Presentation is loading. Please wait.

Presentation is loading. Please wait.

The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the Catheterization Laboratory Mechanisms Mortality Therapeutics PROGRAM CO-CHAIRMAN.

Similar presentations


Presentation on theme: "The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the Catheterization Laboratory Mechanisms Mortality Therapeutics PROGRAM CO-CHAIRMAN."— Presentation transcript:

1

2 The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the Catheterization Laboratory Mechanisms Mortality Therapeutics 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 Womens 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

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

4 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 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 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 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 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

5 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 Womens 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 Hamilton, OntarioCanada Harold L. Dauerman, MD, FACC Director, Cardiovascular Catheterization Laboratories Professor of Medicine University of Vermont Medical Center Fletcher Allen Health Care Burlington, Vermont

6 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

7 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

8 Antiplatelet Therapy in PCI: Focus on Addressing the Triple End Points of Thrombosis, Bleeding, and MortalityConnecting 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

9 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 OASIS-7 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.

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

11 Relative Risk Reduction PCI No PCI CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI) 30% 1 19% 2 STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI) 46% 3 9% 4 TRITON: Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke) 19% 5 Not evaluated 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.

12 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%) No Sig. CAD 3,616CABG 1,809 Clopidogrel in 1 st 7d 7 d 2 d 7d 7d (median) Complete Follow-up 99.8% 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%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d) PCI 17,232 (70%) No PCI 7,855 (30%) Angio 24,769 (99%) No Sig. CAD 3,616 CABG 1,809 CAD 2,430 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

13 Baseline Characteristics and In Hospital Meds BaselineN=25,088 Meds After Rand N=25,088 Age (y) 61.4 GP IIb/IIIa inhibitor 31.8 Female27.4%Statin87.2 UA/NSTEMI70.8% Beta Blocker 82.5 Rand to Angio Rand to Angio 3.4 h ACE/ARB75.7 STEMI29.2%PPI40* Rand to Angio Rand to Angio 0.5 h H2 Blocker 11.3 Diabetes23.4 Prior Stroke 4.1 Ischemic ECG Δ 80.8 Biomarker Biomarker42 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

14 ASA Dose Comparison Primary Outcome and Bleeding ASA 75-100 mg ASA 300-325 mg HR 95% CI P CV Death/MI/Stroke PCI (2N=17,232) 4.24.10.980.84-1.130.76 No PCI (2N=7855) 4.74.40.920.75-1.140.44 Overall (2N=25,087) 4.44.20.960.85-1.080.47 Stent Thrombosis 2.11.90.910.73-1.120.37 TIMI Major Bleed 1.030.970.940.73-1.210.71 CURRENT Major Bleed 2.32.30.990.84-1.170.90 CURRENT Severe Bleed 1.71.71.000.83-1.211.00 No other significant differences between ASA dose groups GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051

15 Clopidogrel Dose Comparison Two Significant Interactions: 1. PCI v No PCI (P=0.016) 2. ASA dose (P=0.043)

16 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 036912151821242730 C Std, A Lo C Std, A Hi C Double, A Lo C Double, A Hi Clopidogrel Standard Clopidogrel Double HRPP Int n ASA 300-325 mg 4.63.80.830.036 0.043 ASA 75-100 mg 4.24.51.070.43 Clopidogrel: Double vs Standard Dose Primary Outcome

17 Clopidogrel: Double vs Standard Dose Primary Outcome and Components StandardDoubleHR 95% CI P Intn P CV Death/MI/Stroke PCI (2N=17,232) 4.53.90.850.74-0.990.036 0.016 No PCI (2N=7855) 4.24.91.170.95-1.440.14 Overall (2N=25,087) 4.44.20.950.84-1.070.370 MI PCI (2N=17,232) 2.62.00.780.64-0.950.012 0.025 No PCI (2N=7855) 1.41.71.250.87-1.790.23 Overall (2N=25,087) 2.21.90.860.73-1.030.097 CV Death PCI (2N=17,232) 1.91.90.960.77-1.190.68 1.0 No PCI (2N=7855) 2.82.70.960.74-1.260.77 Overall (2N=25,087) 2.22.10.960.81-1.140.628 Stroke PCI (2N=17,232) 0.40.40.880.55-1.410.59 0.50 No PCI (2N=7855) 0.80.91.110.68-1.820.67 Overall (2N=25,087) 0.50.50.990.70-1.390.950

18 Clopidogrel Double vs Standard Dose Bleeding Overall Population Clopidogrel StandardN=12579DoubleN=12508HazardRatio 95% CI P CURRENT Major 2.02.51.251.05-1.470.01 CURRENT Severe 1.51.91.231.02-1.490.03 Fatal0.110.13 1.15 1.150.56-2.350.71 ICH0.050.03 0.67 0.670.19-2.370.53 RBC transfusion 2U 1.76 2.21 2.211.261.06-1.510.01 CABG-related Major 0.91.01.100.85-1.420.48

19 Days Cumulative Hazard 0.0 0.004 0.008 0.012 036912151821242730 Clopidogrel Standard Dose Clopidogrel Double Dose 42%RRR HR 0.58 95% CI 0.42-0.79 P=0.001 Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio Confirmed)

20 Clopidogrel: Double vs Standard Dose Major Efficacy Outcomes in PCI Patients Day 30 Clopidogrel Standard N=8684 % Double N=8548 % Hazard Ratio 95% CI P value Stent Thrombosis 2.31.60.710.57-0.890.002 Definite Definite1.20.70.580.42-0.790.001 MI2.62.00.780.64-0.950.012 MI or stent thrombosis 3.73.00.800.68-0.940.008 CV Death 1.91.90.960.77-1.190.68 Stroke0.40.40.880.55-1.410.59 CV Death/MI/Stroke 4.53.90.850.74-0.990.036

21 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 036912151821242730 Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR 0.85 95% CI 0.74-0.99 P=0.036 15% RRR CV Death, MI or Stroke

22 Clopidogrel Double vs Standard Dose Bleeding PCI Population Clopidogrel Standard N= 8684 DoubleN=8548HazardRatio 95% CI P CURRENT Major 1.11.61.441.11-1.860.006 CURRENT Severe 0.81.11.391.02-1.900.034 Fatal0.150.070.470.18-1.230.125 ICH0.0350.0461.350.30-6.040.69 RBC transfusion 2U 0.911.351.491.11-1.980.007 CABG-related Major 0.10.11.690.61-4.70.31

