4 X greater risk2 (includes TIA) Post stroke 2-3 X greater risk2 (includes angina and sudden death) 9 X greater risk3 Assumptions include a 6.8% annual risk of mortality, a 2.0% risk of myocardial infarction, a 1.0% risk of intervention, and a 0.4% risk of amputation. Kenneth Ouriel. Lancet. 2001;358: This chart is based on epidemiological data and is not intended to provide a direct basis for comparison of risks between event categories. Patients with evidence of additional ischemia are at an even greater cross-risk of MI and stroke. 1. Adult Treatment Panel II. Circulation. 1994;89: 2. Kannel WB. J Cardiovasc Risk. 1994;1: 3. Wilterdink JI, Easton JD. Arch Neurol. 1992;49: 4. Criqui MH et al. N Engl J Med. 1992;326: KOIAA Pletaal Training Manual

4 Patholophysiology of PAD
Peripheral arterial disease Level I Level II Level III Level IV Symptoms by decrease of blood flow Decrease of function Ulcer and Necrosis Asymptomatic Numbness Coldness Raynaud’s phenomenon Intermittent Claudication Resting Pain Ulcer Necrosis Carotid artery (Brain) Aorta (to body) Background Diabetic Mellitus Hypertension Hyperlipidemia Superior mesenteric artery & celiac artery (Intestines) Renal artery (Kidneys) Common iliac artery (Legs) Main arteries’ stenosis Progress of stenosis・occlusion Occlusion Narrowed artery Ischemia: decreased oxygen-rich blood to an area, which can cause pain and dysfunction 50% of diameter stenosis 75% of area stenosis 60% of diameter stenosis 84% of area stenosis The major cause of occlusive PAD is arteriosclerosis obliterans, defined as the development of atherosclerotic plaques in the peripheral vasculature. These plaques develop as a result of endothelial activation associated with conditions such as dyslipidemia, diabetes mellitus, hypertension, etc. Plaques resulted din the proliferation of vascular smooth muscle, with subsequent damage to the vascular structure. The lesion themselves can be unstable and rupture, or adjacent smaller vessels experiencing high hemodynamic pressure caused by nearby plaque may rupture. Arterial stenosis impedes blood flow creating ischemia which later decreases normal function of the affected area. Atherosclerotic plaque obstructing 70% or less of a lumen is unlikely to produce ischemic pain at rest, but when the artery is challenged by the increased oxygen demands of exertion, painful leg cramping (intermittent claudication) may occur. Occlusion of the lumen of 90% or more will likely produce pain at rest and even greater pain on exertion. Platelet KOIAA Pletaal Training Manual

5 Major Symptoms of PAD Patients with PAD have a reduced functional capacity that limits their ability to perform daily activities. Abnormal skin color Coldness Cold sensation in one or both legs/ hands Skin (of extremities) turns to a pale or purple color. Numbness sometimes appears together. Rest pain Claudication Occlusion of the lumen of 90% or more will likely produce pain even at rest . Pain in one or both legs on walking, primarily affecting the calves, that does not go away with continued walking and is relieved by rest Atherosclerotic disease in PAD maybe asymptomatic, may produce symptoms with exercise, or in severe cases, mat lead to symptoms at rest. Claudication symptoms are typically localized in the calf or the thigh; rest pain is characteristically in the foot. Clinical Examination through skin color. Ask the patient to raise his two legs against the wall. The color of the an ischemic legs will turn pale upon raising and the temperature is cold. Let the patient put the two legs down afterwards. The color of the normal leg will turn red immediately however, the ischemic leg, the redness is not that intensified as compared to the other leg. The color of the skin is a good basis of diagnosing PAD. Stenosis of the arteries may involve more than 2 arteries at the same time. The location and the distance of the arteries will determine the intensity of the skin color. Other symptoms Erectile dysfunction Peripheral Neuropathy KOIAA Pletaal Training Manual

6 PAD is often Asymptomatic
Leg symptoms: PARTNERS PAD: ABPI ≤ 0.90 Newly diagnosis of PAD (n = 457) No (%) Prior diagnosis of PAD (n = 366) No (%) p value No pain 193 (48.3 %) 84 (25.8 %) < 0.001 Atypical 185 (46.3 %) 201 (61.7 %) Classic rose claudication 22 (5.5 %) 41 (12.6 %) ABPI (SD) 0.78 (0.16) 0.78 (0.23) Rose claudication: exercise induced calf pain, not present at rest, which required stopping, and remitted in 10 minutes or less. Prevalence of PAD in primary care practice is high, yet physician awareness of the PAD diagnosis is relatively low. Underdiagnosis of PAD maybe a barrier to effective secondary prevention of the high ischemic cardiovascular risk associated with PAD. The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program demonstrated the lack of reliability of leg symptoms as the sole indicator of PAD Vasc Med. 2001;6(3 Suppl):9-12 In this study, 48% of newly diagnosed patients and 26% of previously diagnosed patients were asymptomatic (no leg pain). Another 46% of newly diagnosed patients and 62% of previously diagnosed patients presented with atypical leg symptoms. Less than 6% of newly diagnosed patients and 13% of previously diagnosed patients presented with classic Rose claudication. Prior PAD: If it was documented by chart review, if they had prior abnormal vascular laboratory studies confirming PAD, or they had prior limb arterial revascularization, regardless of their ABI value at the survey office visit. Hirsch AT, Criqui MH, Treat-Jacobson D et al. JAMA. 2001;286: Vasc Med. 2001;6Suppl 1:9-12 JAMA. 2001;286(11): KOIAA Pletaal Training Manual

7 Risk Factors of intermittent claudication
Risk factors by intermittent claudication status Risk factors Intermittent claudication with without Odds Ratio p value Male sex (%) 56 42 1.7 0.0001 Mean age (y) 64 60 1.5 High-normal blood pressure (%) 16 19 1.3 0.1302 Stage 1 hypertension (%) 29 28 0.4164 Stage 2 hypertension (%) 36 22 2.2 Diabetes (%) 20 6 2.6 Daily cigarette smoking rate 10 7 1.4 Mean cholesterol (mg/dL) 248 239 1.2 0.0018 Preexisting CHD (%) 34 12 2.7 Statistics based on 26,316 person-examinations (381 with IC and 25,935 without IC). Stage 1 hypertension: systolic blood pressure mmHg; diastolic blood pressure mm Hg. Stage 2 hypertension: systolic blood pressure 160 mmHg; diastolic blood pressure 100 mm Hg. CHD: Coronary Heart Disease In contrast to subjects free of IC, those with IC were more likely to be male; on average were 4 years older; had a higher mean cholesterol level; had higher prevalence of stage 2 or greater hypertension, diabetes, and coronary heart disease; and smoked a greater number of cigarettes per day. In the logistic regression model, male sex, age, and smoking were associated with an 1.5-fold increased risk for IC; diabetes and stage 2 or greater hypertension conferred a >2-fold increased risk; and coronary heart disease nearly tripled the risk for IC. Joanne M Murabito et al. Circulation. 1997;96:44-49 KOIAA Pletaal Training Manual

