1. 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 Invasive

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 P2Y 12 antagonist Ticagrelor is a cyclo-pentyl- triazolo-pyrimidine (CPTP) OH OH O OH N F S N H N N N N F Direct acting – Not a prodrug; does not require metabolic activation – Rapid onset of inhibitory effect on the P2Y 12 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 2-3 days

4. PLATO study design 6–12 months treatment PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator 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 Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding 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) Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

5. PLATO: Overall trial efficacy endpoints All patients* Ticagrelor (n=9,333) Clopidogrel (n=9,291) HR for (95% CI)p value † Primary objective, n (%) CV death + MI + stroke864 (9.8)1,014 (11.7)0.84 (0.77–0.92) <0.001 Secondary objectives, n (%) Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events Myocardial infarction CV death Stroke 901 (10.2) 1,290 (14.6) 504 (5.8) 353 (4.0) 125 (1.5) 1,065 (12.3) 1,456 (16.7) 593 (6.9) 442 (5.1) 106 (1.3) 0.84 (0.77–0.92) 0.88 (0.81–0.95) 0.84 (0.75–0.95) 0.79 (0.69–0.91) 1.17 (0.91–1.52) <0.001 0.005 0.001 0.22 Total death399 (4.5)506 (5.9)0.78 (0.69–0.89) <0.001 The percentages are K-M estimates of the rate of the endpoint at 12 months. Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

6. Invasive Figure 1: Trial profile 18758 patients enrolled 18624 randomly assigned 134 not randomly assigned 5216 non-invasive strategy planned 13408 invasive strategy planned 6676 randomly assigned to clopidogrel (efficacy population) 6732 randomly assigned to ticagrelor (efficacy population) 91 no intake of study drug81 no intake of study drug 6651 safety population6585 safety population Cannon CP, et al. Lancet 2010;375:283–293

7. Invasive Table 1: Baseline characteristics, treatments and interventions Ticagrelor (n=6732) Clopidogrel (n=6676) Age (years; median, IQR)61.0 (53–69)61.0 (53–70) Age ≥75 years843 (12.5%)927 (13.9%) Women1694 (25.2%)1688 (25.3%) Ethnic origin White6138 (91.2%)6056 (90.7%) Black90 (1.3%)101 (1.5%) Oriental409 (6.1%)428 (6.4%) Other94 (1.4%)91 (1.4%) History Myocardial infarction1148 (17.1%)1131 (16.9%) PCI947 (14.1%)885 (13.3%) Coronary artery bypass graft357 (5.3%)380 (5.7%) Transient ischaemic attack145 (2.2%)143 (2.1%) Non-haemorrhagic stroke209 (3.1%)218 (3.3%) Diabetes mellitus1530 (22.7%)1579 (23.7%) Data are number (%), unless otherwise indicated. PCI=percutaneous coronary intervention Cannon CP, et al. Lancet 2010;375:283–293

8. Invasive Table 1: Baseline characteristics, treatments and interventions (cont’d) Ticagrelor (n=6732) Clopidogrel (n=6676) Acute coronary syndrome ST-elevation myocardial infarction3278 (48.8%)3297 (49.5%) Non-ST-elevation myocardial infarction2564 (38.2%)2481 (37.2%) Unstable angina or other873 (13.0%)887 (13.3%) Antithrombotic drug during initial hospital admission Aspirin6584 (97.9%)6544 (98.2%) Unfractionated heparin4440 (66.0%)4404 (66.1%) Low-molecular-weight heparin3185 (47.4%)3133 (47.0%) Fondaparinux124 (1.8%)129 (1.9%) Bivalirudin181 (2.7%)175 (2.6%) Glycoprotein IIb/IIIa inhibitor2368 (35.2%)2362 (35.4%) Clopidogrel (OL before randomisation) <600 mg5646 (83.9%)5638 (84.5%) ≥600 mg1085 (16.1%)1037 (15.5%) Total clopidogrel (OL+IP) before randomisation to 24 h after first dose of IP <600 mg4889 (72.6%)4882 (73.1%) ≥600 mg1842 (27.4%)1792 (26.8%) Data are number (%), unless otherwise indicated. OL=open label. IP=investigational product Cannon CP, et al. Lancet 2010;375:283–293