23 0.501.50 Overall NSTEMI/UA STEMI Male Female Age <= 65 yrs Age > 65 yrs Non-Diabetic Prev Diabetic No Inhosp GPIIb/IIIa GPIIb in hosp No Prot Pump Inhib Prot Pump Inhib Non-smoker Current Smoker ASA Low ASA High 17232 10886 6346 6346 13009 4223 4223 10975 6257 6257 13400 3831 3831 12288 4936 4936 7675 7675 5557 5557 10845 6380 6380 8620 8620 8612 8612 4.5 4.2 5.0 4.1 5.8 3.0 7.1 4.2 5.6 3.9 6.0 3.8 5.7 4.9 3.8 4.2 4.8 3.9 3.6 4.2 3.6 4.6 2.7 6.0 3.6 4.9 3.5 4.7 3.2 4.2 4.6 2.6 4.3 3.5 0.805 0.419 0.702 0.836 0.465 0.408 0.045 0.024 0.501.50 3.7 3.6 4.0 3.5 4.6 2.9 5.2 3.6 4.1 3.1 5.2 3.1 4.8 3.9 3.4 3.6 3.8 3.0 3.1 2.8 3.0 3.0 2.2 4.4 2.8 3.6 2.5 4.1 2.3 3.3 3.5 2.1 3.2 2.7 0.248 0.148 0.418 0.567 0.894 0.613 0.050 0.191 CV Death, MI or Stroke MI or Stent Thrombosis Clopidogrel: Double v Standard Dose PCI Cohort Subgroups Std % Double % Std % Double % Intxn P Double Dose Better Std Dose Better 2N

24 Clopidogrel HR 95% CI P P intn StandardDouble CV Death/MI/Stroke (Overall) ASA High 4.63.80.830.70-0.990.036 0.043 ASA Low 4.24.51.070.91-1.270.42 MI/Stent Thrombosis (PCI pts) ASA High 3.82.70.710.56-0.900.0050.19 ASA Low 3.63.20.890.71-1.120.32 Major Bleed(Overall) ASA High 2.22.41.080.86-1.370.51 0.099 ASA Low 1.92.71.431.13-1.810.003 Clopidogrel: Double vs Standard Dose by ASA Factorial

25 Definite Stent Thrombosis in 4 Groups (Angiographically Proven) Days Cumulative Hazard 0.0 0.004 0.008 0.012 036912151821242730 C Standard, A Low C Standard, A High C Double, A Low C Double, A High Standard Clopidogrel Double Clopidogrel HRPP Int n High ASA 1.20.60.490.003 Low ASA 1.20.80.60.0580.35

26 Conclusions Clopidogrel Dose Comparison 1.Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) in PCI. 2.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). 3.There was a modest excess in CURRENT-defined major bleeds but no difference in ICH, fatal bleeds or CABG-related bleeds.

27 Conclusions ASA Dose Comparison No significant difference in efficacy or bleeding between ASA 300-325 mg and ASA 75-100 mg.

28 Clinical Implications 1.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 MIs and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal, ICH, or CABG-related bleeds. 2.Patients not undergoing PCI should continue to use the standard dose regimen of clopidogrel.

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

30

31 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 Womens Hospital and the VA Boston Healthcare System Senior Investigator, TIMI Study Group Harvard Medical School

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

33 CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients MI, stroke, or death – ITT population * Plus ASA and other standard therapies. Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. Combined endpoint occurrence (%) Months from randomization 27% RRR P=0.02 Placebo*Clopidogrel* 0 5 10 15 8.5% 11.5% 036912

34 Multivariable Predictors of Bleeding Events Discharge to 1 Year (n=1816) Aronow HD, et al. Am Heart J 2008 (published online Nov 2008) Variable Hazard Ratio (95% CI) X2X2X2X2 P value Clopidogrel 1.04 (0.75-1.44) 0.050.82 Age (per 10 years) 1.26 (1.07-1.48) 8.10.005 CABG discharge- 1 year 32.15 (23.10- 44.74) 423.6<0.0001

35 Kaplan Meier Estimates of Bleeding Risk Discharge to 1 Year (n=1816)

36 Timing of Severe or Moderate Bleeding Placebo + ASA Clopidogrel + ASA Days Since Randomization 1560 135270450630810 0.00008 0.00007 0.00006 0.00005 0.00004 0.00003 0.00002 0.00001 0 Hazard Function/d Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

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

38 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) Gilard et al. J Am Coll Cardiol 2008;51:256-60. p<0.0001

39 Intake of PPIs Not Associated With Impaired Response to Clopidogrel Siller-Matula JM, et al. Am Heart J. 2009;157(1):148.e1-148.e5. Platelet reactivity index in the VASP phosphorylation assay in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole. Adenosine diphosphate–induced platelet aggregation 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.

40 Variability in Clopidogrel Responsiveness in a Diverse Population of 544 Serebruany V, Steinhubl S et al. JACC 2005. M ADP Platelet Aggregation M ADP Platelet Aggregation

41 Genetic Variations and Clopidogrel Response Mega JL, Close SL, Wiviott SD, et al. N Engl J Med. 2009;360:354-362. Gene Percent Difference in AUC 0-t P Value CYP2C1932.4.001 CYP2C96.8.59 CYP2B615.7.03 CYP3A55.6.59 CYP1A211.2.45 Pharmacokinetic Response Relative Percent Difference -50-40-30-20-100102030 Pharmacodynamic Response Gene Percent Difference in ΔMPAP ValueCYP2C199.0.001.001 CYP2C90.6.86 CYP2B65.7.012 CYP3A57.5.012 CYP1A20.5.90 Absolute Difference -15-10-5051025

42 Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI Ho PM, et al. JAMA. 2009;301(9):937-944. 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0 0 901802703604505406307208109009901080 Days Since Discharge Proportion of Deaths or Recurrent ACS Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI

43 Risk of Adverse Outcomes Following Hospital Discharge With Concomitant Use of Clopidogrel Plus PPI Primary outcome Death or rehospitalization for ACS Death or rehospitalization for ACS Secondary outcomes Rehospitalization for ACS Rehospitalization for ACS Revascularization procedures Revascularization procedures Death (all-cause) Death (all-cause) Unadjusted OR (95% CI) Adjusted OR (95% CI) Outcome With PPI Without PPI With PPI Without PPI Ho PM, et al. JAMA. 2009;301(9):937-944.

