1. IMPACT OF DURATION AND INTENSITY OF ANTITHROMBOTIC THERAPY C. Moretti WHAT IS KNOWN AND WHAT IS UNKNOWN ON THROMBOTIC RISK ACCORDING TO PATIENT, LESION, DEVICE AND ANTIPLATELET ACTIVITY TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

2. Introduction Evidence supporting DAT for (more than ?) 12 months. Evidence supporting different loading doses. Prasugrel Thrombosis & bleeding risk in daily practice Final remarks Topics

3. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Introduction Evidence supporting DAT for (more than ?) 12 months. Evidence supporting different loading doses. Prasugrel Thrombosis & bleeding risk in daily practice Final remarks Topics

4. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Brainstorming Stent Thrombosis Bleeding risk

5. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Daemen J et al. Lancet 2007;369:667–78 0.6% per year 8146 patients treated with DES (sirolimus or paclitaxel- eluting stents) followed for a mean of 1.7 years (up to 3) Daemen J et al. Lancet 2007;369:667–78 Rotterdam-Bern Registry – long-term incidence of DES thrombosis

6. 4-Year after Cypher FIM Study: Vascular Healing 4-Year after SES Implantation (Pathological Findings) Pt # 4 (Fast release) SEM showed > 95% endothelized stent surface Uncovered stent strut E. Sousa Circulation 2004;110 e5

7. Platelet Activation After PCI Early and Long-term Risk of Ischemic Events Acute thrombosis Subacute thrombosis Death or MI 1 Mak K-H et al. J Am Coll Cardiol. 1996; 27: 494-503 2 Steinhubl S et al. Circulation. 1999; 100: 18 (suppl): I-380. Abstract 1993 Complications of Stent Placement Complications of Atherothrombotic Disease Within 4 weeks Incidence: 0.5%-5.7% 1 1 year Incidence: 15.8% 2 Within 24 hours Incidence: 0.6% 1 TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

8. Multiple ruptured coronary plaques in pts with ACS

9. ~ 1/4 of the 40,258 patients with CAD also have atherothrombotic disease in other arterial territories REACH – 1/4 of patients with CAD also have polyvascular disease CAD PAD 4.7% 8.4% 1.6% CVD 16.6% 44.6% (%s are of total population, n=67,888) Patients with CAD = 59.3% of the REACH Registry population CAD, coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease 4.7% Multiple risk factors only population Adapted from Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295:180–189.

10. REACH – pts with CAD + PAD have ↑ event rates than those with PAD or CAD alone 1-year event rate (%) *TIA, UA, other ischaemic arterial event including worsening of PAD Rates adjusted for age and sex CAD, coronary artery disease; MI, myocardial infarction; REACH, Reduction of Atherothrombosis for Continued Health; TIA, transient ischaemic attack; UA unstable angina Steg PG et al. JAMA 2007;297:1197–1206. 1.6 1.4 0.9 3.6 13.0 1.4 1.0 0.8 3.1 17.4 3.2 1.5 1.2 5.5 23.1 0 5 10 15 20 25 CV deathNon-fatal MINon-fatal strokeCV death, MI or stroke CV death, MI, stroke or hospitalisation* CAD alone (n=28,867) PAD alone (n=3,246) CAD + PAD (n=3,264)

11. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Introduction Evidence supporting DAT for (more than ?) 12 months. Evidence supporting different loading doses. Prasugrel Thrombosis & bleeding risk in daily practice Final remarks Topics

12. CREDO – 1-year primary outcome 27% Relative Risk Reduction Months 306912 0 5 15 10 Death, MI, or Stroke, % P=.02 8.5% 11.5% Clopidogrel n=1053 Placebo n=1063 Adapted from Steinhubl SR, et al. JAMA. 2002;288:2411- 2420. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

13. CURE – primary end point of MI/stroke/CV death (N=12,562) The primary outcome occurred in 9.3% of patients in the clopidogrel + ASA group and 11.4% in the placebo + ASA group Months of Follow-up Clopidogrel + ASA 3 6 9 Placebo + ASA 0 12 Cumulative Hazard Rate 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 20%Relative Risk Reduction P=0.00009 Study subjects had ACS (UA/non–ST-elevation MI) CURE Trial Investigators. N Engl J Med. 2001;345:494-502. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

14. Duke Databank: 6-Month Landmark Analysis- Adjusted Cumulative Rates of Death or Nonfatal MI BMS: 1/2000-7/2005 n = 3,165 DES: 4/2003-7/2005 n= 1,501

15. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Milan/Siegburg/Naples Registry Incidence of Definite ST 6/2002 – 1/2004 n = 3,021 (SES/PES)

16. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Japanese observational (2 yrs) study on 10,778 pts receiving SES. J-Cypher Registry

17. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Thieno- and/or aspirine discontinuation and ST by time interval after stent implantation Kimura T & j-Cypher Registry Investigators. Circulation 2009; 119:987-996

18. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Landmark analysis Clopidogrel and DES use not randomized. Unmeasured prognostic factors Clopidogrel use identified by patient self- report. Limitations

19. Definite/Probable ST: DES Only (N=5743) % of Subjects HR 0.36 [0.22-0.58] P<0.0001 1 year: 0.74% vs 2.05% HR 0.35 [0.21-0.58], P<0.0001 2.31% 0.84% 64% STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL

20. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM GL recommendations for long term AP TX

21. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Introduction Evidence supporting DAT for (more than ?) 12 months. Evidence supporting different loading doses. Prasugrel Thrombosis & bleeding risk in daily practice Final remarks Topics

22. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM 30-day MACE

23. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Adjusted clopidogrel loading doses according to VASP Index A multicentre randomized prospective study. Bonello L. et al 2008 EFFICACYBLEEDING

24. SUMMARY OF EVIDENCE ON CLOPIDOGREL LOADING TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

25. ARMYDA-Reload ACC 2008- G. Di Sciascio, et al STABLEACS 4 8 18 7 600 mg Clopidogrel reloadPlacebo P=0,035 P=0,23

26. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Several trials and guidelines support a clopidogrel loading dose of at least 300 mg. A 600 mg loading dose is recommended in patients at high risk of ischemic events and low bleeding risk who are undergoing PCI. These loading doses should be administered immediately at diagnosis in patients with acute coronary syndromes, and between 2 hours before and just before PCI in stable patients. Known knowns

27. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Introduction Evidence supporting DAT for (more than ?) 12 months. Evidence supporting different loading doses. Novel antiplatelet therapies. Thrombosis & bleeding risk in daily practice Final remarks Topics

28. Prasugrel: me-too drug or something new ? Another irreversible P2Y 12 inhibitor Fewer hepatic steps than clopidogrel required to convert the prodrug to active drug More potent; less variability than clopidogrel

29. Inhibition of aggregation (20 mM ADP) (%) Prasugrel 60 mg Clopidogrel 300 mg Clopidogrel responder* Clopidogrel nonresponder *Responder = ≥25% IPA at 4 and 24 h n=66 Healthy volunteers Prasugrel vs Clopidogrel Crossover Study Inhibition of Aggregation at 24 hrs Brandt J et al. AM. Heart J. 2007;153:66e9-66e16. -20 0 20 40 60 80100 TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

30. Prasugrel 60 mg LD vs Clopidogrel 300 mg or 600 mg LD: Faster Onset and Higher IPA Inhibition of platelet aggregation (%) Mean ± SEM 20 μM ADP Time after LD (hrs) 0 20 40 60 80 100 Clop 300 mg LD 0.250.5124624 Loading Dose † † ‡ † ‡ Clop 600 mg LD * * * * * * Pras 60 mg LD 0 Payne CD. Presented at TCT 2006. * P<.001 vs clop 300 mg or 600 mg LD † P<.001 vs clop 300 mg ‡ P<.05 vs clop 300 mg TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

31. Antiplatelet therapy in ACS

32. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

35. Introduction Evidence supporting DAT for (more than ?) 12 months. Evidence supporting different loading doses. Prasugrel Thrombosis & bleeding risk in daily practice Final remarks Topics

36. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Guideline on antiplatelet management in cardiac surgery Clopidogrel use: increase in blood prodoct usage. sixfold increase in the odds of re-exploration. NO difference in length of stay or mortality

37. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM EACTS RECOMMENDATIONS IF URGENT cardiac surgery is required pts MUST STOP CLOPIDOGREL 5-7 days before surgery AT THE EXPENSE of a 1% increase of risk in MI while awaiting surgery (Grade B). Patients undergoing urgent cardiac surgery with an acute coronary syndrome should continue ASPIRINE up to the day of surgery (Grade B). ASPIRINE should be commenced within 24 h of CABG (Grade A) but there is a trend of benefit if started within 6 h (Grade B). In pts with acute coronary syndrome: consider ASPIRINE & CLOPIDOGREL for 9-12 months (Grade B).

38. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM DAT should be stopped in Aortic aneurysm repair Renal biopsy Intracranial/spinal surgery Prostate/bladder surgery Major cancer surgery Major orthopaedic surgery Resection of colonic sessile polyps > 2 cm

39. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Could you give me a guideline, please ? THROMBOSIS BLEEDING

40. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Withdrawing antiplatelet therapy in pts with intracoronary stents  DAT withdrawal led to a 90-fold increase in cardiovascular risk.  A careful assessment of the relative risks of ischaemic and bleeding events is mandatory.  Bridging anticoagulation ?  Short acting antiplatelet drugs (tirofiban, eptifibatide)?

41. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Introduction Evidence supporting DAT for (more than ?) 12 months. Evidence supporting different loading doses. Prasugrel Thrombosis & bleeding risk in daily practice Final remarks Topics

42. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM “He is truly wise who gains wisdom from another's mishap…”  One year of Clopidogel may be too little…  Room for improvement in AP TX  Premature DAT discontinuation Can have serious consequences

43. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM To keep it simple… FOLLOW THE GL ASSESS RISK & BENEFIT …AND GOOD LUCK !

44. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

51. Patient-related factors – Compliance – Methabolism – Genetic – CV risk factors (obesity, diabetes, smoking,dislypidemia). Variable platelet response to antiplatelet tx Drug-related factors -Dosing -Drug-drug interactions

52. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM Risk and management of upper GI bleeding associated with prolonged DAT after PCI Aspirine amplifies the risk of bleeding (RR x 4-6) – Up to 15% of patient with a history of ulcer bleeding will experience a recurrence within a year. Clopidogrel does not induce new ulcer formation The addition of clopidogrel to aspirine increases the relative risk of bleeding by 50% Most of the bleeding risk appears to occur fairly early after the initiation of DAT. In patients requiring warfarin the addition of DAT is associated with an approximately 3 to 6-fold increase in bleeding events.

53. TURIN, February 26 th -27 th 2009. IV INTERNATIONAL INTERVENTIONAL FORUM

54. V.P. Tan et al, Cardiovascular Revascularization Medicine, 10 (2009) 36 - 44