9. Invasive Table 1: Baseline characteristics, treatments and interventions (cont’d) Ticagrelor (n=6732) Clopidogrel (n=6676) Other drug from randomisation to end of study β blocker5751 (85.5%)5738 (86.1%) Angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker 5851 (87.0%)5786 (86.8%) Cholesterol-lowering (statin)6416 (95.4%)6362 (95.5%) Proton pump inhibitor3659 (54.4%)3578 (53.7%) Invasive procedures during initial hospital admission Coronary angiography6511 (96.7%)6476 (97.0%) Primary PCI* for ST-elevation myocardial infarction 2986 (44.4%)2984 (44.7%) Other PCI † before discharge for first event2173 (32.3%)2155 (32.3%) PCI (total)5159 (76.6%)5139 (77.0%) Coronary bypass surgery before discharge372 (5.5%)410 (6.1%) Data are number (%), unless otherwise indicated. PCI=percutaneous coronary intervention *Any PCI during the first 24 h after randomisation † Any PCI after first 24 h following randomisation in patients with ST-elevation myocardial infarction, or any PCI in patients with non-ST-elevation myocardial infarction Cannon CP, et al. Lancet 2010;375:283–293

10. Invasive Figure 2: Cumulative Kaplan-Meier estimates of time to first primary efficacy endpoint in patients intended to undergo an invasive strategy 0 0 5 10 15 60120180240 300360 Time after randomisation (days) Kaplan-Meier estimated rate (% per year) 8.95 10.65 Number at risk Clopidogrel Ticagrelor 6676 6732 6129 6236 6034 6134 58814815 4889 3680 3735 2965 30485972 Clopidogrel Ticagrelor Cannon CP, et al. Lancet 2010;375:283–293

11. Invasive Table 2: Efficacy of ticagrelor versus clopidogrel Ticagrelor (n=6732) Clopidogrel (n=6676) Hazard ratio (95% CI) p value Primary efficacy endpoint Cardiovascular death+myocardial infarction*+stroke 569 (9.0%)668 (10.7%)0.84 (0.75–0.94)0.0025 Secondary efficacy endpoint All-cause death+myocardial infarction*+stroke595 (9.4%)701 (11.2%)0.84 (0.75–0.94)0.0016 Cardiovascular death+myocardial infarction+ stroke+severe recurrent cardiac ischaemia+ recurrent cardiac ischaemia+transient ischaemic attack+other arterial thrombotic event 830 (13.1%)964 (15.3%)0.85 (0.77–0.93)0.0005 Myocardial infarction*328 (5.3%)406 (6.6%)0.80 (0.69–0.92)0.0023 Cardiovascular death221 (3.4%)269 (4.3%)0.82 (0.68–0.98)0.0250 Stroke75 (1.2%)69 (1.1%)1.08 (0.78–1.50)0.6460 Ischaemic † 59 (0.9%)..1.0000 Haemorrhagic † 12 (0.2%)9 (0.1%)..0.6634 Unknown † 5 (0.07%)1 (0.01%)..0.2187 All-cause death252 (3.9%)311 (5.0%)0.81 (0.68–0.95)0.0103 Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated p values calculated by use of univariate Cox model, unless otherwise indicated *Excludes silent myocardial infarction † Data are number (%), and p values calculated with Fisher’s exact test Cannon CP, et al. Lancet 2010;375:283–293

