24.7% 3.8% 11.8% 29.9% 3.3% 7.4% 19.2% Coexisting Vascular Diseases CAD CVD PAD Lancet. 1996;348:1329–39 Atherothrombosis is commonly found in more than one arterial bed. (CAPRIE study, n = 19,185) Coexistent Stroke Coexistent PAD Coexistent CAD Coexistent Disease (%) CAD PAD CVD Ness J. et al. J Am Geriatr Soc. 1999;47: CVD: Cerebrovascular Disease, CAD: Coronary Arterial Disease, PAD: Peripheral Arterial Disease
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 Kenneth Ouriel. Lancet. 2001;358: Time (years) Patients (%) Survival Myocardial infarction Intervention Amputation 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.
Background Diabetic Mellitus Hypertension Hyperlipidemia Level ILevel IILevel IIILevel IV Symptoms by decrease of blood flow Decrease of function Ulcer and Necrosis Asymptomatic Numbness Coldness Raynauds phenomenon Intermittent Claudication Resting Pain Ulcer Necrosis Patholophysiology of PAD Peripheral arterial disease Carotid artery (Brain) Aorta (to body) Superior mesenteric artery & celiac artery (Intestines) Renal artery (Kidneys) Common iliac artery (Legs) Ischemia: decreased oxygen-rich blood to an area, which can cause pain and dysfunction Narrowed artery Platelet 50% of diameter stenosis 75% of area stenosis 60% of diameter stenosis 84% of area stenosis Main arteries stenosis Progress of stenosis occlusion Occlusion
Major Symptoms of PAD Rest pain Claudication ColdnessAbnormal skin color Cold sensation in one or both legs/ hands 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 Occlusion of the lumen of 90% or more will likely produce pain even at rest. Skin (of extremities) turns to a pale or purple color. Numbness sometimes appears together. Erectile dysfunction Peripheral Neuropathy Other symptoms Patients with PAD have a reduced functional capacity that limits their ability to perform daily activities.
PAD is often Asymptomatic Newly diagnosis of PAD (n = 457) No (%) Prior diagnosis of PAD (n = 366) No (%) p value No pain193 (48.3 %)84 (25.8 %)< Atypical185 (46.3 %)201 (61.7 %)< Classic rose claudication 22 (5.5 %) 41 (12.6 %)< ABPI (SD)0.78 (0.16)0.78 (0.23)< Leg symptoms: PARTNERS Vasc Med. 2001;6Suppl 1:9-12 JAMA. 2001;286(11): 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. PAD: ABPI 0.90
Risk factors Intermittent claudication withwithout Odds Ratio p value Male sex (%) Mean age (y) High-normal blood pressure (%) Stage 1 hypertension (%) Stage 2 hypertension (%) Diabetes (%) Daily cigarette smoking rate Mean cholesterol (mg/dL) Preexisting CHD (%) Risk factors by intermittent claudication status 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 Joanne M Murabito et al. Circulation. 1997;96:44-49 Risk Factors of intermittent claudication
Evaluation of PAD Age 50–69 years and smoking or diabetes Age 70 years Leg pain with exertion Abnormal results on vascular examination of leg Coronary, carotid, or renal arterial disease Measure ankle-brachial index Index 0.91 ~ 1.30 Index 0.90 Index > 1.30 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 Peripheral arterial disease Hiatt WR. N Engl J Med, 2001;344(21):
Symptomatic Outcome Measures Classification of PAD: Fontaines Stages and Rutherfords categories FontaineRutherford StageSymptomGradeCategoryClinical Description IAsymptomatic00 IIaMild claudicationI1 IIb Moderate severe claudication I2Moderate claudication I3Severe claudication IIIIschemic rest pain II4Ischemic rest loss III5Minor tissue loss IVUlceration or GangreneIII6Major tissue loss J Vasc Surg. 2000;31(1 part 2):S38-S39 Am J Cardiol. 2001;87(12A):3D-13D GradeCategoryClinical Description 00Asymptomatic I1Mild claudication I2Moderate claudication I3Severe claudication II4Ischemic rest loss III5Minor tissue loss III6Major tissue loss
Objective Outcome Measures- ABPI (Ankle Brachial Pressure Index) Left-arm systolic pressure DP PT Right-ankle systolic pressure DP PT Left-ankle systolic pressure Interpretation of ABPI > 1.30Non compressible Normal Mild-to-moderate PAD Severe PAD Left ABI = Higher left-ankle pressure Higher arm pressure Right ABI = Higher right-ankle pressure Higher arm pressure DT: Dorsalis Pedis, PT: Posterior Tibial Hiatt WR. N Engl J Med. 2001;344(21): Doppler flowmeter
Pulse Wave Velocity (PWV) PWV(cm/sec) = Distance to be measured Pulse Wave Transmit Time Distance Artery A B Time Stiffness PWV High Low SoftHard Asymptomatic Group (Gray Zone) Symptomatic Group (Abnormal) Normal Increase of PWV shows constant increase for risks of coronary heart disease, stroke and cardiovascular disease.
