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A. Epidemiology navigator

  1. Prevalence of intermittent claudication [1,2,7]
    1. Men: 1-7% in men 50-75 years old
    2. Women: 0.5-2% in women 50-75 years old
    3. Prevalance ~30% in patients at least 70 years of age [2]
    4. True intermittent claudication symptoms present in 20-40% of PAD patients
    5. Ankle-brachial index (ABI) screening in ALL patients with any PAD risk factors [3]
    6. Risk of limb-loss in non-diabetics with PAD is ~2%
  2. Major Subsets of PAD
    1. Diffuse abdominal aortic disease
    2. Femoral - popliteal disease
    3. Iliac disease
  3. PAD and other Atherosclerotic Disease
    1. Common with Real Artery Stenosis
    2. Of patients with coronary artery disease (CAD), PAD occurs in ~20% [4]
    3. Of patients at least 70 years with PAD, 44% do not have CAD [2]
    4. Of the patients with PAD, ~50% have electrocardiographic evidence of CAD
    5. Often found with carotid disease
  4. PAD is a major (>6 fold increase) risk factor for cardiovascular death over 10 years

B. Risk Factors navigator

  1. Smoking (~80% of cases) ~5X risk
  2. Diabetes mellitus (DM) ~3X risk
    1. Duration of DM Type 2 proportional to risk (1.4X to 4.5X over 1-25 years) [38]
    2. Especially for severe claudication and amputation
  3. Hypercholesterolemia
  4. Hypertension (HTN)
  5. Atherosclerosis in other areas
  6. Elevated Serum Homocysteine Levels [5]
  7. Systemic inflammation - elevated C-reactive protein levels (~2 fold risk)
  8. Autoimmune Disease - particularly vasculitis
  9. Anticardiolipin Antibodies (ACL Abs) - found in ~15% of PAD patients; poor prognostic [8]
  10. PAD is an independent risk factor for premature morbidity and mortality [4]

C. Pathogenesis navigator

  1. Atheroma Formation
    1. Usually occurs at vessel bifurcations
    2. Probably due to turbulence ("eddy currents")
  2. Claudication
    1. Increased cardiac output on exercise leads to increased blood flow
    2. This leads to increased blood turbulence in diseased vessels
    3. Turbulant blood flow increases vessel damage
    4. Increases atherosclerotic plaque generation
    5. Systemic inflammation appears to accelerate atherogenesis
    6. Diseased vessels also have reduced vasodilatory responses
    7. Plaque growth and abnormal vasodilitation causes local hypoxia
    8. Local hypoxia leads to acidosis which causes pain (similar to exertional angina)
  3. Chronic severe hypoxia can lead to tissue breakdown and ulceration (see below)
  4. Severe vessel stenosis leads to pain at rest (similar to rest angina)
  5. Plaque rupture and thrombosis may lead to acute peripheral ischemia (see below)
  6. Superficial femoral artery is most commonly involved [24]

D. Symptoms [5,10]navigator

  1. Overview [10]
    1. Intermittent claudication was previously the standard screening method
    2. Many patients with PAD using ABI screening do not have claudication
    3. Other patients with PAD have atypical claudication, pain at rest
    4. Comorbid conditions contribute to atypical symptoms
    5. Therefore, symptoms are an unreliable indicator for presence or extent of PAD
  2. Claudication [4]
    1. Pain on exercise (walking) which resolves on rest
    2. Usually occurs in calfs, but may occur in thighs, hips, and/or gluteal areas
    3. Discomfort or numbness (non-classical claudication) is very common in PAD
    4. True pain on walking only occurs in 20-40% of patients with documented PAD [7]
    5. Intermittent claudication typically occurs with ABI >0.4 to <0.9
    6. ABI is more sensitive than claudication symptoms at predicting prognosis [39]
  3. Pain at Rest
    1. Occurs in advanced disease (typically with ankle-brachial index <0.4)
    2. Usually in foot, worse when leg is raised
    3. Ischemic (arterial) ulceration and gangrene may occur (see below)
  4. Renal Failure - usually with significant renal artery stenosis
  5. Impotence
    1. Likely reduced blood flow to internal pudendal artery
    2. More common in diabetics and in post-surgery (prostate, rectal) patients
  6. Acute Thromboembolic Disease
    1. Acute intermittent cladication
    2. Acute pain at rest
    3. Acutely white, paralysed leg

