Advances in the Medical Management of Peripheral Arterial Disease Randall M. Zusman, MD Associate Professor of Medicine Harvard Medical School Director Division of Hypertension and Vascular Medicine Massachusetts General Hospital Boston, Massachusetts

Key Question How many of your patients with CV risk do you test for peripheral arterial disease? 1. 0%-24% 2. 25%-50% 3. 51%-75% 4. 76%-100% Use your keypad to vote now! ?

Faculty Disclosure  Dr Zusman: advisory board member, research support, speakers bureau: AstraZeneca, Bristol- Myers Squibb Company, Forest Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc, sanofi-aventis Group, Sankyo Co., Ltd.

Learning Objectives  Describe the prevalence and disease burden of PAD  State medical treatments for improving leg symptoms of the patient with PAD  Discuss interventions used to prevent systemic complications in the patient with PAD PAD = peripheral arterial disease.

Key Question How common is PAD? million Americans million Americans million Americans million Americans Use your keypad to vote now! ?

PAD: Scope of the Problem  PAD is caused by atherosclerotic occlusion of the arteries to the legs  Common, but often overlooked  Exact prevalence is unknown  PAD may be asymptomatic or present with atypical symptoms  Approximately 8-12 million Americans have PAD  Associated with significant morbidity and mortality resulting from MI, stroke, death MI = myocardial infarction. American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005; Hiatt WR. N Engl J Med. 2001;344:

PAD: Scope of the Problem StrokePADCHD* Prevalence (millions) PAD affects 8-12 million Americans, second only to CHD* Proportionately, for every 4 patients seen with CHD*, clinicians might expect to see approximately 3 patients with PAD *Includes MI and angina pectoris. CHD = coronary heart disease. American Heart Association. Heart Disease and Stroke Statistics—2005 Update

PAD: Prevalence Increases With Age ABI = ankle-brachial index. Creager M, ed. Management of Peripheral Arterial Disease. Medical, Surgical and Interventional Aspects Rotterdam Study (ABI <.9) San Diego Study (PAD by noninvasive tests) Age Group (y) Patients With PAD (%)

REACH—Scope of the Problem: Cerebro- and Cardiovascular Disease *PAD patients with polyvascular disease had concomitant symptomatic cerebrovascular disease and/or CVD. REACH = REduction of Atherothrombosis for Continued Health. Bhatt DL et al. American College of Cardiology Scientific Session. March 8, Coronary artery Peripheral artery 39.4% 14.2% 9.5% Polyvascular disease 63% of PAD patients had polyvascular* disease N = 7013 Cerebro- vascular

Key Question PAD increases the risk of CHD death by approximately: 1. 1×-2× 2. 3×-4× 3. 5×-6× 4. 6×-7× 5. 7×-8× Use your keypad to vote now! ?

Cause of Death PAD: Increased Risk of Mortality All-Cause Mortality Death From Coronary Heart Disease Relative Risk of Death (95% CI) 3.1 ( ) 6.6 ( ) Patients with large-vessel PAD* are at ~6× the risk of dying from CHD compared with patients without PAD *ABI ≤0.8. Adapted from Criqui MH et al. N Engl J Med. 1992;326:

HOPE PAD: Increased Risk of Mortality HOPE = Heart Outcomes Prevention Evaluation. Ostergren J et al. Eur Heart J. 2004;25: PAD doubled mortality rate (17.5% vs 8.5%) after mean follow-up of 4.5 years P <.0001 Kaplan-Meier Rates Days of Follow-up Clinical PAD SubPAD ABI <0.6 SubPAD ABI 0.6-  0.9 No-PAD & ABI >0.9

PAD in Primary Care: Underdiagnosed  Prevalence is high, yet clinician awareness of PAD diagnosis is relatively low  Simple ABI measurement identifies many patients with previously unrecognized PAD  Atherosclerosis risk factors are prevalent in patients with PAD  Received less intensive treatment for lipid disorders and hypertension  Prescribed antiplatelet therapy less frequently than patients with CVD Hirsch AT et al. JAMA. 2001;286:

NHANES = National Health and Nutrition Examination Survey. PARTNERS = PAD Awareness, Risk, and Treatment New Resources for Survival program. 1. Selvin E, Erlinger TP. NHANES. Circulation. 2004;110: ; 2. Criqui MH et al. Circulation. 1985;71: ; 3. Meijer WT et al. Arterioscler Thromb Vasc Biol. 1998;18: ; 4. Diehm C et al. Atherosclerosis. 2004;172:95-105; 5. Hirsch AT et al. JAMA. 2001;286: PAD: Prevalence in the Primary Care Office Setting 29% 19.8% 19.1% 14.5% 11.7% 4.3% 0%5%10%15%20%25%30%35% The prevalence of PAD in primary care clinics was almost in high-risk patients PARTNERS 5 Age >70, or between with history of diabetes or smoking San Diego 2 Mean age = 66 Diehm 3 Age ≥65 Rotterdam 4 Age >55 NHANES 1 Age ≥70 NHANES 1 Age >40 30%

The authors concluded that up to 90%* of patients with PAD would be missed if healthcare providers relied solely on the classic symptoms of intermittent claudication Healthcare providers should also routinely inquire about atypical symptoms 90% did not have classic intermittent claudication symptoms PARTNERS Detecting PAD With Symptoms *In patients with ABI ≤0.9. Hirsch AT et al. JAMA. 2001;286:

PAD: Symptoms American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005; Criqui MH et al. Vasc Med. 1996;1: Typical Symptoms (Intermittent Claudication) ~10% Exercise calf pain Not present at rest Relieved within 10 minutes by rest Atypical Symptoms ~50% Occlusion may develop slowly, allowing collateral circulation to develop Asymptomatic PAD ~40% Patients With PAD Symptomatic PAD

Adapted from American Diabetes Association. Diabetes Care. 2003;26: PAD: Diagnostic Critical Pathway PAD Diagnosis Vascular Lab Evaluation  Segmental pressures  Pulse volume recordings  Treadmill ABI Not Available ABI Available PAD Diagnosis Referral to Vascular Lab  Assessment of location/ severity is desired  Patients with poorly compressible vessels  Normal ABI where PAD suspicion is high Clinical Evaluation: History and Physical

Key Question The most common risk factor for PAD is: 1. Diabetes 2. Smoking 3. Hypertension 4. Total cholesterol level Use your keypad to vote now! ?

PAD: Common Risk Factors* *PAD diagnosis based on ABI <0.90. Newman AB et al. Circulation. 1993;88: ◄Lesser risk Total cholesterol (10 mg/dL) Hypertension Diabetes Smoking Greater risk ► Patients with diabetes are at a 4x higher risk of developing symptomatic PAD versus the general population 4.05 Age >40 years

PAD: Physical Examination Perform With Patient’s Pants/Shoes Off Examine Limb And Compare With the Opposite Limb Absent/diminished femoral or pedal pulses—especially after exercising the limb Arterial bruits Hair loss Poor nail growth (brittle nails) Dry, scaly, atrophic skin Dependent rubor Pallor with leg elevation after 1 minute at 60º (normal color should return in seconds; >40 seconds indicates severe ischemia) Ischemic tissue ulceration (punched-out, painful, little bleeding), gangrene Gey DC et al. Am Fam Physician. 2004;69: Additional examination by palpation and auscultation to detect abnormal aortic aneurysm or bruit

Concept of ABI Adapted from Weitz JI et al. Circulation. 1996;94: ÷ ≈ 1 ABI is 95% sensitive and 99% specific for angiographically diagnosed PAD Systolic BP in the leg should be approximately the same as that in the arm Therefore, the ratio of systolic BP in the leg versus the arm should be approximately 1 or slightly higher Arm Pressure Leg Pressure

Measuring ABI  Gather equipment needed  Position patient  Measure the brachial BP  Position the cuff above the ankle  Measure pressure in the DP artery  Measure pressure in the PT artery  Repeat the process in opposite leg DP = dorsalis pedis; PT = posterior tibial. American Diabetes Association. Diabetes Care. 2003;26: ; Dormandy JA et al. J Vasc Surg. 2000;31:S1-S296.