Peripheral Vascular Disease PVDTypeVessels involved Peripheral atherosclerotic disease Atherosclerotic Large and medium sized arteries Burgers diseaseInflammatory and thrombotic Small and medium sized arteries and veins Raynauds diseaseVasospasticArterioles Acute arterial occlusion Hemolytic and thromboticArteries Fibromuscular dysplasia Hyperplastic, with or without thrombus formation Small and medium sized arteries Thrombophlebitis (Superficial phlebitis) Inflammatory and ThromboticSuperficial veins Deep vein thrombosisEmbolytic and thromboticDeep veins Varicose veinsStructural defectLeg veins
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 Intermittent claudication, superficial phlebitis Sensation of coldness, numbness, abnormal skin color, ulcerations, necrosis and gangrene in the tips of the fingers Buerger's Disease Overview Manifestations Treatment Incurable/ slow progression Elimination of Smoking Prevention of local tissue damage from cold temperatures, trauma, fungal infections
Vasospasm-induced ischemia of the arterioles in the fingers and toes, and occasionally of the nose and tongue Raynauds disease (primary): without underlying medical problem Raynauds phenomenon (secondary): with underlying medical problem Triphasic color reaction: Red white blue Pain, throbbing sensation and extreme coldness of hands Raynaud's Disease / Phenomenon Overview Manifestations Treatment Protection from cold Mild sedative, prazosin, nifedipine, pentoxifylline Relaxation technique Cessation of smoking to prevent vasoconstriction
Intermittent Claudication Intermittent claudication When walking, pain occurs, but it is gone with resting Maximal walking speed Maximal walking distance Peak VO 2 (Oxygen consumption) Normal = mph PAD = mph Normal = unlimited PAD, 31% difficulty walking in home PAD, 66% difficulty walking ½ block PAD, reduced 50% Otsuka data set. WR Hiatt et al. J Appl Physiol. 1992;73:
Differentiation from Neural Disorder Neural disorder lumbar spinal canal stenosis is very similar with IC Vascular (IC) Pain when walking Stiffness at foot when walking for 4~5 mins. Neural (Lumbar Spinal Canal Stenosis) Pain varied by the motion Not dependent on the distance, irregularly occurs
Am J Cardiol. 2001;87 (suppl):3D-13D What cause intermittent claudication? Atherosclerosis in peripheral arteries of legs Lactic acid and other metabolites washed away on rest During exercise, oxygen demand increases Muscles operate anaerobically Produce lactic acid and other metabolites Leg pain Pathogenesis of Intermittent Claudication Hemodynamic Abnormalities
Pathogenesis of Intermittent Claudication Metabolic and Neurological Abnormalities Creager M, ed. Management of Peripheral Arterial Disease Medical, Surgical, and Interventional Aspects Intermittent Claudication Reduced lower- extremity perfusion Denervation and loss of muscle fibers Increased mitochondrial expression Accumulation of metabolic intermediates Oxidative injury to mitochondrial DNA
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 Consequences of IC/PAD Natural history of IC/PAD 75% experience symptom stabilization or improvement % require revascularization (angioplasty or bypass surgery) 2~4% require amputation Death is usually due to coexisting coronary artery or cerebrovascular disease, not PAD Am J Cardiol. 2001;87 (suppl):3D-13D Follow-up (years) IC Control Survival (%) p20,2000
Obstructive lesion%* Ischemia in Aorta or iliac30 % Buttock Hip Thigh Femoral or popliteal80-90 % Thigh Calf Tibial or peroneal40-50 % Calf Ankle Foot *Percent of IC patients who have an obstructive lesion in the site Common iliac artery Femoral artery Popliteal artery Anterior tibial artery Posterior tibial artery Dosalis pedis artery Sites of Occlusion and Pain Internal iliac artery External iliac artery Deep Femoral artery Peroneal artery
Characteristics of Common Ulcers HL Moore and JV white. PAD Handbook, CRC Press, 2005 Arterial (Ischemic) Main arteries Venous stasis Venous disease Neurotropic (Diabetic) Neuropathy Venous Neutrophic PAD, Burgers 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
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 Epidemiology of diabetic foot ulcer Pathophysiology of diabetic foot ulcer Peripheral Neuropathy Excessive plantar pressure Trauma, especially when repetitive Atherosclerotic peripheral vascular disease Intrinsic wound-healing disturbance A higher rate of onychomycosis Causative Factors Contributory Factors Diabetic Foot Ulcer JAMA. 2005;293:
Improve functional status Preserve the limb Prevent progression of atherosclerosis Reduce cardiac and cerebrovascular mortality To address the risk in cardiovascular events To address limb symptoms Clinical Treatment Goals of PAD Reduce clinical events such as MI and stroke Decrease the need for revascularization and amputation Improve symptoms Improve QOL Improve exercise capacity
Cardiovascular Risk Modication Effect of cardiovascular risk modification therapies on claudication symptoms TreatmentClaudication Symptoms Lipid lowering drugs+ improvement Smoking Cessation+/- improvement ACE InhibitorsNo improvement Antiplatelet TherapiesNo improvement Diabetes TreatmentNo improvement Hypertension TreatmentWorsen ACE: Angiotensin Converting Enzyme Hiatt WR. Curr Drug Targets Cardiovasc Haematol Disord Sep;4(3): Treatment that reduce cardiovascular risk generally do not improve claudication symptoms.