12. Invasive Figure 3: (A) Cumulative Kaplan-Meier estimates of time to myocardial infarction in patients intended to undergo an invasive strategy 0 0 2 4 8 60120180240 300360 Time after randomisation (days) 5.26 6.59 Number at risk Clopidogrel Ticagrelor 6676 6732 6157 6268 6062 6173 59174849 4924 3706 3766 2987 30786010 Clopidogrel Ticagrelor 6 Kaplan-Meier estimated rate (% per year) Cannon CP, et al. Lancet 2010;375:283–293

13. Invasive Figure 3: (B) Cumulative Kaplan-Meier estimates of time to cardiovascular death in patients intended to undergo an invasive strategy 0 0 2 4 8 60120180240 300360 Time after randomisation (days) 3.44 4.33 Number at risk Clopidogrel Ticagrelor 6676 6732 6376 6439 6332 6375 62095114 5141 3917 3591 3164 32336241 Clopidogrel Ticagrelor 6 Kaplan-Meier estimated rate (% per year) Cannon CP, et al. Lancet 2010;375:283–293

14. Invasive Figure 4: Cumulative Kaplan-Meier estimates of time to all-cause mortality in patients intended to undergo an invasive strategy 0 0 2 4 6 60120180240 300360 Time after randomisation (days) Kaplan-Meier estimated rate (% per year) 3.94 5.02 Number at risk Clopidogrel Ticagrelor 6676 6732 6376 6439 6331 6375 62095114 5141 3917 3951 3164 32336241 Clopidogrel Ticagrelor Cannon CP, et al. Lancet 2010;375:283–293

15. Invasive Table 2: Efficacy of ticagrelor versus clopidogrel (cont’d) Ticagrelor (n=6732) Clopidogrel (n=6676) Hazard ratio (95% CI) p value Stent thrombosis (n)49494928.. Definite62 (1.3%)97 (2.0%)0.64 (0.46–0.88)0.0054 Patients with a drug-eluting stent17 (1.3%)25 (1.8%)0.69 (0.37–1.27)0.2304 Patients with a bare-metal stent45 (1.4%)72 (2.1%)0.62 (0.43–0.90)0.0115 Definite or probable104 (2.2%)142 (3.0%)0.73 (0.57–0.94)0.0142 Patients with a drug-eluting stent32 (2.3%)36 (2.5%)0.90 (0.56–1.45)0.6581 Patients with a bare-metal stent72 (2.2%)106 (3.1%)0.67 (0.50–0.91)0.0092 Total (definite, probable or possible)132 (2.8%)179 (3.8%)0.73 (0.59–0.92)0.0068 Patients with a drug-eluting stent41 (3.1%)53 (3.8%)0.78 (0.52–1.17)0.2349 Patients with a bare-metal stent91 (2.7%)126 (3.8%)0.71 (0.55–0.94)0.0142 Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated p values calculated by use of univariate Cox model, unless otherwise indicated Cannon CP, et al. Lancet 2010;375:283–293

16. Invasive Figure 6: (A) Kaplan-Meier estimates of definite (angiographically documented) stent thrombosis during 30 days in patients given ticagrelor versus clopidogrel Number at risk Clopidogrel (<600 mg)3432337533443333332533223316 0 0 1 2 3 5101520 2530 1.41 1.42 Clopidogrel, <600 mg clopidogrel loading dose Clopidogrel, ≥600 mg clopidogrel loading dose Ticagrelor, <600 mg clopidogrel loading dose Ticagrelor, ≥600 mg clopidogrel loading dose Clopidogrel (≥600 mg)1494147014561448144514441452 Ticagrelor (<600 mg) Ticagrelor (≥600 mg) 0.87 0.96 3382332032943284327932753270 1565154515321524152315211525 Kaplan-Meier estimated failure rate (%) Time since percutaneous coronary intervention (days) Cannon CP, et al. Lancet 2010;375:283–293

