Antiplatelet Therapy. Briain Mac Neill
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1 Antiplatelet Therapy Briain Mac Neill Galway University Hospital & National University of Ireland Galway
2 Milestones in ACS Management Anti-Thrombin Rx Heparin LMWH Bivalirudin Anti-Platelet Rx Aspirin GP!!b!!!a Inhib Prasugrel Ticaglelor Cangrelor Treatment Strategy Conservative Early invasive Interventional Techniques 1990 PBA Stenting (5%) Stenting (85%) 2000 IVUS DES Radial 2010 CT 4 th Generation DES 2020 Ischemic risk Bleeding risk
3 Impact of Pharmacoinvasive Therapy in PCI and ACS Benefit Risk Minimizing infarct size Clinical Stabilization Prevention of early (re)infarction Protection of microcirculation Bleeding Reduction of death+mi in high-risk patients Increased mortality
4
5 ACS is a Platelet-Centric Disease Hypercoagulability Restenosis Inflammation Shear Stress, PCI Plaque Rupture Initial Activation TF Thrombin Procoagulant State TF PLT-WBC Aggregation/ Microparticles P-selectin CD-40L Cytokine Release Growth Factor Release Stent Thrombosis Platelet Granule Secretion Membrane PL s X ADP Sustained Activation TxA 2 X Platelet GPIIb/IIIa Activation X GP IIb/IIIa Inhibitor Platelet Aggregation Microaggregates Aspirin Myocardial Infarction
6 Thrombosis RIsk Progression (TRIP) Study Relation Between Platelet Physiology, Inflammation and Disease Activity GPIIb/IIIa- Unstimulated (MFI) GPIIb/IIIa- ADP-Stimulated (MFI) Reactive Platelets p=.051 AS SA UA P=.002 P<.001 AS SA UA AS = Asymptomatic Patients, SA= Stable Angina, UA= Unstable Angina P=.14 CRP (ug/ml) Interleukin-8 (pg/ml) Inflammation p=.006 p=0.2 AS SA UA P<.001 p=.11 AS SA UA Platelet-Fibrin Clot-Strength (mm) Fibrinogen (mg/ml) Prothrombotic State P=.002 P=.053 AS SA UA P=.15 P=.22 AS SA UA A distinct pathophysiological state of heightened platelet reactivity to ADP, platelet activation, hypercoagulability, and inflammation marks the development of symptomatic cardiovascular disease from Reactive chronic stable disease Platelets?? Prothrombotic State Inflammation Gurbel PA et al. J Am Coll Cardiol. 2007;49:196A. (Hypercoagulability) Unstable Coronary Artery Disease
7 Aspirin Effect: CX-1 Inhibition ADP, Collagen, Thrombin Tx A 2 Receptor Non-CX-1 Pathway Receptor Membrane Phospholipids Platelet Activation Arachidonic Acid Aspirin CX-1 TxA 2 Gurbel PA et al. J Am Coll Cardiol. 2007;50:
8 ASA in UA/NSTEMI Death or MI Patients (%) *p =.0005 *p =.012 *p =.008 * p< * * * * 0 Placebo ASA 0 Placebo ASA 0 Placebo ASA 0 Placebo ASA Lewis HD Jr: NEJM : Cairns JA: NEJM : Theroux P: NEJM : The RISC Group: Lancet :
9 Platelet Inhibition With GPIIb/IIIa Inhibitors
10 GPIIb/IIIa Antagonists in PCI 30 Day Death / MI Trial N Risk Ratio & 95% CI Placebo IIb/IIIa EPIC 2, % 6.6% IMPACT-II 4, % 7.0% EPILG 2, % 4.0% CAPTURE RESTRE 1,265 2, % 6.3% 4.8% 5.1% EPISTENT 2, % 5.2% ESPRIT 2, % 6.3% 0.62 (0.55, 0.71) Pooled 16,770 p < % 5.6% IIb/IIIa Antag Better Placebo Better
11 GP IIb/IIIa in Acute MI % p= Abciximab PCI in Acute MI Trials 30 Day Endpoint (D, Re-MI, Urg TVR) 4.6 p= p< No Abciximab Abciximab p=0.01 p= Rapport ISAR 2 Admiral Cadillac ACE PTCA Stent Stent PTCA or Stent Stent N = 483 N = 401 N = 301 N = 2082 N = 400
12 P2Y 12 A Pivotal Platelet Receptor Collagen Shear TxA 2 Amplification Thrombin Membrane Phospholipids TxA 2 Coagulation Procoagulant Surface ADP X P2Y 12 Receptor Activation Prasugrel Tricagrelor Cangrelor PRT128 Granule Secretion Amplification ADP Sustained Activation Inflammation GPIIb/IIIa Activation Platelet Aggregation Gurbel PA et al. Rev Cardiovasc Med. 2006;7:S20-S28.
