1 / 48

Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

Welcome Ask The Experts March 24-27, 2007 New Orleans, LA. AntiPlatelet Therapy in ACS and PCI Stephen D. Wiviott, MD Associate Physician, Cardiovascular Division, Brigham and Women's Hospital Investigator, TIMI Study Group Harvard Medical School Boston, MA.

marshall-porter
Download Presentation

Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

  2. AntiPlatelet Therapy in ACS and PCIStephen D. Wiviott, MDAssociate Physician, Cardiovascular Division, Brigham and Women's Hospital Investigator, TIMI Study Group Harvard Medical School Boston, MA

  3. Antiplatelet Therapy in ACS and PCI: Challenges and Future Directions Stephen D. WiviottCardiovascular DivisionBrigham and Women’s HospitalHarvard Medical School TIMI Study Group

  4. DisclosuresSpeakers Bureau: Pfizer; CME Honoraria: Eli Lilly, Merck, Pfizer, Sankyo; Accumetrics. Consultancies: Amgen, Transform Pharmaceuticals, Forrest Labs, Biogen-Idec, Sanofi-AventisTIMI Study Group Receives Research Funding From: Eli Lilly, Sankyo, Merck, Schering Plough, Pfizer, Sanofi-Aventis, Astra Zeneca, CV Therapeutics, Corvas, Accumetrics

  5. Circ 102: 624,2000 Dual Antiplatelet Rx for PCI % MACE 1.5 1.2 0.9 ISAR FANTASTIC STARS MATTIS CLASSICS

  6. NSTEACS: Clopidogrel (300/75) vs Placebo Primary End Point - MI/Stroke/CV Death 11.4% Placebo + ASA* 9.3% Clopidogrel + ASA* 20% RRR P < 0.001 N = 12,562 0 3 6 9 12 Months of Follow-Up * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  7. Early Effects of Pre-treatment with Clopidogrel – 28 Day Results Death, MI, UTVR- PP Population 10 9 8.3% 18.5% RRR P=0.23 8 7 6.8% 6 Combined Endpoint Occurrence (%) 5 4 3 No-PT - Placebo* PT- Clopidogrel* 2 1 0 0 7 14 21 28 Days From Randomization Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420. PT = Pre-treatment *Plus ASA and other standard therapies

  8. CREDO: Clopidogrel Loading Dose Timing and Risk of MACE Placebo - 2 P=0.020 for treatment/timing interaction - 3 Log Odds of Death, MI or UTVR at 28 Days - 4 Clopidogrel - 5 - 6 0 5 10 15 20 25 30 Hours Prior to PCI of Study Drug Loading Dose Steinhubl, et al

  9. Limitations of Current thienopyridines • Slow onset: requires prolonged pretreatment for PCI efficacy • Bleeding (especially related to CABG) • Modest levels of platelet inhibition • Variability of response

  10. The First Clopidogrel Resistance Study (300 mg): A “Fingerprint” of Clopidogrel Response Variability 2 Hours 24 Hours Resistance = 31% Resistance Resistance = 63% 24 Resistance 20 Patients (%) Patients (%) 12 10 ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] (-30,-20] (-10,0] (10,20] (30,40] (50,60]  Aggregation (%)  Aggregation (%) 5 Days 30 Days 22 Resistance = 15% 28 Resistance = 31% Resistance Patients (%) Patients (%) 11 14 Resistance ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 ≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60  Aggregation (%) (-30,-20] (-10,0] (10,20] (30,40] (50,60]  Aggregation (%) Gurbel PA, et al. Circulation. 2003;107: 2908-2913.

  11. Potential Mechanisms of Response Variability • Extrinsic Mechanisms • Non-compliance • Under-dosing • Drug-drug interactions • Absorption and/or metabolism • Patient Factors (DM, ACS, etc…) • Intrinsic Mechanisms • P2Y12 receptor affinity (ADP or Drug) or number • Variable response to agonist: • Release • GP IIb/IIIa receptor activation Wiviott and Antman Circ 2004

  12. CYP 3A4 Activity* Correlates Inversely with Platelet Aggregation Following Clopidogrel Loading 100 90 80 70 60 50 40 30 20 10 0 Platelet Aggregation (%) r=–0.6 P=0.003 0 .5 1 1.5 2 2.5 3 3.5 4 14CO2 Exhaled/Hour (%) *Erythromycin breath test. Lau WC, et al. Circulation. 2004;109:166-171.

  13. Clinical Importance of Response Variability ? Failure of Therapy Successful Therapy Lesser Response Greater Response Failure of Therapy = Drug Resistance

  14. Clopidogrel Resistance andIncreased Risk of Ischemic Events N = 60 Prim PCI for STEMI 5 µM ADP induced plt agg Death/ACS/CVA by 6 m Clop resist 40 120 40 100 Q1 P=0.007 30 80 Q2 Baseline (%) Percent 60 20 Q3 40 Q4 6.7 10 20 Quartiles of response 0 0 0 0 Q1 Q2 Q3 Q4 1 2 3 4 5 6 Days Matetzky S, et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004 109:3064-3067.