E. Diagnosisnavigator

  1. Clinical Exam [4]
    1. Clinical exam alone is insufficient for screening or ruling out PAD
    2. Lack of claudication or presence of normal pulses reduces risk of moderate or severe PAD
    3. Presence of cool skin, presence of one bruit, or palapable pulse abnormality increases likelihood that PAD is present
    4. Strongly suspect PAD if one foot is significantly cooler (or whiter) than the other
    5. Presence of femoral bruit is helpful for diagnosis
    6. Auscultation of arterial components by handheld Doppler is probably most accurate test
    7. Hairless extremities, foot discoloration, or atrophic skin are not helpful for PAD diagnosis
    8. Must combine physical exam findings with pretest probability
  2. Diminished Peripheral Pulses [4]
    1. Unilateral or reduced pulse in one side greater than other side more specific for PAD
    2. May be most pronounced after exercise
    3. Decreased ankle to brachial pressure index
    4. Assess pulses and peripheral pressures after exercise if normal resting pulses
  3. Screening with ABI [3,4,5]
    1. ABIs (right and left) may be obtained at rest or after exercise
    2. ABI correlates better with leg function (6 minute walking distance) than do symptoms of intermittent claudication [3]
    3. Baseline ABI and nature of leg symptoms predict functional decline at 2 years [39]
    4. ABI > 1.30 implies noncompressible (vascular calcification) artery
    5. ABI 0.91-1.3 is normal range
    6. ABI 0.41-0.9 is mild to moderate PAD
    7. ABI 0.00-0.40 is severe PAD
    8. ABI <0.9 associated with overall >2X increase in cardiovascular events as well as mortality over 10 years [19]
  4. Calculating ABI
    1. Accurate arm pressures can be obtained using doppler ultrasonographic probe
    2. Determine pressures in dorsalis pedis (DP) and tibialis anterior (TA) arteries
    3. To calculate ABIs, use higher of the two arm pressures
    4. For right ABI, use higher of right leg DP or TA with higher of arm pressures
    5. For left ABI, use higher of left leg DP or TA with higher of arm pressures
    6. ABI = highest right or left leg arterial pressure ÷ highest arm pressure
  5. Magnetic Resonance Angiography (MRA) [12]
    1. With gadolinium enhancement and 3-dimensional reconstruction
    2. Very sensitive (98%) and specific (96%) for PAD
    3. Compare with duplex ultrasonography sensitivity (88%) and specificity (95%)
    4. MRA is more sensitive and specific for 50% stenoses or total occlusion than either CT angiography or ultrasonography for lower limb PAD [11]
    5. Therefore, MRA is usually modality of choice for initial diagnosis
  6. Angiography
    1. Gold standard for diagnosis but being replaced by noninvasive methods
    2. Invasive method which requires intravenous contrast agent
    3. Patients with PAD often susceptible to contrast-associated nephropathy
    4. Digital Subtraction Angiography
    5. Aortography with flush to assess renal arteries
  7. Assess renal function including urinalysis (for evidence of renal vascular disease)
  8. Prognostic Markers [9]
    1. D-dimer is a marker for thrombosis (biproduct of cross-linked fibrin)
    2. C-reactive protein (CRP) and serum amyloid A (SAA) are markers of inflammation
    3. Higher levels of D-dimer, SAA, CRP associated with 1.2X higher overall mortality at up 2 years (but not 3 years) after measurement in patients with lower extremity PAD
    4. These markers also predicted cardiovascular mortality within 2 years of measurement
  9. Anticardiolipin Antibodies
    1. IgG ACL Abs are poor prognostic, with increased mortality risk ~2X [8]
    2. These antibodies should be evaluated to help determine treatment strategy

