1. Kenneth W. Mahaffey Daniel M. Wojdyla Stefan K. James Hugo A. Katus Steen Husted Gabriel Steg Christopher P. Cannon Richard C. Becker Claes Held Nardev Khurmi Debra Montgomery Anders Himmelmann Robert A. Harrington Lars Wallentin for the PLATO investigators Characterization of the Myocardial Infarction Endpoints, Impact of Event Adjudication, and Ticagrelor Effects in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

2. Background Clinical Events Committees (CEC) are common for endpoint adjudication In PLATO, a CEC prospectively defined, systematically identified and adjudicated all events In this report, we explore: – Types of MI events reported by site investigators and CEC – The concordance between the site investigators and CEC – The treatment effects observed

3. Worldwide Country Participation Argentin Australia Austria Belgium Brazil Bulgaria Canada Greece Hong Kong Hungary India Indonesia Israel Italy Portugal Romania Russia Singapore Slovakia Spain Sweden Switzerland South Africa South Korea Taiwan Thailand Turkey Ukraine United Kingdom United States China Czech Republic Denmark Finland France Georgia Germany Malaysia Mexico The Netherlands New Zealand Norway Philippines Poland

4. Event Adjudication Process Suspected events identified from: 1.eCRF data (biomarkers; procedures; etc.) 2.Monitors during site visits 3.Endpoint Office personnel 4.Independent Clinical Adjudication Committee Suspected events identified from: 1.eCRF data (biomarkers; procedures; etc.) 2.Monitors during site visits 3.Endpoint Office personnel 4.Independent Clinical Adjudication Committee 1.Notification via Endpoint Office 2.Source documents from site when necessary 3.Review of all clinical data 1.Notification via Endpoint Office 2.Source documents from site when necessary 3.Review of all clinical data Disagree Agree Phase 2 — Committee review Phase 2 — Committee review DONE Phase 1 — MD Reviews

5. MI Definitions Abbreviated Non-procedural MI: CK-MB > ULN or Troponin > 99 th % AND one of the following: 1.Ischemic Symptoms 2.ECG changes indicative of ischemia 3.New Q-waves PCI: CK-MB≥ 3x ULN with 24 hours from a normal or decreasing level or new Q-waves CABG: CK-MB≥ 10x ULN or CK-MB≥5x ULN and new Q-waves Silent MI: New Q-waves without symptoms

6. Events reported by PI N = 2705 Events reported by PI N = 2705 Cardiac Ischemic Event Form STEMI/NSTEMI* diagnosis N = 1198 Cardiac Ischemic Event Form STEMI/NSTEMI* diagnosis N = 1198 Cardiac Ischemic Event Form ‘Other’ diagnoses** N = 1507 Cardiac Ischemic Event Form ‘Other’ diagnoses** N = 1507 Adjudicated as MI by CEC N = 862 Adjudicated as MI by CEC N = 862 Not adjudicated as MI by CEC N = 336 Not adjudicated as MI by CEC N = 336 Adjudicated as MI by CEC N = 187 Adjudicated as MI by CEC N = 187 Not adjudicated as MI by CEC N = 1320 Not adjudicated as MI by CEC N = 1320 Not reported on Cardiac Ischemic Event form N = 251 Not reported on Cardiac Ischemic Event form N = 251 MI events adjudicated by CEC N = 1300 MI events adjudicated by CEC N = 1300 * Include events with final diagnosis “Other” with text suggesting MI **Include events with final diagnosis “Unstable Angina”, “Stable Angina”, and “Other” with text not suggesting MI

7. Event Level Analysis CEC YesNo Investigator Reported Yes862336 No438**— Comparisons: CEC and Site Investigator ** Includes 187 events reported in CIE form but with final diagnosis not STEMI or NSTEMI and 251 events that were not reported in CIE form. Patient Level Analysis CEC YesNo Investigator Reported Yes762272 No38517205 Using the first event for patient with multiple MI events reported or adjudicated Patient Level Analysis – Overall, 96% agreement – Of those reported by site investigator, 74% agreement – Of those reported by CEC 66% agreement

8. CEC MIsInvestigator Reported MIs

9. Disagreements CEC and Site Investigator Reported by CEC but not Site Investigator Reported by Site Investigator but not CEC

10. Type Total # Events # Events Ticagrelor # Events Clopidogrel HR (95% CI) Tic. vs Clop. Any1107 (100%)5085990.840 (0.746 – 0.945) Non Silent1097 (99%)5045930.842 (0.748 – 0.948) Silent11 (1.0%)560.829 (0.253 – 2.716) Non-Procedure Related 652 (59%)3033490.861 (0.738 – 1.005) Procedure Related304 (27.5%)1441600.895 (0.715 – 1.122) PCI Related223 (20%)991240.794 (0.609 – 1.034) CABG Related82 (7%)45371.212 (0.784 – 1.872) Associated with Stent Thrombosis 172 (15.5%)691030.666 (0.491 – 0.903) Treatment Effect by Type of MI CEC MIs The first event of each type counted. On patient with one silent and on non-silent MI

11. TicagrelorClopidogrel HR (95% CI) (Tic vs. Clo) CEC All MI 5085990.840 (0.746–0.945) STEMI 1171590.731 (0.576–0.928) NSTEMI 3564040.875 (0.758–1.008) Not evaluable 45570.785 (0.531–1.160) Q-wave 42460.909 (0.598–1.381) Non Q-wave 3333750.881 (0.761–1.022) Not evaluable 1602080.763 (0.621–0.938) Site Investigator All MI 4595160.883 (0.779–1.001) STEMI 1561960.791 (0.641–0.976) NSTEMI 2873070.929 (0.791–1.091) Other 29310.931 (0.561–1.545) Treatment Effect: CEC and Site Investigator

12. Non-procedural HR 0.86 (0.74–1.01) PCI related HR 0.79 (0.61–1.03) CABG related HR 1.21 (0.78–1.87) Treatment Effect by MI Type CEC MIs TicagrelorClopidogrel

13. Limitations This was pre-specified analysis from PLATO but the trial was not powered to evaluate treatment effect in MI alone or in subtypes of MI Reporting of MI by site investigators used different format than the CEC adjudication forms so direct event level comparisons were difficult We did not contact sites to determine reasons for why the CEC and the site investigators disagreed on individual MI events

14. Summary In PLATO, ticagrelor significantly reduced MI compared with clopidogrel The CEC procedures identified more MI endpoints than reported by the Site Investigators particularly procedural related MIs A consistent treatment effect was observed across most MI subtypes and for events reported by Site Investigators or CEC Comparison of the CEC and Site Investigator showed: – CEC identified 438 events (215 ticagrelor; 223 clopidogrel) not reported by the investigators – CEC disagreed with Site Investigator reporting for 336 events (184 ticagrelor; 152 clopidogrel) Understanding CEC procedures, MI definitions and treatment effects across MI subtypes is important in interpreting trial results