17. Invasive Figure 6: (B) Kaplan-Meier estimates of definite (angiographically documented) stent thrombosis during 360 days in patients given ticagrelor versus clopidogrel Number at risk Clopidogrel (<600 mg)3432328332543158262619921498 0 0 1 2 4 60120180240 300360 1.91 2.29 Clopidogrel (≥600 mg)14941437142311478796861392 Ticagrelor (<600 mg) Ticagrelor (≥600 mg) 1.03 1.48 3382325332203128261619561475 15651512149811829227401455 Kaplan-Meier estimated failure rate (%) 3 Time since percutaneous coronary intervention (days) Clopidogrel, <600 mg clopidogrel loading dose Clopidogrel, ≥600 mg clopidogrel loading dose Ticagrelor, <600 mg clopidogrel loading dose Ticagrelor, ≥600 mg clopidogrel loading dose Cannon CP, et al. Lancet 2010;375:283–293

18. Invasive Figure 7: (A) Kaplan-Meier estimates of total stent thrombosis during 30 days in patients given ticagrelor versus clopidogrel Number at risk Clopidogrel (<600 mg)3432337333413330332233193312 0 0 1 2 3 5101520 2530 2.22 2.23 Clopidogrel, <600 mg clopidogrel loading dose Clopidogrel, ≥600 mg clopidogrel loading dose Ticagrelor, <600 mg clopidogrel loading dose Ticagrelor, ≥600 mg clopidogrel loading dose Clopidogrel (≥600 mg)1494146814541446144314421450 Ticagrelor (<600 mg) Ticagrelor (≥600 mg) 1.42 1.82 3382331732903280327532713266 1565154415321523152215201524 Kaplan-Meier estimated failure rate (%) Time since percutaneous coronary intervention (days) Cannon CP, et al. Lancet 2010;375:283–293

19. Invasive Figure 7: (B) Kaplan-Meier estimates of total stent thrombosis during 360 days in patients given ticagrelor versus clopidogrel Number at risk Clopidogrel (<600 mg)3432327832493154262219891496 0 0 1 2 4 60120180240 300360 3.80 3.81 Clopidogrel, <600 mg clopidogrel loading dose Clopidogrel, ≥600 mg clopidogrel loading dose Ticagrelor, <600 mg clopidogrel loading dose Ticagrelor, ≥600 mg clopidogrel loading dose Clopidogrel (≥600 mg)14941435142111448776841389 Ticagrelor (<600 mg) Ticagrelor (≥600 mg) 2.15 3.12 3382324732143122261119511471 15651512149811829227401455 Kaplan-Meier estimated failure rate (%) 3 Time since percutaneous coronary intervention (days) Cannon CP, et al. Lancet 2010;375:283–293

20. Invasive Figure 8: Cumulative Kaplan-Meier estimates of time to total major bleeding in patients intended to undergo an invasive strategy 0 0 5 10 15 60120180240 300360 Time after randomisation (days) Kaplan-Meier estimated rate (% per year) 11.5 11.6 Number at risk Clopidogrel Ticagrelor 6585 6651 5215 5235 4984 4947 47863753 3726 2754 2741 2496 25034755 Clopidogrel Ticagrelor Cannon CP, et al. Lancet 2010;375:283–293

21. Invasive Table 3: Safety of ticagrelor versus clopidogrel in patients intended to undergo an invasive strategy Ticagrelor (n=6651) Clopidogrel (n=6585) Hazard ratio (95% CI) p value* Primary safety endpoint Total major bleeding689 (11.5%)691 (11.6%)0.99 (0.89–1.10)0.8803 Life-threatening or fatal bleeding366 (6.0%)351 (5.9%)1.04 (0.90–1.20)0.6095 Intracranial bleeding15 (0.3%)11 (0.2%)1.36 (0.63–2.97)0.4364 Other major bleeding340 (5.9%)360 (6.2%)0.94 (0.81–1.09)0.4030 Major bleeding events Non-CABG-related272 (4.7%)235 (4.0%)1.16 (0.97–1.38)0.1040 CABG-related † 430 (7.1%)480 (8.0%)0.89 (0.78–1.01)0.0745 Coronary-procedure-related521 (8.5%)554 (9.2%)0.93 (0.83–1.05)0.2573 Non-coronary-procedure-related26 (0.5%)30 (0.6%)0.87 (0.51–1.46)0.5911 Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated CABG=coronary artery bypass graft; TIMI=Thrombolysis In Myocardial Infarction GUSTO=Global Use of Strategies To Open occluded coronary arteries *Calculated by use of univariate Cox model † Percentages are of total population of patients with CABG-related bleeding. 906 (67.8%) of 1335 patients who had a CABG during the study had PLATelet inhibition and patient Outcomes-defined major bleeding, 673 (50.4%) had TIMI-defined major bleeding, and 165 (12.0%) had severe GUSTO-defined bleeding Cannon CP, et al. Lancet 2010;375:283–293