G. Differential Diagnosis of Leg Discomfort (Box 1, Ref [7])navigator

  1. Multiple causes could be present
  2. Arterial vascular disease (chronic and/or acute)
  3. Arthritis of knees or hips
  4. Ischemic intermittent claudication
  5. Lymphangitis
  6. Mechanical muscle pain
  7. Myositis
  8. Nerve root pain, sciatica
  9. Spinal Stenosis
  10. Peripheral nerve pain (including diabetic neuropathy)
  11. Post-phlebitic syndrome after deep vein thrombosis
  12. Reflex sympathetic distrophy (RSDS)
  13. Thromboangiitis obliterans (Buerger Disease)
  14. Venous claudication
  15. Vasculitis / Arteritis

H. Non-Invasive Treatment of Chronic PAD [13,14]navigator

  1. Most Treatments are Not Specific for PAD
    1. Most patients with symptomatic PAD will die from generalized atherosclerosis
    2. CAD and stroke are more common causes of death than PAD itself in PAD patients
    3. Atherosclerosis risk factor reduction is critical
    4. Antiplatelet therapies are the mainstay of treatment
    5. Decision on invasive versus non-invasive strategies generally patient dependent [24]
  2. Lifestyle
    1. Stop Smoking - strongly consider nicotine replacement and/or buproprion
    2. Exercise - most important active intervention; improves walking distance, prognosis
    3. Other risk factor modification - improved diet, reduce cholesterol
  3. Exercise [15]
    1. Increases functional capacity and reduces symptoms
    2. Improves endothelial vasodilator function, skeletal muscle function
    3. Also reduces blood viscosity and inflammatory responses
    4. Increase exercise as tolerated to near maximal pain, continued at least 6 months
    5. Reduces overall cardiovascular risks
  4. Pharmacologic Risk Factor Modification [7,14]
    1. Cholesterol reduction to LDL <100mg/dL using statins or niacin therapy
    2. Triglycerides reduced to <150mg/dL and HDL increased to >40mg/dL
    3. Cilostazol is specific for PAD improvement (see below) and has best efficacy evidence
    4. Aggressive treatment of HTN; ACE inhibitors (ACE-I) strongly preferred
    5. Control diabetes with glycosylated hemoglobin (HbA1c) goal <7%
    6. Primary prevention with aspirin (ASA) 81-325mg/d (reduces cardiovascular events)
    7. Secondary prevention with clopidogrel 75mg/d (reduces cardiovascular events)
    8. ß-adrenergic blockers can usually be used safely in moderate or mild PAD
  5. Pharmacological Treatment of PAD
    1. Cilostazol (Pletal®) - most effective agent to date for PAD [7,13]
    2. ASA (81-325mg qd) - overall reduction in thromboembolic events >25% [16]
    3. Clopidogrel (Plavix®) reduced overall vascular events [17]
    4. Clopidogrel should be used in ASA intolerant patients
    5. Subcutaneous heparin (12,500 U/day) for 3 months may be beneficial in PAD
    6. Addition of warfarin INR 2.0-3.0 to antiplatelet therapy did not improve outcomes and did increase life-threatening hemorrhage [43]
    7. Picotamide more effective than ASA in type 2 DM patients [23]
    8. Ramipril (Altace®), an ACE-I, significantly improved walk distance in PAD without HTN or diabetes [32]
    9. Proprionyl-L-carnitine 1-3gm daily (divided) has shown some efficacy [18,40]
    10. Proprionyl-L-carnitine is not currently available in the USA
    11. Pentoxifylline (Trental®) is rarely recommended (unclear benefit over placebo) [13]
    12. Thrombolysis - use in acute occlusion
  6. Cilostazol (Pletal®) [13,20,21]
    1. Phosphodiesterase III inhibitor
    2. Peripheral vasodilator and antiplatelet effects
    3. Approved for improving patient's walking distance in PAD
    4. Most potent agent for treatment of symptomatic PAD
    5. Increased walking distance versus pentoxyfylline and placebo in patients with IC
    6. Dose is 100mg po bid for most patients
    7. Reduce dose to 50mg po bid for patients on CYP3A4 or CYP2C9 inhibitors including erythromycin, diltiazem, azole antifungals, omeprezole (avoid grapefruit juice)
    8. Contraindicated in patients with congestive heart failure
    9. Side effects include headache, diarrhea, palpitations, dizziness
  7. ASA [16]
    1. ASA 325mg po qd reduces risk of need for peripheral artery surgery
    2. Claudication is not reduced by ASA
    3. Overall, ASA 81-160mg po qd reduced thromboembolic disease >25%
    4. Heparin 12,500 U/day added to 50mg/d ASA may improve PAD symptoms
  8. Clopidogrel (Plavix®) [17]
    1. Both ticlopidine and clopidogrel block ADP dependent platelet activation
    2. Ticlopidine reduces need for vascular surgery in patients with claudication by ~50%
    3. Ticlopidine improves long term peripheral graft patency by 15-20%
    4. Clopidogrel is as or more effective than ticlopidine without hematologic risks [17]
    5. Clopidogrel is tolerated by aspirin sensitive patients
    6. Clopidogrel dose is 75mg qd po
  9. Cholesterol Reduction
    1. Statins are the mainstay of therapy
    2. Pravastatin reduced cholesterol levels but not angiographic femoral atherosclerosis
    3. High dose (40mg/d) simvastatin for 6 months improved walking distance, ABI, and claudication in patients with PAD [25]
    4. Atorvastatin (Lipitor®) or rusovastatin (Crestor®) are probably as or more effective
  10. Angiogenic Growth Factors: VEGF
    1. Vascular Endothelial Growth Factor (VEGF)
    2. Fibroblast Growth Factor (FGF)
  11. VEGF [27]
    1. Very potent inducer of new vascular structures, including collateral vessels
    2. VEGF-gene transfer to site of limb ischemia can induce new vessels to grow
    3. Symptomatic and angiographic improvement documented
  12. Recombinant FGF2 [28]
    1. FGF2 causes proliferation of endothelial cells in vitro, angiogenesis in vivo
    2. Administered intra-arterial in patients with intermittent claudication
    3. Single dose recombinant FGF2 30µg/kg improved walking time significantly
  13. Agents with Minimal or No Efficacy
    1. Pentoxifylline (Trental®) inferior to cilostazol and is no longer recommended
    2. Prostaglandin E1 (alprostadil-alpha-cyclodextrine) had minimal efficacy in short term [29]
    3. Vasodilators
    4. Estrogens
    5. Reduction of iron stores had no effect on outcomes in PAD patients [6]
  14. Concomitant Problems
    1. Atenolol and nifedipine (or related dihydropyridine calcium blocker) often used in combination for treatment of HTN
    2. Combination, but neither agent alone, reduced walking distance of patients with claudication
    3. Peripheral ulcers may progres to gangrene
    4. Chronic ischemia can lead to requirement for amputation (particularly in diabetics)