44 14.8 16.2 13.2 9.2 10.8 7.7 0 5 10 15 20 PPI at baseline (N=374) No PPI at baseline (N=1742) Primary 1-Year Endpoint: Death, MI or Stroke AllN=2116PlaceboN=1063 ClopidogrelN=1053 Results – 1 Year Endpoint from CREDO Unadjusted Data P=0.001 P=0.45 Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

45 28 Days Death/MI/ UTVR Adjusted OR (95% CI) p- value* One Year Death/MI/ Stroke Adjusted HR (95% CI) p- value Clopidogrel / PPI (n=179) 18/179 (10.2) 1.8 (0.99, 3.23) 0.051 23/179 (13.2) 1.6 (1.02, 2.63) 0.043 Clopidogrel / No PPI (n=874) 47/874 (5.4) 66/874 (7.7) * Multivariate logistic regression model: PPI vs. no PPI within treatment stratum Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum Results – Clopidogrel Group Adjusted Data Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

46 28 Days Death/MI/ UTVR Adjusted OR (95% CI) p- value* One Year Death/MI/ Stroke Adjusted HR (95% CI) p- value Placebo / PPI (n=195) 19/195 (9.8) 1.4 (0.81, 2.41) 0.221 31/195 (16.2) 1.6 (1.03, 2.34) 0.035 Placebo / No PPI (n=868) 64/868 (7.4) 91/868 (10.8) * Multivariate logistic regression model: PPI vs. no PPI within treatment stratum Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum Results – Placebo Group Adjusted Data Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

47 Results – 1 Year Primary Endpoint Randomized Therapy Death, MI or Stroke Adjusted HR (95% CI) P-value Placebo (N=195) 16.2%0.77 (0.45, 1.33) 0.35 Clopidogrel (N=179) 13.2% Randomized Therapy Death, MI or Stroke Adjusted HR (95% CI) P-value Placebo (N=868) 10.8%0.75 (0.55, 1.03) 0.08 Clopidogrel (N=874) 7.7% PPI at Baseline No PPI at Baseline P-value for interaction between randomized therapy and baseline PPI P=0.69 P=0.69 Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

48 THE LANCET

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

50 Type of PPI Clopidogrel HR (95% CI) CV death, MI or stroke Prasugrel HR (95% CI) CV death, MI or stroke Omeprazole (n=1675) 0.91 (0.72-1.15)1.04 (0.81-1.34) Pantoprazole (n=1844) 0.94 (0.74-1.18)1.09 (0.86-1.39) Esomeprazole (n=613) 1.07 (0.75-1.52)0.86 (0.55-1.33) Lansoprazole (n=441) 1.00 (0.63-1.59)0.98 (0.61-1.57) Risk of CV Events with Different Types of PPIs Rabeprazole not included due to small sample size (n=66)

51 Clopidogrel and the Optimization of GI Events Trial – COGENT

52 Conclusions Dual antiplatelet therapy reduces important ischemic events after PCI, ACSDual antiplatelet therapy reduces important ischemic events after PCI, ACS GI bleeding is the most common form of major bleeding that occursGI bleeding is the most common form of major bleeding that occurs Logical, though not proved, that prophylactic PPI reduces this GI bleedingLogical, though not proved, that prophylactic PPI reduces this GI bleeding Patients prescribed PPI are a higher risk than those who are notPatients prescribed PPI are a higher risk than those who are not While pathways for an interaction exist, unclear degree of clinical relevanceWhile pathways for an interaction exist, unclear degree of clinical relevance

53 Antiplatelet Therapy in High Risk Patients: Does One Size Fit All? Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories Professor of Medicine Professor of Medicine University of Vermont

54 . An 87-year-old woman presents with a non ST-elevation MI to a community hospital. She lives independently and takes care of her disabled husband. Hemodynamically, she is stable, but has pulmonary edema. She is transferred to UVM for cath/PCI. Her creatinine is 1.3 and the Hct is 34. PMH includes NIDDM and gastroesophageal reflux. LAD has slow flow. Adapted from HL Dauerman, New Insights into Atherothrombosis 2009 (Editor DL Bhatt )

55 Defining Current Options for Antiplatelet Therapy 1.Should this community hospital have a single algorithm for care? 2.Upstream or downstream GPI? 3.Clopidogrel or prasugrel? 4.What if this patient was in your emergency department?

56 STEMI: The Vermont Algorithm UFH (60 U/Kg) Beta Blockers only if HTN UFH or Bivalirudin Beta Blockers ONLY if HTN PCI Capability or < 60 minute Transfer Time No PCI Capability and > 60 minute Transfer Time Primary PCI with Stenting: GPI/Thrombectomy if Large Thrombus or as Bailout; Otherwise, Bivalirudin Alone 90 minutes To Open Artery Lytic LyticContraindicated Emergent Transfer Full Dose Ly tic and UFH Transfer from Community ER To PCI Site If no CP and less than 50% ST Elevations, PCI at 12-24 Hours with Stent If Reperfusion Fails, Emergent PCI with Stent ASA/Clopidogrel Statin Groin Closure Cardiac Rehab Lopressor 12.5 bid Transfer Rescue PCI: Class I Indication The NSTEMI Paradigm of 4-48 Hours ASA 325 po Clopidogrel 600 po Clopidogrel 300 po Continue bivalirudin for 2 hours after PCI

57 Guigliano, R NEJM 2009: The EARLY ACS TRIAL No Clear Benefit of Upstream GPI One Size Does Fit All Giugliano, NEJM 2009

58 FINESSE: Keeping the Simple Algorithm Intact FINESSE: Keeping the Simple Algorithm Intact End point Primary PCI (%) Abciximab -facilitated (%) Combination (abciximab/ reteplase)- facilitated (%) p, combination- facilitated vs primary PCI p, combination- facilitated vs abciximab- facilitated Cardiogenic shock 6.84.85.3NSNS VF0.40.20.6NSNS TIMI major bleeding 2.64.14.80.025NS TIMI minor bleeding 4.36.09.7<0.0010.006 TIMI major or minor bleeding 6.910.114.5<0.0010.008 Ellis SG et al. N Engl J Med 2008;358:2205-2217