8 Evaluation of PAD Age 50–69 years and smoking or diabetes
Leg pain with exertion Abnormal results on vascular examination of leg Coronary, carotid, or renal arterial disease Measure ankle-brachial index Index > 1.30 Index 0.91 ~ 1.30 Index  0.90 Pulse-volume recording Toe-pressure measurement Duplex ultrasonography Measure ankle-brachial index after treadmill test Normal results: no peripheral arterial disease Abnormal results Normal postexercise ankle-brachial index: no peripheral arterial disease Decreased postexercise ankle-brachial index Evaluate other causes of leg symptoms Patients should be evaluated for peripheral arterial disease if they are at increased risk because of their age or the presence of atherosclerotic risk factors, have leg pain on exertion, or have distal limb ulceration for which the history and examination do not provide an obvious explanation. Index > 1.30 Additional vascular studies can be performed, including pulse-volume recording, measurement of pressure in the first toe, or duplex ultrasonographic imaging of the peripheral vessels, to determine whether peripheral arterial disease is present. Index 0.91 ~ 1.30 An ankle–brachial index value that is over 0.90 at rest but decreases by 20 percent after exercise is diagnostic of peripheral arterial disease. Index ≤ 0.90 The patient probably has peripheral arterial disease, and no additional tests are necessary. Peripheral arterial disease Hiatt WR. N Engl J Med, 2001;344(21): KOIAA Pletaal Training Manual

9 Symptomatic Outcome Measures
Classification of PAD: Fontaine’s Stages and Rutherford’s categories Fontaine Rutherford Stage Symptom Grade Category Clinical Description I Asymptomatic IIa Mild claudication 1 IIb Moderate severe claudication 2 Moderate claudication 3 Severe claudication III Ischemic rest pain II 4 Ischemic rest loss 5 Minor tissue loss IV Ulceration or Gangrene 6 Major tissue loss Grade Category Clinical Description Asymptomatic I 1 Mild claudication 2 Moderate claudication 3 Severe claudication II 4 Ischemic rest loss III 5 Minor tissue loss 6 Major tissue loss J Vasc Surg. 2000;31(1 part 2):S38-S39 Am J Cardiol. 2001;87(12A):3D-13D Fontaine’s Stages Fontaine Stage I is characterized by a decrease in the blood flow could result to numbness and cold sensation, Raynaud’s phenomena and there are cases that even with more than 50% stenosis, the patients remains asymptomatic. Intermittent claudication falls under Fontaine Stage II. Patients complain of pain while walking and relieve with rest. Fontaine Stage III and IV are characterized by resting pain and ulcer necrosis respectively. Rutherford’s Categories Category 0 indicates the asymptomatic state; category 1, mild; 2, moderate claudication; and 3, severe claudication; 4, ischemic rest pain; 5, minor tissue loss; and 6, major tissue loss. KOIAA Pletaal Training Manual

10 Objective Outcome Measures- ABPI (Ankle Brachial Pressure Index)
Interpretation of ABPI > 1.30 Non compressible Normal Mild-to-moderate PAD Severe PAD Doppler flowmeter Left-arm systolic pressure Right ABI = Higher right-ankle pressure Higher arm pressure Left ABI = Higher left-ankle pressure Higher arm pressure Right-ankle systolic pressure DP PT DP PT Left-ankle systolic pressure How to do the ABPI (=ABI) Assessment? ABPI is calculated by dividing the higher ankle systolic blood pressure and the higher brachial systolic blood pressure. The pressure should be measured in both arms: use the higher value. It is preferable to have the patient rest, quite and supine for at least 5 minutes before the pressures are measured. This ensures that any changes in the pressure that may have occurred due to previous walking have a chance to stabilize. Notice: limitation in diabetic patients In diabetic patients like those undergoing dialysis do have heavily calcified vessels, the arteries are frequently noncompressible. This results in an artificially elevated ankle pressure, which can cause misdiagnosis and underestimation of the severity of the disease. If the ABPI cannot be measured accurately, the toe pressure may be substituted. DT: Dorsalis Pedis, PT: Posterior Tibial Hiatt WR. N Engl J Med. 2001;344(21): KOIAA Pletaal Training Manual

11 Pulse Wave Velocity (PWV)
Distance Artery A B Time PWV(cm/sec) = Distance to be measured Pulse Wave Transmit Time Stiffness PWV High Low Soft Hard Asymptomatic Group (Gray Zone) Symptomatic (Abnormal) Normal Increase of PWV shows constant increase for risks of coronary heart disease, stroke and cardiovascular disease. PWV is the speed of the pulse wave to transmit a given distance between 2 sites of the arterial system. The velocity is determined by the elastic and geometric properties of the arterial wall. Pulse wave velocity (PWV) is known to be an indicator of arterial stiffness, and has been regarded as a marker reflecting vascular damages. Drawbacks of PWV It cannot be used for measurement if arteriosclerosis is present in the arm. Blood pressure, autonomic nerve function or the pressure exerted by any stimulus on artery influences PWV. VS-1000 This is a medical equipment similar with the Doppler, it is capable of measuring the pressure of lower and upper limb at the same time, and is capable of measuring PWV. This was used in PADSEARCH. Quick and Accurate Measurement of PWV and ABI Simple Operation Stress Test Mode Results “at a glance” Vasera (VS-1000) KOIAA Pletaal Training Manual

