ACRIN CV CommitteeOctober 2010

Udo Hoffmann, MD

Rule Out Myocardial Ischemia/Infarction Using Computer Assisted Tomography

A Multicenter, Randomized, Diagnostic Efficiency Trial

Triage Decision

Follow-Up

Index Hospitalization

Screening

Consent & Randomization

InterventionCardiac CT**Standard of Care

Tim

e

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 function2

Secondary Endpoints

Primary EndpointLength 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

External Advisory CommitteeEugene 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 CommitteeJerome 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 SitesPrincipal 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

CT Scan

No CAD

Non-ObstructiveCAD

InconclusiveCT

Stenosis

Normal LV Function

Normal LV Function

Normal LV Function

Normal LV Function

Abnormal LV Function

Abnormal LV Function

Abnormal LV Function

Abnormal LV Function

ACS

ACS

No ACS

No ACS

No ACS

No ACS

No ACS

No ACS

ACS

ACS

ACS

ACS

n=176

n=114

n=33

n=33

n=167

n=103

n=28

n=14

n=9

n=11

n=5

n=19

48 Hours

6 Hours

72 Hours

24 Hours

72 Hours

24 Hours

72 Hours

24 Hours

72 Hours

24 Hours

72 Hours

48 Hours

n=4

n=3

n=2

n=3

n=2

n=17

n=99

n=8

n=26

n=2

n=12

n=2

No ACS 5 Hours

No ACS 8 Hours

CT Scan

No CAD

Non-ObstructiveCAD

InconclusiveCT

Stenosis

Normal LV Function

Normal LV Function

Normal LV Function

Normal LV Function

Abnormal LV Function

Abnormal LV Function

Abnormal LV Function

Abnormal LV Function

ACS

ACS

No ACS

No ACS

No ACS

No ACS

No ACS

No ACS

ACS

ACS

ACS

ACS

n=176

n=114

n=33

n=33

n=167

n=103

n=28

n=14

n=9

n=11

n=5

n=19

48 Hours

6 Hours

72 Hours

24 Hours

72 Hours

24 Hours

72 Hours

24 Hours

72 Hours

24 Hours

72 Hours

48 Hours

n=4

n=3

n=2

n=3

n=2

n=17

n=99

n=8

n=26

n=2

n=12

n=2

No ACS 5 Hours

No ACS 8 Hours

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

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LOS - Power Evaluation

- Standard of Care – observed from ROMICAT-I - CTA – predicted

Sub Group Proportion LOS Mean ± SD

Normal LV function without CAD 48.6% 6 ± 6.12 hours

Normal LV function with non-obstructive CAD 28.8%, 10 ± 8.16 hours

All other conditions 22.6% 40 ± 8.16 hours

ED LOS Accuracy

Rate Assumption

Estimated Mean (± SD) LOS

Estimated Difference in Means

(hours) Power Standard of Care

N=500CTA

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

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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

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• Overview Data Collection

• Update Enrollment/Patient population

• Update Secondary Data Collection

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

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Overall Enrollment

Start of Enrollment: April 23rd 201010

Tot

al E

nrol

lmen

t

0

100

200

300

Week

0 10 20 30

ROMICAT II: Actual vs. Expected Enrollment

ExpectedActual0 10

2030

4050

6070

8090

100

115130

145160

175190

205220

235250

265280

019

2931444857

64

73808799

113

136150

169 182

Overall Enrollment - Milestones

Year 1stQuarter 2nd Quarter 3rd Quarter 4th Quarter Total

2010  - 120 176 176 472

2011 176 184 168 - 528

Total 176 304 344 176 1000

11

% T

arg

eted

En

roll

men

t

0

20

40

60

80

100

Month

MAR10 JUN10 SEP10 DEC10 MAR11 JUN11 SEP11

Figure 1: Percent of Targeted Enrollment by Month(Expected Enrollment of 1000 Patients)

EnrolledExpected0

1.4

4.67.9

12.6

17.922

0

4 8

1217.9

23.729.6

35.541.3

47.253.1

58.964.8

70.9

Enrollment and Screening by Site and Week

Site # Enrolled# Weeks Since 1st Enrollment

Average Weekly

Enrollment

Screened & Enrolled Total# of Subjects % Enrolled

Baystate 32 22 1.5 438 7.3

BIDMC 15 15 1.4 238 6.3

Kaiser 54 22 2.5 200 27.0

MGH 37 22 1.7 435 8.5

Tufts 19 21 0.9 219 8.7

UMM 30 19 1.6 457 6.6

Wash U 32 22 1.5 423 7.6

Overall 219 22 10.0 2410 9.1

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Study Population Demographics

Age Male Female Total

40s 5324.3%

2913.3%

8237.6%

50s 5123.4%

3717.0%

8840.4%

60s 188.3%

219.6%

3917.9%

70s 41.8%

52.3%

94.1%

Total 12659.5%

9242.2%

218100.0%

Ethnicity Frequency Percent

NOT Hispanic or Latino 193 88.1

Hispanic or Latino 16 7.3

Unknown/not specified 10 4.6

Race Frequency Percent

White 145 66.2

Black or African Native 68 31.1

Asian 4 2.4

American Indian or Alaskan Native 1* 0.5

Not reported 2 0.9

Native Hawaiian or Pacific Islander 0 0

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* This AI/AN subject is also counted as White

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Activities for Enrollment

• PI/SC visit all sites – Grand Rounds• Weekly PI/CRC calls• Website/Newsletter• Monitoring Visits (MGH, Baystate)

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Secondary Aims - Data Collection

• Cost Data

• CT Reader Certification

• CT Core Lab Over Reads

• Discharge Diagnosis

• Blood Biomarker Study

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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

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

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CTA Testing Software

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Coronary CTA and Invasive Coronary Angio

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CT Reader Certification Initial Results

CT readers (n) % correct (range) % overcall % undercall

Overall

24 76% (62-84%) 14% 12%

By Site

MGH 3 79% (76-80%) 13% 10%

Wash U 5 78% (72-84%) 11% 11%

Tufts 3 76% (68-80%) 14% 10%

Baystate 4 78% (64-84%) 13% 10%

UMM 3 75% (74-76%) 14% 19%

Kaiser 3 70% (62-76%) 15% 15%

BIDMC 3 72% (64-76%) 14% 14%

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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

BIDMC Baystate MGH UMM Wash U Total

No 325.00

515.63

1437.84

30100.00

1651.61

68

Yes 975.00

2784.38

2362.16

00.00

1548.39

74

Total 12 32 37 30 31 142

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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

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• 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

Thank you!!