I. Invasive Treatment of PAD [7]navigator

  1. Percutaneous Transluminal Angioplasty
    1. Improved methods in iliac and femoral-popliteal occlusion
    2. Probably better in chronic ischemia with stenosis than with true occlusion [1]
    3. Outcomes similar at 5 years for angioplasty and surgery in sevre ischemia of the leg [26]
    4. In general, stenotic area should be <10cm for adequate results
    5. increasingly used for lesions 10-15cm in length
    6. Excimer laser mediated atherosclerosis obliteration associated with good outcomes [30]
    7. Overall success rates are >80% for initial angioplasty ± stent [31]
    8. Two year patency rates following angioplasty ± stents were ~70% [31]
    9. Use of paclitaxel-coated balloons during angioplasty reduced restenosis / clinical events [22]
    10. Risks include peripheral embolization and arterial rupture
    11. With Excimer laser, major complication rate was 1.4% (1% due to embolic events)
  2. Stenting
    1. Angioplasty with optional stent placement for iliac disease was as effective and less expensive than mandatory stent placement [31]
    2. However, improved methods for recanalization make mandatory stent placement an attractive option [30]
    3. For superficial femoral artery atherosclerosis, nitinol (nickel-titanium) stenting is superior to balloon angioplasty [24,41]
    4. For superficial femoral artery atherosclerosis, balloon angioplasty is superior to stainless steel stenting [24]
    5. Excimer laser based angioplasty + Stent associated with 76% patency at 3 years [30]
  3. Bypass Surgery
    1. Generally recommended for lesions >15-20cm long
    2. Arterial bypass with saphenous vein or synthetic graft
    3. Synthetic graft material includes dacron and Gortex®
    4. Warfarin INR 3.0-4.5 superior to aspirin after inguinal vein graft for preventing graft occlusion and subsequent ischemic events [33]
  4. Cell Based Angiogenesis [34]
    1. Endothelial cells derived from CD34+ bone marrow stem cells
    2. Autologous implantation of bone marrow mononuclear cells may form new vessels
    3. New vessel collatoral formation documented in patients with PAD
    4. Excellent increase in collatorals, symptoms and pain-free walking time
    5. Angiogenic factors or gene transfers showing initial promise (see above)