12 Peripheral Vascular Disease
PVD Type Vessels involved Peripheral atherosclerotic disease Atherosclerotic Large and medium sized arteries Burger’s disease Inflammatory and thrombotic Small and medium sized arteries and veins Raynaud’s disease Vasospastic Arterioles Acute arterial occlusion Hemolytic and thrombotic Arteries Fibromuscular dysplasia Hyperplastic, with or without thrombus formation Small and medium sized arteries Thrombophlebitis (Superficial phlebitis) Inflammatory and Thrombotic Superficial veins Deep vein thrombosis Embolytic and thrombotic Deep veins Varicose veins Structural defect Leg veins This table classifies PVD by pathophysiological type and indicates which vessels are involved. Intermittent Claudication: a pain or discomfort associated with exercise Acute Limb Ischemia: Any sudden decrease or worsening in limb perfusion causing a potential threat to extremity viability (2000 TASC recommendation 45) Critical Limb Ischemia: The term critical limb ischemia should be used for all patients with chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease. The term critical limb ischemia implies chronicity and is to be distinguished from acute limb ischemia. (2000 TASC recommendation 73) KOIAA Pletaal Training Manual

13 Most of patients are male
Buerger's Disease Overview Inflammation and thrombus formation in the small and medium-sized arteries and in the superficial veins of the extremities More commonly in the legs than in the arms Cigarette smoking is highly associated More frequent incidence in men under age 40 Manifestations Intermittent claudication, superficial phlebitis Sensation of coldness, numbness, abnormal skin color, ulcerations, necrosis and gangrene in the tips of the fingers Treatment Incurable/ slow progression Elimination of Smoking Prevention of local tissue damage from cold temperatures, trauma, fungal infections Thromboangitis Obliterans (TAO or Buerger’s disease) is a disorder involving inflammation and thrombus formation in the small and medium-sized arteries and in the superficial veins of the extremities, more commonly in the legs than in the arms. Other vessels may also be affected. Cigarette smoking is highly associated with Buerger's disease, which occurs more frequently in men under age 40. Manifestations of Buerger’s disease include symptoms of intermittent claudication and superficial phlebitis. Raynaud phenomenon often coexists with Buerger’s disease. Patients with Buerger’s disease may complain of sensations of coldness, numbness, tingling, and burning in the affected extremities. Severe ischemia may cause nail changes, ulcerations, and gangrene in the tips of fingers. Arteriosclerosis Obliterans (ASO) Thromboangitis Obliterans (TAO) Onset (Age) ≥ 50 20 ~ 40 Sex Male prevalent Most of patients are male Smoking Moderate Heavy smoker Diabetic Mellitus Many Rare Hypertension Atherosclerosis + - Arterial Calcification KOIAA Pletaal Training Manual

14 Raynaud's Disease / Phenomenon
Overview Vasospasm-induced ischemia of the arterioles in the fingers and toes, and occasionally of the nose and tongue Raynaud’s disease (primary): without underlying medical problem Raynaud’s phenomenon (secondary): with underlying medical problem Manifestations Triphasic color reaction: Red  white  blue Pain, throbbing sensation and extreme coldness of hands Treatment Protection from cold Mild sedative, prazosin, nifedipine, pentoxifylline Relaxation technique Cessation of smoking to prevent vasoconstriction Raynaud’s Disease is a transient condition in which the fingers or toes start throbbing and turns to a whitish color because of vasospasm of the small arteries. Typically, the constricted blood vessel will obstruct blood vessels temporarily, and the fingers will slowly turn from white to blue due to the lack of oxygen. The vessels will then reopen hence blood flow is restored and so is the color of the digits. Individuals with this syndrome may experience pain, throbbing sensation and extreme coldness of hands. Primary Raynaud (also called Raynaud’s disease), the more common occurs in over 50% of cases. It is not associated with any underlying medical problem. Women are affected about five times more often than men, and the age of presentation is usually between 20 and 40 years. Secondary Raynaud (Raynaud’s phenomenon) occurs in the presence of other medical condition, such as: Collagen vascular diseases – scleroderma, systemic lupus erytheromatosus Arterial occlusive diseases – ASO, TAO Pulmonary Hypertension Neurologic disorders – Intervertebral disk disease, spinal cord tumor Blood dyscrasias – Cold agglutinnins Trauma – eletric shock, piano playing Drugs – Egort derivatives, methysergide, vinclastine, cisplatin KOIAA Pletaal Training Manual

15 Intermittent Claudication
When walking, pain occurs, but it is gone with resting Maximal walking speed Normal = mph PAD = mph Maximal walking distance Normal = unlimited PAD, 31% difficulty walking in home PAD, 66% difficulty walking ½ block Peak VO2 (Oxygen consumption) What is intermittent claudication? The word “claudication” is derived from the Latin word “claudicatio,” meaning “to limp.” The term “intermittent claudication” has thus come to mean leg pain sufficient to cause the patient to stop, which is produced by exercise and relieved by rest, and is caused by arterial occlusive disease. It could be added that the pain is reproducibly caused by a given degree of exercise and relieved within minutes by rest. One who claudicates is called a claudicant, although the term claudicator is also frequently used. PAD, reduced 50% Otsuka data set. WR Hiatt et al. J Appl Physiol. 1992;73: KOIAA Pletaal Training Manual

16 Differentiation from Neural Disorder
Neural disorder lumbar spinal canal stenosis is very similar with IC Vascular (IC) Neural (Lumbar Spinal Canal Stenosis) Pain when walking Stiffness at foot when walking for 4~5 mins. Pain varied by the motion Not dependent on the distance, irregularly occurs Vascular (IC) Claudication begins after a reproducible length of ambulation and resolves within a few minutes after the patient stops walking, even if he or she remains standing. Neural (Lumbar Spinal Canal Stenosis) Claudication-like symptoms may also arise from spinal stenosis that is due to narrowing of the lumbar spinal canal. These symptoms often include numbness and weakness in the lower extremity that are produced by standing or bending backward at the hips rather than just ambulating. The symptoms are relieved, not simply by rest, but also by sitting down or leaning forward to straighten out the lumbar spine. 監修:済生会福岡総合病院院長 岡留健一郎 KOIAA Pletaal Training Manual

17 Pathogenesis of Intermittent Claudication Hemodynamic Abnormalities
What cause intermittent claudication? Atherosclerosis in peripheral arteries of legs During exercise, oxygen demand increases Muscles operate anaerobically Produce lactic acid and other metabolites Leg pain Lactic acid and other metabolites washed away on rest <Hemodynamic Abnormalities> 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/sec in the femoral artery. At these rates, atherosclerotic plaque obstructing 70% or less of a lumen is unlikely to produce ischemic pain at rest. However, 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/sec. At this pace, a stenosis of even 50% can cause a significant pressure and flow gradient leading to inadequate oxygen delivery. <Abnormal metabolism in anaerobic condition> The accumulation of metabolic intermediates such as acylcarnitines Impaired synthesis of phosphocreatinine Supranormal levels of adenosine diphosphates Am J Cardiol. 2001;87 (suppl):3D-13D KOIAA Pletaal Training Manual