22. Invasive Table 3: Safety of ticagrelor versus clopidogrel in patients intended to undergo an invasive strategy (cont’d) Ticagrelor (n=6651) Clopidogrel (n=6585) Hazard ratio (95% CI) p value* Major or minor bleeding events Total961 (16.0%)883 (14.7%)1.09 (0.99–1.19)0.0700 Non-CABG-related523 (8.9%)416 (7.1%)1.26 (1.11–1.43)0.0004 CABG-related † 464 (7.7%)516 (8.7%)0.89 (0.79–1.01)0.0710 Coronary-procedure-related645 (10.5%)652 (10.7%)0.98 (0.88–1.10)0.7768 Non-coronary-procedure-related42 (0.7%)50 (0.9%)0.84 (0.56–1.26)0.3998 Transfusion of blood products PRBCs or whole blood531 (8.9%)525 (8.7%)1.01 (0.89–1.14)0.9095 Platelets98 (1.6%)114 (1.9%)0.85 (0.65–1.12)0.2506 TIMI-defined cutoff point for major bleeding Total476 (7.9%)474 (7.9%)1.00 (0.88–1.14)1.0000 Non-CABG-related160 (2.8%)130 (2.2%)1.23 (0.98–1.55)0.0814 CABG-related † 322 (5.3%)354 (5.9%)0.90 (0.78–1.05)0.1914 Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated CABG=coronary artery bypass graft; PRBCs=packed red blood cells TIMI=Thrombolysis In Myocardial Infarction GUSTO=Global Use of Strategies To Open occluded coronary arteries *Calculated by use of univariate Cox model † Percentages are of total population of patients with CABG-related bleeding. 906 (67.8%) of 1335 patients who had a CABG during the study had PLATelet inhibition and patient Outcomes-defined major bleeding, 673 (50.4%) had TIMI-defined major bleeding, and 165 (12.0%) had severe GUSTO-defined bleeding Cannon CP, et al. Lancet 2010;375:283–293

23. Invasive Table 3: Safety of ticagrelor versus clopidogrel in patients intended to undergo an invasive strategy (cont’d) Ticagrelor (n=6651) Clopidogrel (n=6585) Hazard ratio (95% CI) p value* TIMI-defined cutoff point for minor bleeding Total219 (3.8%)220 (3.7%)0.99 (0.82–1.19)0.9218 Non-CABG-related119 (2.1%)101 (1.7%)1.18 (0.90–1.53)0.2329 CABG-related † 102 (1.8%)122 (2.1%)0.83 (0.64–1.08)0.1665 TIMI-defined cutoff point for major or minor bleeding Total675 (11.2%)678 (11.3%)0.99 (0.89–1.10)0.8573 Non-CABG-related270 (4.6%)227 (3.9%)1.19 (1.00–1.42)0.0561 CABG-related † 424 (7.0%)476 (8.0%)0.88 (0.78–1.01)0.0630 GUSTO-defined severe bleeding All185 (2.9%)198 (3.2%)0.91 (0.74–1.12)0.3785 Non-CABG-related120 (2.0%)103 (1.8%)1.09 (0.83–1.43)0.5227 CABG-related † 69 (1.1%)97 (1.5%)0.73 (0.53–1.00)0.0520 Cannon CP, et al. Lancet 2010;375:283–293 Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated CABG=coronary artery bypass graft; TIMI=Thrombolysis In Myocardial Infarction GUSTO=Global Use of Strategies To Open occluded coronary arteries *Calculated by use of univariate Cox model † Percentages are of total population of patients with CABG-related bleeding. 906 (67.8%) of 1335 patients who had a CABG during the study had PLATelet inhibition and patient Outcomes-defined major bleeding, 673 (50.4%) had TIMI-defined major bleeding, and 165 (12.0%) had severe GUSTO-defined bleeding