J. Arterial Ulcers [35]navigator

  1. Usually occurs in moderate to severe CVD
    1. Concomitant cardiac or cerebrovascular disease
    2. Claudication typically present
    3. Impotence
    4. Pain in distal foot
    5. Venous disease in ~25% of cases
  2. Risk Factors
    1. Smoking
    2. DM
    3. HTN
    4. Lack of exercise
  3. Symptoms and Signs
    1. Abnormal pedal pulses often with cool limbs
    2. Check ankle-brachial index: reduced in PAD
    3. Femoral bruit
    4. Ulcers usually deep, located over bony prominances
    5. Ulcers usually with sharply demarcated borders, yellow base, or necrosis
    6. Exposure of tendons
  4. Treatment
    1. Control of underlying medical conditions
    2. Exercise, increasing as tolerated
    3. Revascularization as needed
    4. Antiplatelet agents: aspirin and/or clopidogrel

K. Acute Atheroembolic Diseasenavigator

  1. Symptoms
    1. Pain -dysesthesia
    2. Loss of Sensation
    3. Paralysis - requires emergent intervention
    4. Pulselessness - loss only by doppler is significant
    5. Pallor -may be vasospasm; not very specific
  2. Etiology
    1. Embolic or Thrombotic
    2. Dissection of atheroma
  3. Embolic
    1. Acute onset
    2. Cardiac Risks: Valve disease, Metal valve, Atrial Fibrillation, (Anterior) MI
    3. Other Risks: Coagulopathy, Endovascular Mechanisms, Vascular Procedures
    4. Claudication not usually part of history
    5. Anti-phospholipid antibodies may be a risk factor
  4. Thrombotic
    1. Formation of clot on ruptured plaque
    2. Patients often have claudication at baseline
    3. Other extremity often shows signs of insufficient arterial flow
    4. Known atherosclerotic disease
  5. Treatment
    1. Heparinization: 5000-7500U Bolus then 800-1200U/hr
    2. Ultrasound with doppler
    3. Surgical Intervention, angioplasty, or thrombolysis with urokinase [26,36]
    4. In general, ~6 hours are required for ischemic necrosis and/or permanent damage
    5. Surgical bypass and balloon angioplasty have similar outcomes at 6 months and 5.5 years for treatment of critical acute leg ischemia; angioplasty costs less [26]
    6. Loss of sensation / paralysis suggests poor prognosis, suppports very early intervention
    7. Catheter directed thrombolysis may be preferred to surgery [1]
    8. Catheter directed intra-arterial urokinase (UK) is effective in 70-80% of patients [36]
    9. UK has higher hemorrhage (~12%) rates than vascular surgery (~5%), but is less invasive
    10. Abciximab (anti-platelet agent, ReoPro®) added to UK increases amputation-free survival inpatients with acute peripheral artery occlusion [37]
    11. Tissue plasminogen activator (TPA) thrombolysis may also be used
  6. Microvascular Arterial Disease
    1. Blue toes or other end organ damage
    2. Cholesterol emboli, platelet emboli most common causes
    3. Treatment: aspirin + heparin
  7. Prevention
    1. Moderate dose (81-325mg/day) ASA benefit in prevention of arterial occlusion
    2. Study done in surgical patients with ASA started within 24 hours of procedure
    3. Small benefit in reducing claudication, anginal attacks, and non-fatal heart attacks

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