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Kenneth W. Mahaffey Daniel M. Wojdyla Stefan K. James Hugo A. Katus Steen Husted

Characterization of the Myocardial Infarction Endpoints, Impact of Event Adjudication, and Ticagrelor Effects in the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Kenneth W. Mahaffey Daniel M. Wojdyla Stefan K. James Hugo A. Katus Steen Husted Gabriel Steg

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Kenneth W. Mahaffey Daniel M. Wojdyla Stefan K. James Hugo A. Katus Steen Husted

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  1. Characterization of the Myocardial Infarction Endpoints, Impact of Event Adjudication, and Ticagrelor Effects in the Platelet Inhibition and Patient Outcomes (PLATO) Trial 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

  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 China Czech Republic Denmark Finland France Georgia Germany Greece Hong Kong Hungary India Indonesia Israel Italy Malaysia Mexico The Netherlands New Zealand Norway Philippines Poland Portugal Romania Russia Singapore Slovakia Spain Sweden Switzerland South Africa South Korea Taiwan Thailand Turkey Ukraine United Kingdom United States

  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 • Notification via Endpoint Office • Source documents from site when necessary • Review of all clinical data Phase 1 — MD Reviews Agree Disagree Phase 2 — Committee review DONE

  5. MI DefinitionsAbbreviated Non-procedural MI: CK-MB > ULN or Troponin > 99th % AND one of the following: • Ischemic Symptoms • ECG changes indicative of ischemia • 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 Cardiac Ischemic Event Form STEMI/NSTEMI* diagnosis N = 1198 Cardiac Ischemic Event Form ‘Other’ diagnoses** N = 1507 Not adjudicated as MI by CEC N = 336 Not adjudicated as MI by CEC N = 1320 Not reported on Cardiac Ischemic Event form N = 251 Adjudicated as MI by CEC N = 862 Adjudicated as MI by CEC N = 187 * 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 MI events adjudicated by CEC N = 1300

  7. Comparisons: CEC and Site Investigator Patient Level Analysis • Overall, 96% agreement • Of those reported by site investigator, 74% agreement • Of those reported by CEC 66% agreement Using the first event for patient with multiple MI events reported or adjudicated ** 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.

  8. CEC MIs Investigator Reported MIs

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

  10. 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. Treatment Effect: CEC and Site Investigator

  12. Treatment Effect by MI TypeCEC MIs Ticagrelor Clopidogrel 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)

  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

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