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

2. Triage Decision Follow-Up Index Hospitalization Screening Consent & Randomization Intervention Cardiac CT**Standard of Care Time AdmissionDischarge Patients with Acute Chest Pain at Low to Intermediate Risk for ACS* Patient Management: Diagnostic Testing, Interventions, Diagnosis, Discharge 48-72 hour phone call DischargeAdmission 28-day Phone Interview 1 year Phone Interview 48-72 hour phone call Study Design *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. Secondary Endpoints Primary Endpoint Length of Hospital Stay Tertiary Endpoints Cost and Cost-Effectiveness Incremental Value of CTA over a CAC scan 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 Institutional and Caregiver Characteristics associated with primary and secondary outcomes Incremental Value of LV function over a CTA Radiation Exposure during index hospitalization and follow-up Study Endpoints 3

4. External Advisory Committee Eugene Braunwald, MD - Chair Center for Cost-Effectiveness and Decision Analysis (DACE) Scott Gazelle, MD MPH PhD Data Safety and Monitoring Board (DSMB) CLINICAL COORDINATING CENTER (CCC) Udo Hoffmann, MD MPH James Udelson, MD Steering Committee Jerome Fleg, MD (NIH – PO) Ruth Kirby (NIH) Quynh Truong, MD MPH DATA COORDINATING AND STATISTICAL CENTER (DCSC) David Schoenfeld, PhD Clinical Events Committee (CEC) Stephen D. Wiviott, MD Clinical Sites Principal Investigator 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) Study Team 4

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

6. LOS - Power Evaluation - Standard of Care – observed from ROMICAT-I - CTA – predicted Sub GroupProportionLOS Mean ± SD Normal LV function without CAD48.6%6 ± 6.12 hours Normal LV function with non-obstructive CAD28.8%,10 ± 8.16 hours All other conditions22.6%40 ± 8.16 hours ED LOS Accuracy Rate Assumption Estimated Mean (± SD) LOS Estimated Difference in Means (hours)Power Standard of Care N=500 CTA N=500 50%40.5 (± 43.2)37.6 (± 50.0)-2.9 17% 60%40.5 (± 43.2)33.7 (± 47.4)-6.8 66% 65%40.5 (± 43.2)31.8 (± 46.8)-8.7 86% 70%40.5 (± 43.2)29.8 (± 45.5)-10.7 97% 80%40.5 (± 43.2)25.8 (± 42.0)-14.7>99% 90%40.5 (± 43.2)22.0 (± 38.1)-18.5 >99% 100%40.5 (± 43.2)18.4 (± 33.8)-22.1 >99% Powers to Detect Estimated Differences in Mean LOS depending on accuracy of assumptions 6

7. 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

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

9. Data Collection Randomization - web-based RS2 system Data Capture - electronic medical record managed by web-based Research Electronic Data Capture (REDCap) database system 1.Main Record: 25 forms with 1271 fields 2.Screening Record: 1 form with 35 fields 3.CEC Adjudication: 5 forms with 108 fields 4.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 23 rd 2010 10

11. Overall Enrollment - Milestones Year1 st Quarter2 nd Quarter3 rd Quarter4 th QuarterTotal 2010 - 120176 472 2011176184168-528 Total176 304 344 1761000 11

12. Enrollment and Screening by Site and Week Site# Enrolled # Weeks Since 1st Enrollment Average Weekly Enrollment Screened & Enrolled Total # of Subjects% Enrolled Baystate32221.54387.3 BIDMC15 1.42386.3 Kaiser54222.520027.0 MGH37221.74358.5 Tufts19210.92198.7 UMM30191.64576.6 Wash U32221.54237.6 Overall2192210.024109.1 12

13. Study Population Demographics Age MaleFemaleTotal 40s 53 24.3% 29 13.3% 82 37.6% 50s 51 23.4% 37 17.0% 88 40.4% 60s 18 8.3% 21 9.6% 39 17.9% 70s 4 1.8% 5 2.3% 9 4.1% Total 126 59.5% 92 42.2% 218 100.0% Ethnicity FrequencyPercent NOT Hispanic or Latino19388.1 Hispanic or Latino167.3 Unknown/not specified104.6 Race FrequencyPercent White14566.2 Black or African Native6831.1 Asian42.4 American Indian or Alaskan Native 1*0.5 Not reported20.9 Native Hawaiian or Pacific Islander00 13 * This AI/AN subject is also counted as White

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

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

16. 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

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 CT readers (n)% correct (range)% overcall% undercall Overall 2476% (62-84%)14%12% By Site MGH379% (76-80%)13%10% Wash U578% (72-84%)11% Tufts376% (68-80%)14%10% Baystate478% (64-84%)13%10% UMM375% (74-76%)14%19% Kaiser370% (62-76%)15% BIDMC372% (64-76%)14% 20

21. 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. Patient consented ?Site BIDMCBaystateMGHUMMWash UTotal No3 25.00 5 15.63 14 37.84 30 100.00 16 51.61 68 Yes9 75.00 27 84.38 23 62.16 0 0.00 15 48.39 74 Total1232373031142

22. 22 ROMICAT II – Updated Timeline 10/09start 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

23. 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

24. Thank you!!