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Naotsugu Oyama, MD, PhD, MBA

A Trial of PLAT elet inhibition and Patient O utcomes . Naotsugu Oyama, MD, PhD, MBA. Presentation Objectives. To share the scientific evidence in the PLATO trial, related to the efficacy of ticagrelor , in the treatment of a broad spectrum of ACS patients

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Naotsugu Oyama, MD, PhD, MBA

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  1. A Trial of PLATelet inhibition and Patient Outcomes Naotsugu Oyama, MD, PhD, MBA

  2. Presentation Objectives • To share the scientific evidence in the PLATO trial, related to the efficacy of ticagrelor, in the treatment of a broad spectrum of ACS patients • To review the safety profile of ticagrelor to facilitate effective management of your ACS patients

  3. PLATO Study PLATO study tested the hypothesis that… ticagrelor will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS as compared to clopidogrel and this would be achieved with a clinically acceptable bleeding rate and overall safety profile 18,624 patients 43 countries 862 sites • Philippine Heart Center • Philippine General Hospital • The Medical City • St. Lukes Medical Center • Perpetual Succour Hospital • Cebu Doctors University Hospital • Davao Doctors Hospital PLATO Study: • 43 countries • 862 sites • 18,624 patients • 78 Filipino participants Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  4. PLATO: Study Population Only STEMI patients intended for primary PCI included Adapted from James S, et al. Am Heart J. 2009;157:599–605.

  5. PLATO: Study Design Primary efficacy endpoint: Composite of CV death, MI (excluding silent MI), or stroke Ticagrelor (n=9,333) 180-mg loading dose 90 mg bid + ASA maintenance dose • All patients were hospitalized with symptom onset <24 hours • Patients could be taking clopidogrel at time of randomization N=18,624 Patients with ACS(UA, NSTEMI, or STEMI*) Primary safety endpoint: Total PLATO major bleeding‡ 300-mg loading dose† 75 mg qd + ASA maintenance dose Clopidogrel (n=9,291) Randomization Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Screening <24h Month 1 Month 3 Month 6 Month 9 Month 12 *STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI. †A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel, with an additional 300 mg allowed at the discretion of the investigator. ‡The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major bleeding event. • Initial Treatment approaches: • Medically managed (n=5,216 — 28.0%) • Invasively managed (n=13,408 — 72.0%) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. James S, et al. Am Heart J. 2009;157:599–605.

  6. PLATO Study: Summary • PLATO (N Engl J Med. 2009;361:1045–1057) was a pivotal clinical study, comparing ticagrelor to the current standard of care, clopidogrel. • A total of 18,624 patients with ACS were randomised early after admission to the hospital─within 24 hours of symptom onset and generally prior to angiography. • Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. • James S, et al. Am Heart J. 2009;157:599–605. • Cannon CP, et al. Lancet.2010;375:283–293.

  7. PLATO Study: Summary • The study was designed to reflect clinical practice: • Allowed prior clopidogrel use • Included both intent for invasive management (72%) and intent for medical management (28%) • PLATO allowed up to 600-mg clopidogrel loading dose pre-PCI • PLATO enrolled a broad spectrum of patients with ACS (UA, NSTEMI, or STEMI). • Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. • James S, et al. Am Heart J. 2009;157:599–605. • Cannon CP, et al. Lancet.2010;375:283–293.

  8. Efficacy Results

  9. PLATO: Baseline Characteristics Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  10. PLATO: Primary Efficacy Endpoint(Composite of CV Death, MI, or Stroke) 8,628 8,460 8,219 6,743 5,161 4,147 8,521 8,362 8,124 6,650 5,096 4,047 0–30 Days 0–12 Months 13 12 11.7 Clopidogrel 11 10 Ticagrelor 9.8 9 Clopidogrel 8 5.4 7 Cumulative Incidence (%) 6 ARR=0.6% RRR=12% P=0.045 HR: 0.88 (95% CI, 0.77−1.00) ARR=1.9% RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, 0.77–0.92) 5 4 4.8 3 Ticagrelor 2 1 0 0 2 4 6 8 10 12 No. at risk Months After Randomization 9,333 Ticagrelor Clopidogrel 9,291 Both groups included aspirin. *NNT at one year. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  11. PLATO: Secondary Efficacy Endpoints Cardiovascular Death Myocardial Infarction 6.9 7 7 Clopidogrel 6 6 5.8 Clopidogrel 5.1 Ticagrelor 5 5 4.0 4 4 Cumulative Incidence (%) Cumulative Incidence (%) Ticagrelor 3 3 ARR=1.1% RRR=16% Calculated NNT=91 P=0.005 HR: 0.84 (95% CI, 0.75–0.95) ARR=1.1% RRR=21% NNT=91 P=0.001 HR: 0.79 (95% CI, 0.69–0.91) 2 2 1 1 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months After Randomisation Months After Randomisation Rate of stroke for Ticagrelor was not different from clopidogrel (1.3% vs 1.1% ), P=0.225. Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement.TICAGRELOR: Summary of Product Characteristics, 2010.

