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The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the

Mechanisms ● Mortality ● Therapeutics. The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the Catheterization Laboratory. PROGRAM CO-CHAIRMAN Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI

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The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the

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  1. Mechanisms ● Mortality ● Therapeutics The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the Catheterization Laboratory PROGRAM CO-CHAIRMAN Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Chief of Cardiology, VA Boston Healthcare System | Director, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare System | Senior Investigator, TIMI Group | Harvard Medical School | Boston, Massachusetts PROGRAM CO-CHAIRMAN Shamir Mehta, MD, MSc, FACC, FRCPC Director, Interventional Cardiology | Hamilton Health Sciences | Associate Professor | McMaster University | Hamilton, Ontario, Canada

  2. Welcome and Program Overview CME-accredited symposium jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLCMission statement: Improve patient care through evidence-based education, expert analysis, and case study-based managementProcesses: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studiesCOI: Full faculty disclosures provided in syllabus and at the beginning of the program

  3. Program Educational Objectives As a result of this session, participants will be able to: • Optimize anti-ischemic efficacy, while reducing bleeding related complications and adverse events in high risk, complex patients requiring antiplatelet therapy in the setting of PCI • Compare anti-ischemic effects, mortality data, bleeding complications, and drug-drug interactions among indicated antiplatelet agents in the setting of cardiac catheterization • Analyze, compare, and assess the clinical implications of recent landmark trials in antiplatelet therapy among them, the CURRENT-OASIS 7, PLATO, and TRITON-TIMI 38 trials; and how to make risk-directed decisions in the setting of PCI • List the safety, efficacy, and mortality reducing implications of new dosing strategies for established oral antiplatelet therapies and their implications for PCI-based management of high risk ACS and STEMI

  4. Program Faculty Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Program Co-Chairman Chief of Cardiology VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program,   Brigham and Women’s Hospital and the VA Boston Healthcare System Senior Investigator, TIMI Group Harvard Medical School Boston, Massachusetts Sunil V. Rao, MD Director of Cardiac Catheterization Laboratories Veterans Administration Medical Center Division of Cardiovascular Medicine Duke University Medical Center Durham, North Carolina Shamir Mehta, MD, MSc, FACC, FRCPC (Program Co-Chairman) Director, Interventional Cardiology Hamilton Health Sciences Associate Professor | McMaster University Hamilton, Ontario Canada Harold L. Dauerman, MD, FACC Director, Cardiovascular Catheterization Laboratories Professor of Medicine University of Vermont Medical Center Fletcher Allen Health Care Burlington, Vermont

  5. Faculty COI Financial Disclosures Shamir Mehta, MD, MSc, FACC, FRCPC Grant/Research Support: Bristol-Myers Squibb Company, GlaxoSmithKline, sanofi-aventis Consultant: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Eli Lilly and Company, GlaxoSmithKline, Pfizer Inc, sanofi-aventis Honorarium: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Eli Lilly and Company, GlaxoSmithKline, Pfizer Inc, sanofi-aventis Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Consultant: Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, Takeda, The Medicines Company, Vertex. Principal Investigator for several potentially related studies. His institution has received funding from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, sanofi-aventis, The Medicines Company. This presentation discusses off-label and/or investigational uses of various drugs and devices

  6. Faculty COI Financial Disclosures Harold L. Dauerman, MD, FACC Current Research Grants: Medtronic, Abbott Vascular, Boston Scientific Current Advisory Board or Consulting: BMS, The Medicines Company, St. Jude Medical, Abbott Vascular Sunil V. Rao, MD Consultant, Honoraria: Sanofi-Aventis/BMS, The Medicines Company, Terumo Corporation, Astra Zeneca, Eli Lilly/Daiichi-Sankyo Research Funding: Cordis Corporation, Momenta Pharmaceuticals, Portola Pharmaceuticals Off-label uses: 600 mg dose of Clopidogrel

  7. Antiplatelet Therapy in PCI: Focus on Addressing the Triple End Points of Thrombosis, Bleeding, and Mortality—Connecting Evidence Across Recent Landmark Studies Where Do New Trials, New Potencies, and New Dosing Strategies Take Us? And How Should They Direct Our Care in the Cardiac Catheterization Laboratory? Moving into a New Era of Interventional Care Shamir Mehta, MD, MSc, FACC, FRCPC Director, Interventional Cardiology Hamilton Health Sciences Associate Professor McMaster University Hamilton, Ontario, Canada

  8. OASIS-7 CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI Shamir R. Mehta on behalf of the CURRENT Investigators Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts.

  9. Background Clopidogrel • Clopidogrel 300 mg followed by 75 mg daily reduces major CV events across the spectrum of ACS and PCI • Recent data suggest that doubling the loading and maintenance doses of clopidogrel results in a higher and more rapid antiplatelet effect Aspirin • Dose of ASA varies between Europe and North America • No large-scale RCT’s have compared high (300-325 mg) versus low (75-100) dose aspirin in patients with ACS undergoing PCI

  10. Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCI 1. Mehta SR, et al. Lancet 2001; 358(9281):527-33. 2. Fox KAA, et al. Circulation 2004;110:1202-8 3. Sabatine MS, et al. JAMA 2005; 294(10):1224-32. 4. Chen ZM Lancet 2005;366:1607-21 5. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.