18 Pathogenesis of Intermittent Claudication Metabolic and Neurological Abnormalities
Atherosclerotic lesions and increased blood viscosity result in reduced blood flow to the lower extremities. In patients with PAD, metabolic abnormalities develop in the skeletal muscles of the lower extremities. These abnormalities include impairment of the activity of the mitochondrial electron-transport chain in the ischemic muscles and accumulation of intermediates of oxidative metabolism (acylcarnitines). Distal axonal denervation and subsequent muscle atrophy also contribute to the development of IC, as do oxidative injury to mitochondrial DNA, altered mitochondrial enzyme content and activity, and accumulation of metabolic intermediates such as acyl-Coenzyme A, the result of incomplete fatty acid, protein, and carbohydrate metabolism. Creager M, ed. Management of Peripheral Arterial Disease Medical, Surgical, and Interventional Aspects. 2000 KOIAA Pletaal Training Manual

19 Consequences of IC/PAD
Natural history of IC/PAD 5 10 15 20 40 60 80 100 IC Control Survival (%) 75% experience symptom stabilization or improvement. 15-20% require revascularization (angioplasty or bypass surgery) 2~4% require amputation Death is usually due to coexisting coronary artery or cerebrovascular disease, not PAD Follow-up (years) 日本脈管学会編:「下肢閉塞性動脈硬化症の診断・治療指針」、協和企画:p20,2000 Decreased quality of life Limit activities of daily living Limit recreational activities Possible amputation(s) with progression of underlying PAD Decreased life expectancy PAD shortens life expectancy by 10 years Increased mortality rate 3 fold increased risk of death from all causes and 6 fold increase in risk of cardiovascular related death in patients with large vessel PAD compared with age and gender-matched patients with same risk factors but without PAD Several studies conducted over the past 40 years have confirmed that approximately 75% of all IC patients experience symptom stabilization or improvement over their lifetime without the need for intervention. Interestingly, the trend toward stabilization or clinical improvement holds despite arteriographic evidence for disease progression in a majority of this patient population. Symptoms worsen in approximately one quarter of all IC patients, most commonly during the first year (7% to 9%) and subsequently at rates of 2% to 3% per year. It has been estimated that approximately 5% will undergo an intervention within 5 years of their initial diagnosis. As observed in large studies with unselected populations, only approximately 2% to 4% will ever require a major amputation. Am J Cardiol. 2001;87 (suppl):3D-13D KOIAA Pletaal Training Manual

20 Sites of Occlusion and Pain
Common iliac artery Obstructive lesion %* Ischemia in Aorta or iliac 30 % Buttock Hip Thigh Femoral or popliteal 80-90 % Calf Tibial or peroneal 40-50 % Ankle Foot Internal iliac artery External iliac artery Deep Femoral artery Femoral artery Popliteal artery Anterior tibial artery Peroneal artery *Percent of IC patients who have an obstructive lesion in the site Posterior tibial artery The location of the pain is the key to the site of arterial occlusion; depending on the level and extent of the arterial occlusive disease, claudication may affect the buttock, thigh, calf, and, rarely, the foot. Calf claudication is typically a result of disease in the superficial femoral artery. Hip, thigh, and buttock claudication occurs with narrowing of the aorta and iliac arteries. Dosalis pedis artery KOIAA Pletaal Training Manual

21 Lower Limb Pulse Examination Point
Lower limb arteries Popliteal artery Femoral artery Femoral vein No1 No2 No3 Dorsalis pedis artery ① Common iliac artery ② Internal iliac artery ③ External iliac artery ④ Deep femoral artery ⑤ Superficial femoral artery ⑥ Popliteal artery ⑦ Anterior tibial artery ⑧ Dorsalis pedis artery ⑨ Posterior tibial artery No4 Posterior tibial artery No5 Palpation of all arterial pulses, including the brachial, femoral, popliteal, and pedal arteries, should be performed. Palpation can be done by pressing the index/middle finger on the pulses. Femoral artery can be palpated at the outer surface of the upper thighs while the popliteal artery is located at the back of the knees. The location of the posterior tibial pulse is behind the medial malleolus, and the dorsal pedis pulse runs along the dorsum of the foot between the first and second metatarsal bones. Pulses are graded as normally present (easily palpable), diminished (difficult to palpate), or absent. Patients with a palpable femoral pulse but absent pedal pulse will have disease confined to the leg vessels, whereas a diminished or absent pedal pulses indicates disease of the aorta or iliac arteries. 平井都始子 他 Medical Technology. 1997;25(5): KOIAA Pletaal Training Manual

22 Characteristics of Common Ulcers
Arterial (Ischemic) Main arteries Venous stasis Venous disease Neurotropic (Diabetic) Neuropathy Venous Neutrophic PAD, Burger’s Acute occlusion Toes, foot Malleolar Sole and pressure points of foot Severe Mild None Irregular, pale base Irregular, pink base Often deep, infected Origin Cause Location Pain Appearance Neuropathy and peripheral artery disease often occur together in people who have diabetes. Nerve damage (neuropathy) in the feet can result in a loss of foot sensation and changes in the sweat-producing glands. As a result, a person may not feel the development of foot calluses or cracks, increasing the risk of injury or infection. Treatment Overall treatment options Antibiotics, if an infection is present Anti-platelet or anti-clotting medications to prevent a blood clot Topical wound care therapies Venous ulcers are treated with compression of the leg to minimize edema or swelling. Compression treatments include wearing compression stockings, multilayer compression wraps, etc. Arterial ulcer treatments vary, depending on the severity of the arterial disease. Depending on the patient’s condition, the physician may recommend invasive testing, endovascular therapy or bypass surgery to restore circulation to the affected leg. Treatment for neurotrophic ulcers includes avoiding pressure and weight-bearing on the affected leg until the ulcer has started to heal. Regular debridement (the removal of necrotic or infected tissue) is usually necessary before a neurotrophic ulcer can heal. Frequently, special shoes or orthotic devices must be worn. HL Moore and JV white. PAD Handbook, CRC Press, 2005 KOIAA Pletaal Training Manual

