1. Leadership. Knowledge. Community. Canadian Cardiovascular Society Antiplatelet Guidelines Antiplatelet Therapy for Vascular Prevention in Patients with Peripheral Arterial Disease Working Group: A. Roussin, MD, FRCP; Thomas F. Lindsay, MD, CM, FRCSC

2. Objectives Interpret the Canadian Cardiovascular Society Guideline recommendations regarding the use of antiplatelet therapy in patients with peripheral arterial disease. Appropriately use antiplatelet agents in patients with symptomatic versus asymptomatic PAD. Appropriately use antiplatelet agents in patients following peripheral vascular surgery. © 2011 - TIGC

3. Case A 50-year old male patient, treated for dyslipidemia and hypertension with both a statin and a ACEI, reports new onset of leg pain when walking. He has recently quit smoking. There are no symptoms suggestive of CAD or CVD. The physical examination is unremarquable except for a left femoral bruit and diminished tibial pulsations on the same side. © 2011 - TIGC

4. Antiplatelet management What antiplatelet therapy, if any, would you suggest ? A.No antiplatelet therapy B. ASA 80 mg C. Clopidogrel 75 mg D. ASA 80 mg + Clopidogrel 75 mg © 2011 - TIGC

5. Asymptomatic “PAD” ASA ineffective (but ABI 0.86…) Fowkes et al. JAMA 2010 CAD event with or without mortality, stroke or revascularization

6. © 2011 - TIGC Asymptomatic “PAD” and Diabetes ASA ineffective (but ABI 0.9…) POPADAD Belch J et al. BMJ 2008

7. Antiplatelet therapy impact APT coll. Study BMJ 2002; 324: 71-86

8. Clopidogrel : CAPRIE Study RRR according to entry criteria ASA better Clopidogrel better Relative risk reduction (%) 010203040 - 40 - 30 - 20 - 10 All patients Stroke MI Claudication 8.7 7.3 - 3.7 23.8 ARR / yr 5.83  5.32 7.71  7.15 4.84  5.03 4.86  3.71 10.74  8.35 Claudication or Stroke with previous MI 22.7 CAPRIE. Lancet 1996; 348:pp. 1 329 à 1 339.

9. 9 ®® Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease 1.For patients with asymptomatic PAD with an ABI <0.9, low- dose ASA (75-162 mg daily) may be considered for those at high risk because of associated atherosclerotic risk factors in the absence of risk factors for bleeding (Class IIb, Level C). 2.For patients with symptomatic PAD without overt CAD or cerebrovascular disease, low-dose ASA (75-162 mg daily) or clopidogrel 75 mg daily is recommended providing the risk for bleeding is low (Class IIb, Level B). The choice of drug may depend on patient preference and cost considerations.

10. 10 ®® 3.For patients allergic or intolerant to ASA, use of clopidogrel is suggested (Class IIa, Level B). 4.For patients with intermittent claudication, dipyridamole should not be used in addition to ASA (Class III, Level C). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

11. Overall Population: Primary efficacy outcome (MI, stroke, or CV death) † † First Occurrence of MI (fatal or non-fatal), stroke (fatal or non- fatal), or cardiovascular death *All patients received ASA 75-162mg/day Median follow-up was 28 months Cumulative event rate (%) 0 2 4 6 8 Months since randomization 0 612182430 Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22 Bhatt D et al. NEJM 2006

12. Primary efficacy end point (MI, Stroke and CV death) CHARISMA (CH) vs CAPRIE (CP) 28 months ASA ASA + Clop. RRR P value 12 months ASA ASA + Clop. ARR Per year Events saved/ 1000pts/yr ASA + Clop. NNT Per yr If p < 0.05 CH: ALL 7.3%6.8%7%0.223.12%2.91%0.21%2.1476 AT7.9%6.9%13%0.0463.39%2.96%0.43%4.3233 RF5.5%6.6%-20%0.22.36%2.83%-0.88%-4.8 CP: ALL 5.83%200 MI/PAD4.8% PAD/Str. Prev. MI 10.7%42

13. 13 ®® 5.For patients with intermittent claudication, using clopidogrel 75 mg daily in addition to ASA 75-162 mg daily is not recommended unless the patient is judged to be at high vascular risk along with a low risk of bleeding (Class IIb, Level B). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

14. Warfarin Antiplatelet Vascular Evaluation Study Design - 2161 PAD Patients Follow-up - q 3 mo. x 30-42 mo. AP only (1,081 patients) AP + OAC (1,080 patients) 42 mo. or Final Visit PAD Patients 2-4 weeks AP + OAC (INR 1.8-3.5) Rand AP only Run-In AP + OAC Central randomization, 80 centres, 7 countries, open trial, blinded adjudication Anand S et al. TIGC oct 2006

