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

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

PLATO Study PLATO Study: 43 countries 862 sites 18,624 patients 78 Filipino participants 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 Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. 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 Population Only STEMI patients intended for primary PCI included Adapted from James S, et al. Am Heart J. 2009;157:599–605.

180-mg loading dose Ticagrelor (n=9,333) * 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. 90 mg bid + ASA maintenance dose 300-mg loading dose † 75 mg qd + ASA maintenance dose Clopidogrel (n=9,291) Primary efficacy endpoint: Composite of CV death, MI (excluding silent MI), or stroke Primary safety endpoint: Total PLATO major bleeding ‡ N=18,624 Patients with ACS (UA, NSTEMI, or STEMI*) <24hMonth 1Month 3Month 6Month 9Month 12Screening Visit 2Visit 3Visit 4Visit 5Visit 6 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. Randomization All patients were hospitalized with symptom onset <24 hours Patients could be taking clopidogrel at time of randomization PLATO: Study Design

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.

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.

Efficacy Results

PLATO: Baseline Characteristics Characteristic Ticagrelor (n=9,333) Clopidogrel (n=9,291) Median age, years62.0 Age ≥75 years, n (%)1,396 (15.0)1,482 (16.0) Women, n (%)2,655 (28.4)2,633 (28.3) CV risk factors, n (%) Habitual smoker3,360 (36.0)3,318 (35.7) Hypertension6,139 (65.8)6,044 (65.1) Dyslipidemia4,347 (46.6)4,342 (46.7) Diabetes mellitus2,326 (24.9)2,336 (25.1) History, n (%) MI1,900 (20.4)1,924 (20.7) PCI1,272 (13.6)1,220 (13.1) CABG532 (5.7)574 (6.2) ECG at study entry, n (%) ST-segment elevation, persistent3,497 (37.5)3,511 (37.8) ST-depression4,730 (50.7)4,756 (51.2) T-wave inversion2,970 (31.8)2,975 (32.0) Troponin-I positive, n (%)7,965 (85.3)7,999 (86.0) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

Both groups included aspirin. *NNT at one year. PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke) No. at risk Clopidogrel Ticagrelor 9,291 9,333 Months After Randomization 8,521 8,628 8,362 8,460 8,1246,650 6,743 5,096 5,161 4,047 4,1478, Cumulative Incidence (%) 11.7 Clopidogrel 9.8 Ticagrelor ARR=0.6% RRR=12% P=0.045 HR: 0.88 (95% CI, 0.77−1.00) 0–30 Days Clopidogrel Ticagrelor ARR=1.9% RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, 0.77–0.92) 0–12 Months

Months After Randomisation Cumulative Incidence (%) Clopidogrel Ticagrelor Clopidogrel Ticagrelor Months After Randomisation Myocardial Infarction Cardiovascular Death Cumulative Incidence (%) PLATO: Secondary Efficacy Endpoints Rate of stroke for Ticagrelor was not different from clopidogrel (1.3% vs 1.1% ), P= 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, 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) Both groups included aspirin.

PLATO: Invasive and Non-invasive management Patient presents with ACS (n=18,624) Invasive treatment (n=15,991) Intent for invasive treatment (n=13,408) Non-invasive management (n=3033) Intent for non-invasive management (n=5216) Initial investigator intent (as per clinical practice) James S, et al. BMJ 2011;342:d3527. Change in circumstances (n=2183)

CV death, MI or stroke (%) Non-invasive HR, 0.85, 95% CI: (0.73–1.0) Invasive HR, 0.84, 95% CI: (0.75–0.94) Number at risk: Invasive Ticagrelor Clopidogrel Non-invasive Ticagrelor Clopidogrel Days after randomization Primary Outcome: Invasive and Non-Invasive James S, et al. BMJ 2011;342:d3527.

PLATO Efficacy Results Summary In PLATO, Ticagrelor significantly reduced the composite of CV death, MI or stroke vs clopidogrel at 1 year (1.9% ARR, 16% RRR, P<0.001, NNT=54) Ticagrelor significantly reduced CV mortality vs clopidogrel (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, Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

PLATO Efficacy Results Summary The absolute risk reduction with Ticagrelor vs clopidogrel 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, Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

Safety Results

P=0.43 HR: 1.04 (95% CI, 0.95–1.13) PLATO: Primary Safety Endpoint PLATO-defined Total Major Bleeding (%) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Days From First Dose Clopidogrel Ticagrelor 11.2% 11.6% P=NS No. at risk Clopidogrel Ticagrelor 9,186 9,235 7,305 7,246 6,930 6,826 6,6705,209 5,129 3,841 3,783 3,479 3,4336,545 Both groups included aspirin.

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

PLATO Safety Results Summary No increase in overall PLATO-defined major bleeding with ticagrelor vs clopidogrel. Non-CABG major bleeding and major + minor bleeding were more frequent with ticagrelor vs clopidogrel. No increase in overall fatal/life-threatening bleeding with ticagrelor vs clopidogrel. There are more dyspnea-related events associated with Ticagrelor vs clopidogrel, 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.

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.

Clinical Summary of Ticagrelor Based on PLATO Ticagrelor significantly reduces the combined risk of CV death, MI, or stroke vs clopidogrel in patients with ACS. Ticagrelor significantly reduced CV mortality vs clopidogrel. The absolute risk reduction with ticagrelor vs clopidogrel 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.

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

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