23 Diabetic foot ulcer Epidemiology of diabetic foot ulcer
The annual population-based incidence ranges from 1.0% to 4.1%1 and the prevalence ranges from 4% to 10%, which suggests that the lifetime incidence may be as high as 25%.2,3 Diabetes underlies up to 8 of 10 nontraumatic amputations, of which 85% follow a foot ulcer.2 Pathophysiology of diabetic foot ulcer Causative Factors Contributory Factors Atherosclerotic peripheral vascular disease Intrinsic wound-healing disturbance A higher rate of onychomycosis Peripheral Neuropathy Excessive plantar pressure Trauma, especially when repetitive 1. Reiber GE. In: Bowker JH, Pfeifer MA, eds. The Diabetic Foot. St Louis, Mo: Mosby; 2001:13-32. 2. Presented at: International Consensus on the Diabetic Foot; May 22-24, 2003; Noordwijkerhout, the Netherlands. 3. Lavery LA et al. Diabetes Care. 2003;26: Pathophysiology of Diabetic Foot Ulcers Causative Factors. Peripheral neuropathy must usually be profound before leading to loss of protective sensation; the consequent vulnerability to physical and thermal trauma increases the risk of foot ulceration 7-fold. Excessive plantar pressure is related to both limited joint mobility and to foot deformities. Trauma: Among 669 persons with a foot ulcer, 21% were attributed to rubbing from foot wear, and 11% were linked to injuries (mostly falls Contributory Factors. Atherosclerotic peripheral vascular disease Twice as common in persons with diabetes as in persons without diabetes Intrinsic wound-healing disturbance Impaired collagen cross-linking and matrix metalloproteinase function Immunologic perturbations, especially in polymorphonuclear leukocyte function. A higher rate of onychomycosis: can lead to skin disruption Diabetic Foot Ulcer JAMA. 2005;293: KOIAA Pletaal Training Manual

24 Clinical Treatment Goals of PAD
Improve functional status Preserve the limb Prevent progression of atherosclerosis Reduce cardiac and cerebrovascular mortality Reduce clinical events such as MI and stroke Improve symptoms Improve QOL Improve exercise capacity Decrease the need for revascularization and amputation To address the risk in cardiovascular events To address limb symptoms PAD is highly associated with critical coronary and carotid artery disease that predispose these patients to a marked increase risk of myocardial infarction, ischemic stroke, and vascular death. Primary Goal Aggressive management of cardiovascular risk factors to prevent the progression of leg arterial disease and also to reduce the risk of ischemic events.  Antiplatelet therapy, angiotensin-converting enzyme (ACE) inhibitor drugs, Statin Secondary Goal Severity of limb symptoms should be assessed  Structured exercise program, Pletaal KOIAA Pletaal Training Manual

25 Cardiovascular Risk Modication
Effect of cardiovascular risk modification therapies on claudication symptoms Treatment Claudication Symptoms Lipid lowering drugs + improvement Smoking Cessation +/- improvement ACE Inhibitors No improvement Antiplatelet Therapies Diabetes Treatment Hypertension Treatment Worsen Treatment that reduce cardiovascular risk generally do not improve claudication symptoms. PAD is a major manifestation of systemic atherothrombosis that affects a large segment of the adult population. The major treatment goals for this population are to address the marked increase risk in cardiovascular events and then secondarily to treat the disability and reduced exercise tolerance. Once patients have had a complete assessment and management of their risk factor, the second major of consideration is to address their limb symptoms. An important observation is that treatments that reduce cardiovascular risks generally do not improve their claudication symptoms. This claudication must be treated on its own merits. ACE: Angiotensin Converting Enzyme Hiatt WR. Curr Drug Targets Cardiovasc Haematol Disord Sep;4(3):227-31 KOIAA Pletaal Training Manual

26 Treatment of PAD Adjuvant therapy: Exercise, Medication Intravascular treatment: Minimally invasive treatment using catheter or stent Surgical treatment: Bypass Treatment of peripheral arterial disease Fontaine classification Level I Level II Level III Level IV Exercise Medication Risk factor Reduction Intravascular treatment Medication Surgical treatment Intravascular treatment Medication Treatment of PAD according to Fontaine’s Classification: Several treatment options are currently available. These are the adjuvant therapy, Intravascular treatment and surgical bypass. Pharmacotherapy is usually recommended for patients under Level I, II and early level III Many patients belong to level II, exercise and medication like Pletaal could significantly relief claudication. The main stream of treatment for Fontaine’s Level IV is intravascular surgery. However, medication is needed after the intervention. If symptoms worsens, then bypass surgery should be considered. 監修/星野俊一 ほか:日常みられる下肢閉塞性動脈硬化症の診療ガイドブック, p23, キタメディア, 2002 KOIAA Pletaal Training Manual

27 VASCULAR SURGERY Introduction of TASC Number 1, Part 2:S93
SUPPLEMENT TO In order to ensure an appropriate management algorithms and to achieve the optimal outcome for PAD patients, a group of experts in managing these patients had formulated the TransAtlantic Inter-Society Consensus (TASC). The TASC Working Group consisted of 14 MD societies across United States & Europe who had formulated the TASC Guidelines in the management of PAD based in current evidence-based medicine. J O U R N A L O F VASCULAR SURGERY VOLUME 31 NUMBER 1 PART 2 JANUARY 2000 TASC Management of Peripheral Arterial Disease (PAD) TransAtlantic Inter-Society Consensus (TASC) Number 1, Part 2:S93 Section A: Introduction Section B: Intermittent Claudication Section C: Acute Limb Ischemia Section D: Critical Limb Ischemia Developed by the 107 Recommendations 47 Critical Issues A. Introduction A1. Objectives and Methodology of the Consensus Process A2. Epidemiology, Natural History, Risk Factors A3. Outcome Assessment Methodology in Peripheral Arterial Disease A4. Economic Aspects of Peripheral Arterial Disease B. Intermittent Claudication B1. Introduction and Characterization of Patients B2. Evaluation B3. Outcome Assessment of Intermittent Claudication in Clinical Practice. B4. Treatment of Intermittent Claudication B5. Economic Aspects of Intermittent Claudication B5. Clinical Trial Issues in Intermittent Claudication C. Acute Limb Ischemia C1. Definition and Nomenclature for Acute Limb Ischemia C2. Evaluation C3. Outcome Assessment Methodology in Acute Limb Ischemia C4. Treatment for Acute Limb Ischemia C5. Economic Aspects of Acute Limb Ischemia C6. Clinical Trial Issues in Acute Limb Ischemia D. Chronic Critical Limb Ischemia C1. Definition and Nomenclature for Chronic Critical Limb Ischemia C3. Outcome Assessment Methodology in Chronic Critical Limb Ischemia C4. Treatment for Chronic Critical Limb Ischemia C5. Economic Aspects of Critical Leg Ischemia C6. Clinical Trial Issues in Critical Leg Ischemia TASC Working Group Mosby J Vasc Surg. 2000;31(1 Part 2):S1-S296 KOIAA Pletaal Training Manual

