1. Peripheral Arterial Disease: missed opportunity for cardiovascular intervention Subhash Banerjee, MD Chief, Division of Cardiology VA North Texas Healthcare System Associate Prof. in Medicine UT Southwestern Med. Ctr. Oct. 2013 NIC Kolkata 2013

2. Worldwide PAD Trends (2013) 54·8 million in southeast Asia Fowkes et al. Lancet 2013

3. 0%5%10%15%20%25%30%35% 29% 11.7% 19.8% 19.1% 14.5% 4.3% Prevalence of PAD PARTNERS 5 Aged >70 years, or 50–69 years with a history diabetes or smoking San Diego 2 Mean age 66 years Diehm 4 Aged 65 years Rotterdam 3 Aged >55 years NHANES 1 Aged 70 years NHANES 1 Aged >40 years NHANES=National Health and Nutrition Examination Study; PARTNERS=PAD Awareness, Risk, and Treatment: New Resources for Survival [program]. 1. Selvin E, Erlinger TP. Circulation. 2004;110:738-743. 2. Criqui MH, et al. Circulation. 1985;71:510-515. 3. Diehm C, et al. Atherosclerosis. 2004;172:95-105. 4. Meijer WT, et al. Arterioscler Thromb Vasc Biol. 1998;18:185-192. 5. Hirsch AT, et al. JAMA. 2001;286:1317-1324. In a primary care population defined by age and common risk factors, the prevalence of PAD was approximately one in three patients

4. Gender Differences in the Prevalence of PAD Adapted from Diehm C. Atherosclerosis. 2004;172:95-105 with permission from Elsevier. Prevalence (%) Women Men 6880 Consecutive Patients (61% Female) in 344 Primary Care Offices <70 0 2 4 6 8 10 12 14 16 70–7475–7980–84>85 Age (years) 18

5. PAD: More Prevalent Than Many Leading Diseases Source: American Cancer Society, American Heart Association, Alzheimers Disease Education/Referral Center, American Diabetes Association, SAGE Group Disease Prevalence (Millions) 17 12.6 12 8.9 4.8 5 4

6. Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192. Relative Risk Smoking Diabetes Hypertension Hypercholesterolemia Hyperhomocysteinemia Renal insufficiency Age (per 10 years) ReducedIncreased Risk Factors for PAD 123 456 0

7. Diabetes Increases the Risk of PAD 22.4* 19.9* 12.5 0 5 10 15 20 25 Normal Glucose Tolerance Impaired Glucose Tolerance Diabetes Prevalence of PAD (%) Impaired glucose tolerance was defined as oral glucose tolerance test value ≥140 mg/dL but <200 mg/dL. *P .05 vs. normal glucose tolerance. Lee AJ, et al. Br J Haematol. 1999;105:648-654.

8.  Age <50 years with diabetes, and one additional risk factor (e.g., smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)  Age 50 to 69 years and history of smoking or diabetes  Age ≥70 years  Leg symptoms with exertion (suggestive of claudication) or ischemic rest pain  Abnormal lower extremity pulse examination  Known atherosclerotic coronary, carotid, or renal artery disease Based on the epidemiologic evidence, an “at risk” population for PAD can be defined as: Individuals “At Risk” for Lower Extremity PAD ACC/AHA PAD Guidelines 2011

9. Using the Ankle-Brachial Index (ABI) ABI=ankle-brachial index; DP=dorsalis pedis; PT=posterior tibial; SBP=systolic blood pressure. Right ABI 80/160=0.50 Brachial SBP 160 mm Hg PT SBP 120 mm Hg DP SBP 80 mm Hg Brachial SBP 150 mm Hg PT SBP 40 mm Hg DP SBP 80 mm Hg Left ABI 120/160=0.75 Highest brachial SBP Highest of PT or DP SBP ABI (Normal >0.90)

