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Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient

Invasive. Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient O utcomes trial. Outcomes in patients with a Planned Invasive Strategy. The PLATO trial was funded by AstraZeneca

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Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient

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  1. Invasive Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATelet Inhibition and patient Outcomes trial Outcomes in patients with a Planned Invasive Strategy The PLATO trial was funded by AstraZeneca Dr. Cannon discloses research grants/support from the following companies: Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering Plough Partnership, Novartis and Takeda; and equity in Automedics Medical Systems

  2. PLATO background In STEMI and UA/NSTEMI, current guidelines recommend 12 months of aspirin and clopidogrel Efficacy of clopidogrel is hampered by slow and variable transformation to the active metabolite (e.g. 2C19) modest and variable platelet inhibition  risk stent thrombosis and MI in poor responders Irreversible effect – and increased risk of bleeding if urgent CABG is required PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation; STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction

  3. 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 circulating platelets within ~48 hours

  4. PLATO study design NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624) Clopidogrel-treated or -naive; randomized <24 hours of index event At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy Clopidogrel (n=6,676) 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 (n=6,732) 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12 months treatment Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator

  5. Baseline and index event characteristics

  6. Procedures and timing* * Time between randomization and first procedure

  7. Co-medication

  8. Clopidogrel / Ticagrelor treatment

  9. Primary endpoint: CV death, MI or stroke 15 Clopidogrel 10.65 10 9.02 K-M estimated rate (% per year) Ticagrelor 5 HR: 0.84 (95% CI = 0.75–0.94), p=0.0025 0 0 300 360 60 120 180 240 Days after randomization No. at risk Ticagrelor 6,732 6,236 6,134 5,972 4,889 3,735 3,048 Clopidogrel 6,676 6,129 6,034 5,881 4,815 3,680 2,965 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

  10. Hierarchical testing of major efficacy endpoints *The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. †By univariate Cox model

  11. Cardiovascular death Myocardial infarction 8 8 Clopidogrel 6.6 6 6 5.3 Clopidogrel Cumulative incidence (%) Cumulative incidence (%) Ticagrelor 4.3 4 4 3.4 Ticagrelor 2 2 HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomization Days after randomization No. at risk 6,732 6,439 6,375 6,241 5,141 3,591 3,233 Ticagrelor 6,732 6,268 6,173 6,010 4,924 3,766 3,078 6,676 6,376 6,332 6,209 5,114 3,917 3,164 Clopidogrel 6,676 6,157 6,062 5,917 4,849 3,706 2,987

  12. All-cause mortality 6 Clopidogrel 5.08 4 3.94 Ticagrelor K-M estimated rate (% per year) 2 HR 0.81 (95% CI = 0.68–0.95), p=0.01 0 0 300 360 60 120 180 240 Days after randomization No. at risk Ticagrelor 6,732 6,439 6,375 6,241 5,141 3,951 3,233 Clopidogrel 6,676 6,376 6,331 6,209 5,114 3,917 3,164

  13. Stent thrombosis ¶ Evaluated in patients with any stent during the study Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization* By univariate Cox model

  14. Primary efficacy endpoint by clopidogrel loading dose KM % atMonth 12 Hazard Ratio(95% CI) TotalPatients p value(Interaction) Characteristic Ti. Cl. HR (95% CI) Clopidogrel loading dose (Pre-rand. + Study drug) 0.917 9314 300 mg 9.5 11.2 0.85 (0.74, 0.96) 600 mg 4091 8.0 9.5 0.83 (0.67, 1.03) 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better

  15. Primary safety event: Major bleeding* 15 Clopidogrel 11.6 Ticagrelor 11.5 10 K-M estimated rate (% per year) 5 HR 0.99 (95% CI = 0.89–1.10), p=0.88 0 0 60 120 180 240 300 360 Days after randomization No. at risk Ticagrelor 6,651 5,235 4,947 4,755 3,726 2,741 2,503 Clopidogrel 6,585 5,215 4,984 4,786 3,753 2,754 2,496 * PLATO definitions

  16. 8 Ticagrelor 6.0 6 5.9 Clopidogrel 4 2 HR 1.04 (95% CI = 0.90–1.20), p=0.61 0 0 60 120 180 240 360 300 Days from first IP dose No. at risk Ticagrelor 6,651 5,387 5,113 4,945 3,890 2,866 2,634 Clopidogrel 6,585 5,400 5,180 5,009 3,934 2,898 2,635 Life-threatening or fatal bleeding* K-M estimated rate (% per year) * PLATO definitions

  17. Total major bleeding 13 NS Ticagrelor Clopidogrel 12 11.6 11.5 11 NS 10 8.9 NS 8.8 9 8.0 8.0 8 NS 7 K-M estimated rate (% per year) 6.0 5.9 6 5 4 3 2 NS 1 0.2 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; NS = not significant

  18. Non-CABG and CABG-related major bleeding NS 13 Ticagrelor Clopidogrel 11.6 11.5 12 4.7 11 10 NS 4.1 9 Non-CABG 8.0 8.0 8 7 2.3 K-M estimated rate (% per year) 2.8 6 5 NS 4 3.2 CABG 2.9 3 1.7 2 1.9 1 0 PLATO major bleeding TIMI major bleeding GUSTO severe bleeding* *Preliminary – from eCRF

  19. Bradycardia-related events and other findings *p values calculated using Fisher’s Exact test

  20. Therapeutic considerations Based on 1,000 patients admitted to hospital for ACS and planned for invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in 11 fewer deaths 13 fewer myocardial infarctions 6 fewer cases with stent thrombosis No increase in major bleeding or need for transfusion 6 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnoea Treating 59 patients with ticagrelor instead of with clopidogrel for one year will prevent one event of CV death, MI or stroke Treating 88 will save one life (in one year)

  21. Conclusions Ticagrelor, the reversible, more intense P2Y12 antagonist, is a more effective alternative to clopidogrel for one year in ACS patients managed with an invasive strategy, for the continuous prevention of ischemic events, stent thrombosis and death without an increase in major bleeding

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