28 Complete Management Algorithm
TransAtlantic Inter-Society Consensus : TASC History and physical examination Ankle-brachial pressure index Confirmation PAD with intermittent claudication Assess cardiovascular risk factors +Assess disability symptom severity Initial evaluation ・ Hemoglobin ・ Serum creatinine ・ Smoking ・ Lipid profile ・ Hypertension ・ Diabetes Treadmill and/or ・ SF-36 questionnaire ・ WIQ questionnaire Mild symptoms- not disabled Moderate symptoms-disabled Severe symptoms-disabled Special investigations: ・ Hyper-coagulability screen ・ Homocysteine level ・ LP(a) ・ Other Encourage supervised walking exercise program/ consider pharmacotherapy Continue Successful outcome unsuccessful Continue noninvasive measures Locate lesion using: ・ Segmental limb pressure ・ PVR or VWF ・ Duplex scanning ・ MRA ・ Modify risk factors ・ Antiplatelet therapy SF-36=medical outcomes Short Form 36 questionnaire WIQ=Walking Impairment Questionnaire PVR=Pulse Volume Recording VWF=Velocity Waveform Analysis MRA=Magnetic Resonance Angiography * disability as defined by the individual patient Complete management algorithm for intermittent claudication: Two objectives of management for PAD: Symptom Improvement: this could be attained through supervised exercise and pharmacotherapy with Pletaal. SF-36 and WIQ help to assess the improvement in the quality of life and walking distance of these patients. If symptoms improve then continuation of noninvasive measures is encouraged. If not, then surgical therapy is recommended. *Pletaal is well established drug for improving symptoms of IC. 2. Prevention of Vascular Events: identification of risk factors and further confirmation by doing laboratory examinations would aid the doctors in establishing the risks of patients to having cardiovascular events. Modification of risk factors and antiplatelet therapy are the major considerations in preventing these events. Aspirin and Clopidogrel are the drugs which proven its worth in improving prognosis. * Pletaal, being an antiplatelet like Aspirin and Clopidogrel, might have something to do with prognosis improvement. However, clinical trials must be done. Endovascular or surgical therapy J Vasc Surg. 2000;31(1 Part 2):S1-S296 KOIAA Pletaal Training Manual

29 Potential Favorable Effects of Exercise Training
↑ Nitric oxide synthase Improved endothelial function ↑ Prostacyclin ↓ Free Radical Reduced Inflammation ↑ Vascular Endothelial Growth Factor Possible vascular angiogenesis Exercise Training ↑ Muscle oxidative activity Improved muscle metabolism ↑ Muscle enzyme activity ↑ Muscle acylcarnitine homeostasis Recommendation 29 ↓ Blood viscosity ↑ RBC filterability Improved hemorheology Exercise training in intermittent claudication A program of exercise therapy (preferably supervised) should be always be considered as part of the initial treatment for patients with intermittent claudication. Exercise Therapy Frequency: 3-5 supervised session/week Duration: 35 to 50 minutes of exercise/session Type of exercise: treadmill or track walking to near maximal claudication pain Length: 3 to 6 months Results : 100%-150% improvement in maximal walking distance Improvement in quality of life ↓ RBC aggregation N Eng J Med ;347(24): KOIAA Pletaal Training Manual

30 Risk Factor Modification (TASC)
Recommendation 22 Smoking cessation in peripheral arterial disease Recommendation 23 Control of diabetes in peripheral arterial disease Recommendation 24 Diabetic foot care in peripheral arterial disease Recommendation 25 Lipid control in peripheral arterial disease Recommendation 26 Control of hypertension in peripheral arterial disease Recommendation 27 Hypercoagulable states in intermittent claudication Recommendation 7 Hyperhomocysteinemia in peripheral arterial disease Smoking cessation Smoking correlated more closely with the development of intermittent claudication than did any other risk. (Geriatrics. 1973;28:61-68) Lipid control It has not been shown that treating dyslipidemia decreases cardiovascular morbidity and mortality in patients with PAD. (Cochrane Database Sys Rev. 2000;2:CD000123) In contrast to the lack of effect on ischemic events, the severity of claudication was reduced by lipid-lowering treatment. (Lancet 1994;344: ) Hypertension Hypertension is associated with the development of atherosclerosis, particularly in the coronary and cerebral circulations, as well as with a two- to threefold increased risk of claudication. However, the effects of treating hypertension on the natural history of atherosclerotic disease have not been evaluated in patients with PAD specifically. Hyperhomocysteinemia The rate of progression of intermittent claudication has also been found to be significantly associated with plasma homocysteine levels (J Vasc Surg. 1991;13: ). There are currently, however, no studies examining whether treating this problem reduces ischemic events. J Vasc Surg. 2000;31(1 part 2):S1-S296 KOIAA Pletaal Training Manual

31 Pharmacotherapy (TASC) to address the marked increase risk in cardiovascular events
Recommendation 28 Antiplatelet in PAD All patients with peripheral arterial disease (whether symptomatic or asymptomatic) should be considered for treatment with low-dose Aspirin or other approved antiplatelet (unless contraindicated), to reduce the risk of cardiovascular morbidity and mortality. J Vasc Surg. 2000;31(1 Part 2): S1-S296 Ticlopidine Ticlopidine has been shown to reduce the risk of stroke and fatal and nonfatal myocardial infarction by 29% compared with placebo. J Intern Med. 1990;227:301-8 Clopidogrel In CAPRIE study, Clopidogrel showed an overall RRR 8.7% in the risk reduction compared to Aspirin among the total population of more than 3,000 patients in each group (P = 0.04). In the PAD subgroup, clopidogrel (as compared with aspirin) resulted in a 23.8% relative risk reduction of ischemic stroke, MI, or vascular death, although the 95% confidence interval was wide (8.9%-36%). The Antiplatelet Trialists Collaboration reviewed 189 controlled studies involving secondary prevention of cardiovascular events in over 100,000 patients with cardiovascular symptoms. Overall, there was a 25% decrease in fatal and nonfatal MI, stroke, and vascular death. Fewer than 4,000 patients with PAD were entered (in 28 studies). They showed identical benefit to the overall group, but, because of the low numbers, this was not statistically significant. The benefit persisted for at least 3 years and was similar for aspirin, at dosages ranging from 75 to 350 mg/d. (BMJ 1988;296: )  Antiplatelet-drug therapy reduced the risk of fatal or nonfatal cardiovascular events from 11.9% in control group to 9.5% percent in the treatment group. Ticlopidine Enthusiasm for this drug is tempered by the substantial risk of thrombocytopenia neutropenia, and thrombotic thrombocytopenic purpura. Clopidogrel There were differences in the treatment effect among patients with stroke, myocardial infarction, and PAD. In the 6,452 patients with PAD, the primary end point occurred at an annual rate of 4.9% in patients given aspirin and 3.7% in patients given clopidogrel, an adjusted risk reduction of 23.8%. This treatment effect was greater than that in patients with myocardial infarction or stroke. Lancet. 1996;227: KOIAA Pletaal Training Manual

