Il clopidogrel in associazione all’ASA nella pratica clinica

1. Minimaster Cuore e diabetePrevenzione delle recidive e aderenza alle terapieCardioprotezione farmacologica: il punto sul clopidogrelMassimo Uguccioni Roma

2. Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste un’indicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca Il clopidogrel in associazione all’ASA nella pratica clinica

3. Clopidogrel Evidence: ACS (Non-STEMI - UA) Aspirin + Clopidogrel Aspirin + Placebo Rate of death, myocardial infarction, or stroke 20% RRRP<0.001 0 3 6 9 12 Months of Follow Up Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial 12,562 patients with a NSTEMI-ACS randomized to daily aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg) for 3-12 months (average 9) The CURE Trial Investigators. NEJM. 2001;345:494-502

4. 15 12.6% Placebo‡ Clopidogrel‡ 31% RRR 10 8.8% CV-death or MI (%) 5 P = 0.002N = 2658 0 0 100 200 300 400 Days of follow-up PCI-CURE and CREDOLong-Term Benefits of Clopidogrel in PCI Patients PCI – Cure CREDO 15 Placebo* Clopidogrel* 11.5% 27% RRR 10 8.5% MI, Stroke or Death (%) 5 P=0.02 N = 2116 0 0 3 6 9 12 Months From Randomization Mehta et al. Lancet 2001;358:527-533 Steinhubl S et al. JAMA. 2002; 288:2411-2420 †up to 12 months ‡plus ASA and other standard therapies

5. Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste un’indicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca Il clopidogrel in associazione all’ASA nella pratica clinica

6. Clopidogrel Reduced Clinical Events by 20% at 30 Days Placebo (14.1%) 15 20%* p=0.03 10 Clopidogrel (11.6%) Patients with endpoint (%) 5 0 0 5 10 15 20 25 30 Time (days) *Odds ratio in CV death, MI or recurrent ischemia leading to urgent revascularization Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

7. Clopidogrel Reduced the Composite of Death, MI or Stroke by 9% Placebo (10.1%) RRR=9% p=0.002 10 9 Clopidogrel (9.3%) 8 7 6 Events (%) 5 4 3 2 1 0 0 7 14 21 28 Days (up to 28 days) RRR = relative risk reduction Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.

8. Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste un’indicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca Il clopidogrel in associazione all’ASA nella pratica clinica

9. CHARISMA Primary Outcome (MI, Stroke, or CV Death) Placebo + ASA7.3% Clopidogrel + ASA6.8% P = 0.22 Cumulative Event Rate (%) RRR: 7.1% [95% CI: -4.5%, 17.5%]P=0.22 0 6 12 18 24 30 Months Since Randomization First occurrence of fatal or non-fatalMI, fatal or non-fatal stroke, or CV death All patients received ASA (aspirin) 75-162 mg/day Bhatt DL et al. N Engl J Med 2006;354:1706–1717.

10. Effect of aspirin plus clopidogrel on the primary endpoint (MI, stroke, CV death) in patients with risk factors or established disease Van de Werf, F. Eur Heart J Suppl 2007 9:D3-9D

11. Absolute benefit and bleeding hazard of combined treatment with clopidogrel plus aspirin

12. Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste un’indicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca Il clopidogrel in associazione all’ASA nella pratica clinica

13. Clopidogrel Recommendations Start and continue clopidogrel 75 mg/d in combination with aspirin for post ACS or post PCI with stent placement patients for up to 12 months for post PCI-stented patients >1 month for bare metal stent, >3 months for sirolimus-eluting stent >6 months for paclitaxel-eluting stent *Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

14. Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste un’indicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca Il clopidogrel in associazione all’ASA nella pratica clinica

15. Comparison of treatment of STEMI patients at discharge in ACS-I and ACS-II in 34 centres European Heart Survey (2000-04) Mandelzweig, L. et al. Eur Heart J 2006 27:2285-2293;

16. Comparison of treatment of N-STEMI patients at discharge in ACS-I and ACS-II in 34 centres European Heart Survey (2000-04) Mandelzweig, L. et al. Eur Heart J 2006 27:2285-2293;

17. Variations Among Hospitals430 CRUSADE hospitals Acute Discharge Peterson et al, JAMA 2006;295:1863-1912

18. Paradoxical Discharge Care Patterns (n = 74,217 patients in CRUSADE)

19. Late DES Thrombosis Independent Predictors of Late Thrombosis Iakovou JAMA 2005; 293: 2126-30

20. Stent Thrombosis Rates Selected Patient Characteristics *AntiplateletTherapyDiscontinuation PriorBrachy RenalFailure Bifurcation ULM Diabetes UA Jeremias P et al Circulation 2004; 293:2126 *Premature discontinuation

21. Mortality from 1 to 12 months after MI in relation to thienopyridine therapy at 1 month after MI Premier Registry 19-center study – 500 DES treated 13.6% stop therapy in 30 days Spertus, J. A. et al. Circulation 2006;113:2803-2809