24. Invasive Figure 9: Rates of bleeding according to different definitions CABG=coronary artery bypass graft; PLATO=PLATelet inhibition and patient Outcomes TIMI=Thrombolysis In Myocardial Infarction GUSTO=Global Use of Strategies To Open occluded coronary arteries. Non-CABG-related bleeding only p=0.8803 0 Kaplan-Meier estimated rate (% per year) PLATO-defined major bleeding 1 2 3 4 5 6 7 8 9 10 12 11 13 TIMI-defined major bleeding GUSTO-defined severe bleeding 11.56 11.45 p=1.000 7.93 7.91 p=0.3785 3.24 2.94 TicagrelorClopidogrel TicagrelorClopidogrelTicagrelorClopidogrel CABG-related bleeding only Both non-CABG-related and CABG-related bleeding Cannon CP, et al. Lancet 2010;375:283–293

25. Invasive Ticagrelor ClopidogrelPatientsHazard ratio (95% CI) Characteristic p value (interaction) Overall treatment effect Primary efficacy endpoint Final diagnosis STEMI NSTEMI/UA/other ACS Time from index event to treatment <12 h ≥12 h Sex Male Female 0.20.5 1.02.0 Ticagrelor better Clopidogrel better 13408 6575 6805 7808 5407 10026 3382 668 (10.7%) 293 (9.5%) 372 (11.8%) 350 (9.7%) 306 (11.9%) 469 (10.0%) 199 (12.5%) 569 (9.0%) 250 (8.1%) 316 (9.7%) 295 (8.0%) 264 (10.3%) 399 (8.3%) 170 (10.8%) 0.84 (0.75–0.94) 0.86 (0.72–1.02) 0.83 (0.71–0.96) 0.82 (0.70–0.95) 0.87 (0.74–1.03) 0.84 (0.74–0.96) 0.84 (0.68–1.03) 0.7544 0.5697 0.9429 Age <65 years ≥65 years 8206 5200 318 (8.3%) 349 (14.4%) 260 (6.7%) 308 (12.6%) 0.81 (0.68–0.95) 0.87 (0.75–1.02) 0.4857 Weight <60 kg ≥60 kg 879 12484 61 (14.2%) 600 (10.3%) 48 (12.0%) 515 (8.7%) 0.84 (0.57–1.22) 0.84 (0.75–0.95) 0.9681 Figure 5: Hazard ratios of benefit with ticagrelor versus clopidogrel for primary efficacy endpoint according to patient subgroups, and clopidogrel dosing before randomisation and percutaneous coronary intervention Hazard ratio (95% CI) Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated Vertical dashed line represents the hazard ratio for the overall treatment effect STEMI=ST-elevation myocardial infarction; NSTEMI=non-ST-elevation myocardial infarction UA=unstable angina; ACS=acute coronary syndrome Cannon CP, et al. Lancet 2010;375:283–293

