Platelet Inhibition and Beyond Christian W. Hamm Medical Clinic I University Hospital Giessen & Kerckhoff Heart and Thorax Center Bad Nauheim, Germany
Affiliation/Financial Relationship Conflict of Interest Disclosure Christian W. Hamm Company 1. Honoraria for lectures Abbott, AstraZeneca, Berlin Chemie, Boehringer. MSD Ingelheim, BMS, Brahms, Daiichi Sankyo, Essex, GSK, Medtronic, Lilly, SanofiAventis, Iroko, Pfizer, Roche, 2. Honoraria for advisory board activities AstraZeneca, BRAHMS, Boehringer Ingelheim, Medtronic 3. Participation in clinical trials AstraZeneca, MSD, Braun, Boston Scientific, Takeda, GSK, The Med. Comp. 4. Financial shares and options: no
Anti-Platelet Therapy Oral Clopidogrel Prasugrel - Aspirin Activation - - ADP COX Thrombocyte PAR-1 Vorapaxar GP IIb/IIIa - Fibrinogen Thrombocyte IV GP IIb/IIIa Inhibitors Aggregation
P2Y 12 Receptor Blockade ADP P2Y 12 P2Y 1 C C C C Ca 2+ initiation AMPc amplification Savi et al., Thromb Haemost 2000 Savi et al., BBRC 2001
P2Y 12 Inhibitors Clopidogrel Prasugrel Class Thienopyridine Thienopyridine Triazolopyrimidine Binding Irreversible Irreversible Reversible Activation Prodrug, limited by metabolisation Prodrug, not limited by metabolisation Active drug Nonresponders Yes No No Onset of Effect 2 4 h 30 min 30 min Duration of Effect 3 10 days 5 10 days 3 4 days Withdrawal Before Major Surgery 5 days 7 days 5 days Adapted from Hamm CW, et al. Eur Heart J. 2011;32:2999 3054. www.escardio.org/guidelines. 5
Metabolism of P2Y 12 Inhibitors Prasugrel Clopidogrel Mod. NEJM 2009
Binding Sites to P2Y 12 Birkeland et al. BJM, 2010
Antiplatelet Effect Clopidogrel vs. Gurbel, Circulation
PRU PRU Prasugrel vs. : Platelet Inhibition 350 300 250 280.3 277.4 Prasugrel 400 375 350 325 300 275 Prasugrel Baseline PR lower Quartile Baseline PR upper Quartile 200 150 100 P<0.001 90.8 P<0.001 111.4 250 225 200 175 150 125 50 0 34.1 32.1 Tag 0 Tag 15 Tag 30 100 75 50 25 0 Baseline N=44 N=43 Prasugrel N=42 Alexopoulos et al. JACC 2012;60:193-199
PLATO Study Design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300-mg loading dose, then 75-mg qd maintenance 180-mg loading dose, then 90-mg bid maintenance; (additional 90 mg pre-pci) 6 12-Month Exposure Primary End Point: CV Death + MI + Stroke Primary Safety End Point: Total major bleeding PLATO, Platelet Inhibition and Patient Outcomes. James S, et al. Am Heart J. 2009;157:599 605. 10
Cumulative incidence (%) K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel HR 0.84 (95% CI 0.77 0.92), p=0.0003 11.7 9.8 0 60 120 180 240 300 360 No. at risk Days after randomisation 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Cumulative incidence (%) Cumulative incidence (%) Secondary efficacy endpoints over time Myocardial infarction Cardiovascular death 7 Clopidogrel 6.9 7 6 5 5.8 6 5 Clopidogrel 5.1 4 4 4.0 3 3 2 2 1 0 HR 0.84 (95% CI 0.75 0.95), p=0.005 1 0 HR 0.79 (95% CI 0.69 0.91), p=0.001 No. at risk 0 60 120 180 240 300 360 Days after randomisation 0 60 120 180 240 300 360 Days after randomisation 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8,626 7119 5,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8,589 7079 5,441 4,364