  11. Study Design, Flow and Compliance • 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) • Planned Early (<72 h) Invasive Management with intended PCI • Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) • 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) • Planned Early (<72 h) Invasive Management with intended PCI • Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose(600 mg then150 mg/d x 7d then 75 mg/d) vsStandard dose(300 mg then 75 mg/d) ASA: High Dose(300-325 mg/d) vsLow dose(75-100 mg/d) Angio 24,769 (99%) No PCI 7,855 (30%) PCI 17,232 (70%) No Sig. CAD 3,616 CABG 1,809 No Sig. CAD 3,616 CABG 1,809 CAD 2,430 Compliance: Clopidogrel in 1st 7d 7 d 2 d 7d 7d (median) Complete Follow-up 99.8% Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI

  12. Baseline Characteristics and In Hospital Meds Variables equally balanced among the randomized groups *38.6% low dose ASA v 41.4% high dose ASA and 40% standard dose clopidogrel v 40% high dose clopidogrel

  13. ASA Dose ComparisonPrimary Outcome and Bleeding GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051 No other significant differences between ASA dose groups

  14. Clopidogrel Dose Comparison • Two Significant Interactions: • PCI v No PCI (P=0.016) • ASA dose (P=0.043)

  15. Clopidogrel: Double vs Standard Dose Primary Outcome 0.05 C Std, A Hi C Double, A Lo C Std, A Lo 0.04 C Double, A Hi 0.03 Cumulative Hazard 0.02 0.01 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  16. Clopidogrel: Double vs Standard DosePrimary Outcome and Components

  17. Clopidogrel Double vs Standard DoseBleeding Overall Population

  18. Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio Confirmed) Clopidogrel Standard Dose 0.012 42% RRR 0.008 Cumulative Hazard Clopidogrel Double Dose 0.004 HR 0.58 95% CI 0.42-0.79 P=0.001 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  19. Clopidogrel: Double vs Standard DoseMajor Efficacy Outcomes in PCI Patients

  20. Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients CV Death, MI or Stroke Clopidogrel Standard 15% RRR 0.04 Clopidogrel Double 0.03 Cumulative Hazard 0.02 HR 0.85 95% CI 0.74-0.99 P=0.036 0.01 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  21. Clopidogrel Double vs Standard DoseBleeding PCI Population

  22. Clopidogrel: Double v Standard DosePCI Cohort Subgroups CV Death, MI or Stroke MI or Stent Thrombosis 2N Std % Double % Intxn P Std % Double % Intxn P Overall 17232 4.5 3.9 3.7 3.0 NSTEMI/UA 10886 4.2 3.6 3.6 3.1 0.805 0.248 STEMI 6346 5.0 4.2 4.0 2.8 Male 13009 4.1 3.6 3.5 3.0 0.419 0.148 Female 4223 5.8 4.6 4.6 3.0 Age <= 65 yrs 10975 3.0 2.7 2.9 2.2 0.702 0.418 Age > 65 yrs 6257 7.1 6.0 5.2 4.4 Non-Diabetic 13400 4.2 3.6 3.6 2.8 0.836 0.567 Prev Diabetic 3831 5.6 4.9 4.1 3.6 No Inhosp GPIIb/IIIa 12288 3.9 3.5 3.1 2.5 0.465 0.894 GPIIb in hosp 4936 6.0 4.7 5.2 4.1 No Prot Pump Inhib 7675 3.8 3.2 3.1 2.3 0.408 0.613 Prot Pump Inhib 5557 5.7 4.2 4.8 3.3 Non-smoker 10845 4.9 4.6 3.9 3.5 0.045 0.050 Current Smoker 6380 3.8 2.6 3.4 2.1 ASA Low 8620 4.2 4.3 3.6 3.2 0.024 0.191 ASA High 8612 4.8 3.5 3.8 2.7 Double Dose Better Std Dose Better Double Dose Better Std Dose Better 0.50 1.50 0.50 1.50

  23. Clopidogrel: Double vs Standard Dose by ASA Factorial

  24. Definite Stent Thrombosis in 4 Groups (Angiographically Proven) C Standard, A Low 0.012 C Standard, A High C Double, A Low 0.008 Cumulative Hazard C Double, A High 0.004 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  25. ConclusionsClopidogrel Dose Comparison • Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) in PCI. • In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for CABG). • There was a modest excess in CURRENT-defined major bleeds but no difference in ICH, fatal bleeds or CABG-related bleeds.

  26. ConclusionsASA Dose Comparison • No significant difference in efficacy or bleeding between ASA 300-325 mg and ASA 75-100 mg.

