Stephan Windecker Department of Cardiology Swiss Cardiovascular Center and Clinical Trials Unit Bern Bern University Hospital, Switzerland

Transcription

1 Advances in Antiplatelet Therapy in PCI and ACS Stephan Windecker Department of Cardiology Swiss Cardiovascular Center and Clinical Trials Unit Bern Bern University Hospital, Switzerland

2 Targets for Platelet Inhibition

3 Mode of Action of Antiplatelet Drugs Schömig A. N Engl J Med 2009;361: Limitations of Clopidogrel 1. Delayed onset of action 2. Large interindividual variability in platelet response 3. Irreversibility of inhibitory action

4 IPA % (20 µm ADP) Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI *** *** Prasugrel 60 mg *** 60 *** 40 Clopidogrel 600 mg 20 ***p< Prasugrel vs. Clopidogrel IPA=inhibition of platelet aggregation; PCI=Percutaneous coronary intervention Hours Wiviott SD et al. Circulation 2007;116(25):

5 IPA at 24 hours (%) Interpatient Variability Healthy Volunteer Crossover Study N=66 Interpatient Variability Clopidogrel Responder Clopidogrel Non-responder -20 Response to Clopidogrel 300 mg Response to Prasugrel 60 mg From Brandt JT AHJ 153: 66e9,2007

6 Ticagrelor and Inhibition of Platelet Aggregation Gurbel PA al. Circulation 2009

7 Ticagrelor and Inhibition of Platelet Aggregation in Clopidogrel-Nonresponsive Patients Gurbel PA et al. Circulation 2010;121:

8 Clopidogrel vs Prasugrel and Ticagrelor Inhibition of Platelet Aggregation Prasugrel and ticagrelor show more rapid onset of platelet inhibition than clopidogrel Prasugrel and ticagrelor afford greater inhibition of platelet aggregation than clopidogrel Prasugrel and ticagrelor provide more predictable inhibition of platelet aggregation than clopidogrel Offset of Inhibition of Platelet Aggregation Ticagrelor shows more rapid offset than clopidogrel after discontinuation

9 TRITON-TIMI 38

10 Primary Endpoint (%) Triton TIMI 38 Prasugrel vs. Clopidogrel Wiviott SD et al. N Engl J Med 2007;357: Primary Endpoint: CV Death, MI, Stroke Clopidogrel 12.1 (781) 10 5 HR 0.77 P= HR 0.80 P= Prasugrel 9.9 (643) HR 0.81 ( ) P= NNT= 46 0 ITT= 13,608 LTFU = 14 (0.1%) Days

11 Triton TIMI 38 Prasugrel vs. Clopidogrel Risk Reduction (%) Endpoint Absolute Relative P value Primary: CV death/ Nonfatal <0.001 MI/ Nonfatal stroke CV Death Nonfatal MI <0.001 Urgent target vessel revascularization <0.001 Stent thrombosis <0.001 Recurrent MI followed by CV death

12 PLATO

13 Ticagrelor versus Clopidogrel in ACS Wallentin L al. N Engl J Med 2009;361: Primary Endpoint: CV Death, MI or Stroke 11.7% 9.8% p= HR 0.84 (95% CI ) RRR = 16%, ARR = 1.87%, NNT = 54

14 Ticagrelor versus Clopidogrel in ACS Wallentin L al. N Engl J Med 2009;361: Individual Ischemic Endpoints 12 HR= 0.78 ( ) P<0.01 HR=0.79 ( ) P=0.001 HR=0.84 ( ) P=0.005 HR=1.17 ( ) P=0.22 P= ,5 5,9 4 5,1 5,8 6,9 1,5 1,3 1,1 1,1 0 All Cause Death CV Death MI Stroke Ischemic Stroke Ticagrelor Clopidogrel