  15. Platelet Reactivity* Correlateswith CK-MB Release: CLEAR Platelet Study 100 P<0.001 90 80 P<0.001 P=0.015 70 60 Mean Platelet Reactivity 50 40 30 20 10 0 CK-MB(NL) CK-MB(>1-3x ULN) CK-MB(>3x ULN) *5 m ADP. Gurbel PA, et al. Circulation. 2005;111:1153-1159.

  16. The Clopidogrel REsistance andStent Thrombosis (CREST) Study Platelet Reactivity in Patients with SAT(N=20) versus no SAT (N=50) P<0.001 For Each LTA – 5 M ADP (%) LTA – 20 M ADP (%) Gurbel PA, et al. J Am Coll Cardiol. 2005 (in press).

  17. Increase the Dose: (300 mg vs 600 mg) 33 300 mg Clopidogrel 30 600 mg Clopidogrel 27 Resistance = 28% (300 mg) 24 Resistance = 8% (600 mg) 21 18 Patients (%) 15 12 9 6 3 0 ≤-30 (-20,-10] (0,10] (20,30] (40,50] (60,70] (-30,-20] (-10,0] (10,20] (30,40] (50,60] > 70 D Aggregation (5 µM ADP-induced Aggregation) at 24 Hours Gurbel PA, et al. J Am Coll Cardiol. 2005;45:1392-1396.

  18. ISAR - CHOICE Metabolite Concentrations Platelet Aggregation Von Beckenrath et al Circ 2005

  19. ARMYDA-2 Trial: Primary endpoint 255 patients with stable CAD or UA/NSTEMI 4-8 hours prior to PCI 13% received IIb/IIa inhibitors and 20% drug-eluting stents Primary Composite of death, MI, and target vessel revascularization p = 0.04 Primary Endpoint: Composite of death, MI, or target vessel revascularization (TVR) at 30 days Circulation 2005

  20. CURRENT/OASIS 7 Clopidogrel optimal loading dose Usageto Reduce Recurrent EveNTs/Optimal Antiplatelet Strategyfor InterventionS Patients with UA/NSTEMI planned for early invasive Strategy; ie, intend for PCI as early as possible within 24 hrs RANDOMIZE Clopidogrel High-Dose Group Clopidogrel 600 mg loading dose day 1 followed by 150 mg from days 2 to 7; 75 mg from days 8 to 30 Clopidogrel Standard-Dose Group Clopidogrel 300 mg (+ placebo) day 1 followedby 75 mg (+ placebo) from days 2 to 7;75 mg from days 8 to 30 RANDOMIZE RANDOMIZE ASA high-dose group At least 300 mg day 1; 300–325 mgfrom days 2 to 30 ASA low-dose group At least 300 mg day 1; 75–100 mgfrom days 2 to 30 ASA high-dose group At least 300 mg day1; 300–325 mgfrom days 2 to 30 ASA low-dose group At least 300 mg day 1; 75–100 mgfrom days 2 to 30 PCI: Percutaneous coronary intervention UA/NSTEMI: Unstable angina/non-ST-segment elevation myocardial infarction

  21. Sem Vasc Med 3:113, 2003 Sankyo Ann Report 51:1,1999 O CH3 O C O O O CH3 CH3 O O C C N N O O C S S N N F Cl C H S S 3 Cl Cl 85% Inactive MetabolitesEsterases O O O N N HOOC N HOOC O O * HS S F OCH3 * HS F Cl Active Metabolite Active Metabolite Change the Agent? Pro-drug Clopidogrel Prasugrel Hydrolysis (Esterases) Oxidation (Cytochrome P450)

  22. Inhibition of Platelet Aggregation(IPA) at 24 Hours (Healthy Volunteers) 100.0 80.0 Interpatient Variability 60.0 Inhibition of Platelet Aggregation (%) 40.0 Interpatient Variability 20.0 0.0 Clopidogrel Responder Clopidogrel Non-responder -20.0 Response to Prasugrel Response to Clopidogrel *Responder =  25% IPA at 4 and 24 h Brandt, Payne, Wiviott et al AHJ 2007

  23. Inhibition of Platelet Aggregation (Stable Atherosclerosis) 70 Maintenance dose (MD) Loading dose (LD) 60 50 40 Mean IPA (%) 30 20 Prasugrel (40 mg LD/5 mg MD) Prasugrel (40 mg LD/7.5 mg MD) 10 Prasugrel (60 mg LD/10 mg MD) 0 Prasugrel (60 mg LD/15 mg MD) Clopidogrel (300 mg LD/75 mg MD) - 10 7/1 7/2 1/0 1/2 1/4 1/6 28/0 28/2 28/4 28/6 Day/Hour Post Dosing Jernberg, T et al EHJ 2006