Calculating ABI Higher right ankle pressure (DP or PT pulse) Higher arm pressure (either arm) = Right Leg ABI Left Leg ABI Higher left ankle pressure (DP or PT pulse) Higher arm pressure (either arm) = ABI Interpretation ≤0.90 is diagnostic of PAD Hiatt WR. N Engl J Med. 2001;344:

ABI Workshops  Demonstrations available throughout the day

PARTNERS Incorporating ABI Into Primary Care Weekly Increase in ABI Use in Office 358% Monthly Increase in ABI Use in Office 300% 88% Mohler, ER et al. Vasc Med. 2004;9: Clinicians thought it feasible to incorporate ABI into daily practice After Clinicians Participated in PARTNERS:

Adapted from American Diabetes Association. Diabetes Care. 2003;26: PAD: Diagnostic Critical Pathway PAD Diagnosis Vascular Lab Evaluation  Segmental pressures  Pulse volume recordings  Treadmill ABI Not Available ABI Available PAD Diagnosis Referral to Vascular Lab  Assessment of location/ severity is desired  Patients with poorly compressible vessels  Normal ABI where PAD suspicion is high Clinical Evaluation: History and Physical

Holland T. Ostomy Wound Manage. 2002;48: Vascular Laboratory Results: Segmental Pressures Segmental pressures can help localize lesion Considered abnormal when there is a >20 mm Hg difference between adjacent segments within the same leg and between the original segment and the corresponding segment on the contralateral leg Brachial Brachial artery Upper thigh Proximal femoral artery Lower thigh Distal femoral artery Calf DP, PT, and proximal arteries Ankle PT or DP artery

Provides Segmental Waveform Analysis, A Qualitative Assessment of Blood Flow Data provided by Mark Creager, MD. Holland T. Ostomy Wound Manage. 2002;48: Normal PAD Normal tracing includes initial systolic peak with a dicrotic wave on the down slope Vascular Laboratory Test: Pulse Volume Recordings Upper Thigh Lower Thigh CalfAnkle Abnormal tracing characterized by a rounded systolic peak that is lower, as well as the lack of a dicrotic wave on the downslope

Adapted from American Diabetes Association. Diabetes Care. 2003;26: Atypical Symptoms for PAD PAD Diagnosis Treadmill Test: Function Testing to Aid Diagnosis Treadmill Function Testing Patients with claudication will normally display a drop in ankle pressure after exercise May also be used to assess treatment efficacy and evaluate overall physical function Normal ABI with typical symptoms of claudication ABI Suspect PAD Clinical Evaluation: History and Physical

Key Question The goals of therapy for PAD are: 1. Relieve exertional symptoms 2. Improve walking capability 3. Improve quality of life 4. Relieve ischemic pain at rest 5. Heal ischemic ulceration 6. Prevent limb loss 7. All of the above Use your keypad to vote now! ?

PAD: Treatment Goals  For patients with claudication  Relieve exertional symptoms  Improve walking capability  Improve quality of life  For patients with critical leg ischemia  Same as above, and Relieve ischemic pain at rest Heal ischemic ulceration Prevent limb loss Hiatt WR. N Engl J Med. 2001;344:

PAD: Aggressive Risk Factor Modification Essential—1 Smoking Cessation Goal: Abstinence ↓ Severity of claudication (probably) Slows progression to critical leg ischemia ↓ MI risk, vascular deaths Pharmacotherapy (NRT, nortriptyline, clonidine, bupropion) + counseling Exercise Goal: As frequently and as long as possible ↑ Peak walking time ↑ Peak oxygen consumption ↑ Pain-free walking time ↑ Quality of life ↑ Routine daily activities Therapeutic exercise training NRT = nicotine replacement therapy. Gey DC et al. Am Fam Physician. 2004;69: ; Hiatt WR. N Engl J Med. 2001;344: ; Stewart KJ et al. N Engl J Med. 2002;347:

PAD: Aggressive Risk Factor Modification Essential—Smoking Cessation Jorenby DE et al. N Engl J Med. 1999;340: Placebo Nicotine replacement Buproprion Bupropion and nicotine replacement Percentage of Patients Abstaining 6 months12 months

CPT = current procedural terminology. 1. Gardner AW et al. JAMA. 1995;274: ; 2. Kanjwal MK et al. JK–Practitioner. 2004;11: Distance to Maximal Claudication Pain Distance to Onset of Claudication Pain At 6 months 122% 179% Percentage Increase Meta-Analysis Supervised Exercise Essential to Improve Intermittent Claudication Symptoms AMA has published a CPT code for supervised PAD rehabilitation (93668) 2 Greatest improvement: Sessions lasted >30 min 3 sessions/wk Walk to near-maximal pain >6-month program

PAD: Aggressive Risk Factor Modification Essential—2 Treat Hyperlipidemia Goal: LDL <100 mg/dL ↓ Serum cholesterol ↑ Endothelial function ↓ Disease progression Modifies other atherosclerotic risks Statins Niacins Treat Hypertension Goal: <140/90 mm Hg <130/80 mm Hg (diabetes or renal insufficiency) Data support aggressive treatment; impact on PAD outcomes unclear ACE inhibitors Beta-blockers can be used Control Diabetes Goal: A1C <7% or as close to normal (<6%) as possible ↓ CVD and MI rates; trend for PAD outcomes ↓ Limb infection, amputation ↓ Microvascular complication risk Diet, exercise, pharmacotherapy A1C = glycosylated hemoglobin. Gey DC et al. Am Fam Physician. 2004;69: ; Hiatt WR. N Engl J Med. 2001;344: ; Norgren L et al. J Vasc Surg. 2007;45:S5A-S67.

HPS PAD: Aggressive Risk Factor Modification Essential—Lipids HPS = Heart Protection Study. HPS Collaborative Group. MRC/BHF. Lancet. 2002;360:7-22. Type of major vascular event Simvastatin- Allocated (10269) Placebo- Allocated (10267) Event Rate Ratio (95% CI) Coronary events 0.73 ( ) P < ( ) P < ( ) P < ( ) P < Nonfatal MI357 (3.5%)574 (5.6%) Coronary death587 (5.7%)707 (6.9%) Subtotal: major coronary events 898 (8.7%)1212 (11.8%) Strokes Nonfatal strokes366 (3.6%)499 (4.9%) Fatal strokes96 (0.9%)119 (1.2%) Subtotal: any strokes444 (4.3%)585 (5.7%) Revascularization Coronary513 (5.0%)725 (7.1%) Noncoronary450 (4.4%)532 (5.2%) Subtotal: any revascularization939 (9.1%)1205 (11.7%) Any Major Vascular Event2033 (19.8%)2585 (25.2%) Simvastatin BetterPlacebo Better

HOPE PAD: Aggressive Risk Factor Modification Essential—Antihypertensive Therapy HOPE Study Investigators. N Engl J Med. 2000;342: No. of Patients Incidence of Composite Outcome in Placebo Group Overall PAD No PAD Relative Risk in Ramipril Group

PAD: Antiplatelet and Vasodilator Therapy ASA mg/d PO Recommended by ACCP; not FDA-approved Clopidogrel 75 mg/d PO Fewer side effects than ASA in CAPRIE trial; significantly less TTP risk than ticlopidine Pentoxifylline 1.2 g/d PO Some effect on walking ability; insufficient data to support widespread use Cilostazol 100 mg BID PO Correct dosage critical; avoid in patients with CHF; reduce dose in patients taking CCBs; GI side effects ACCP = American College of Chest Physicians; ASA = aspirin; CAPRIE = Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events; CCB = calcium channel blocker; CHF = chronic heart failure; GI = gastrointestinal; TTP = thrombotic thrombocytopenic purpura. Adapted from Gey DC et al. Am Fam Physician. 2004;69:

8.7% Overall RRR (P =.045)* Months of Follow-up Cumulative Event Rate (%) Clopidogrel ASA Median follow-up = 1.91 years 5.32% 5.83% Subjects had a recent MI, recent ischemic stroke, or symptomatic PAD (N = 19,185) *ITT analysis: RRR = relative risk reduction. CAPRIE Steering Committee. Lancet. 1996;348: CAPRIE Clopidogrel Versus ASA: MI, Ischemic Stroke, or Vascular Death

CAPRIE Safety Profile Patients with a history of ASA intolerance were excluded from CAPRIE. PLAVIX Prescribing Information. Data on file, Sanofi-Synthelabo Inc. Although the risk of myelotoxicity with clopidogrel appears to be low, this possibility should be considered when a patient receiving clopidogrel has fever or another sign of infection. % Patients Clopidogrel (n = 9599) ASA* (n = 9586) GI hemorrhage Hospitalization due to GI hemorrhage GI ulcers Intracranial hemorrhage Severe neutropenia

Tolerability Profile* *ASA-intolerant patients excluded. PLAVIX Prescribing Information. Data on file, Sanofi-Synthelabo Inc. CAPRIE % Patients Clopidogrel (75 mg/d) ASA* (325 mg/d) Abdominal pain Purpura (bruising) Dyspepsia Diarrhea Rash Pruritus Discontinuation due to adverse GI events Gastritis0.81.3

PAD: When to Refer  Primary care team is not confident making the diagnosis or lacks resources required to make such a diagnosis  Patient has continued symptoms despite a reasonable trial and adherence to best medical therapy  Patient has critical limb ischemia (rest pain, gangrene, or ulceration)

Case Study

Patient Case Study  58-year-old Latino male  History of diabetes and hypertension  Treated episodically at local clinic  No current medications  Has taken antihypertensive and oral hypoglycemic agents in the past

Patient Case Study  Physical examination  Height: 5'9″  Weight: 190 lb  BMI: 28.1 kg/m 2  Waist circumference: 40″  BP: 168/110 mm Hg  Pulse: 72 bpm BMI = body mass index.

Presenting Symptoms  Presents to the clinic after referral from emergency department where he was evaluated and discharged after an episode of chest pain  Coronary event ruled out by labs and diagnostic studies  Admits that he has never been on medication for more than 3 months at a time  Has no health benefits and works as a construction worker  Does not drink alcohol but smokes 1 pack/day x 30 years  Complains of fatigue and inability to maintain his current productivity at the work site

Laboratory Results  Lipid panel  Total cholesterol: 346 mg/dL  LDL: 170 mg/dL  HDL: 29 mg/dL  Triglyceride: 280 mg/dL  A1C: 9.2%  BUN and creatinine: 19/1.4 mg/dL BUN = blood urea nitrogen; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

Physical Examination  CV: RRR S1 and S2 with no murmurs or gallops  Chest: clear to A/P  Abdomen: rotund, but no pulsatile masses or distention  Vascular: no bruits; upper extremity pulses—normal limits  Lower extremity pulses reveal normal femoral bilaterally  Right popliteal, DP, and PT palpable  Left shows decreased popliteal, DP, and PT  Musculoskeletal: no evidence of foot ulceration or dependent rubor  Neurologic: sensory function intact in upper and lower extremities

Decision Point What is this patient’s risk category? 1. High 2. Moderately high 3. Moderate 4. Either moderate or moderately high 5. Low Use your keypad to vote now! ?

Therapeutic Considerations  Diagnostic intervention  Evaluate vascular status ABI results Right = 1.00 Left = 0.56  Appropriate management includes:  Control BP  Manage dyslipidemia and diabetes  Initiate antiplatelet therapy  Smoking cessation  Exercise program  Follow-up in 1 month

Q & A

PCE Takeaways

PCE: PAD Takeaways  PAD is underrecognized and undertreated  ABI can identify PAD  Aggressive lifestyle changes and drug therapy can save lives

Key Question Will you use ABI testing to diagnose patients at risk for PAD? 1. Not likely 2. Somewhat likely 3. Very likely 4. Extremely likely Use your keypad to vote now! ?