59 Bleeding Complications and the Elderly Patient Ahmed and Dauerman, Circulation: Cardiovascular Interventions September 2009 Major vascular complications, %* *Arterial injury and/or arterial injury-related bleeding among women N=13,653 patients undergoing PCI P<0.001

60 Both Bleeding and Thrombotic Events Matter CK-MB Symptomatic MI TVR DEATH TVR Bleeding CK-MB Symptomatic MI DEATH GPI Antagonists Bivalirudin 1998 2009 Adapted from Dauerman HL, J Am Coll Feb 2007 Prasugrel and Ticagrelor

61 Wiviott, S. D. et al. Circulation 2007;116:2923-2932 Prevention of Thrombotic Complications: Pharmacology of New ADP Receptor Antagonists Novel ADP receptor antagonists: Ticagrelor and prasugrel Novel ADP receptor antagonists: Ticagrelor and prasugrel More potent inhibition of platelet aggregation More potent inhibition of platelet aggregation Earlier inhibition of platelet aggregation Earlier inhibition of platelet aggregation PRINCIPLE-TIMI44: Phase II pharmacokinetic study PRINCIPLE-TIMI44: Phase II pharmacokinetic study Vasodilator-stimulated phosphoprotein (VASP): Assessment of the extent of phosphorylation of VASP reflects specifically inhibition of the P2Y12 receptor Vasodilator-stimulated phosphoprotein (VASP): Assessment of the extent of phosphorylation of VASP reflects specifically inhibition of the P2Y12 receptor

62 Stent Thrombosis and TRITON TIMI 38 0 1 2 3 0306090180270360450 HR 0.48 P <0.0001 Prasugrel Clopidogrel 2.4 (142) NNT= 77 1.1 (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844 Wiviott SD et al NEJM 2007;357: 2001.

63 An 87-Year-Old Woman Presents with a NSTEMI to a Community Hospital: Should the 2010 algorithm include prasugrel 60 mg load in ED or prior to transfer for all ACS patients? Clopidogrel 600 mg load? Other ? Adapted from HL Dauerman, New Insights into Atherothrombosis 2009 (Editor DL Bhatt)

64 Challenges in Developing ACS Algorithms Challenges in Developing ACS Algorithms Acute Dose: 162 vs 325 mg Chronic Dose: 81 vs 325 CURRENT OASIS-7: S. Mehta, ESC 2009 Safety/efficacy for 300 mg in elderlySafety/efficacy for 300 mg in elderly Unknown risk of 600 mg loading doseUnknown risk of 600 mg loading dose 12 month compliance12 month compliance Defining optimum loading dose Defining optimum loading dose Defining optimum timing of load Defining optimum timing of load Defining maintenance dose Defining maintenance dose 12 month compliance 12 month compliance No safety or efficacy data Risk/benefit in patients with high Risk/benefit in patients with high incidence of bleeding complications incidence of bleeding complications Risk/benefit in patients with increased Risk/benefit in patients with increased potential for CABG during follow up potential for CABG during follow up 12 month compliance 12 month compliance Potential for switching high bleeding risk Potential for switching high bleeding risk patients to clopidogrel after 30 days. patients to clopidogrel after 30 days. HL Dauerman, Am J Cardiology 2009 HL Dauerman, Am J Cardiology 2009 FibrinolysisPrimary PCI Aspirin Clopidogrel Prasugrel

65 Alexander, K. P. et al. Circulation 2007;115:2549-2569 The Platelet Gap in Clinical Trials: TRITON TIMI 3813% Elderly Enrollment TRITON TIMI 3813% Elderly Enrollment NSTE ACS Populations (n=1,190,721) Proportion of Age Group > 75 Years (%) 18% 38%

66 We Can Not Have a Simple Statewide ACS Algorithm with Prasugrel We Can Not Have a Simple Statewide ACS Algorithm with Prasugrel

67 B OVERALL No GPI GPI DES BMS DM No DM >75 65-74 <65 Female Male STEMI UA/NSTEMI 0.5 12 Prasugrel Better Clopidogrel Better HR Age Risk Reduction (%) 18 21 12 25 14 6 14 30 20 18 21 16 19 21 CV Death, MI, Stroke: Is Prasugrel Effective in the Elderly? CrCl > 60 CrCl < 60 14 20 Wiviott SD, NEJM 357: 2001-2015, 2007

68 Net Clinical Benefit Analysis: Do Not Load Prasugrel For Our 87-Year-Old Patient OVERALL >=60 kg < 60 kg < 75 >=75 No Yes 0.512 Prior Stroke / TIA Age Wgt Risk (%) + 37 -16 -16 +3 -14 -13 Prasugrel Better Clopidogrel Better HR P int = 0.006 P int = 0.18 P int = 0.36

69 Antman, E. M. et al. J Am Coll Cardiol 2008;51:2028-2033 Selective Cardiology-Guided Loading and Continuation Selective Cardiology-Guided Loading and Continuation

70 Controlling Bleeding Risk with a Switching Strategy for Prasugrel: Prasugrel 10 mg = Clopidogrel 600 mg Payne et al. Platelets. 2008;19(4):275-281

71 Newer Drugs for ACS and STEMI: Mortality Benefit Can Not Be Ignored September 1, 2009

72 Should This Reversible Drug Become a Standard? Side Effects and Non-CABG Related Bleeding Complications A. Schomig, NEJM Editorial, 2009

73 Defining Current Options for Antiplatelet Therapy Defining Current Options for Antiplatelet Therapy 1.Should this community hospital have a single algorithm for care? 2.Upstream or downstream GPI? 3.Clopidogrel or prasugrel? 4.What if this patient was in your emergency department? If a default universal algorithm is used, then it must default to safety: clopidogrel load only. If a default universal algorithm is used, then it must default to safety: clopidogrel load only. No GPI upstream or downstream. No GPI upstream or downstream. ASA 325 mg po x 1, clopidogrel 600 po x 1, 150 po qd in hospital, then 75 qd for 1 year with ASA 81 qd indefinitely. ASA 325 mg po x 1, clopidogrel 600 po x 1, 150 po qd in hospital, then 75 qd for 1 year with ASA 81 qd indefinitely. PPI was not initially given but 4 weeks later, reflux occurred, and PPI was initiated. No change in Tx. PPI was not initially given but 4 weeks later, reflux occurred, and PPI was initiated. No change in Tx. The future of the PCI center: EDASA 325 mg and then decision re: prasugrel vs clopidogrel by telephone consult with interventional cardiologist in cath lab or on cardiac floor. The future of the PCI center: EDASA 325 mg and then decision re: prasugrel vs clopidogrel by telephone consult with interventional cardiologist in cath lab or on cardiac floor.

