acrin cv committee october 2010 udo hoffmann, md rule out myocardial ischemia/infarction using...
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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
5
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
6
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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
8
• 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
9
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
12
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
13
* This AI/AN subject is also counted as White
14
Activities for Enrollment
• PI/SC visit all sites – Grand Rounds• Weekly PI/CRC calls• Website/Newsletter• Monitoring Visits (MGH, Baystate)
15
Secondary Aims - Data Collection
• Cost Data
• CT Reader Certification
• CT Core Lab Over Reads
• Discharge Diagnosis
• Blood Biomarker Study
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
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
CTA Testing Software
18
Coronary CTA and Invasive Coronary Angio
19
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%
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.
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
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
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
Thank you!!
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