22. Cardiac rehospitalization from 1 to 12 months after MI in relation to thienopyridine therapy at 1 month Premier Registry 19-center study Spertus, J. A. et al. Circulation 2006;113:2803-2809

23. 8 % (95% CI) p 7.2 Percent Cumulative Incidence Rate DES-C DES+C DES-C -4.1 0.02 DES+C BMS-C -2.9 0.01 6.0 BMS-C 6 DES+CBMS+C -2.4 0.16 BMS+C BMS+C BMS-C -0.5 0.70 DES-C BMS-C 1.2 0.44 5.5 4 DES+C 3.1 2 0 6 24 12 18 Duke Databank 6-Month Landmark AnalysisAdjusted Cumulative Rates of Death or Nonfatal MI n=4666 Months Eisenstein, E et al. JAMA 2007; 297(2):159-68

24. Antiplatelet treatment at the time of DES thrombosis in 152 patients Windecker, S. et al. Circulation 2007;116:1952-1965

25. Results: Predictors of inappropriate clopidogrel use

26. Results: Incidence of MI by adherence to clopidogrel HR 1.35(1.08-1.70)p=0.009

27. Dual anti-platelet discontinuation DM ACS / AMI Low EF Renal Failure Bifurcations Longer stent length Residual dissection Small stent diameter Stent underexpansion Malapposition Who Should Not Get DES in 2007? Predictors of Stent Thrombosis Patient Factors Lesion Factors

28. ACC/AHA 2007: Long-Term Treatment UA/NSTEMI Groups at Discharge Medical RxNo Stent Bare Metal Stent Drug-Eluting Stent ASA 162-325 mg/d for 3-6 mothen 75-162 mg/d indefinitely Clopidogrel 75 mg/d for at least 1 yr (Class I, LOE B) ASA 75-162 mg/d indefinitely Clopidogrel 75 mg/d> 1 mo (Class I, LOE A)up to 1 yr (Class I, LOE B) ASA 162-325 mg/d for 1 mothen 75-162 mg/d indefinitely Clopidogrel 75 mg/dfor at least 1 mo and up to 1 yr (Class I, LOE B) Indication for Anticoagulation No Yes Add Warfarin (Class IIb, LOE B) Continue dual antiplatelet Rx Anderson HV et al. ACC/AHA UA/NSTEMI Guideline Revision. JACC 2007; 50:e1–157

29. Study Population: 127 VHA Hospital ACS Registry: Oct 2003-March 2005 Admitted with ACS between 10/03 to 9/04 Discharged on clopidogrel Total duration of clopidogrel treatment : 50th (25th-75th) Medical (n=1569): 281 days (120-417) PCI (n=1568): 310 days (182-410) All-cause death/MI after stopping clopidogrel Determined for each 90 day period Is There Clinical Evidence of Clopidogrel Rebound? Ho PM, et al. JAMA 2008;299(5):532-539

30. PCI Therapy: Event rates after stopping clopidogrel

31. Medical Therapy: Event rates after stopping clopidogrel

32. Platelet aggregation (A) and inhibition of platelet aggregation (B) (baseline and 30 days) after stimulus with ADP in doses of 75 mg and 150 mg in diabetic patients Angiolillo, D. J. et al. Circulation 2007;115:708-716

33. Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste un’indicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca Il clopidogrel in associazione all’ASA nella pratica clinica

34. Uomo di 55 anni ex-fumatore; accusa tosse persistente. Rx torace: opacità vicino al bronco lobare superiore destro Tre mesi prima SCA trattata con impianto di DES sulla DA prossimale Si rende necessaria una biopsia bronchiale Presentazione del caso clinico Riddell, J. W. et al. Circulation 2007;116:e378-e382

35. Flow chart to determine the risk of stent thrombosis in non cardiac surgery Expert opinion Riddell, J. W. et al. Circulation 2007;116:e378-e382

36. Chirurgia odontoiatrica

37. Si decide per la sospensione del clopidogrel cinque giorni prima della biopsia con ripresa con dose da carico il primo giorno postoperatorio La terapia con aspirina non viene sospesa Gestione del caso clinico Riddell, J. W. et al. Circulation 2007;116:e378-e382

38. AHA/ACC/SCAI/ACS/ADA Science Advisory

39. 1. Patients should be specifically instructed before hospital discharge to contact their cardiologist before stopping any anti-platelet therapy 2. Healthcare providers who perform invasive or surgical procedures and are concerned about periprocedural and postprocedural bleeding must be made aware of the potentially catastrophic risks of premature discontinuation of thienopyridine 3.For patients treated with DES who are to undergo subsequent procedures that mandate discontinuation of thienopyridine therapy, aspirin should be continued if possible and the thienopyridine restarted as soon as possible after the procedure because of concerns about late-stent thrombosis. Summary and Recommendations

40. While in-hospital antiplatelet therapy is improving, still potential for optimization More complete treatment, particularly high risk More appropriate drug dosing in diabetics? Greater potential for improving outpatient care Better patient adherence Better understanding of optimal therapy duration Protocols for safe drug withdrawal Conclusions