Diffuse Vascular Disease (Focus on Peripheral Arterial Disease [PAD])

1. Case Study: Diane Leary Diffuse Vascular Disease (Focus on Peripheral Arterial Disease [PAD])

2. Learning Objectives At the end of this session, participants should be able to: • Identify patients with peripheral arterial disease (PAD) • Apply Canadian guidelines for the screening and management of PAD • Identify patients with diffuse vascular disease and implement strategies for the prevention of atherothrombotic events in these patients

3. Patient Presentation • Diane is a 65-year-old retired school teacher • She complains of left calf pain when walking a couple of blocks; the pain goes away after she rests for 5 minutes • No other complaints

4. History • NSTEMI 20 months ago • Carotid bruit • Hypertension • Type 2 diabetes (diagnosed 5 years prior) • Hyperlipidemia • No family history of diabetes or cardiovascular disease • Former smoker NSTEMI: non-ST-elevation myocardial infarction

5. Medications • ASA 81 mg/day • Ramipril 10 mg/day • Metformin 500 mg tid • Atorvastatin 20 mg/day • Metoprolol 25 mg bid ASA: acetylsalicylic acid

6. Physical Examination • Height: 1.65 m • Weight: 81.6 kg • BMI: 29 kg/m2 • Waist circumference: 104 cm • BP in-office: 128/72 mmHg • Heart rate: 80 bpm • Left femoral bruit • Carotid bruit • Bilateral reduced pedal pulses BMI: body mass index; BP: blood pressure

7. Laboratory Investigations • FPG: 6.2 mmol/L • A1C: 7.5% • Lipids at desired values • TC < 5.2 mmol/L • TG < 2.3 mmol/L • HDL-C > 1.20 mmol/L (female) • LDL-C < 2.0 mmol/L • TC/HDL-C < 4.0 • Urine ACR: 1.9 mg/mmol • Complete blood count within normal limits • ECG normal FPG: fasting plasma glucose; A1C: hemoglobin A1C; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TG: triglycerides; ACR: albumin-to-creatinine ratio; ECG: electrocardiogram

8. Question 1 What is your initial diagnosis?

9. Key Points • Patient presents with typical symptom of PAD (intermittent claudication) and has a number of risk factors for the disease • Basic screening should include directed history and physical exam focusing on femoral bruits and pedal pulses • Non-invasive evaluation should include an ABI ABI: ankle-brachial index

10. Risk Factors for PAD • Risk factors for PAD are similar to those for atherosclerosis in other beds and include: • Smoking and diabetes are the most predictive for development of symptomatic claudication Teo KK. Can J Cardiol. 2005;21(12):997–1006.

11. Varied Presentation of PAD PAD can be silent or cause symptoms ranging from pain to critical limb ischemia McDermott MM et al. JAMA 2001;286:1599-1606.

12. REACH RegistryAtherothrombosis: Overlapping Manifestations of Disease The REACH Registry found overlapping manifestations of disease in patients with CAD, CVD, and PAD • 61% of PAD patients also had symptomatic disease in the coronary or cerebral circulation • 40% of CVD patients also had symptomatic disease in the coronary or peripheral circulation • 25% of CAD patients also had symptomatic disease in the cerebral or peripheral circulation 18.3% of patients in the REACH Registry did not have manifestations of atherothrombosis, but were included based on risk factors CAD: coronary artery disease; CVD: cerebrovascular disease; PAD: peripheral arterial disease Bhatt DL, et al; for the REACH Registry Investigators. JAMA. 2006;295:180-189.

13. * * * Prevalence of PAD (%) Normal glucose tolerance Impaired glucose tolerance Diabetes Increased Risk of PAD with Diabetes Impaired glucose tolerance was defined as oral glucose tolerance test value ≥140 mg/dL <200 mg/dL. * P≤0.05 vs. normal glucose tolerance. Lee AJ, et al. Br J Haematol. 1999;105:648–654.