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 Exercise Medication Risk factor Reduction Intravascular treatment Medication Surgical treatment Intravascular treatment Medication, p23,, 2002 Level ILevel IILevel IIILevel IV
Introduction of TASC Number 1, Part 2:S93 VASCULAR Management of Peripheral Arterial Disease (PAD) TransAtlantic Inter-Society Consensus (TASC) TASC SURGERY J O U R N A L O F SUPPLEMENT TO VOLUME 31 NUMBER 1 PART 2 JANUARY 2000 Mosby Section A: Introduction Section B: Intermittent Claudication Section C: Acute Limb Ischemia Section D: Critical Limb Ischemia Developed by the TASC Working Group 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 Vasc Surg. 2000;31(1 Part 2):S1-S Recommendations 47 Critical Issues
Complete Management Algorithm History and physical examination Ankle-brachial pressure index Confirmation PAD with intermittent claudication Assess cardiovascular risk factors Assess disability symptom severity Special investigations: Hyper-coagulability screen Homocysteine level LP a Other 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 Encourage supervised walking exercise program/ consider pharmacotherapy Locate lesion using: Segmental limb pressure PVR or VWF Duplex scanning MRA TransAtlantic Inter-Society Consensus : TASC Mild symptoms- not disabled Moderate symptoms- disabled Severe symptoms- disabled ContinueSuccessful outcomeunsuccessful Continue noninvasive measures Endovascular or surgical therapy Treadmill and/or SF-36 questionnaire WIQ questionnaire Initial evaluation Hemoglobin Serum creatinine Smoking Lipid profile Hypertension Diabetes J Vasc Surg. 2000;31(1 Part 2):S1-S296
Potential Favorable Effects of Exercise Training Nitric oxide synthase Prostacyclin Free Radical Vascular Endothelial Growth Factor Muscle oxidative activity Muscle enzyme activity Muscle acylcarnitine homeostasis Blood viscosity RBC filterability RBC aggregation Exercise Training Improved endothelial function Reduced Inflammation Possible vascular angiogenesis Improved muscle metabolism Improved hemorheology N Eng J Med. 2002;347(24):
Risk Factor Modification (TASC) Recommendation 22Smoking cessation in peripheral arterial disease Recommendation 23Control of diabetes in peripheral arterial disease Recommendation 24Diabetic foot care in peripheral arterial disease Recommendation 25Lipid control in peripheral arterial disease Recommendation 26Control of hypertension in peripheral arterial disease Recommendation 27Hypercoagulable states in intermittent claudication Recommendation 7Hyperhomocysteinemia in peripheral arterial disease J Vasc Surg. 2000;31(1 part 2):S1-S296
Pharmacotherapy (TASC) to address the marked increase risk in cardiovascular events 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 Recommendation 28 Ticlopidine Clopidogrel 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 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%). Lancet. 1996;227:
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, Naftidrofuryl, Buflomedil, Pletaal J Vasc Surg. 2000;31(1 Part 2):S1-S296 Pharmacotherapy (TASC)-2000 Established Drugs with Proven but Small Benefit in Improving Claudication
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 Antiplatelet drugs (Aspirin/Ticlopidine) Pharmacotherapy (TASC)-2000 Drugs With Minimal or No Benefit in Improving Claudication J Vasc Surg. 2000;31(1 Part 2):S1-S296 Vasodilators α blockers, papaverine, β 2 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 Others Ketanserin, Verapamil, Isovolemic hemodilytion, Amiophylline, Vitaime E, Defibrotide
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. Carnitine Pharmacotherapy (TASC)-2000 Incompletely Studied Drugs With Potential Benefit in Improving Claudication J Vasc Surg. 2000;31(1 Part 2):S1-S296 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.
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]. Cilostazol (Pletaal ® ) 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 PGE 1 may have modest benefits, the overall evidence does not support the use of this drug class for claudication (Reiter et al. 2004). Publication: 2005 Representative of Asia Prof.H. Shigematsu,Tokyo Univ.
Antithrombotic therapy in peripheral arterial occlusive disease: Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy ACCP: American College of Chest Physicians CHEST Sep;126(3 Suppl):609S-626S 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). 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. Chronic Limb Ischemia (ACCP) 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. ACCP: American College of Chest Physicians CHEST Sep;126(3 Suppl):609S-626S
Pharmacotherapy (American Family Physician) DrugsDosageComments 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 Clopidogrel75 mg qd Fewer side effects than aspirin in the CAPRIE trial, significantly less risk for TTP than ticlopidine Pentoxifylline400 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 Ticlopidine500 mg bidExtensive hemodynamic monitoring for risk of TTP Am Fam Physician Feb 1;69(3):525-32
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 Lipid metabolism improvement TG HDL ApoB RLP DHA Blood flow improvement Vasodilation (High femoral artery selectivity) RBC deformability Improvement of Symptom Risk factor Modification + Improving QOL among PAD or IC patients Addressing the increase risk in cardiovascular events Prevention of Diabetic complication