15 Major Bleeding: 3.9% HR=1.64, 95% CI ,045 Patients

16 (%) Risk of Bleeding With DAPT Serebruany VL et al. Fund Clin Pharmacology 2008;22: RCTs With 129,314 Patients Comparing Single versus Dual Antiplatelet Therapy % RR=1.56 ( ) % RR=1.47 ( ) RR=1.10 ( ) RR=1.07 ( ) Minor Bleeding Major Bleeding Fatal Bleeding Intracranial Hemorrhage Single APT DAPT

17 Risk of Bleeding With DAPT in Long- versus Short-term Studies Bowry DK et al. Am J Card 2008;101: RCTs With 91,744 Patients Comparing Single versus Dual Antiplatelet Therapy Long-term Studies OR= 1.80 ( ) Short-term Studies OR= 1.07 ( )

18 % Events 4 2 Triton TIMI 38 Prasugrel vs. Clopidogrel Wiviott SD et al. N Engl J Med 2007;357: Clopidogrel Prasugrel 1,8 2,4 Bleeding Events Safety Cohort 1,4 0,9 0,9 (N=13,457) 1,1 ICH in Pts w Prior Stroke/TIA (N=518) Clop 0 (0) % Pras 6 (2.3) % (P=0.02) 0 TIMI Major Bleeds 0,4 0,3 0,3 0,1 Life Threatening Nonfatal Fatal ICH ARD 0.6% HR 1.32 P=0.03 NNH=167 ARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0.3% P=0.002 ARD 0% P=0.74

19 Triton TIMI 38 Prasugrel vs. Clopidogrel Wiviott SD et al. N Engl J Med 2007;357: CABG and Non-CABG Related Bleeding 15 13,4 10 HR= 4.73 ( ) P<0.001 HR= 1.32 ( ) P= ,2 1,8 2,4 0 CABG TIMI Major Bleeding Clopidogrel Non-CABG TIMI Major Bleeding Prasugrel

20 Early and Late Risks of Prasugrel Over Clopidogrel in ACS Patients Undergoing PCI Antman E et al. J Am Coll Cardiol 2008;51: Major Bleeding 0-3 Days Days

21 Ticagrelor versus Clopidogrel in ACS Wallentin L al. N Engl J Med 2009;361: CABG and Non-CABG Related Bleeding 11.6% 11.2% p= HR 0.84 (95% CI ) RRR = 16%, ARR = 1.87%, NNT = 54

22 Ticagrelor versus Clopidogrel in ACS Wallentin L al. N Engl J Med 2009;361: CABG and Non-CABG Related Bleeding HR= 1.04 ( ) P= 0.43 HR= 1.19 ( ) P= 0.03 HR= 1.03 ( ) P= 0.57 HR= 1.25 ( ) P= ,2 11,6 10 7,7 7,9 5 3,8 4,5 2,2 2,8 0 Plato Major Bleeding Non-CABG PLATO major TIMI Major Bleeding Non-CABG TIMI major Clopidogrel Ticagrelor

23 Risk of Definite Stent Thrombosis Cook, Windecker. Circulation 2009;119:657-9 Stable Angina UA/ NSTEMI STEMI Bare Metal Stents 0-0.5% % 2.9% Drug-Eluting Stents % % 3.1% Risk of Early Stent Thrombosis

24 Platelet Reactivity and Risk of Early Stent Thrombosis Sibbing D et al. J Am Coll Cardiol 2009;53: Multiple Electrode Platelet Aggregometry (Point-of-Care Analysis) consecutive patients between 02/2007 and 04/ P< P=0.13 P< Definite ST Probable ST Definite/ Probable ST Normal Responders (N=1285) Low Responders (N=323)

25 Endpoint (%) Triton TIMI 38 Prasugrel vs. Clopidogrel Wiviott SD et al. N Engl J Med 2007;357: Stent Thrombosis (ARC Definite + Probable) 3 Any Stent at Index PCI N= 12,844 Clopidogrel 2.4 (142) 2 1 HR 0.48 P < NNT= 77 Prasugrel 1.1 (68) Days