15. Co-Primary end-point 1 CV death, MI, stroke OAC+AP AP Anand S et al. TIGC oct 2006

16. Co-Primary end-point 2 CV death, MI, stroke, severe ischemia OAC+AP AP Anand S et al. TIGC oct 2006

17. Life-threatening bleeding OAC+AP AP P<0.001 Anand S et al. TIGC oct 2006

18. WAVE: Outcomes in PAD patients End point Warfarin + ASA, n=1080 (%) Aspirin only, n=1081 (%) Hazard ratiop First primary end point* 12.213.30.920.49 Second primary end point † 15.917.40.910.38 Life-threatening bleeding 41.23.41<0.001 Moderate bleeding 2.91.02.820.0018 *CV death, MI, and stroke †CV death, MI, stroke, and severe ischemia in the coronary or peripheral arteries

19. 19 ®® 7.For patients with symptomatic PAD without compelling indications for oral anticoagulation such as atrial fibrillation or venous thromboembolism, oral anticoagulation should not be added to antiplatelet therapy (Class III, Level B). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

20. 20 ®®

21. Back to our case A 50 year old male patient, treated for dyslipidemia and hypertension with both a statin and a ACEI, reports new onset of leg pain when walking. He has recently quit smoking. There are no symptoms suggestive of CAD or CVD. The physical examination is unremarquable except for a left femoral bruit and diminished tibial pulsations on same side. © 2011 - TIGC

22. Antiplatelet management What antiplatelet therapy, if any, would you suggest ? A. No antiplatelet therapy B. ASA 80 mg C. Clopidogrel 75 mg D. ASA 80 mg + Clopidogrel 75 mg © 2011 - TIGC

23. “What if” Peripheral angioplasty Same patient comes back to you after having a stent implanted in his left iliac artery. Would that change your choice of antiplatelet therapy? © 2011 - TIGC

24. 24 ®® 9.Long-term antiplatelet therapy with ASA 75-162 mg daily should be given to patients who undergo lower-extremity balloon angioplasty with or without stenting for chronic symptomatic PAD (Class IIa, Level C). Anticoagulation with heparin or vitamin K antagonists should be avoided in this setting (Class III, Level B). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

25. “What if” Infrainguinal reconstruction Same patient comes back to you after undergoing a femoro-popliteal bypass. Would that change your choice of antiplatelet therapy? © 2011 - TIGC

26. 26 ®® 10.For all infrainguinal reconstructions, low-dose ASA (75- 162 mg daily) should be given (Class IIa, Level B). In those with infrainguinal grafts and a high risk of thrombosis or limb loss, combination therapy with a vitamin K antagonist and ASA may be of benefit (Class IIb, Level C). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

27. “What if” AAA Same patient comes back. A 4 cm wide abdominal aortic aneurism is described on a recent abdominal echo. How would that change your choice of antiplatelet therapy? © 2011 - TIGC

28. 28 ®® 11.Low-dose ASA (75-162 mg daily) may be considered for all patients with an AAA, particularly those with clinical or subclinical PAD (Class IIb, Level C). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

29. 29 ®®

30. “What if” Atrial fibrillation Same patient comes back. A recent ECG shows atrial fibrillation. How would that change your choice of antiplatelet therapy? © 2011 - TIGC

31. 31 ®® 8.For patients with symptomatic PAD with an indication for oral anticoagulation such as atrial fibrillation, venous thromboembolism, heart failure or mechanical valves, antiplatelet therapy should not be added to oral anticoagulation (Class III, Level A). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

32. “What if” ACS Same patient comes back He was recently hospitalized for a ACS and underwent a coronary angioplasty along with two stents deployed How would that change your choice of antiplatelet therapy? © 2011 - TIGC

33. 33 ®® 6.For patients with symptomatic PAD with overt CAD or cerebrovascular disease, antiplatelet therapy as indicated for the CAD and/or cerebrovascular status I s recommended (Class I, Level A). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

34. “What if” TIA Same patient comes back. Reports a recent 20 minutes right brachio-facial weakness. How would that change your choice of antiplatelet therapy? © 2011 - TIGC

35. 35 ®® 6.For patients with symptomatic PAD with overt CAD or cerebrovascular disease, antiplatelet therapy as indicated for the CAD and/or cerebrovascular status is recommended (Class I, Level A). Antiplatelet therapy for vascular prevention in patients with peripheral arterial disease

36. © 2011 - TIGC