32 Pentoxifylline, Naftidrofuryl, Buflomedil, Pletaal
Pharmacotherapy (TASC) Established Drugs with Proven but Small Benefit in Improving Claudication Pentoxifylline, Naftidrofuryl, Buflomedil, Pletaal Recommendation 30 Pharmacotherapy for symptoms of intermittent claudication Although some controlled clinical trials with Pentoxifylline, Naftidrofuryl, Buflomedil, and recently Cilostazol (Pletaal®), have shown statistically significant improvement in walking distance, the average benefit was small. Greater benefit, observed in minority of patients, may warrant a short course of therapy with continued use of such agents if sufficient benefit is observed. Recent clinical trials have shown a greater benefit of Cilostazol (Pletaal®), for both walking distance and quality of life, which may warrant more widespread use. However, currently there are insufficient data to recommend the routine use of pharmacotherapy in all patients with claudication. Pentoxifylline In early controlled trials, the actual improvement over placebo from entry to 6 months in ACD was 18%, but this difference was not statistically significant. (Am Heart J. 1982;104:66-72) A more recent study confirmed these results, with a 21% improvement over placebo (p = 0.09). The study showed that a subgroup of patients with symptoms for longer than a year and an ABPI < 0.80 responded better to the drug. (Circulation. 1989;80: ) Naftidrofuryl In four placebo-controlled studies, Naftidrofuryl was more effective than placebo in improving walking distance (Angiology. 1986;37(3): , J Cardiovasc Pharmacol. 1990;16 Suppl 3:S75-S80, VASA. 1988;24:27-32, J Cardiovasc Pharmacol. 1984;23 Suppl 3:S44-S47) and a further study showed no significant difference. (Angiology. 1994;35(11): ) Buflomedil Two relatively small studies, conducted more than 10 years ago, showed a significantly greater improvement in absolute walking distance with Buflomedil compared with placebo. (Angiology. 1984;35: , International Symposium on Ischemic Disease and the Microcirculation. Frankfurt, Zuckschwerdt 1989:80-84) J Vasc Surg. 2000;31(1 Part 2):S1-S296 KOIAA Pletaal Training Manual

33 Antiplatelet drugs (Aspirin/Ticlopidine)
Pharmacotherapy (TASC) Drugs With Minimal or No Benefit in Improving Claudication Antiplatelet drugs (Aspirin/Ticlopidine) Aspirin: No studies have shown a benefit of Aspirin in the treatment of claudication, although there is one study that presented suggestive evidence that Aspirin slowed progression of atherosclerosis assessed by serial angiography. Ticlopidine: Ticlopidine may reduce the severity of claudication and the need for vascular surgery. Balsano F. J Lab Clin Med. 1989;114:84-91, Eur J Vasc Endovasc Surg. 1995;10:69-76 Vasodilators α blockers, papaverine, β2 agonist, calcium channel blocker, angiotensin converting enzyme inhibitor Arteriolar vasodilators were the first class of agents used to treat claudication. These drugs have not been shown to have clinical efficacy in randomized, controlled trials. BMJ. 1991;303: , N Engl J Med. 1979;300: , J Vasc Med Biol. 1993;4:23-28 Ticlopidine In two randomized, placebo-controlled trials to improve claudication symptoms and exercise performance. However, only one of these studies, by Balsano et al, had evaluable data. In that trial, treadmill testing was performed on the flat, and therefore, the clinical benefits of the drug may have been overestimated because of the very low treadmill workload. Vasodilator in the exercising claudicant, vessels in ischemic areas are already maximally dilated, so vasodilator drugs will only create a steal phenomena by dilating vessels in normally perfused tissues (primarily proximal muscles), thus shifting the distribution of blood flow away from muscles supplied by obstructed arteries. Others Ketanserin, Verapamil, Isovolemic hemodilytion, Amiophylline, Vitaime E, Defibrotide J Vasc Surg. 2000;31(1 Part 2):S1-S296 KOIAA Pletaal Training Manual

34 Vascular endothelial growth factor (VEGF)
Pharmacotherapy (TASC) Incompletely Studied Drugs With Potential Benefit in Improving Claudication Carnitine Supplementation of patients with carnitine improves ischemic muscle metabolism. Carnitine, and an acyl form of carnitine (propionyl-l-carnitine), are drugs that have been shown to increase exercise performance and improve claudication symptoms in several clinical trials. Prostaglandins Critical Issue 8: There is a need to investigate the possibly greater efficacy of prostanoids in patients with intermittent claudication, because most randomized, open or double-blind trials with intra arterial or intravenous prostanoids have been performed in patients with the last stage of critical limb ischemia. Predictors to select the most suitable patients for prostanoid treatment need to be determined. Vascular endothelial growth factor (VEGF) Early phase I and phase II trials are now in progress to determine whether this novel therapy has a clinical application in patients with claudication and severe leg ischemia. Prostaglandin The experience with orally active prostaglandins in claudication is more limited. e.g. Beraprost(a PGI2 Analog that is orally active) A single phase II dose-ranging study has been published in which 164 patients were randomized to placebo or three doses of drug. The improvement in absolute claudication distance over placebo was as follows: 60 μg/d produced a 48%increase, and 120 μg/d a 51% increase, 180 μg/d a 31% increase. None of these changes was statistically significant. A concern was that at the highest dose, 62% of the patients reported side effects of headache, flushing, and gastrointestinal intolerance. Several phase III trials are evaluating the effectiveness of these drugs in claudication, and it is hoped that these studies will clarify the utility of this class of drug. Vascular endothelial growth factor (VEGF) VEGF and basic fibroblast growth factor (bFGF) are mitogenic agents for the development of new collateral channels in models of peripheral ischemia. VEGF has been shown to augment collateral vessel development and increase capillary density in skeletal muscle in a rabbit model. This effect has been observed when the VEGF protein is administered by intraarterial infusion and when the DNA encoding for VEGF is given by intramuscular injection. J Vasc Surg. 2000;31(1 Part 2):S1-S296 KOIAA Pletaal Training Manual