74 Conclusions Antiplatelet Therapy Across the Spectrum Algorithms for ACS and STEMI care have advanced care in terms of quality and efficiency Algorithms for ACS and STEMI care have advanced care in terms of quality and efficiency Some aspects of our algorithms can be simple and clearer (GPI use, aspirin and clopidogrel dosing) Some aspects of our algorithms can be simple and clearer (GPI use, aspirin and clopidogrel dosing) The advent of prasugrel and ticagrelor potentially removes the decision re: choice of a second antiplatelet agent from the emergency department and back into the realm of cardiology-based clinical judgment. The advent of prasugrel and ticagrelor potentially removes the decision re: choice of a second antiplatelet agent from the emergency department and back into the realm of cardiology-based clinical judgment. One Size Does Not Fit All

75 Sunil V. Rao MD Director of Cardiac Catheterization Laboratories The Duke Clinical Research Institute The Durham VA Medical Center Duke University Medical Center Bleeding is the Red line in the sand for Antiplatelet therapy: Avoiding Complications in the Cath Lab & Beyond

76 Bleeding and antiplatelet therapy Bleeding and antiplatelet therapy Issues we will discuss Reducing events among clopidogrel hyporesponders is a clinical priority Reducing events among clopidogrel hyporesponders is a clinical priority Intensification of antiplatelet effect is associated with improvement in some ischemic outcomes, but what about the bleeding? Intensification of antiplatelet effect is associated with improvement in some ischemic outcomes, but what about the bleeding? Acute – CABG-related bleeding Acute – CABG-related bleeding Chronic bleeding risk Chronic bleeding risk Can we compare safety results from different clinical trials? Can we compare safety results from different clinical trials? In the modern era of multiple antiplatelet options, what factors must be weighed in making the therapeutic decision? In the modern era of multiple antiplatelet options, what factors must be weighed in making the therapeutic decision?

77 The Current Egalitarian Strategy of Antiplatelet Therapy During And After PCI: The More The Merrier for Everyone! Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA Reduction in Ischemic Events Increase in Major Bleeds Adapted from Gibson, AHA 2007 Increasingly narrow therapeutic window

78 IPA Responses to Clopidogrel Δ 5µM ADP-Induced Platelet Aggregation (%) -20[-10,0][11,20][31,40][51,60][71,80][91,100] Number of Patients Greater antiplatelet effect may address this group What effect does greater platelet inhibition have on bleeding? Adapted from: Serebruany V et al. J Am Coll Cardiol. 2005.

79 Risk vs. Benefit – What Affects Efficacy and Safety?

80 Major Bleeding: Incidence* in Clinical Trials with Active Agent Clop + ASA Pras + ASATicag + ASAClop + ASA 600mg + 325 mg Yusuf S NEJM 2001 Wiviott SD NEJM 2007 Wallentin L NEJM 2009 Mehta SR NEJM 2009

81 Definition TIMI 1 GUSTO 2 CURE 3 CURE 3 TrialTRITONCHARISMACURE Major – fatal / life threatening or severe bleeding Fatal / life threatening (related to instrumentation, spontaneous, trauma), ICH, Hb 5 g/dL, or absolute HCT 15% Fatal, ICH, or causes haemodynamic compromise and requires intervention Fatal / Life threatening Fatal, ICH, requires surgery, hypotension requiring inotropes, Hb 5 g/dL, or transfusion 4 U Other major Disabling, intraocular with vision loss, or transfusion 2-3 U ICH = intracranial haemorrhage; PLATO = Platelet Inhibition and Patient Outcomes. 1.Chesebro, JH et al. Circulation 1987 2.GUSTO Investigators. NEJM 1993 3. Yusuf S, et al. N Engl J Med. 2001;345:494-502. 4. Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851. PLATO 4 PLATO Fatal / Life threatening Fatal, ICH, intrapericardial with tamponade, hypovolaemic shock / hypotension requiring pressors or surgery, Hb >5 g/dL, or transfusion 4 U Other major Disabling (intraocular with permanent vision loss), Hb 3-5 g/dL, or transfusion 2-3 U Major Bleeding Data Elements

82 Bleeding and Evidence-based Therapies N=2498 ACS patients from the PREMIER Registry Discharge ASA and thienopyridine Pts. with bleeding vs. pts. without bleeding Wang TY, et. al. Circulation 2008 Discharge 1 Month 6 Months 1 Year Aspirin OR (95% CI) Thienopyridine 0.5 1.0 2.0 0.45 (0.31, 0.64) 0.68 (0.50, 0.92) 0.63 (0.46, 0.87) 0.62 (0.42, 0.91) 0.94 (0.66, 1.34) 0.83 (0.59, 1.17) 1.06 (0.78, 1.45) 1.12 (0.81, 1.55)

83 Nuisance Bleeding and Drug Discontinuation N=2360 unselected pts. receiving DES N=2360 unselected pts. receiving DES Prospective data collection Prospective data collection Major events adjudicated Major events adjudicated Serebruany bleeding classification Serebruany bleeding classification* Roy P, et. al. AJC 2008 *Alarming bleeding = ICH, life-threatening, + transfusion Internal bleeding = hematoma, epistaxis, mouth or vaginal, Melena, IO, hematuria or hematemesis Nuisance bleeding = bruising, petechiae, ecchymosis % discontinued

84 PREMIER Registry: Mortality Among Patients Continuing vs Discontinuing Thienopyridine Therapy Spertus JA, et al. Circulation. 2006 1510 5 0 Mortality (%) 0123456789101112 ContinuedDiscontinued P<0.001 Months

85 CURE – Major Bleeding *Includes fatal bleeding **Includes life-threatening & fatal bleeding Yusuf S, et. al. NEJM 2001 P=NS P=0.13 P=0.001 %

86 Clopidogrel and ASA for NSTE ACS CABG-Related Bleeding in CURE p=0.001 Clopidogrel d/c > 5 days Clopidogrel d/c > 5 days Clopidogrel d/c < 5 days Clopidogrel d/c < 5 days Cure Investigators, NEJM 2001