10. Interpreting the Ankle-Brachial Index ABIInterpretation 1.00–1.39Normal 0.91–0.99Borderline 0.41–0.90Mild-to-moderate disease ≤0.40Severe disease ≥1.40Non-compressible (DM & CKD) ACC/AHA PAD Guidelines 2011

11. Ankle Brachial Index (ABI) Diagnostic test SensitivitySpecificity ABI < 0.9095%100% Pap smear30-87%86-100% Fecal occult blood 37-78%87-98% Mammography75-90%90-95% Arch Intern Med. 2003;163:884-892

12. 29% of Patients in a Target Population Were Diagnosed With PAD Using An Office-Based ABI Patients diagnosed with PAD PAD only PAD and CVD PARTNERS: Prevalence of PAD and Other CVD in Primary Care Practices 29% 44% 56% ABI=ankle-brachial index; CVD=cardiovascular disease.Hirsch, AT et al. JAMA. 2001;286:1317-24.

13. Association Between ABI and All ‑ Cause Mortality* Baseline ABI Total Mortality (%) Age range=mid- to late-50s; ABI=ankle-brachial index; *Median duration of follow-up was 11.1 (0.1–12) years. O’Hare AM et al. Circulation. 2006;113:388-393. N=5748 Risk increases at ABI values below 1.0 and above 1.4

14. Clinical Presentation of PAD ~15% Classic (Typical) Claudication ~33% Atypical Leg Pain (functionally limited) 50% Asymptomatic 1%-2% Critical Limb Ischemia (CLI) Claudication: impairs patient quality of life by causing painful cramps and dysfunction while walking CLI: rest pain, non-healing or poorly healing ulcers, or gangrene Do you have leg pain?

15. Long-Term Survival in Patients With PAD Criqui MH et al. N Engl J Med. 1992;326:381-386. Normal subjects Asymptomatic PAD Symptomatic PAD Severe symptomatic PAD 100 75 50 25 024681012 Survival (%) Year 624 men and women who were residents of a predominantly white, upper-middle-class community in southern CA

16. Natural History of Atherosclerotic Lower Extremity PAD PAD Population (50 years and older) Initial clinical presentation Asymptomatic PAD 20%-50% Atypical leg pain 40%-50%Claudication10%-35% Critical limb ischemia 1%-2% Progressive functional impairment 1-year outcomes Alive w/ 2 limbs 50% Amputation25% CV mortality 25% 5-year outcomes (to next slide) Hirsch AT, et al. Circulation. 2006;113:e463-654.

17. Claudication10%-35% 5-year outcomes Limb morbidity Stable claudication 70%-80% Worsening claudication 10%-20% Critical limb ischemia 1%-2% Amputation (see CLI data) CV morbidity & mortality Nonfatal CV event (MI or stroke) 20% Mortality15%-30% CV causes 75% 75% Non-CV causes 25% Hirsch AT, et al. Circulation. 2006;113:e463-654. Asymptomatic PAD 20%-50% Atypical leg pain 40%-50% For each of these PAD clinical syndromes Natural History of Atherosclerotic Lower Extremity PAD CLI=critical limb ischemia; CV=cardiovascular; MI=myocardial infarction

18. PAD: More Prevalent and More Deadly Than Many Leading Diseases Disease Prevalence (Millions) Colorectal Cancer 39% 30% 28% 21% 14% PADStrokeCAD Breast Cancer Source: American Cancer Society, American Heart Association, Alzheimers Disease Education/Referral Center, American Diabetes Association, SAGE Group Five-Year Mortality Rate 17 12.6 12 8.9 4.8 5 4

19. Prevalence of Abnormal ABI in Patients with Established CAD ABI<0.9 (58.4%) ABI=0.9-1.4 (38.7%) ABI>1.4 (2.9%) Banerjee et al. ACC 2013

20. Cardiovascular Events Based on ABI Values and Presence of Diabetes Mellitus p=0.006 p=0.40 p=0.29 Death Non-fatal myocardial infarctionStroke Repeat coronary revascularization MACE Banerjee et al. ACC 2013