14. Question 2 What additional investigations would you perform?

15. Key Points: Diagnosis of PAD • History • Edinburgh Questionnaire • Physical examination • Bruit • Peripheral pulses • Non-invasive tests • ABI • Arterial Duplex Adapted from Roussin A, et al. Can J Cardiol. 2005;21(12):997–1006.

16. CCS Guidelines: Diagnosis of PAD Roussin A, et al. Can J Cardiol. 2005;21(12):997–1006.

17. Edinburgh Questionnaire • Do you get a pain or discomfort in your leg(s) when you walk? • YES (If patient answers no, then stop here) • Does this pain ever begin when you are standing still or sitting? • NO • Do you get it when you walk uphill or hurry? • YES • Do you get it when you walk at an ordinary pace on level ground? • YES(Answer may also be ‘no’ depending on severity of claudication) • What happens to it if you stand still? • Pain usually disappears in 10 minutes or less (pain continuing for more than 10 minutes is not consistent with PAD) • Where do you get this pain or discomfort? • Patient marks calf and/or thigh and/or buttock • (A positive diagnosis of PAD requires the responses indicated in yellow for all questions) Leng GC, et al. J Clin Epidemiol. 1992;45:1101–1109.

18. Higher right-ankle pressure Higher arm pressure RIGHT ABI Right-arm systolic pressure Left-arm systolic pressure Higher left-ankle pressure Higher arm pressure LEFT ABI INTERPRETATION OF ABI >1.30 0.91-1.30 0.41-0.90 0.00-0.40 Noncompressible Normal Mild-to-moderate peripheral arterial disease Severe peripheral arterial disease DP PT DP PT Left-ankle systolic pressure Right-ankle systolic pressure Measuring ABI Adapted from Roussin A, et al. Can J Cardiol 2005;21(12):997-1006.

19. Question 3 What if the patient’s pedal pulses were palpable and there were no bruits? Would this change your diagnosis?

20. Key Point • Palpable pedal pulses and an absence of femoral bruits do not preclude PAD

21. PAD Regardless of Claudication • Value of physical examination relative to presence of PAD McGee SR, et al. Arch Intern Med. 1998;158:1357–1364.

22. Case Evolution • Based on your clinical examination, you diagnose Diane with PAD. You perform further investigations and find that she has an ABI of 0.65, which confirms your diagnosis. Significance of ABI values ►

23. Question 4 • How would you manage this patient’s: • claudication? • overall vascular risk?

24. Key Points: Objectives of PAD Therapy • Prevent death and disability • Reduce risk of MI (PAD quadruples MI risk) • Reduce risk of stroke (PAD triples stroke risk) • Relieve symptoms • Improve QOL • Improve walking ability • Save limbs • Prevent major amputations • Avoid tissue loss QOL: quality of life

25. Survival Following Diagnosis of PAD by Diabetes Status 100 No diabetes 90 80 Proportion alive (%) Diabetes 70 60 50 40 30 20 10 0 14 6 13 15 7 9 12 3 4 11 5 8 10 1 2 Time (years) Migliaccio-Walle K, et al. Can J Diabetes. 2007;31(2):140-147.

26. CCS Guidelines for PAD: Risk Reduction Strategies Anand SS, et al. Can J Cardiol. 2005;21(12):997–1006.

27. Risk Factor Management • Smoking cessation • Weight reduction • Regular physical activity • LDL-C < 2.0 mmol/L • Glycosylated hemoglobin < 6.0% • BP < 140/90 mmHg; < 130/80 mmHg in patients with diabetes • Platelet inhibition Hiatt WR. N Engl J Med. 2001;344:1608-1621. McPherson R, et al. Can J Cardiol. 2006;22:913-927. CDA 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Available at http://www.diabetes.ca/cpg2003 2007 CHEP Recommendations. Available at www.hypertensions.ca

28. CCS Guidelines for PAD: Pharmacologic Approach Medical therapies to reduce cardiovascular events in PAD Anand SS, et al. Can J Cardiol. 2005;21(12):997–1006.