35 Cilostazol (Pletaal®), 2005 (TASC)
Recommendation 16: Pharmacotherapy for symptoms of intermittent claudication A 3- to 6-month course of Pletaal should be first-line pharmacotherapy [B] for the relief of claudication symptoms, as evidence shows both an improvement in treadmill exercise performance and in quality of life [A]. Controlled data also support the efficacy of Naftidrofuryl [A] and only minimally support the efficacy of pentoxifylline [A]. Prostaglandins Several studies have been performed with oral Beraprost. While there was a positive trial in Europe, there have been two negative trials in the USA (Labs et al. 1999; Lievre et al. 2000; Mohler et al. 2003b). While intravenous administration of PGE1 may have modest benefits, the overall evidence does not support the use of this drug class for claudication (Reiter et al. 2004). Note Publication: 2005 Representative of Asia Prof.H. Shigematsu,Tokyo Univ. KOIAA Pletaal Training Manual

36 Chronic Limb Ischemia (ACCP)
Antithrombotic therapy in peripheral arterial occlusive disease: Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy 1. Aspirin We recommend lifelong aspirin therapy, 75 to 325 mg/d, in comparison to no antiplatelet therapy in patients with clinically manifest coronary or cerebrovasculardisease (Grade 1A) and in those without clinically manifest coronary or cerebrovascular disease (Grade 1C). 2. Ticlopidine We recommend clopidogrel over ticlopidine (Grade 1C). 3. Clopidogrel We recommend clopidogrel in comparison to no antiplatelet therapy (Grade 1C), but suggest that aspirin be used instead of clopidogrel (Grade 2A). ACCP: American College of Chest Physicians CHEST Sep;126(3 Suppl):609S-626S KOIAA Pletaal Training Manual

37 Chronic Limb Ischemia (ACCP)
4. Cilostazol (Pletaal®) For patients with disabling intermittent claudication who do not respond to conservative measures (risk factor modification and exercise therapy) and who are not candidates for surgical or catheter-based intervention, we suggest Pletaal (Grade 2A). We suggest that clinicians not use Pletaal in those with less-disabling claudication (Grade 2A). Underlying values and preferences: The recommendation against Pletaal for those with less-disabling claudication places a relatively low value on small possible improvements in function in the absence of clear improvement in health-related quality of life. 5. Pentoxifylline We recommend against the use of pentoxifylline (Grade 1B). 6. Prostaglandins For limb ischemia, we suggest clinicians not use prostaglandins (Grade 2B). Underlying values and preferences: The recommendation places a low value on achieving small gains in walking distance in the absence of demonstrated improvement in quality of life. American doctor’s opinion… Pletaal appears to be an appropriate therapy for patients with disabling claudication who are not candidates for revascularization. However, its high cost, modest effect on walking distance, lack of demonstrated benefit in improving health-related quality of life, and the salutary effects of exercise therapy and risk factor modification argue against its routine use in patients with less-disabling intermittent claudication. Pletaal has weak platelet inhibitory effects, and there are no data to support its use as an antiplatelet agent. Antiplatelet therapy with aspirin or clopidogrel should be continued in patients receiving Pletaal. CHEST Sep;126(3 Suppl):609S-626S ACCP: American College of Chest Physicians CHEST Sep;126(3 Suppl):609S-626S KOIAA Pletaal Training Manual

38 Pharmacotherapy (American Family Physician)
Drugs Dosage Comments Aspirin mg qd Recommended by the American College of chest Physicians for PAD, but the FDA found insufficient evidence to approve labeling for this indication Clopidogrel 75 mg qd Fewer side effects than aspirin in the CAPRIE trial, significantly less risk for TTP than ticlopidine Pentoxifylline 400 mg tid May have a small effect on walking ability, but insufficient data to support widespread use Cilostazol (Pletaal®) 100 mg bid Correct dosing is critical Avoid in patients with heart failure Reduce dosing to 50 mg twice per day in patients taking calcium channel blockers May cause loose stools and gastric upset Ticlopidine 500 mg bid Extensive hemodynamic monitoring for risk of TTP Experimental Therapies Drugs Dosage Comments Naftidrofuryl 600 mg qd Serotonin antagonist; increased walking distance in several trials, but use remains controversial; approved in Europe Propionyl levocarnitine 2 g qd No significant evidence Prostaglandinsa 120 µg qd Inconsistent results in recent trials Gene induced angiogenesis with endothelial growth factor Promising results in uncontrolled trials Ginko biloba extract Effective, but study methodology questionable Hyperbaric oxygen Extensive; results equivocal Am Fam Physician Feb 1;69(3):525-32 a Beraprost, Iloprost, Prostaglandin E1 KOIAA Pletaal Training Manual

39 Role of Pletaal in PAD + Drug of Choice for the treatment of PAD
Inhibition of thrombus formation ↓ Platelet aggregation Vascular normalization Endothelium protection Antiproliferation on VSMC Promote Angiogenesis Improvement of Symptom + Risk factor Modification Blood flow improvement ↑ Vasodilation (High femoral artery selectivity) ↑ RBC deformability Lipid metabolism improvement ↓ TG ↑ HDL ↓ ApoB ↓ RLP ↑ DHA Features Advantage Benefits 1. Vasodilating effect Increases blood flow of the lower extremities Faster and greater reduction in ischemic symptoms such as I.C. and ulcer sizes Improve QOL of the patients 2. Hemorrheology effect 3. Promote angiogenesis 4. Antiplatelet effect (thru different path way from major competitors & Synergistic effect) Inhibits thrombus or occlusion Synergistic and safe combination therapy with other antiplatelet agents (e.g. Aspirin, Clopidogrel) Safe usage for long term therapy 5. Mechanism should be determined.. Low bleeding tendency 6. HDL ↑ & TG, RLP-C ↓ Improves lipid profile ☞ Risk factor modification Decreases risks of cardiovascular events 7. Protective effect on endothelium Prevents the progression of atherosclerosis 8. Inhibits VSMC proliferation 9. Reversible effect on the platelet Short wash-out period Patient could undergo any emergency surgery without the risk of bleeding complications Improving QOL among PAD or IC patients Addressing the increase risk in cardiovascular events Prevention of Diabetic complication KOIAA Pletaal Training Manual

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