13 CURE Primary End Point: MI/Stroke/CV Death Cumulative Hazard Rate Placebo + Aspirin * (n=6303) + Aspirin * (n=6259) Months of Follow-up 20% Relative Risk Reduction p < N=12,562 * In addition to other standard therapies Yusuf S: N Engl J Med 2001;345:
14 Across Spectrum of CAD Acute STEMI UA/NSTEMI PCI Long-term 2 o (1º) prevention CLARITY * CURE CRED CAPRIE CHARISMA CMMIT (CCS-2) Lancet 1996 CLARITY $ 20%CV death/mi/ re-isch CMMIT!9%death/ MI/stroke $ 18.4%CV death/mi/ stroke $ 26.9% death/mi/ stroke $ 8.7% risk reduction death/mi/ stroke $ 7%CV death/mi/ stroke STEMI UA/NSTEMI PCI MI/Stroke/PAD High-Risk Vascular Disease 30 Days + Benefit 1 Year 1 Year 1-3 Years + Benefit + Benefit + Benefit Up to 3.5 years Benefit in symptomatic patients only * vs. placebo. + ASA. vs. ASA.
15 Potential Sites for Response Variability Intestinal absorption Poor compliance Inadequate administration Variable absorption Drug-drug interactions Hepatic metabolism Cytochrome P450 pathway Genetic polymorphisms CYP enzymes Drug-drug interactions Active metabolite P2Y 12 receptor (irreversible inhibition) GP IIb/IIIa receptor expression Genetic polymorphisms P2Y 12 receptor Alternate pathways of platelet activation release of circulating ADP Higher baseline platelet reactivity Genetic polymorphisms Donoghue M and Wiviott SD Circulation 2007
16 Response Variability: Change the Agent? C CH 3 N S Cl Pro-drug C N S F C H 3 Prasugrel 85% Inactive Metabolites Esterases Hydrolysis (Esterases) S N F S N C Cl S CH 3 C N Cl CH 3 xidation (Cytochrome P450) HC * HS Active Metabolite N Cl CH 3 HC N * HS F Active Metabolite Herbert JM, Savi P. Sem Vasc Med. 2003;3:
17 Prasugrel More Effective Platelet Inhibition Prasugrel vs IPA in healthy subjects 2 More potent More rapid in onset More consistent inhibition of platelet aggregation (IPA) Less frequent poor IPA response More efficient generation of its active Inhibition of Platelet Aggregation (%) Pras 60/10 Clop 600/75 Clop 300/ / /. 5 1 / 1 1 / 2 1 / 4 1 / 6 2 / 0 3 / 0 4 / 0 5 / 0 6 / 0 7 / 0 8 / 0 9 / 0 1. Wiviott SD et al. Am Heart J. 2006;152: Time Post-dose (Day/Hour) 2. Payne CD et al. Am J Cardiol. 2006;98:S8.
18 TRITN-TIMI-38 Primary Endpoint- CV Death, MI, Stroke 15 Bleeding Events = Prasugrel (1.4%) vs. (0.9%), p= % Primary Endpoint (%) HR 0.80 P= HR 0.77 P= Prasugrel % HR 0.81 p= ~ 10% Recurrent Ischemic Events - What is the Reason for Treatment Failure? - Ceiling effect of P2Y 12 blocker? - Selected patients with high platelet reactivity? - ther unblocked pathways? e.g. Thrombin - PAR-1? Days Wiviott SD et al. N Engl J Med. 2007;357:
19 DISPERSE 2 Effect of Ticagrelor on Platelet Aggregation in ACS Storey et al. J Am Coll Cardiol. 2007;50:1852.
20 PLAT study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) -treated or -naive; randomised within 24 hours of index event (N=18,624) If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-pci) 6 12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
21 K-M estimate of time to first primary efficacy event Cumulative incidence (%) Ticagrelor HR 0.84 (95% CI ), p= No. at risk Days after randomisation Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
22 Change the Route of Administration S N H N N Increased affinity C F 3 4Na + P P Cl Cl P H N H N S Cangrelor ATP derivative that is a selective and reversible PGY 12 inhibitor Increased stability Administered intravenously Dose-dependent platelet inhibition At high dose achieves nearly 100% of ADP-induced platelet aggregation Adapted from: Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606.