29. CCS Guidelines:Antithrombotic Therapies *Not available in Canada Anand SS, et al. Can J Cardiol. 2005;21(12):997–1006.

30. Supervised Exercise in the Management of Symptomatic PAD • Exercise prescription is fundamental for all patients with claudication • Supervised programs have patients walk to the point of moderate pain, followed by rest and repeat exercise • Benefit is observed as early as 4 weeks and continues to improve for at least 1 year Anand SS, Turpie AGG, et al. Can J Cardiol. 2005;21(12):997–1006.

31. Question 5 Could warfarin be added to antiplatelet therapy in patients with PAD?

32. WAVE: Warfarin Antiplatelet Vascular Evaluation WAVE Trial Investigators. N Engl J Med. 2007;357(3):217-27.

33. Question 6 Given this patient’s history of ACS and current diagnosis of PAD (ie, diffuse vascular disease), how long should she remain on the prescribed antiplatelet regimen? Review pathophysiology & epidemiology of polyvascular disease and atherothrombosis ►

34. Key Points • High risk of CV death, MI, stroke or hospitalization in patients with diffuse vascular disease1 • Aggressive risk reduction strategies and dual antiplatelet therapy should be considered for these patients • Currently no guideline recommendations on the optimal duration of antiplatelet therapy in patients with diffuse vascular disease; however, many experts would agree that this patient requires lifelong antiplatelet therapy • CCS recommends lifelong antiplatelet therapy in PAD2 • CHARISMA showed that patients with a prior atherothrombotic event (MI, stroke or PAD) benefit from long-term dual antiplatelet therapy (median follow-up 27 months), but at the cost of an increased rate of bleeding3 CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance 1. Steg PG, et al.; for the REACH Registry Investigators. JAMA. 2007;297:1197-206. 2. Abramson BL, et al. Can J Cardiol. 2005;21(12):997–1006. 3. Bhatt DL, et al.; CHARISMA Investigators. J Am Coll Cardiol. 2007;49(19):1982-8.

35. REACHMajor endpoints as a Function of Single vs Multiple and Overlapping Locations † P<0.001 (ref class: CAD alone) § P<0.001 (ref class: PAD alone) ‡ P<0.001 (ref class: CAD + CVD) Steg PG, et al.; for the REACH Registry Investigators. JAMA. 2007;297:1197-206.

36. CCS Guidelines:Antithrombotic Therapies Anand SS, et al. Can J Cardiol. 2005;21(12):997–1006.

37. CAPRIE:Clopidogrel vs. ASA in Multi-bed Disease 15 10.74% 22.7% 10 8.35% Annual event rate (%) Relative Risk Reduction 164 events 196 events 5 0 Clopidogrel ASA Events = ischemic stroke, MI or vascular death CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-39.

38. 10 Placebo + ASA 8.8 % Clopidogrel + ASA 7.3 % 8 6 Primary outcome event rate (%) 4 RRR: 17.1 % [95% CI: 4.4%, 28.1%] P=0.01 2 0 0 6 12 18 24 30 Months since randomization CHARISMA:Primary Endpoint (MI/Stroke/CV Death) in Patients with Previous MI, IS, or PAD “CAPRIE-like Cohort” N=9,478 Bhatt DL, et al.; CHARISMA Investigators. J Am Coll Cardiol. 2007;49(19):1982-1988.

39. CHARISMA:Primary and Secondary Safety Endpoints Bhatt DL, et al.; CHARISMA Investigators. J Am Coll Cardiol. 2007;49(19):1982-1988.

40. CHARISMA:Timing of Severe or Moderate Bleeding 0.00008 Placebo + ASA Clopidogrel + ASA 0.00007 0.00006 0.00005 Hazard Function/d 0.00004 0.00003 0.00002 0.00001 0 135 270 450 630 810 15 60 Days Since Randomization Bhatt DL, et al.; CHARISMA Investigators. J Am Coll Cardiol. 2007;49(19):1982-1988.