87 Events Saved vs Life-threatening Bleeding Over Time: Net Clinical Benefit of Clopidogrel Yusuf S et al for the CURE Trial Investigators. Circulation. 2003;107:966

88 *Other standard therapies were used as appropriate.. CURE: Major Bleeding by Aspirin Dose Through Follow-Up Peters RJ, et al. Circulation. 2003 Aspirin Dose Placebo + Aspirin* Clopidogrel + Aspirin* 75-100 mg1.9%3.0% 101-199 mg2.8%3.4% 200-325 mg3.7%4.9%

89 ClopidogrelHR 95% CI P P intn StandardDouble CV Death/MI/Stroke (Overall) ASA High4.63.80.830.70-0.990.036 0.043 ASA Low4.24.51.070.91-1.270.42 MI/Stent Thrombosis (PCI pts) ASA High3.82.70.710.56-0.900.0050.19 ASA Low3.63.20.890.71-1.120.32 Major Bleed (Overall) ASA High2.22.41.080.86-1.370.51 0.099 ASA Low1.92.71.431.13-1.810.003 Clopidogrel: Double vs Standard Dose by ASA Factorial Mehta SR, et. al. NEJM 2009 TIMI Major bleeding: 600 mg vs. 300 mg Clop – 0.5% vs. 0.5%, P=0.50 325 mg ASA vs. 100 mg ASA – 1.03% vs. 0.97%, P=0.71

90 Clopidogrel and bleeding Adding clopidogrel to ASA increases bleeding risk overall Adding clopidogrel to ASA increases bleeding risk overall No increase in life-threatening or fatal bleeding No increase in life-threatening or fatal bleeding Increased risk of CABG-related bleeding, but to reduce this risk, discontinue clopidogrel 5d prior Increased risk of CABG-related bleeding, but to reduce this risk, discontinue clopidogrel 5d prior Higher clopidogrel and ASA dose associated with better ischemic outcomes in PCI patients Higher clopidogrel and ASA dose associated with better ischemic outcomes in PCI patients Increased bleeding risk, but no increase in fatal bleeding or TIMI major bleeding Increased bleeding risk, but no increase in fatal bleeding or TIMI major bleeding

91 -20.0 0.0 20.0 40.0 60.0 80.0 100.0 Inhibition of platelet aggregation (%) Response to prasugrelResponse to clopidogrel Clopidogrel responder Clopidogrel non-responder Interpatient variability Responder = 25% IPA at 4 and 24 hours Brandt JT, et al. Am Heart J. 2007;153:66.e9-e16. Clopidogrel vs. Prasugrel At 24 hrs (healthy volunteers) Overcoming clopidogrel hyporesponsiveness Change the drug

92 Bleeding Events Safety Cohort (N=13,457) % Events 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% P=0.74 ARD 0.3% P=0.002 Clopidogrel Prasugrel ICH in Pts w Prior Stroke/TIA (N=518) ICH in Pts w Prior Stroke/TIA (N=518) Clop 0 (0) % Pras 6 (2.3)% (P=0.02)

93 TRITON-TIMI 38 Early and late non CABG bleeding Wiviott S, et. al. NEJM 2007

94 Net Clinical Benefit: Bleeding Risk Subgroups Post-hoc Analysis OVERALL 60 kg 60 kg < 60 kg < 75 75 75 No Yes 0.512 Prior stroke / TIA Age Wgt Risk (%) + 54 -16 -16 +3 -14 -13 HR P int =.006 P int =.18 P int =.36 Wiviott SD, NEJM, 2007

95 Modified Folts Model of Thrombosis and Haemostasis in Anaesthetised Dogs Balancing Efficacy and Safety: Antithrombotic Effect vs Bleeding Time *A compound chemically indistinguishable from prasugrel. Adapted from van Giezen JJJ, et al. 9th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology 2008 9th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology 2008 AZD6140Clopidogrel AZD11703072*

96 PLATO - Total Major Bleeding Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; * Proportion of patients (%); NS = not significant NS NS NS NS NS 0 K-M estimated rate (% per year) PLATO major bleeding 1 2 3 4 5 6 7 8 9 10 12 1113 TIMI major bleeding Red cell transfusion * PLATO life- threatening/ fatal bleeding Fatal bleeding 11.6 11.2 7.9 7.7 8.98.9 5.85.8 0.30.3 TicagrelorClopidogrel Wallentin L, et. al. NEJM 2009

97 PLATO - Non-CABG and CABG-related Major Bleeding p=0.026 p=0.025 NS NS 9 K-M estimated rate (% per year) Non-CABG PLATO major bleeding 8 7 6 5 4 3 2 1 0 Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding 4.5 3.8 2.8 2.2 7.4 7.9 5.3 5.8 TicagrelorClopidogrel Wallentin L, et. al. NEJM 2009

98 Offset of Ticagrelor and Clopidogrel Storey RF, et. al. JACC 2007 After 24 hrs, the antiplatelet effect of Ticagrelor is higher than Clopidogrel In PLATO, Ticagrelor was discontinued 24-72h before CABG, allowing drug to wear off ? If the non-CABG related bleeding is higher because of the persistent greater effect

99 Newer Oral Antiplatelet Agents Prasugrel and ticagrelor provide greater platelet inhibition compared with clopidogrel Prasugrel and ticagrelor provide greater platelet inhibition compared with clopidogrel Prasugrel is associated with increases in major bleeding, fatal bleeding, and CABG-related bleeding Prasugrel is associated with increases in major bleeding, fatal bleeding, and CABG-related bleeding Unacceptable risks in age > 75 yrs, Weight 75 yrs, Weight < 60 kg, Prior stroke/TIA Ticagrelor associated with improved survival and no increase in bleeding overall, but increases in non- CABG related bleeding Ticagrelor associated with improved survival and no increase in bleeding overall, but increases in non- CABG related bleeding

100 Making Decisions: The Clinical Necessity of Comparing Across Trials CURRENT PCI N=17,232TRITONN=13,608PLATON=18,624 CV Death, MI or Stroke 15% 15% 21% (w high dose ASA) 21% (w high dose ASA) 19% 19% 16% 16% 16% in death 16% in death Definite Stent Thrombosis 42% 42% 51% (w high dose ASA) 51% (w high dose ASA) 58% 58% 33% 33% TIMI Major Bleed No increase 32% 32% No increase CABG-related Bleeding No increase 4-fold 4-fold No increase 19-25% in non-CABG bld 19-25% in non-CABG bld Fatal bleedingNo increase 4-foldNo increase