26 Ticagrelor versus Clopidogrel in ACS Wallentin L al. N Engl J Med 2009;361: Stent Thrombosis 4 HR=0.67 ( ) P=0.009 HR=0.75 ( ) P=0.02 HR=0.77 ( ) P= Definite Probable or Definite Definite, Probable or Possible Ticagrelor Clopidogrel

27 Anti-trombotic therapy - ESC STEMI Guidelines 2008 Adjunctive therapy: primary PCI Aspirin: A bolus of mg (chewable) or mg i.v. followed by life long therapy. I B Clopidogrel: Bolus (300 mg) or 600 mg. Heparin: I C 100 U/kg (60 U/kg with GP IIb/IIIa) I C Glycoprotein IIb/IIIa inhibitor Abciximab (60 U/kg with GP IIb/IIIa) IIa A

28 TRITON-TIMI 38: Study Design Distribution of Patients in STEMI Cohort Double-blind, double-dummy, parallel, randomised controlled trial All ACS/PCI patients N = Randomised patients with STEMI N = 3534 UA/NSTEMI n = Clopidogrel 300 mg LD/75 mg MD n = 1765 Prasugrel 60 mg LD/10 mg MD n = patients did not receive study drug or undergo PCI Primary PCI n = 2438 Secondary PCI n = 1094 Clopidogrel n = 1235 Prasugrel n = 1203 Clopidogrel n = 530 Prasugrel n = 564 ACS = acute coronary syndrome; LD = loading dose; MD = maintenance dose; NSTEMI = non- ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction; UA = unstable angina Montalescot G et al. Lancet 2009;373(9665):

29 Proportion of patients (%) STEMI Cohort: Primary Endpoint (CV death, MI and Stroke at 15 Months) Montalescot G et al. Lancet 2009;373: Clopidogrel Prasugrel p=0.002 RRR=32% 10.0 p=0.02 RRR=21% HR=0.79 ( ) NNT=42 0 Age-adjusted HR=0.81 ( ) Time (days)

30 Proportion of patients (%) STEMI Cohort: Stent Thrombosis ARC definite/probable Montalescot G et al. Lancet 2009;373: Clopidogrel Prasugrel p=0.008 RRR=51% p=0.02 RRR=42% HR=0.58 ( ) NNT=83 Age-adjusted HR=0.59 ( ) Time (days)

31 Proportion of patients (%) STEMI Cohort: TIMI Major Non-CABG Bleeding Montalescot G et al. Lancet 2009;373: Clopidogrel Prasugrel p= HR=1.11 ( ) NNH=333 Age-adjusted HR=1.19 ( ) Time (days)

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37 Clopidogrel vs Prasugrel Potency More rapild onset of IPA More potent and reliable IPA Irreversible Benefit Lower rate of MI and ST Similar rate of overall or CV mortality Bleeding More CABG and non-cabg related major bleeding caution in patients with unknown coronary anatomy caution in patients at high risk of bleeding STEMI Benefit without increased bleeding risk Clopidogrel vs Ticagrelor Potency More rapid onset and offset of IPA More potent and reliable IPA Reversible Benefit Lower rate of MI and ST Lower overall and CV mortality Bleeding More non-cabg related caution in patients at high risk of bleeding STEMI Benefit without increased bleeding risk Compliance Dyspnea Twice daily intake

38 Guideline Recommendations STEMI Thienopyridine Loading STEMI - Thienopyridine Duration UA/NSTEMI Thienopyridine Loading UA/NSTEMI - Thienopyridine Duration Elective PCI Thienopyridine Loading Elective PCI - Thienopyridine Duration Clopidogrel mg Prasugrel 60 mg Ticagrelor AHA/ACC I C I B ESC I C/B > 12 months I B IIa C Clopidogrel mg Prasugrel Ticagrelor DES > 12 months BMS > 1 month, ideally 12 months I C II a I B I B IB I C IB I B I B Clopidogrel mg I C I C DES > 12 months BMS > 1 month, ideally 12 months I B I B I C I A

