Ticagrelor. Platelet Inhibition and Beyond. Christian W. Hamm

Transcription

1 Platelet Inhibition and Beyond Christian W. Hamm Medical Clinic I University Hospital Giessen & Kerckhoff Heart and Thorax Center Bad Nauheim, Germany

2 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

3 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

4 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

5 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:

6 Metabolism of P2Y 12 Inhibitors Prasugrel Clopidogrel Mod. NEJM 2009

7 Binding Sites to P2Y 12 Birkeland et al. BJM, 2010

8 Antiplatelet Effect Clopidogrel vs. Gurbel, Circulation

9 PRU PRU Prasugrel vs. : Platelet Inhibition Prasugrel Prasugrel Baseline PR lower Quartile Baseline PR upper Quartile P< P< Tag 0 Tag 15 Tag Baseline N=44 N=43 Prasugrel N=42 Alexopoulos et al. JACC 2012;60:

10 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:

11 Cumulative incidence (%) K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) Clopidogrel HR 0.84 (95% CI ), p= 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

12 Cumulative incidence (%) Cumulative incidence (%) Secondary efficacy endpoints over time Myocardial infarction Cardiovascular death 7 Clopidogrel Clopidogrel HR 0.84 (95% CI ), p= HR 0.79 (95% CI ), p=0.001 No. at risk Days after randomisation Days after randomisation 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8, ,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, ,441 4,364

13 Mean Number of Events (CVD/MI/stroke) Clinical Events per Patient Total n= p= Total n= Clopidogrel days Kohli P, et al. JACC 2012

14 # Events Reduction of Clinical Events under in PLATO n = > 1 event p= 0.01 n = 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

15 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

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17 Prozent der jeweiligen Population PLATO: Distribution of ASA Dose 70 Region: US Non-US Median ASS Dose (mg) modifiziert nach FDA Advisory Committee Members Memorandum 29 th June 2010

18 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

19 Hazard Ratio, T:C Optimal ASA Dose Primary Endpoint US 325 mg US 81 mg US Non-US ASS Dose (mg) Modified after FDA Advisory Committee Members Memorandum 29 th June 2010

20 Kaplan-Meier Estimated Event Rate (%) KAPLAN-MEIER PLOT OF ICAC-ADJUDICATED PRIMARY ENDPOINT BY TREATMENT GROUP AND ASA DOSE CATEGORY PLATO FULL ANALYSIS SET 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 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) Days From Randomization Briefing Document for Cardiovascular and Renal Drugs Advisory Committee Meeting, 83

21 Platelet aggregates per ml of blood Warner TD et al. Br J Clin Pharmacol Feb 15. Mahaffey KW et al. Circulation 2011; Jun 27. Mod. Borgdorff P. et al. Journal of the American College of Cardiology :4 ( ) 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) Thromboxan TxA 2 Prostacyclin PGI Platelet aggregation

22 Cumulative incidence (%) Endpoint (%) Clopidogrel CV Death / MI / Stroke Clopidogrel Prasugrel HR 0.84 (95% CI ), p= Days after randomisation Days PLATO TRITON

23 Adenosine Metabolism Thrombocyts cardiomyocyts, Exogen ATP ADP AMP Adenosin Xanthine/ Uric Acid Hypoxanthine Erythrocyts, Granulocyts Nucleosidetransport Erythrocyts Endothelial cells

24 V.L. Serebruany. Eur H J, 2010

25 Adenosine Effects on Myocardium Headrick et al., BBA 1808: , 2011

26 Increases Blood Flow AstraZeneca, in File

27 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: ); P = Number at risk T C Time after randomisation (months) * Within 7 days of last intake of study drug ** received at least one dose of study medication

28 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 Clopidogrel T vs. C: HR 0.46 (95% CI: ); P = Clopidogrel Number at risk T C Time after randomisation (months) * Within 7 days of last intake of study drug ** received at least one dose of study medication

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30 Thank you! KERCKHOFF KLINIK

31 What do the Guidelines Recommend? KERCKHOFF KLINIK

32 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 (0.99, 2.64) >100 < (0.40, 1.33) Non-US (0.71, 2.14) >100 < (0.71, 1.42) (0.69, 0.87) N = Anzahl Patienten; E = primäre Endpunkt Ereignisse Better Clopidogrel Better /12 modifiziert nach Mahaffey KW et al. et al, Circulation 2011; Jun 27. [Epub ahead of print]

33 Recommendations for Oral Antiplatelet Agents (1) Recommendations Class Level Aspirin should be given to all patients without contraindications at an initial loading dose of mg, and at a maintenance dose of 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. when ticagrelor is commenced). European Heart Journal (2011) 32: doi: /eurheartj/ehr236 I I I A A B