Mean Number of Events (CVD/MI/stroke) Clinical Events per Patient Total n=1225 0.12 p= 0.003 0.10 Total n=1057 0.08 0.06 0.04 0.02 0.00 Clopidogrel 0 50 100 150 200 250 300 350 days Kohli P, et al. JACC 2012
# Events Reduction of Clinical Events under in PLATO 2500 2000 1500 n = 2030 740 > 1 event p= 0.01 n = 2290 834 1000 500 1290 1456 1. Event Further events 0 Clopidogrel inkl. CV Death/MI/Stroke/SRI/RI/TIA/ATE (severe) recurrent ischemia (SRI/RI), transient ischemic attack (TIA), arterial thromboses (ATE) Kohli P, et al. JACC 2012
versus Clopidogrel Invasive/ Non-invasive (sub-analysis of PLATO Trial) Cumulative all-cause mortality in patients intended for invasive and noninvasive management. James et al, ESC 2010
Prozent der jeweiligen Population PLATO: Distribution of ASA Dose 70 Region: US Non-US 60 50 40 30 20 10 0 0 50 100 150 200 250 300 350 400 450 500 Median ASS Dose (mg) modifiziert nach FDA Advisory Committee Members Memorandum 29 th June 2010
ICAC-adjudicated primary endpoint by ASA dose category and treatment for US and non-us ASA Acetylsalicylic acid CI Confidence interval E Events HR Hazard ratio N Number of patients Briefing Document for Cardiovascular and Renal Drugs Advisory Committee Meeting, 81
Hazard Ratio, T:C Optimal ASA Dose 3.0 2.5 Primary Endpoint US 325 mg 2.0 1.5 1.0 US 81 mg US Non-US 0.5 0.0 0 50 100 150 200 250 300 350 ASS Dose (mg) Modified after FDA Advisory Committee Members Memorandum 29 th June 2010
Kaplan-Meier Estimated Event Rate (%) KAPLAN-MEIER PLOT OF ICAC-ADJUDICATED PRIMARY ENDPOINT BY TREATMENT GROUP AND ASA DOSE CATEGORY PLATO FULL ANALYSIS SET 16 14 High-dose ASA defined as median daily dose of 300 mg. Low-dose ASA defined as median daily dose of <300 mg. Tica: ASS High 12 10 8 6 4 2 0 ASS Low (<300mg) : ASS High ( 300mg) : Clop: ASS High Clop: ASS Low Tica: ASS Low HR (95% CI), 0.79 (0.71, 0.88) HR (95% CI), 1.45 (1.01, 2.09) 0 60 120 180 240 300 360 Days From Randomization Briefing Document for Cardiovascular and Renal Drugs Advisory Committee Meeting, 83
Platelet aggregates per ml of blood Warner TD et al. Br J Clin Pharmacol. 2011 Feb 15. Mahaffey KW et al. Circulation 2011; Jun 27. Mod. Borgdorff P. et al. Journal of the American College of Cardiology 2006 48:4 (817-823) ASA-Hypothesis: High dose ASA blocks PGI 2 -Production Low dose ASS High dose ASS Dose dependent Platelet aggregation 1 Cox-1 (Thrombozyt) Cox-2 (Endothel) 3000 2000 Thromboxan TxA 2 Prostacyclin PGI 2 1000 Platelet aggregation
Cumulative incidence (%) Endpoint (%) 12 10 8 6 Clopidogrel 15 10 CV Death / MI / Stroke Clopidogrel Prasugrel 4 2 5 0 HR 0.84 (95% CI 0.77 0.92), p=0.0003 0 60 120 180 240 300 360 Days after randomisation 0 0 30 60 90 180 270 360 450 Days PLATO TRITON
Adenosine Metabolism Thrombocyts cardiomyocyts, Exogen ATP ADP AMP Adenosin Xanthine/ Uric Acid Hypoxanthine Erythrocyts, Granulocyts Nucleosidetransport Erythrocyts Endothelial cells
V.L. Serebruany. Eur H J, 2010
Adenosine Effects on Myocardium Headrick et al., BBA 1808: 1413-1428, 2011
Increases Blood Flow AstraZeneca, in File