101 PRT060128 (Elinogrel) – A Reversible P2Y12 Inhibitor PRT060128 (Elinogrel) – A Reversible P2Y12 Inhibitor N= 50 pts with HPR on 75 mg clopidogrel daily0 20 40 60 80 ScreenPredose4h6h24h 7-10 d Maximum Aggregation (%) p<0.001 p<0.001 5 M ADP-Induced Aggregation Gurbel PA, AHA 2008

102 INNOVATE-PCI Trial 800 elective PCI patients Clopidogrel -Load - 90d therapy PRT 128 -IV - Oral for 90d 24 hr death/MI/TVR 60d death/MI/TVR 24 hr & 60d Clinically relevant major/minor bleeding 24 hr & 60d Nuisance bleeding 24 hr & 60d TIMI Major and Minor bleeding 800 elective PCI patients Clopidogrel -Load - 90d therapy PRT 128 -IV - Oral for 90d 24 hr death/MI/TVR 60d death/MI/TVR 24 hr & 60d Clinically relevant major/minor bleeding 24 hr & 60d Nuisance bleeding 24 hr & 60d TIMI Major and Minor bleeding

103 Bleeding and Antiplatelet Therapy Conclusions (1) Several options for oral antiplatelet therapy now exist (with more coming) Several options for oral antiplatelet therapy now exist (with more coming) New options address undertreatment New options address undertreatment Increase ASA + Clopidogrel dose Increase ASA + Clopidogrel dose Prasugrel Prasugrel Ticagrelor Ticagrelor Efficacy signal improved with all of the above strategies compared with control arm with some caveats Efficacy signal improved with all of the above strategies compared with control arm with some caveats CURRENT – PCI subgroup experienced benefit CURRENT – PCI subgroup experienced benefit TRITON – No medical therapy; No benefit in age 75 years, prior TIA/Stroke, low body weight TRITON – No medical therapy; No benefit in age 75 years, prior TIA/Stroke, low body weight

104 Bleeding and Antiplatelet Therapy Bleeding and Antiplatelet Therapy Conclusions (2) With similar efficacy signals across trials, assessing bleeding is important Differing definitions across trials make it difficult to compare, but… Differing definitions across trials make it difficult to compare, but… General concepts General concepts Clopidogrel + ASA = greater bleeding than ASA alone Clopidogrel + ASA = greater bleeding than ASA alone Prasugrel + ASA = greater bleeding than clopidogrel + ASA Prasugrel + ASA = greater bleeding than clopidogrel + ASA Ticagrelor + ASA = greater non-CABG related bleeding than clopidogrel + ASA (but no difference in CABG-related bleeding) Ticagrelor + ASA = greater non-CABG related bleeding than clopidogrel + ASA (but no difference in CABG-related bleeding)

105 Bleeding and Antiplatelet Therapy Conclusions (3) In the era of three therapeutic options to increase the efficacy of antiplatelet agents, the literature provides support for the following strategies to reduce bleeding risk: Clopidogrel – Discontinue prior to CABG, reduce ASA dose Clopidogrel – Discontinue prior to CABG, reduce ASA dose Prasugrel – No clear strategy to reduce bleeding risk and maintain the efficacy signal Prasugrel – No clear strategy to reduce bleeding risk and maintain the efficacy signal Ticagrelor – Need more data on how to reduce non-CABG related bleeding risk Ticagrelor – Need more data on how to reduce non-CABG related bleeding risk

106 Case Study in Antiplatelet Therapy Audience Response System Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories Professor of Medicine Professor of Medicine University of Vermont

107 A 62-Year-Old Male Presents With Chest Pain for Four Hours to a Non-PCI Community Hospital 28 Miles by Highway Community ED Activates UVM Cath Lab: Prepare Transfer for Primary PCI

108 Question # 1 Question # 1 The initial ED antiplatelet therapy should be: a)ASA 325 mg and then 325 qd indefinitely b)ASA 81 mg and then 81 qd indefinitely c)ASA 325 mg and then change to 81 mg after 24 hours d)ASA 325 mg and then change to 81 mg at discharge e)ASA 325 mg and then change to 81 mg after a month or if GI side effects

109 ASA Dose Comparison Primary Outcome and Bleeding ASA Dose Comparison Primary Outcome and Bleeding ASA 75-100 mg ASA 300-325 mg HR 95% CI P CV Death/MI/Stroke PCI (2N=17,232) 4.24.10.980.84-1.130.76 No PCI (2N=7855) 4.74.40.920.75-1.140.44 Overall (2N=25,087) 4.44.20.960.85-1.080.47 Stent Thrombosis 2.11.90.910.73-1.120.37 TIMI Major Bleed 1.030.970.940.73-1.210.71 CURRENT Major Bleed 2.32.30.990.84-1.170.90 CURRENT Severe Bleed 1.71.71.000.83-1.211.00

110 Question # 2 The current STEMI algorithm mandates 600 mg clopidogrel prior to transfer: However, some cardiologists would like this algorithm to be updated. You would: a)Replace clopidogrel 600 mg with prasugrel 60 mg for all STEMI patients b)Put prasugrel in community algorithm with guidelines to use only in selected patients, based on bleeding risks c)Require a phone call to a cardiologist to determine, on an individual patient basis whether clopidogrel or prasugrel is optimal d)No longer give clopidogrel prior to transfer: rather, await arrival at PCI center for decision on second antiplatelet agent by cath lab team e)Do not change the algorithm: Continue 600 mg clopidogrel loading as standard of care

111 The ED Attending Gathers More Clinical Information NIDDM NIDDM No prior h/o bleeding No prior h/o bleeding HTN and Cr 1.6 HTN and Cr 1.6 No prior stroke/TIA No prior stroke/TIA Remote smoker; COPD on PRN Inhaler Remote smoker; COPD on PRN Inhaler Occasional reflux symptoms Occasional reflux symptoms

112 Question # 3 The Patient is Being Packaged for Transfer: What Is Your Antiplatelet Therapy of Choice Now? a)Give 600 mg clopidogrel in ED prior to transfer for PCI b)Give 60 mg prasugrel in ED prior to transfer for PCI c)Define anatomy and, if not surgical, give 600 mg of clopidogrel d)Define anatomy, and if not surgical, give 60 mg prasugrel e)Give a GPI to almost all STEMI patients; then, give clopidogrel 600 mg after anatomy defined.