39 Yearly incidence (%) Incidence of Bleeding in Relation to Antithrombotic Therapy Sørensen R et al. Lancet 2009;374: Single Therapy Dual Therapy Triple Therapy 12, ,6 4,6 4,3 3,7 5, patients with MI between

40 Risk of Bleeding and Mortality After Acute MI in Relation to Antithrombotic Therapy Sørensen R et al. Lancet 2009;374:

41 Management of Antithrombotic Therapy in Afib Patients With ACS and/or Undergoing PCI ESC WG Thrombosis Consensus Document: Lip G et al. Eur Heart J 2010;31: Hemorrhagic Risk Clinical Setting Stent Type Recommendation Low or intermediate Elective BMS 1 month: ASA, Clop, OAC Lifelong: OAC alone Elective DES 3 months: ASA, Clop, OAC 3-12 months: Clop, OAC Lifelong: OAC alone ACS BMS/DES 6 months: ASA, Clop, OAC 6-12 months: Clop, ASA or Clop Lifelong: OAC alone High Elective BMS 2-4 weeks: ASA, Clop, OAC Lifelong: OAC alone ACS BMS 4 weeks: ASA, Clop, OAC 1-12 months: Clop, ASA or Clop Lifelong: OAC alone

42 Concurrent DAPT Studies Timeline to Final Data Collection DAPT Study, n = 20,165 REAL-LATE, n = 2,000 RCT > 12 m ZEST-LATE, n = 2,000 OPTIDUAL, n = 1,966 ISAR-SAFE, n = 6,000 RCT < 12m ITALIC, n = 3,200 OPTIMIZE, n = 3,120 Second Gen. DES (Colombo), n = 4,000 ADAPT-DES, n = 11,000 PARIS, n = 5,011 Registries

43 Triton TIMI 38 Prasugrel vs. Clopidogrel by Diabetes Status: Primary End Point Wiviott SD et al. Circulation 2008;118: Primary End Point (%) Diabetes Mellitus Days No Diabetes Mellitus HR 0.70 ( ), P<0.001 HR 0.86 ( ), P = Clopidogrel 17.0 Prasugrel P interaction = Days Clopidogrel 10.6 Prasugrel 9.2

44 Triton TIMI 38 Prasugrel vs. Clopidogrel Wiviott SD et al. Circulation 2008;118: Non-CABG TIMI Major Bleeding 5 Diabetes Mellitus No Diabetes Mellitus HR 1.06 ( ), P = 0.81 HR 1.43 ( ), P = TIMI Major Bleeding (%) Clopidogrel 2.6 Prasugrel Clopidogrel 2.4 Prasugrel Days P Days interaction = 0.29

45 Odds/Hazard Ratio Diabetes as Predictor of Stent Thrombosis 5 OR=2.0 ( ) OR=2.8 ( ) OR=2.7 ( ) HR=3.7 ( ) HR=2.0 ( ) HR=2.2 ( ) HR=1.75 ( ) IDDM IDDM IDDM Diabetes Diabetes Diabetes Diabetes Kuchulakanti Circ 2006 Urban Circ 2006 Machecourt JACC 2007 Iakovou JAMA 2005 Daemen Iijima Lancet 2007 Am J Card 2007 De la Torre JACC 2008

46 Triton TIMI 38 Prasugrel vs. Clopidogrel Wiviott SD et al. Circulation 2008;118: Stent Thrombosis Diabetes Mellitus No Diabetes Mellitus 5 HR 0.52 ( ), P = HR 0.45 ( ), P<0.001 Stent Thrombosis (%) Clopidogrel 3.6 Prasugrel Clopidogrel 2.0 Prasugrel Days Days P interaction = 0.63