  24. In Vitro Antiplatelet Effects of Active Metabolites in PRP (B) Human (A) Rat 80 70 Platelet aggregation (%) Platelet aggregation (%) 60 60 * 50 40 ** ** Prasugrel AM (IC50 = 51 μM) Prasugrel AM (IC50 = 26 μM) 40 30 ** ** Clopidogrel AM (IC50 = 41 μM) Clopidogrel AM (IC50 = 21 μM) ** ** 20 20 ** ** 10 ** ** ** ** 0 0 1000 100 0 1 1 10 10 100 0 1000 Concentration (μM) Concentration (μM) * P < 0.05 ** P < 0.01 vs. control Ogawa, et al ESC 2005.

  25. Insights into Potency : Active Metabolite Levels in Humans (Crossover Study) 1000 Prasugrel 60 mg Clopidogrel 300 mg 100 Plasma Concentration (ng/ml) 10 1 0.1 0 6 12 18 24 Time in Hr ISTH 2005 Payne et al, P0952

  26. Wiviott et al Circ 2005 STUDY DESIGN PCI with stenting (N=900) Study Drug in lab; Stratify for GP IIb/IIIa PRASUGREL LD 40 mg MD 7.5 mg N=200 PRASUGREL LD 60 mg MD 10 mg N=200 PRASUGREL LD 60 mg MD 15 mg N=250 CLOPIDOGREL LD 300 mg MD 75 mg N=250 Maintenance Rx for 30 days 1o endpoint: Significant (non-CABG) bleeding through 30 D 2o endpoints: CV MACE through 30 D, Major Bleeding, Component Clinical Endpoints

  27. Wiviott et al Circ 2005 10 EP: Significant Non-CABG Bleeding 30 D Clop. vs Prasugrel Dose Ranging P = 0.77 P= NS Prasugrel LD/MD Treatment Group 3/199 4/200 4/251 R/N 3/254 11/650

  28. Wiviott et al Circ 2005 MI at 30 D RR=0.72 [0.4,1.2] P = 0.23 P= NS Treatment Group Prasugrel LD/MD R/N 20/254 37/650 14/199 13/200 10/251

  29. Implications In patients undergoing PCI, prasugrel: • Demonstrated a similar safety profile to standard dose clopidogrel • Resulted in non-significant, but lower rates of ischemic events compared to patients treated with standard doses of clopidogrel QUESTION: Would prasugrel, with higher and more consistent levels of platelet inhibition, be superior to clopidogrel in reducing ischemic events in a trial powered to detect a clinically significant difference?

  30. STUDY DESIGN ACS (STEMI or UA/NSTEMI) & Planned PCI Enrollment Complete January 2007 N= 13,000 ASA Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1o endpoint: CV death, MI, Stroke 2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Wiviott et al, AHJ 2006

  31. Implications • Establish the safety and efficacy of prasugrel compared to clopidogrel in patients with ACS undergoing PCI in this registry pathway trial • Proof of Concept: • Does an agent that has higher inhibition of platelet aggregation and less “thienopyridine resistance” result in improved clinical outcomes in an adequately powered clinical trial? Wiviott et al, AHJ 2006

  32. Hypotheses In the follow up phase, beyond completion of TRITON – TIMI 38*: • Patients withdrawn from thienopyridine at study completion will have a higher rate of stent thrombosis than those continuing therapy in the registry follow up period • Patients treated with DES will have higher rates of stent thrombosis than those treated with BMS over the entire treatment period (trial plus registry) *Analyses adjusted for baseline, procedural features, and propensity for clopidogrel use

  33. Summary of Analytical Groups and Trial/ Registry Timing Trial Duration Registry Duration 6-15 Months 24 M Following LPV in TRITON – TIMI 38 TRITON – TIMI 38 Clinical Trial Continue DES Open Label Thienopyridine Discontinue Prasugrel vs Clopidogrel Continue BMS Discontinue 30 - 54 Months Registry + Trial Duration

  34. * Pras 10 mg * * * Clop 600 mg Pras 60 mg * * † * * † * * * * † § Clop 75 mg ! * ! Clop 75 mg Clop 300 mg * p<0.001 vs. Clop 300 mg or 600 mg LD † p<0.001 vs. Clop 300 ! p<0.05 vs. Clop 300§p<0.05 vs Clop 300/75 Prasugrel 10 mg MD vs. Clopidogrel 75 mg MD: Higher IPA During Maintenance Dosing Loading Dose Maintenance Doses 100 80 60 Inhibition of Platelet Aggregation (%) 40 20 mean ± SEM 20 μM ADP 0 0.5 0 0.25 1 2 4 6 24 3 4 5 6 7 8 9 Time Hours Days