113 Non-Surgical Anatomy PCI Anatomy Defined as Below Low Risk STEMI AnatomyHigh Risk STEMI Anatomy

114 Question # 4 You Have to Make A Choice NowNot Surgical Anatomy a)High risk anatomy: 60 mg prasugrel b)High risk anatomy: but still 600 mg clopidogrel c)Will wait and see how the PCI goes, and then decide post-PCI on choice of antiplatelet agent d)Depends if I am using a GPIif GPI is used, clopidogrel 600 mg is my choice. e)Other factors will guide my prasugrel vs clopidogrel decision

115 Question 5: RCA Was Stented with DES Clopidogrel 600 mg Was Already Loaded Prior to Transfer: How Will I Continue to Sequence Antiplatelet Therapy? Question 5: RCA Was Stented with DES Clopidogrel 600 mg Was Already Loaded Prior to Transfer: How Will I Continue to Sequence Antiplatelet Therapy? a)Clopidogrel 150 mg qd x 7 days, then 75 qd b)Clopidogrel 150 qd in hospital, then 75 qd c)Clopidogrel 75 qd x 12 months d)Switch to prasugrel 10 mg qd x 15 months e)Switch to prasugrel 10 mg qd for 30 days and then clopidogrel 75 qd x 11 months

116 Days Cumulative Hazard 0.0 0.004 0.008 0.012 036912151821242730 Clopidogrel Standard Dose Clopidogrel Double Dose 42%RRR HR 0.58 95% CI 0.42-0.79 P=0.001 Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis

117 Clopidogrel Double vs Standard Dose Bleeding PCI Population Clopidogrel Standard N= 8684 DoubleN=8548HazardRatio 95% CI P TIMI Major 1 0.50.51.060.70-1.610.79 CURRENT Major 2 1.11.61.441.11-1.860.006 CURRENT Severe 3 0.81.11.391.02-1.900.034 Fatal0.150.070.470.18-1.230.125 ICH0.0350.0461.350.30-6.040.69 RBC transfusion 2U 0.911.351.491.11-1.980.007 CABG-related Major 0.10.11.690.61-4.70.31 1 ICH, Hb drop 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2 Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or Hb 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of 4 units

118 Question 6: RCA Stented with DES Prasugrel was loaded prior to transfer or in cath lab: Follow-Up oral antiplatelet therapy should consist of... a) Prasugrel 10 mg po qd in hospital, then switch to clopidogrel 75 qd x 12 months b) Prasugrel 10 mg po qd x 7 days, then clopidogrel 75 qd x 12 months c) Prasugrel 10 mg po qd x 30 days, then clopidogrel 75 mg x 11 months. d) Prasugrel 10 mg po qd for a minimum of 12 months e) Clopodigrel 150 mg po qd 7 days and then 75 mg po for 12 months

119 Antman, E. M. et al. J Am Coll Cardiol 2008;51:2028-2033 Prasugrel for 3 Days, 30 Days or 15 Months? Prasugrel for 3 Days, 30 Days or 15 Months?

120 Question # 7 Question # 7 The patient has a history of GE Reflux and is committed to dual antiplatelet therapy for 12 months. He is placed on long- term clopidogrel therapy: You would... a)Give any PPI for 12 months b)Not give any PPI unless patient develops GI symptoms c)Give only pantoprozole, not omeprazole, for 12 months d)Give PPI only if using prasugrel e)Give H2-blocker and use PPI only if symptoms occur

121 0.501.50 Overall NSTEMI/UA STEMI Male Female Age <= 65 yrs Age > 65 yrs Non-Diabetic Prev Diabetic No Inhosp GPIIb/IIIa GPIIb in hosp No Prot Pump Inhib Prot Pump Inhib Non-smoker Current Smoker ASA Low ASA High 17232 10886 6346 6346 13009 4223 4223 10975 6257 6257 13400 3831 3831 12288 4936 4936 7675 7675 5557 5557 10845 6380 6380 8620 8620 8612 8612 4.5 4.2 5.0 4.1 5.8 3.0 7.1 4.2 5.6 3.9 6.0 3.8 5.7 4.9 3.8 4.2 4.8 3.9 3.6 4.2 3.6 4.6 2.7 6.0 3.6 4.9 3.5 4.7 3.2 4.2 4.6 2.6 4.3 3.5 0.805 0.419 0.702 0.836 0.465 0.408 0.045 0.024 0.501.50 3.7 3.6 4.0 3.5 4.6 2.9 5.2 3.6 4.1 3.1 5.2 3.1 4.8 3.9 3.4 3.6 3.8 3.0 3.1 2.8 3.0 3.0 2.2 4.4 2.8 3.6 2.5 4.1 2.3 3.3 3.5 2.1 3.2 2.7 0.248 0.148 0.418 0.567 0.894 0.613 0.050 0.191 CV Death, MI or Stroke MI or Stent Thrombosis Clopidogrel: Double v Standard Dose PCI Cohort Subgroups Std %Double %Std %Double %Intxn P Double Dose Better Std Dose Better 2N

122 Question 8: The NICE (UK) Group has recommended prasugrel only if patient has STEMI, Diabetes or Stent Thrombosis on Clopidogrel a)Agreewill use prasugrel only for these indications b)Disagreewill use prasugrel more broadly c)Disagreewill use prasugrel in less patients due to CURRENT OASIS- 7 data and high-dose clopidogrel option d)Disagreebased on CURRENT OASIS-7, clopidogrel remains standard of care

123 Question 9: Youre at TCT 2010 and ticagrelor has been approved: For this STEMI patient, you will: a)Start with ticagrelor b)Start with clopidogrel c)Start with prasugrel d)Depends on cost of ticagrelor e)Depends on whether GPI is being used for STEMI f)Need more trial data and analysis


Download ppt "The Evolving Science and Controversial Landscape of Antiplatelet Therapy in the Catheterization Laboratory Mechanisms Mortality Therapeutics PROGRAM CO-CHAIRMAN."

Similar presentations


Ads by Google