Cumulative incidence (%) Storey RF, et al. JACC 2012; 59 (13, Suppl.): E482 Time to Pulmonary AE on Treatment* Pulmonary Infection or Sepsis 5 Safety Population**: 18,421 ACS patients 4 3 Clopidogrel 2 1 T vs. C: HR 0.83 (95% CI: 0.71-0.98); P = 0.024 0 Number at risk T C 0 2 4 6 8 10 12 Time after randomisation (months) 9235 7581 7178 6890 5427 4002 3617 9186 7609 7285 7003 5514 4080 3693 * Within 7 days of last intake of study drug ** received at least one dose of study medication
Cumulative incidence (%) Storey RF, et al. JACC 2012; 59 (13, Suppl.): E482 Time to death following pulmonary AE on-treatment* an exploratory post-hoc analysis 2.0 Safety Population**: 18,421 ACS patients 1.5 1.0 Clopidogrel T vs. C: HR 0.46 (95% CI: 0.31-0.70); P = 0.001 Clopidogrel 0.5 0 Number at risk T C 0 2 4 6 8 10 12 Time after randomisation (months) 9235 8852 8751 8554 7067 5438 4382 9186 8786 8701 8514 7023 5387 4320 * Within 7 days of last intake of study drug ** received at least one dose of study medication
Thank you! KERCKHOFF KLINIK
What do the Guidelines Recommend? KERCKHOFF KLINIK
vs. Clopidogrel nach Region und ASS- Dosis in PLATO PLATO: Primärer Endpunkt (CV-Mortalität, MI, Schlaganfall) Region ASS Dosis Clopidogrel (mg) N E N E HR (95% CI) US 300 324 40 352 27 1.62 (0.99, 2.64) >100 <300 22 2 16 2 100 284 19 263 24 0.73 (0.40, 1.33) Non-US 300 140 28 140 23 1.23 (0.71, 2.14) >100 <300 503 62 511 63 1.00 (0.71, 1.42) 100 7449 546 7443 699 0.78 (0.69, 0.87) 0.125 0.5 1.0 2 4 8 N = Anzahl Patienten; E = primäre Endpunkt Ereignisse Better Clopidogrel Better 2014803/12 modifiziert nach Mahaffey KW et al. et al, Circulation 2011; Jun 27. [Epub ahead of print]
Recommendations for Oral Antiplatelet Agents (1) Recommendations Class Level Aspirin should be given to all patients without contraindications at an initial loading dose of 150-300 mg, and at a maintenance dose of 75-100 mg daily long-term regardless of treatment strategy. A P2Y 12 inhibitor should be added to aspirin as soon as possible and maintained over 12 months, unless there are contraindications such as excessive risk of bleeding. A proton pump inhibitor (preferably not omeprazole) in combination with DAPT is recommended in patients (180 with mg a history loading of gastrointestinal dose, haemorrhage 90 mg or peptic twice ulcer, and appropriate for patients with multiple other risk factors (H. elicobacter I daily) A is pylori infection, age 65 years, concurrent use of anticoagulants or steroids). Prolonged or permanent withdrawal of P2Y 12 inhibitors within 12 months after ischaemic I C the index event is discouraged events unless (e.g. clinically elevated indicated. troponins), regardless recommended for all patients at moderate-to-high risk of of initial treatment strategy and including those pre- (180 mg loading dose, 90 mg twice daily) is recommended for all patients moderate-to-high risk of ischaemic events (e.g. elevated troponins), treated regardless of with initial treatment clopidogrel strategy and including (which those pre-treated should with be discontinued I B clopidogrel (which should be discontinued when ticagrelor is commenced). Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended for P2Y 12 -inhibitor-naïve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of lifethreatening bleeding or other contraindications. www.escardio.org/guidelines when ticagrelor is commenced). European Heart Journal (2011) 32:2999 3054 doi:10.1093/eurheartj/ehr236 I I I A A B