ACRIN CV Committee October 2010 Udo Hoffmann, MD

1. Rule Out Myocardial Ischemia/Infarction Using Computer Assisted Tomography A Multicenter, Randomized, Diagnostic Efficiency Trial ACRIN CV Committee October 2010 Udo Hoffmann, MD

2. Study Design Screening Patients with Acute Chest Pain at Low to Intermediate Risk for ACS* Time Consent & Randomization Intervention Standard of Care Cardiac CT** Triage Decision Discharge Admission Admission Discharge Index Hospitalization Patient Management: Diagnostic Testing , Interventions, Diagnosis, Discharge Follow-Up 48-72 hour phone call 48-72 hour phone call 28-day Phone Interview 1 year Phone Interview • *low-intermediate risk for ACS • 1000 adults (≥40-75 yrs) without known CAD • present with ACP (>5min) to the ED at 7 sites • w/o ischemic ECG changes • further risk stratification required • **Coronary morphology +/- LV function 2

3. Study Endpoints Primary Endpoint Length of Hospital Stay Secondary Endpoints Rates of Direct ED Discharge Time to Diagnosis No. of invasive coronary angiograms and revascularizations Rates of MACE after ED discharge **, 28 days, and one year Health care utilization after 28 days and one year Cost and Cost-Effectiveness Tertiary Endpoints Institutional and Caregiver Characteristics associated with primary and secondary outcomes Incremental Value of CTA over a CAC scan Incremental Value of LV function over a CTA Radiation Exposure during index hospitalization and follow-up 3

4. Study Team Data Safety and Monitoring Board (DSMB) Clinical Sites Principal Investigator CLINICAL COORDINATING CENTER (CCC) Udo Hoffmann, MD MPH James Udelson, MD DATA COORDINATING AND STATISTICAL CENTER (DCSC) David Schoenfeld, PhD Beth Israel Deaconess Medical Center, Boston, MA (Thomas Hauser) Baystate Medical Center, Springfield, MA (J. Hector Pope) Kaiser Foundation Hospital – Fontana, CA (Eric Chou) Washington University, St. Louis, MI (Pamela Woodard) Tufts Medical Center, Boston, MA (Scott Weiner) University of Maryland Medical Center, Baltimore, MD (Charles White) Massachusetts General Hospital, Boston, MA (J. Toby Nagurney) Center for Cost-Effectiveness and Decision Analysis (DACE) Scott Gazelle, MD MPH PhD Clinical Events Committee (CEC) Stephen D. Wiviott, MD Steering Committee Jerome Fleg, MD (NIH – PO) Ruth Kirby (NIH) Quynh Truong, MD MPH External Advisory Committee Eugene Braunwald, MD - Chair 4

5. Simulation of Primary Endpoint LOS Distribution of CT results and association with clinical outcomes within the study population – observed from ROMICAT I and predicted LOS 5

6. LOS - Power Evaluation - Standard of Care – observed from ROMICAT-I - CTA – predicted Powers to Detect Estimated Differences in Mean LOS depending on accuracy of assumptions 6

7. DSMB Recommendations • Approve length of stay (LOS) as the primary endpoint • Do not recommend the use of risk factors or risk scores as inclusion criterion • Physician-based assessment of “patient needs further risk stratification” as an inclusion criteria • Guidelines for patient management • Both prospective and retrospective CT imaging (lower dose) • Over-read CT for incidental findings and feedback to clinical sites 7

8. Overview Data Collection Update Enrollment/Patient population Update Secondary Data Collection 8

9. Data Collection Randomization - web-based RS2 system Data Capture - electronic medical record managed by web-based Research Electronic Data Capture (REDCap) database system Main Record: 25 forms with 1271 fields Screening Record: 1 form with 35 fields CEC Adjudication: 5 forms with 108 fields CT Core Lab Over read: 2 forms with 26 fields Data Monitoring - automated weekly report including enrollment, screening, completeness, and accuracy – presented and reviewed by the Steering Committee 9

10. Overall Enrollment Start of Enrollment: April 23rd 2010 10

11. Overall Enrollment - Milestones 11

12. Enrollment and Screening by Site and Week 12

13. Study Population Demographics * This AI/AN subject is also counted as White 13

14. Activities for Enrollment PI/SC visit all sites – Grand Rounds Weekly PI/CRC calls Website/Newsletter Monitoring Visits (MGH, Baystate) 14

15. Secondary Aims - Data Collection Cost Data CT Reader Certification CT Core Lab Over Reads Discharge Diagnosis Blood Biomarker Study 15

16. Cost Data Collection Six of seven sites agreed on providing cost data Pilots are initiated at these sites Initial outpatient costs range from $1,100 – $3,300 per patient 16

17. CT Reader Certification • Why? To ensure uniformity and high quality of CT readers across the 7 clinical sites • How? Five instructor led cases, followed by 50 individual test cases with correlation of coronary CTA with invasive coronary angiography • Individual feedback provided after all readers certified 17

18. CTA Testing Software 18

19. Coronary CTA and Invasive Coronary Angio 19

20. CT Reader Certification Initial Results 20

21. Biomarker Study Methods: Hs –troponin at 0, 2, and 4 hours collection at sites, local storage, central measurement Primary Hypothesis: Hs-troponin followed by cardiac CTA will be more cost effective as compared to competing strategies in ED patients. Secondary Hypotheses: 1) Hs-troponin can accurately predict the presence of ACS much earlier than standard troponin. 2) Hs-troponin in combination with cardiac CT will predict one year MACE better than either strategy alone and better than standard troponin in combination with cardiac CT. 3) Elevated levels of hs-troponin will be associated with abnormal diagnostic test findings in both arms including presence and extent of CAD (CT), impaired regional LV function (CT or echo); myocardial perfusion defects (CT or SPECT), and ECG changes. 21

22. ROMICAT II – Updated Timeline 10/09 start of NIH funding 09/09-04/10 pre-enrollment period 04/10-12/11 enrollment period 01/12-06/12 follow-up and final database 06/12-03/13 data analysis 01/13-09/13 cost and cost effectiveness 22

23. Add sites (October/November 2010) Supplement for one year follow-up Common CT database with other large studies (PROMISE, RESCUE, ISCHEMIA) 3nd DSMB meeting – review of mid enrollment period - 04/2011 Next Steps/Timeline 23

24. Thank you!!