C. Michael Gibson, M.S., M.D.

1. C. Michael Gibson, M.S., M.D. State of the Art in the Adjudication of Cardiovascular Endpoints Harvard Medical School

2. Goal of Universal Definitions • In the conduct of non-inferiority trials, definitions with increased specificity minimize bias towards showing non-inferiority • The increased specificity of the new definitions requires careful design of eCRFs and careful collection of source documents so sufficient information is available to permit adjudication • If source documents are not collected to adjudicate events, “true positive” events may not be adjudicated as such leading to lower event rates, and reduced power to demonstrate non-inferiority (or superiority as well)

3. FDA Standardized Definitions for CV Outcomes Trials • July 2009 Initial Draft definitions issued • Nov 2009 – Feb 2010 variety of working group meetings to discuss definitions • March 2010 Revised draft definitions issued • Targeted completion of draft definitions late 2Q2010 - definitions will be posted for 30 days for public comment • Ultimate goal is a white paper (late 2010?) • CRF standardization possibly to complete mid-2011 • Stakeholders: FDA, CDER, CPI, ACC, ACROs, CROs, CDISC, CTTI, HL7, NHLBI, PhRMA, pharmaceutical industry • Working group representatives: Cleveland Clinic, Columbia, Duke Cardiovascular Research Institute, HCRI, TIMI, Brigham & Women’s, St. Louis University, PERFUSE/Beth Israel, FDA neurology working group

4. Where Can You Find The New Definitions? Dr. Gibson is Founder and Editor-in-Chief of WikiDoc, the world’s largest on line medical encyclopedia (www.wikidoc.org) Non-profit foundation, no pharma or device support Over 71,000 chapters, >1,800 contributors, about 500,000 revisions • http://en.wikidoc.org/index.php/Clinical_event_adjudication

5. Evolving Challenges in Adjudication • Event driven trials require the occurrence of a pre-specified number of adjudicated events • There is therefore a need for real time adjudication of events

6. Evolution of the CEC Process

7. Myocardial Infarction Issues: • Type of MI important: CEC adjudicates type of MI (spontaneous, demand, CABG, periprocedural) • Size of MI important: Cardiologist often unconcerned with higher rates of small MIs • Timing of MI important: Is benefit early in treatment course after loading dose, or late in course during maintenance dose • Multiple MIs important: Does the drug reduce second and third events during maintenance dose phase

8. Myocardial Infarction Issues: Silent MI Questions • What is incidence of Silent MI? • What is prognosis of Silent MI vs. Symptomatic MI? • Can incidence of Silent MI be modified by therapy? • Would it be scientifically important/interesting • Can inclusion of silent MIs in the endpoint shorten the duration of a trial?

9. Criteria for Silent MI or Prior MI (with or without Symptoms) No evidence of acute MI AND any one of the following criteria: • Appearance of new persistent pathological Q waves. A confirmatory ECG is recommended if there have been no clinical symptoms or history of myocardial infarction. • Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause • Pathological findings of a healed or healing myocardial infarction

10. ECG Regression of MI • Q waves regress within 2 yrs in 10% anterior wall MI and 25% of inferior MI (Arch Int Med 1960, 106, 628-33) • Overall, 20% of pts that survive MI have a normal ECG 4 yrs after the index event (Lancet 1967, 1, 1194-7)

11. Unrecognized Myocardial Infarction

12. Silent MI Incidence Depends on Follow-Up Sheifer et al: Ann Int Med 2001; 135:801-811

13. Silent MI in FIELD Study9597 Pts with DM Overall Incidence 4.1% Clinical MI 2.7% Silent MI 36.8% were silent Burgess DC. EHJ. 2009

14. BARI 2D 2368 pts with angiographically proven CAD 279 - 1st MIs (12.4% at 5 yrs) 243 - Non-fatal 1st MIs Chaitman BR. Circulation. 2009;120:2529-2540

15. Treatment Effect on MI Type Burgess DC. EHJ. 2009

16. Impact Of Including Silent MI As Part Of The The MI Endpoint Assume An Event Driven Trial With Approximately 1000 Events: Shortening a trial’s timeline by 7 to 11 months could significantly reduce costs

17. Operational Issues in Assessing Silent MI • Timepoints • Most logical times to collect the ECGs are at baseline and at the end of the study. • Unless the anticipated rate of silent MI is known, it may not help that much in speeding up trial as the ECG adjudication happens after the last visit, and you would not know until the end of the trial if you are on target with respect to the event rate. • An assessment of silent MIs halfway through the trial may help in estimating the rate of silent MIs at the end of the trial to assure you are on target.

18. Hospitalization for Unstable Angina: In or Out? • Under discussion: Definition of hospitalization, escalation of pharmacotherapy • Example: a patient is hospitalized with cardiac symptoms, no biomarkers are measured, no procedures undertaken, but treated medically and released in < 24 hrs? Is this hosp for UA? Under the current definition - NO One of the more debated events Definition continues to evolve 18

19. Stroke Definitions

20. Impact of New Definitions on Clinical Trials • Specificity: Rigorous definitions and CEC process will increase specificity in classification of events, & minimize bias in determining non-inferiority • Sensitivity: The following will increase the number of events • Sensitive MI definitions so that unstable angina cases may be reclassified as MI • Potential to include “silent MIs” in endpoints • Reclassification of prior TIAs as strokes if there is an imaging abnormality • Net Impact: Ascertainment of more events will lead to realistic sample sizes and feasible timelines