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Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATO trial

Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATO trial. August 30, 2009 at 08.00 CET. PLATO background. In NSTE-ACS and STEMI, current guidelines recommend 12 months aspirin and clopidogrel Efficacy of clopidogrel is hampered by

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Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATO trial

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  1. Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATO trial

  2. August 30, 2009 at 08.00 CET

  3. PLATO background • In NSTE-ACS and STEMI, current guidelines recommend 12 months aspirin and clopidogrel • Efficacy of clopidogrel is hampered by • slow and variable transformation to the active metabolite • modest and variable platelet inhibition • increased risk of bleeding • risk of stent thrombosis and MI in poor responders PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation; STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction

  4. H O N N N H H O N F O N N F S O H Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP) • Direct acting • Not a prodrug; does not require metabolic activation • Rapid onset of inhibitory effect on the P2Y12 receptor • Greater inhibition of platelet aggregation than clopidogrel • Reversibly bound • Degree of inhibition reflects plasma concentration • Faster offset of effect than clopidogrel • Functional recovery of all circulating platelets

  5. 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; (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

  6. PLATO – a global trial Argentina Australia Austria Belgium Brazil Bulgaria Canada China Czech Republic Denmark Finland France Georgia Germany Greece Hong Kong Hungary India Indonesia Israel Italy Malaysia Mexico The Netherlands Norway Slovakia Spain Sweden Switzerland South Africa South Korea Taiwan Thailand Turkey Ukraine United Kingdom United States Philippines PolandPortugal Romania Russia Singapore

  7. Baseline and index event characteristics

  8. Study medication

  9. K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 13 12 11.7 Clopidogrel 11 10 9.8 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 4 3 2 HR 0.84 (95% CI 0.77–0.92), p=0.0003 1 0 0 60 120 180 240 300 360 Days after randomisation No. at risk Ticagrelor 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

  10. Primary efficacy endpoint over time (composite of CV death, MI or stroke) 8 8 6.60 Clopidogrel 6 6 Clopidogrel 5.43 5.28 4.77 4 Cumulative incidence (%) Cumulative incidence (%) 4 Ticagrelor Ticagrelor 2 2 HR 0.88 (95% CI 0.77–1.00), p=0.045 HR 0.80 (95% CI 0.70–0.91), p<0.001 0 0 31 90 150 270 330 0 10 20 30 210 Days after randomisation Days after randomisation* No. at risk Ticagrelor 9,333 8,942 8,827 8,763 8,543 7,028 4,822 8,673 8,397 6,480 Clopidogrel 9,291 8,875 8,763 8,688 8,437 6,945 4,751 8,688 8,286 6,379 *Excludes patients with any primary event during the first 30 days

  11. Hierarchical testing major efficacy endpoints The percentages are K-M estimates of the rate of the endpoint at 12 months.

  12. Secondary efficacy endpoints over time Cardiovascular death Myocardial infarction 7 7 6.9 Clopidogrel 6 6 5.8 Clopidogrel 5.1 5 5 Ticagrelor 4.0 4 4 Ticagrelor Cumulative incidence (%) Cumulative incidence (%) 3 3 2 2 1 1 HR 0.84 (95% CI 0.75–0.95), p=0.005 HR 0.79 (95% CI 0.69–0.91), p=0.001 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomisation Days after randomisation No. at risk 9,333 8,294 8,822 8,626 7119 5,482 4,419 Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,291 8,865 8,780 8,589 7079 5,441 4,364 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109

  13. Stent thrombosis (evaluated in patients with any stent during the study) *Time-at-risk is calculated from first stent insertion in the study or date of randomisation

  14. Time to major bleeding – primary safety event 15 Ticagrelor 11.58 11.20 10 Clopidogrel K-M estimated rate (% per year) 5 HR 1.04 (95% CI 0.95–1.13), p=0.434 0 0 60 120 180 240 300 360 Days from first IP dose No. at risk Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479

  15. Total major bleeding 13 NS Ticagrelor Clopidogrel 12 11.6 11.2 11 NS 10 8.9 8.9 NS 9 7.9 7.7 8 NS 7 K-M estimated rate (% per year) 5.8 5.8 6 5 4 3 2 NS 1 0.3 0.3 0 PLATO major bleeding TIMI major bleeding Red cell transfusion* PLATO life-threatening/fatal bleeding Fatal 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

  16. Non-CABG and CABG-related major bleeding 9 Ticagrelor Clopidogrel NS 7.9 8 7.4 7 NS 5.8 6 5.3 p=0.026 5 K-M estimated rate (% per year) 4.5 3.8 4 p=0.025 2.8 3 2.2 2 1 0 Non-CABGPLATO majorbleeding Non-CABGTIMI major bleeding CABGPLATO major bleeding CABG TIMI major bleeding

  17. Holter monitoring & Bradycardia related events

  18. Other findings *p values were calculated using Fischer’s exact test

  19. Other findings – laboratory parameters Values are mean %  SD; *p values were calculated using Fisher’s exact test

  20. Therapeutic considerations • Based on 1,000 patients admitted to hospital for ACS, using ticagrelor instead of clopidogrel for 12 months resulted in • 14 fewer deaths • 11 fewer myocardial infarctions • 6–8 fewer cases with stent thrombosis • No increase in bleedings requiring transfusion • 9 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnoea • Treating 54 patients with ticagrelor instead of with clopidogrel for one year will prevent one event of CV death, MI or stroke

  21. Conclusions • Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with ST- and non-ST-elevation ACS provides • Reduction in myocardial infarction and stent thrombosis • Reduction in cardiovascular and total mortality • No change in the overall risk of major bleeding Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of ischaemic events, stent thrombosis and death in the acute and long-term treatment of patients with ACS

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