41. Take-Home Messages • Patients with PAD are at increased risk of diffuse vascular disease (ie, CAD and CVD) • Screen for PAD through history (Edinburgh Questionnaire) and physical examination (femoral bruits and pedal pulses) • Definitive diagnosis of PAD requires an ABI < 0.9 • Aggressive risk factor management should be considered for patients with diffuse vascular disease • Long-term dual antiplatelet therapy can also be considered in selected cases but it is important to weigh the benefits against the higher risk of bleeding

42. HYPERLINKS

43. Significance of ABI Values

44. > 1.1 0.9 – 1.1 0.7 – 0.9 0.5 – 0.7 < 0.5 GetABI: Mortality (All-cause) by ABI Category Diehm C. Presented at ESC Congress. Vienna, Austria. September 4, 2007.

45. 60 All-cause mortality Vascular disease mortality 50 40 Percent (%) 30 20 10 0 <0.60 (n=25) 1.0-<1.10 (n=980) 0.90-<1.0 (n=195) 0.60-<0.70 (n=21) 0.70-<0.80 (n=40) 0.80-<0.90 (n=130) Strong Association Between Decreased ABI & Increased Risk for Vascular Death Baseline ABI* RETURN *Mean participant follow-up 8.3 years Resnick HE, et al. Circulation. 2004;109:733-739.

46. Pathophysiology, Epidemiology & Burden of Atherothrombosis

47. Smooth muscle cell progression, plaque progression Accumulation of lipids Inflammation Normalartery Pathophysiology of Atherothrombosis Atherosclerosis + Thrombus Formation Rupture of Fibrous Cap Erosion of Endothelium Erosion of Calcium Nodule Intraplaque Hemorrhage Atherosclerosis leads to any number of four possible types of thrombus formation • Munger MA et al. J Am Pharm Assoc. 2004;44(suppl 1):s5-s13. • Libby P et al. Circulation. 2005;111:3481-3488.

48. Atherothrombosis Can Manifest in Multiple Vascular Beds • Atherothrombosis is a process that includes the following clinical consequences: • Ischemic stroke, MI, and PAD • Patients with atherothrombosis have thrombus formations that can manifest in multiple vascular beds throughout the body Munger MA et al. J Am Pharm Assoc. 2004;44(suppl 1):s5-s13.

49. Atherothrombosis: Disease Overlap Coronary artery disease (CAD) Cerebrovascular disease (CVD) 13% 9% 14% 5% Peripheral Arterial Disease (PAD) Patients with > 1 manifestation = 41% Aronow WS, Ahn C. Am J Cardiol. 1994;74:64-65.

50. Epidemiology of Atherothrombotic Manifestations in Canada Prevalence (Patients with disease history) Incidences per year Mortality Patients with a history of atherothrombosis are most likely to die of a recurrent atherothrombotic event5,6,7 Stroke 1.0%1 Stroke 40,000 – 50,0001 MI 2.7% (men)2 1.5% (women)2 MI 75,0001 PAD 3.0% (10.5 million†4 in North America) PAD Variable depending on population3 MI=myocardial infarction; PAD=peripheral arterial disease. †PAD patients in North America (USA and Canada): symptomatic (37.5%) and asymptomatic (62.5%). 1. Heart and Stroke Foundation of Canada. 5. Hardie K, et al. Stroke. 2003;34:1842-1846. 2. Manuel DG, et al. Can J Cardiol. 2003;19:997-1004. 6. Taneja AK, et al. Eur Heart J. 2004;25:2013-2018. 3. Ouriel K. Lancet. 2001;358:1257-1264. 7. Hirsch AT, et al. J Am Coll Cardiol. 2006;47:1239-1312. 4. Weitz JI, et al. Circulation. 1996;94:3026-3049.