26. Invasive Ticagrelor ClopidogrelPatientsHazard ratio (95% CI) p value (interaction) 0.20.5 1.02.0 Ticagrelor better Clopidogrel better 262 13128 17 (14.4%) 649 (10.6%) 19 (13.9%) 550 (8.9%) 0.96 (0.50–1.84) 0.84 (0.75–0.94) 0.7177 12661 737 598 (10.1%) 70 (20.0%) 511 (8.5%) 58 (17.8%) 0.84 (0.75–0.95) 0.85 (0.60–1.20) 0.9509 8660 4730 422 (10.5%) 244 (10.8%) 349 (8.5%) 220 (9.8%) 0.81 (0.70–0.94) 0.90 (0.75–1.08) 0.3715 Hazard ratio (95% CI) Yes Aspirin during first hospital admission No Previous CABG No Yes No Characteristic Glycoprotein IIb/IIIa during first hospital admission Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated Vertical dashed line represents the hazard ratio for the overall treatment effect CABG=coronary artery bypass graft Figure 5: Hazard ratios of benefit with ticagrelor versus clopidogrel for primary efficacy endpoint according to patient subgroups, and clopidogrel dosing before randomisation and percutaneous coronary intervention (cont’d) Diabetes mellitus No Yes 10289 3109 459 (9.6%) 209 (14.2%) 390 (8.0%) 179 (12.4%) 0.83 (0.73–0.95) 0.88 (0.72–1.07) 0.6440 Previous myocardial infarction No Yes 11119 2279 495 (9.5%) 173 (16.3%) 425 (8.0%) 144 (13.5%) 0.85 (0.75–0.97) 0.81 (0.65–1.01) 0.7235 Cannon CP, et al. Lancet 2010;375:283–293 Troponin I Positive Negative 11329 1713 576 (10.8%) 58 (7.6%) 486 (9.0%) 66 (8.1%) 0.84 (0.75–0.95) 1.04 (0.73–1.48) 0.2548

27. Invasive Ticagrelor ClopidogrelPatientsHazard ratio (95% CI) p value (interaction) 0.20.5 1.02.0 Ticagrelor better Clopidogrel better Hazard ratio (95% CI) Characteristic Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated Vertical dashed line represents the hazard ratio for the overall treatment effect OL=open label; IP=investigational product Figure 5: Hazard ratios of benefit with ticagrelor versus clopidogrel for primary efficacy endpoint according to patient subgroups, and clopidogrel dosing before randomisation and percutaneous coronary intervention (cont’d) Cannon CP, et al. Lancet 2010;375:283–293 11284 2122 9771 3634 585 (11.0%) 83 (8.5%) 514 (11.2%) 154 (9.1%) 498 (9.3%) 71 (7.0%) 431 (9.3%) 138 (7.9%) 0.85 (0.75–0.95) 0.81 (0.59–1.12) 0.83 (0.73–0.95) 0.87 (0.69–1.10) 0.8295 0.7332 <600 mg ≥600 mg <600 mg ≥600 mg OL clopidogrel dose before randomisation Total clopidogrel (OL+IP) before randomisation to 24 h after first dose IP 1173 865 9743 1627 67 (12.3%) 73 (18.0%) 458 (10.1%) 70 (9.1%) 58 (10.3%) 57 (13.7%) 370 (8.0%) 84 (11.1%) 0.86 (0.60–1.22) 0.75 (0.53–1.07) 0.80 (0.70–0.91) 1.21 (0.86–1.66) 0.1095 Geographic region Asia and Australia Central and South America Europe, Middle East, Africa North America

28. Invasive Dyspnea All patients Ticagrelor (n=6,732) Clopidogrel (n=6,676)p value * Dyspnea, % Any dyspnea event Requiring discontinuation of study- treatment 15.4 0.9 10.4 0.3 <0.0001 *p values calculated using Fisher’s Exact test Cannon CP, et al. Lancet 2010;375:283–293

29. Invasive 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 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) Cannon CP, et al. Lancet 2010;375:283–293, presented TCT 2009

30. Invasive Conclusions Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned. These results also support the idea that increased inhibition of platelet P2Y12 receptors can achieve substantial reduction in the rate of mortality when not associated with an increase in the rate of major bleeding. Cannon CP, et al. Lancet 2010;375:283–293