23 CHAMPIN Trials Study Designs Randomised, Double Blind, Controlled Trials of patients undergoing PCI CHAMPIN PHENIX n=10,942 mitt SA / NSTE-ACS / STEMI P2Y 12 naïve Placebo or clopidogrel before or after PCI Cangrelor bolus then infusion R 600 mg or 300 mg oral 600 mg oral CHAMPIN PCI n=8667 mitt SA / NSTE-ACS / STEMI Placebo or clopidogrel before PCI Cangrelor bolus then infusion 600 mg oral 600 mg oral CHAMPIN PLATFRM n=5301 mitt SA / NSTE-ACS P2Y 12 naïve Placebo or clopidogrel after PCI Cangrelor bolus then infusion 600 mg oral 600 mg oral hours PCI ~30
24 Summary of Clinical Efficacy: Pooled Analysis Death / MI / IDR / ST R (95% CI) p value p for interaction PLATFRM 0.72 (0.53, 0.97) PCI 0.90 (0.72, 1.14) PHENIX 0.79 (0.67, 0.93) Pooled 0.81 (0.71, 0.91) ST PLATFRM 0.31 (0.11, 0.85) PCI 0.73 (0.33, 1.59) PHENIX 0.62 (0.43, 0.90) Pooled 0.59 (0.43, 0.80) Death / MI / IDR PLATFRM 0.72 (0.53, 0.97) PCI 0.90 (0.72, 1.14) PHENIX 0.80 (0.67, 0.95) Pooled 0.81 (0.71, 0.92) Death / QMI / IDR PLATFRM 0.55 (0.33, 0.93) PCI 0.66 (0.42, 1.05) PHENIX 0.76 (0.53, 1.11) Pooled 0.68 (0.52, 0.87) Cangrelor better Comparator better Steg GS, Bhatt DL, Hamm CW et al. Harrington RA. Lancet 2013 at
25 Protease-activated receptor-1 (PAR-1) antagonists Thrombin Prasugrel Ticagrelor Cangrelor Vorapaxar Atopaxar Platelet PAR-4 ADP P2Y 12 PAR-1 TBX A 2 TBXA 2 -R Anionic phospholipid surfaces Vorapaxar / Atopaxar: First-in-class ral PAR-1 inhibitor Metabolism: Primarily hepatic via CYP 3A4 Terminal half-life: ~ hrs Prior trials: No increase in bleeding and fewer MIs ASA GP IIb/IIIa Chackalamannil S, J Med Chem, 2006
26 Trial Design Placebo NSTE Acute Coronary Syndromes 1:1 Randomized Double-blind Key inclusion criteria Within 24 hrs of symptoms ábiomarkers or ECG changes 1 other high-risk feature Vorapaxar Loading: 40 mg Maintenance: 2.5 mg daily Follow-up: 1, 4, 8, 12 months, then every 6 months Standard of care based on practice guidelines Efficacy Endpoints Primary: CV death, MI, stroke, hospitalization for ischemia, urgent revascularization Key Secondary: CV death, MI, stroke Bleeding Endpoints: GUST moderate or severe and clinically significant TIMI bleeding
27 Primary Endpoint CV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization 20% 15% Placebo Vorapaxar 2-year KM rate 19.9% 18.5% Placebo Vorapaxar Event Rate 10% 5% HR (95% CI): 0.92 (0.85, 1.01) P-value= % Months from Randomization No. at risk Placebo Vorapaxar
28 Future Developments New Targets
29 Future Developments Individualised Targets
30 Impact of Pharmacoinvasive Therapy in PCI and ACS Benefit Risk Minimizing infarct size Clinical Stabilization Prevention of early (re)infarction Protection of microcirculation Bleeding Reduction of death+mi in high-risk patients Increased mortality?
31 Ischemic vs Bleeding Risk in ACS Aggressiveness of Antithrombotic Therapy
32 Antiplatelet Therapy Briain Mac Neill Galway University Hospital & National University of Ireland Galway
33 Mechanism of Response Variability Bisulfate P-glycoprotein (MDR1 3435T genotype) 2 Limited absorption capacity with ceiling effect at 600mg loading dose? Hepatic P450 Cytochromes Intestinal Absorption 15% CYP3A4 CYP3A5 CYP2C19 CYP1A2 CYP2B6, 2C19 Multistep Conversion Active Thiol Metabolite P2Y 12 Receptor Esterases 85% lipophilic statins Genetic polymorphisms Genetic polymorphisms Inhibition of Platelet Aggregation (Wide Response Variability) 1 Inactive Carboxylic Acid Metabolite Smoking, proton pump inhibitors ~30% 75mg/day for 30days Post-PCI ~30%-40% 300 mg load Post-PCI ~1.4x 150mg/d vs. 75mg/d for 30days Post-PCI 3 1. Gurbel PA et al. Thromb Res. 2007;120: Taubert et al. Clin Pharmacol. 2006;80: von Beckerth et al. Eur Heart J.2007;28:
34 Potential Relationship Between Bleeding and Mortality Major Bleeding Hypotension Cessation of ASA/ Transfusion Ischemia Stent Thrombosis Inflammation Mortality Bhatt DL et al. In Braunwald: Harrison s nline 2005.
35 Milestones in ACS Management Anti-Thrombin Rx Heparin LMWH Bivalirudin [ Fondaparinux ] Anti-Platelet Rx Ticaglelor Aspirin GP IIb/IIIa Prasugrel Cangrelor Treatment Strategy Conservative Early invasive PRISM-PLUS REPLACE 2 ICTUS ESSENCE PURSUIT TACTICS TIMI-18 CURE ASIS-5 SYNERGY ISAR-REACT 2 ACUITY PCI ~ 5% stents ~85% stents Drug-eluting stents Ischemic risk Bleeding risk
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