21. Freedom From MACE Banerjee et al. ACC 2013 Hazard ratio (HR) and 95% confidence interval (CI) for MACE in patients with: DM and normal ABI (HR=1.7, 95% CI: 0.71-4.06, P=0.24) no DM and abnormal ABI (HR=2.03, 95% CI: 0.83-4.98, P=0.12) and DM with abnormal ABI (HR=4.85, 95% CI: 2.22-10.61, p=0.0001) compared to the reference or control group (no DM and normal ABI) DM: diabetes mellitus ABI: ankle-brachial index

22. Cardiovascular Events in Patients with PAD Ann Surg 1984;199:223-33 Potential reasons for excess CV events:  Increased vasospasm  Increased burden of ‘vulnerable’ atheroma  Systemic vascular inflammation  Reduced fibrinolytic activity  Hypercoagulability  Reduced positive vascular remodeling Lumen LumenAtheroma Vessel wall

23. Progression of Coronary Atherosclerosis in PAD CAD: coronary artery disease PAD: peripheral arterial disease Hussein et al. J Am Coll Cardiol, 2011; 57:1220-1225 3,479 patients with CAD from 3 statin RCT 216 with PAD & 3,263 without concomitant PAD Serial Intravascular ultrasound assessments Change in % atheroma volume + remodelling - remodelling p = 0.009 +0.58 ± 0.38 +0.23 ± 0.3

24. Benefit from LDL Reduction Retained in PAD CAD: coronary artery disease PAD: peripheral arterial disease LDL: low density lipoprotein Hussein et al. J Am Coll Cardiol, 2011; 57:1220-1225 3,479 patients with CAD from 3 statin RCT 216 with PAD & 3,263 without concomitant PAD Serial Intravascular ultrasound Assessments:  More extensive atherosclerosis  Greater calcifications  More constrictive remodeling  Greater disease progression of atherosclerosis  PAD patients retain the ability to derive a benefit from intensive risk modification strategies Change in Total atheroma volume (mm 3 ) LDL<70 No PAD LDL<70PAD LDL>70 LDL>70PAD –3.0 ± 1.9 1.0 ± 1.4 –3.3 ± 1.1 –1.6 ± 1.0 p = 0.04 p < 0.001

25. CAPRIE – study design 19 185 patients with recent IS, recent MI or established PAD Clopidogrel 75 mg od versus aspirin 325 mg od Follow-up of 1–3 years (mean 1.91 years) Combined primary endpoint of IS, MI or vascular death CAPRIE Steering Committee. Lancet 1996;348:1329–1339.

26. 1 CAPRIE Steering Committee. Lancet 1996;348:1329–1339. 2 Antiplatelet Trialists' Collaboration. BMJ 1994;308:81–106. 3 Fisher LD. J Am Coll Cardiol 1998;31(Suppl A):49A. CAPRIE – efficacy profile of clopidogrel Time from Randomization (Months) Event rate/1000 patients/year 0369121518212427303336 Event rate per year Placebo 3 * Aspirin 1 Clopidogrel 1 7.7% 5.8% 5.3% * extrapolated curve 3 Based on the APTC findings, 2 in a population similar to CAPRIE, for each 1000 patients treated per year, aspirin can be expected to prevent 19 events and clopidogrel, 24. 1 0 40 80 120 160 8.7% relative risk reduction, p = 0.043 58 77 53 24 19

27. Antiplatelet Therapy in PAD Aspirin + Clopidogrel (75 mg per day) to reduce the risk CV events, not at an increased risk of bleeding. I I I IIa IIb III I I I IIa IIb III I I I IIa IIb III IIa IIb III Antiplatelet therapy is indicated to reduce the risk of CV events. Clopidogrel only as an alternative to Aspirin. I I I IIa IIb III I I I IIa IIb III I I I IIa IIb III IIa IIb III Antiplatelet therapy is indicated to reduce the risk of CV events in asymptomatic individuals with ABI 0.91- 0.99 (C); ABI<0.91 (A) I I I IIa IIb III I I I IIa IIb III I I I IIa IIb III IIa IIb III ACC/AHA PAD Guidelines 2011