  35. PRINCIPLE – TIMI 44 (PCI Subjects Only) – Phase I Protocol Design PHASE I Planned Elective PCI Aggregometry*and Biomarkers√ N < 180 CLOPIDOGREL Naive Planned GP IIb/IIIa Prohibited ASA Clopidogrel 600 mg Prasugrel 60 mg 0.5, hour post-LD Aggregometry* and Biomarkers√ Diagnostic Catheterization Anatomy Suitable for PCI Post Cath† aggregometry †Or 2 h whichever is sooner N = 100 PCI 6, 18-24 h, Aggregometry*, biomarkers Primary Endpoint: Mean IPA (6h) in all treated subjects

  36. PRINCIPLE – TIMI 44 (PCI Subjects Only) – Phase II Protocol Design Confidential PCI PHASE II Clopidogrel 150 mg x14d Prasugrel 10 mg x 14d 14 d clinical events, biomarkers √, aggregometry*, CROSSOVER Prasugrel 10 mg x 14 d Clopidogrel 150 mg x14d 30 d clinical events,biomarkers √, aggregometry* Primary Endpoint: Mean IPA (14d&30d) in all treated subjects √ Biomarkers (VASP, CD40L, P-selectin, LPA, Tn, CK-MB, CRP, MPO) *Aggregometry: Primary (20 uM ADP), secondary (5 uM ADP), Accumetrics

  37. Change the Agent?AZD6140 Characteristics • Class: CPTP* (non-thienopyridine) • Reversible platelet P2Y12 receptor antagonist • Orally active • Rapid onset of action (2 h) with or without a loading dose • Acts directly (no metabolic activation required) • Plasma t½ ~12 h (BID Drug) AZD6140 *cyclo-pentyl-triazolo-pyrimidine

  38. AZD6140 90 mg AZD6140 180 mg AZD6140 270 mg CLOP 300 mg Maximal and Final IPA on Day 1 Clopidogrel Naive Patients Maximal Extent Final Extent 100 100 75 75 IPA (%) Mean ± SEM 50 50 25 25 0 0 0 2 4 8 12 0 2 4 8 12 Time, h Time, h P<0.0176 for all AZD6140 groups vs clopidogrel at 4 h P<0.0002forall AZD6140 groups vs clopidogrel at 4 h

  39. UA/NSTEMI (mod-high risk) STEMI (if primary PCI) All Receiving ASA Clopidogrel Treated or Naïve n=18,000 pts Clopidogrel If pretreated, no additional load; if naïve, standard 300 mg load, then 75 mg od maintenance (additional 300 mg allowed pre-PCI) AZD6140 180 mg load, then 90 mg bid maintenance (additional 90 mg pre-PCI) 12 month maximum exposure (Min=6 mo, max=12 mo, mean=11 mo) Primary Endpoint: CV Death/MI/Stroke Secondary EP: CV Death/MI/Stroke/Revascularization with PCI; CV Death/MI/Stroke; Severe Recurrent Ischemia ClinicalTrials.gov Identifier: NCT00391872

  40. Change The Agent and the Route: Cangrelor? • Low volume of distribution, extensively protein bound • Short half-life (3-5 min), full recovery 20 min • Unlike thienopyridines, direct P2Y12 inhibition, independent of CYP 3A4 metabolism • ? Competitive inhibition of clopidogrel

  41. Clopidogrel Response Variability: Change the Dose and the Route of Administration? 100 8 + Placebo + Aspirin/heparin/GTN 7 80 6 5 60 Inhibition of Aggregation (%) Fold Increase in Bleeding Time 4 40 3 Aggregation 2 20 Bleeding time 1 0 0 7 15 20 45 60 min 500 1000 2000 50 100 Recovery period Cangrelor (ng.kg-1.min-1) Stepped infusion period Nassim MA. J Am Coll Cardiol. 1999;33:225A.

  42. CHAMPION PCI (Phase III) UA, MI, or ACS n=9,000 Double-blind CLOPIDOGREL CANGRELOR Primary Objective: Superiority or noninferiority of cangrelor versus clopidogrel for PCI 1o endpoint: All-cause mortality, MI, and IDR in the 48 hours after randomization 2o endpoints: All-cause mortality and MI at 48 hours Accessed September25, 2006, at http://www.clinicaltrials.gov/ct/show/NCT00305162?order=1.

  43. Summary • ADP induced platelet activation plays a central role in ACS and PCI complications • Thienopyridines have become a key component of therapy • Current thienopyridines have important limitations including response variability • Agents in development offer improved pharmacological profiles, and results of ongoing trials will determine clinical efficacy

  44. Question & Answer

  45. Thank You! Please make sure to hand in your evaluation and pick up a ClinicalTrialResults.org flash drive

More Related