  12. PLATO: Invasive and Non-invasive management Patient presents with ACS (n=18,624) Initial investigator intent (as per clinical practice) Intent for invasive treatment(n=13,408) Intent for non-invasive management(n=5216) Change in circumstances (n=2183) Invasive treatment(n=15,991) Non-invasive management(n=3033) James S, et al. BMJ2011;342:d3527.

  13. Primary Outcome: Invasive and Non-Invasive Non-invasiveHR, 0.85, 95% CI: (0.73–1.0) CV death, MI or stroke (%) InvasiveHR, 0.84, 95% CI: (0.75–0.94) Days after randomization Number at risk: InvasiveTicagrelor6732 6236 6134 5972 4889 3735 3048Clopidogrel 6676 6129 6034 5881 4815 3680 2965 Non-invasiveTicagrelor2601 2392 2326 2247 1854 1426 1099Clopidogrel 2615 2392 2328 2243 1835 1416 1109 James S, et al. BMJ2011;342:d3527.

  14. PLATO Efficacy Results Summary • In PLATO, Ticagrelorsignificantly reduced the composite of CV death, MI or stroke vsclopidogrel at 1 year (1.9% ARR, 16% RRR, P<0.001, NNT=54) • Ticagrelorsignificantly reduced CV mortality vsclopidogrel (1.1% ARR, 21% RRR, P=0.001) • Risk of CV death and MI were both significantly reduced • Risk of stroke was not significantly different • Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. • TICAGRELOR: Summary of Product Characteristics, 2010. • Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  15. PLATO Efficacy Results Summary • The absolute risk reduction with Ticagrelorvsclopidogrel starts early and continues to build over the full 1 year treatment period. • In PLATO, for every 91 ACS patients treated with Ticagrelor for 1 year, instead of clopidogrel, 1 CV death was prevented (NNT=91). • The effect of Ticagrelor over clopidogrel appears consistent across many subgroups. • Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. • TICAGRELOR: Summary of Product Characteristics, 2010. • Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  16. Safety Results

  17. PLATO: Primary Safety Endpoint No. at risk 9,235 Ticagrelor 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 Ticagrelor 11.6% P=NS 11.2% Clopidogrel 10 PLATO-defined Total Major Bleeding (%) 5 P=0.43 HR: 1.04 (95% CI, 0.95–1.13) 0 0 60 120 180 240 300 360 Days From First Dose Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  18. PLATO: Bleeding P = 0.008 NS NS K-M Estimated Rate (% Per Year) NS P = 0.03 NS CABG-Major Bleeding Non-CABG-Major Bleeding Major and Minor Bleeding Major Bleeding Life-threatening/Fatal Bleeding Fatal Bleeding All values presented by PLATO criteria. Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

  19. PLATO Safety Results Summary • No increase in overall PLATO-defined major bleeding with ticagrelorvsclopidogrel. • Non-CABG major bleeding and major + minor bleeding were more frequent with ticagrelorvsclopidogrel. • No increase in overall fatal/life-threatening bleeding with ticagrelorvsclopidogrel. • There are more dyspnea-related events associated with Ticagrelorvsclopidogrel, however most events were mild to moderate in intensity and often resolved without a need for treatment. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. TICAGRELOR: Summary of Product Characteristics, 2010.

  20. PLATO Safety Results Summary • Ticagrelor should be used with caution in patients at risk of bradycardic events. • Creatinine levels may increase during treatment with ticagrelor; renal function should be checked after 1 month and thereafter according to routine medical practice. • Please reference the label for all precautions and warnings. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. TICAGRELOR: Summary of Product Characteristics, 2010.

  21. Clinical Summary of Ticagrelor Based on PLATO • Ticagrelor significantly reduces the combined risk of CV death, MI, or stroke vsclopidogrel in patients with ACS. • Ticagrelor significantly reduced CV mortality vsclopidogrel. • The absolute risk reduction with ticagrelorvsclopidogrel starts early and continues to build over the full 1 year of treatment. • Ticagrelor is effective in a broad spectrum of ACS patients. TICAGRELOR: Summary of Product Characteristics, 2010.

  22. Clinical Summary of Ticagrelor Based on PLATO • There is no increase of overall major bleeding with ticagrelorvsclopidogrel: • No increase in life-threatening/fatal bleeding with ticagrelorvsclopidogrel • Major and minor bleeding was more common with ticagrelorvsclopidogrel • Non-CABG-Major bleeding was more common with ticagrelorvsclopidogrel • There are more dyspnea-related events associated with ticagrelorvsclopidogrel, however most events were mild to moderate in intensity and often resolved without a need for treatment. TICAGRELOR: Summary of Product Characteristics, 2010.

  23. Thank You

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