28. Effect of Smoking Cessation on Survival Years Postoperative Faulkner KW, et al. Med J Aust. 1983;1:217-219. 133 Patients observed after bypass graft or lumbar sympathectomy Cumulative Survival (%)

29. Atorvastatin in Patients With Claudication and PAD PFWT=pain-free walking time. *P=.03. No change in ABI over 12 months. Mohler ER et al. Circulation. 2003;108:1481-1486. * BaselineMonth 3Month 6Month 12 Mean change from baseline in PFWT (sec) 0 25 50 75 100 125 10 mg Placebo 80 mg n=354 ABI<0.9 or 20% decrease in exercise ABI LDL<160 mg/dl

30. Intensive Antihypertensive Therapy in PAD: The ABCD Trial 0 10 20 30 40 = 227 Moderate treatment n = 227 Odds of MI, Stroke or Vascular Death Baseline ABI 0.10.20.30.40.50.60.70.80.91.01.11.21.3 = 227 Intensive treatment n = 227 *enalapril or nisoldipine *enalapril or nisoldipine Mehler, et al. Circulation. 2003;107;753-756. ABCD: Appropriate Blood Pressure Control in Diabetes Odds are calculated using moderate treatment and a baseline ABI of 1.0 as a reference 5050

31. Difficulties for treatment specific to the femoro-popliteal segment Extension / Contraction Torsion Compression Flexion Hostile environment for stent implantation

32. Endovascular Interventional Toolbox Laser Cryoplasty Silverhawk Nitinol self-expanding Stents

33. Primary Patency (%, 95% CI) Durability Durability of Endovascular Procedures Mean 1-year data 2-year data 3-year data 4-year data 5-year data Femoropopliteal Stent 020 406080100 Infrapopliteal PTA Femoropopliteal PTA Iliac PTA Iliac Stent Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.CI=confidence interval; PTA=percutaneous transluminal angiography

34. Claudication Treatment Comparative Effectiveness (CLEVER Study 6m) Hirsch et al. AHA 2011 “Late-breaking Trial Peak Walking Time (min) Change from baseline at 6m Pair-wise comparisons Difference (min) p Exercise vs. Medical4.6 (95% CI, 2.7-6.5)<0.001 Stenting vs. Medical2.5 (95% CI, 0.6-4.4)0.02 Exercise vs. Stenting2.1 (95% CI, 0.0-4.2)0.04 Claudication Onset Time (min) Change from baseline at 6m Pair-wise comparisons Difference (min) p Exercise vs. Medical2.2<0.003 Stenting vs. Medical2.90.0006 Exercise vs. Stenting0.70.43 0.7 3.0 3.6 Stenting QOL > Exercise QOL or Medical Rx QOL

35. Endovascular intervention is not indicated as prophylactic therapy in an asymptomatic patient with lower extremity PAD. There is no evidence that any symptomatic clinical outcome can be improved, or adverse limb event averted (including amputation) by any prophylactic revascularization method, including angioplasty or vascular surgical bypass. Revascularization for Claudication

36. Surgery Cardiology

37. Interdisciplinary Interdisciplinary Approach to PAD Antiplatelet Smoking cessationExercise Cilostazol Endovascular Surgical Statin ACE PTA-Surgical Bridge

38. Take Home Message  PAD is a common, yet serious, disease that raises the risk of heart attack and stroke  PAD is not always symptomatic and may be silent in a vast majority of patients  Evaluation of PAD should be part of routine physical examination  Appropriate and timely interventions (medical & revascularization) can significantly improve cardiovascular outcomes

39. http://www.xlpad.org/