  27. Clinical Implications • For every 1,000 patients with ACS receiving PCI, using double-dose clopidogrel for 7 days instead of standard dose will prevent an additional 6 MI’s and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal, ICH, or CABG-related bleeds. • Patients not undergoing PCI should continue to use the standard dose regimen of clopidogrel.

  28. CURRENT-PCI findings  How to translate into practice? OPTION 2 OPTION 1 ACS(UA/NSTEMI or STEMI) ACS(UA/NSTEMI or STEMI) 300 mg load before Angiography 600 mg load beforeAngiography PCI No PCI PCI No PCI + 300 mg load No additional load Double dose (150 mg/day)for 6 days then75 mg/day 75 mg/day Double dose (150 mg/day)for 6 days then75 mg/day 75 mg/day

  29. Clopidogrel and Proton Pump Inhibitors – Is There an Interaction? Deepak L. Bhatt MD, MPH, FACC, FAHA Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare System Senior Investigator, TIMI Study Group Harvard Medical School

  30. ADP Receptors Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.

  31. CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients MI, stroke, or death – ITT population 15 Placebo* Clopidogrel* 11.5% 27% RRR P=0.02 10 8.5% Combined endpoint occurrence (%) 5 0 0 3 6 9 12 Months from randomization * Plus ASA and other standard therapies. Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.

  32. Multivariable Predictors of Bleeding EventsDischarge to 1 Year (n=1816) Aronow HD, et al. Am Heart J 2008 (published online Nov 2008)

  33. Kaplan Meier Estimates of Bleeding RiskDischarge to 1 Year (n=1816)

  34. 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, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

  35. Algorithm to Assess GI Risk With Antiplatelet Therapy Need for antiplatelet therapy Yes Assess GI risk factors History of ulcer complication History of ulcer disease (nonbleeding) Dual antiplatelet therapyConcomitant anticoagulant Test for H pylori; treat if infected Yes No Yes PPI More than one risk factor: Aged 60 years or more Corticosteroid use Dyspepsia or GERD symptoms Yes Bhatt DL, Scheiman J, Abraham NS, et al. Circulation 2008.

  36. Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite PPIs are strong inhibitors of CYP2C19 activity Clopidogrel and PPIs – The OCLA study PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP) p<0.0001 Gilard et al. J Am Coll Cardiol 2008;51:256-60.

  37. Intake of PPIs Not Associated With Impaired Response to Clopidogrel Adenosine diphosphate–induced platelet aggregation in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole. Platelet reactivity index in the VASP phosphorylation assay in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole. Data are presented as mean and 95% CI. PPI, proton pump inhibitor; VASP, vasodilator-stimulated phosphoprotein. Siller-Matula JM, et al. Am Heart J. 2009;157(1):148.e1-148.e5.

  38. Variability in Clopidogrel Responsiveness in a Diverse Population of 544 D 5mM ADP Platelet Aggregation Serebruany V, Steinhubl S et al. JACC 2005.

  39. Genetic Variations and Clopidogrel Response Pharmacokinetic Response -50 -40 -30 -20 -10 0 10 20 30 Relative Percent Difference Pharmacodynamic Response -15 -10 -5 0 5 10 25 Absolute Difference Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362.

  40. Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0 Proportion of Deaths or Recurrent ACS 90 180 270 360 450 540 630 720 810 900 990 1080 0 Days Since Discharge Ho PM, et al. JAMA. 2009;301(9):937-944.

  41. Risk of Adverse Outcomes Following Hospital Discharge With Concomitant Use of Clopidogrel Plus PPI Unadjusted OR (95% CI) Adjusted OR (95% CI) Outcome Without PPI With PPI Without PPI With PPI Ho PM, et al. JAMA. 2009;301(9):937-944.

  42. Results – 1 Year Endpoint from CREDO Unadjusted Data Primary 1-Year Endpoint: Death, MI or Stroke 20 P=0.45 PPI at baseline (N=374) P=0.001 16.2 15 No PPI at baseline (N=1742) 14.8 13.2 10 10.8 9.2 7.7 5 0 All N=2116 Placebo N=1063 Clopidogrel N=1053 Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

  43. Results – Clopidogrel Group Adjusted Data * Multivariate logistic regression model: PPI vs. no PPI within treatment stratum † Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

  44. Results – Placebo Group Adjusted Data * Multivariate logistic regression model: PPI vs. no PPI within treatment stratum † Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

  45. Results – 1 Year Primary Endpoint PPI at Baseline P-value for interaction between randomized therapy and baseline PPI P=0.69 No PPI at Baseline Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

  46. THE LANCET

  47. Primary endpoint stratified by use of a PPI PPI use at randomization (n= 4529) Clopidogrel Prasugrel CV death, MI or stroke CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11 PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20 Days

  48. Risk of CV Events with Different Types of PPIs Rabeprazole not included due to small sample size (n=66)

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