Transcript Project Update: ROMICAT II

Rule Out Myocardial Ischemia/Infarction Using
Computer Assisted Tomography
A Multicenter, Randomized, Diagnostic Efficiency Trial
ACRIN CV Committee
October 2010
Udo Hoffmann, MD
Time
Study Design
Patients with Acute Chest Pain at Low to Intermediate Risk for ACS*
Screening
Consent & Randomization
Standard of Care
Discharge
Admission
Cardiac CT**
Admission
Discharge
Patient Management: Diagnostic Testing , Interventions, Diagnosis, Discharge
48-72 hour phone call
Intervention
Triage Decision
Index Hospitalization
48-72 hour phone call
28-day Phone Interview
Follow-Up
1 year Phone Interview
2
*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
Study Endpoints
Length of Hospital Stay
Primary Endpoint
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
Secondary Endpoints
Health care utilization after 28 days and one year
Cost and Cost-Effectiveness
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
Tertiary Endpoints
Study Team
Data Safety and Monitoring Board
(DSMB)
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)
Center for Cost-Effectiveness and Decision
Analysis (DACE)
Kaiser Foundation Hospital – Fontana, CA
(Eric Chou)
Clinical Events Committee (CEC)
Washington University, St. Louis, MI
(Pamela Woodard)
Steering Committee
Tufts Medical Center, Boston, MA
(Scott Weiner)
Scott Gazelle, MD MPH PhD
Stephen D. Wiviott, MD
Jerome Fleg, MD (NIH – PO)
Ruth Kirby (NIH)
Quynh Truong, MD MPH
External Advisory Committee
Eugene Braunwald, MD - Chair
4
Clinical Sites
Principal Investigator
University of Maryland Medical Center,
Baltimore, MD
(Charles White)
Massachusetts General Hospital, Boston, MA
(J. Toby Nagurney)
Simulation of Primary Endpoint LOS
n=176
n=167
Normal LV
Function
No ACS
5 Hours
n=9
Abnormal
LV Function
No ACS
8 Hours
ACS
48 Hours
No ACS
6 Hours
ACS
72 Hours
No ACS
24 Hours
ACS
72 Hours
No ACS
24 Hours
ACS
72 Hours
No ACS
24 Hours
ACS
72 Hours
No ACS
24 Hours
ACS
72 Hours
No ACS
48 Hours
No CAD
n=4
n=103
n=114
Non-Obstructive
CAD
Normal LV
Function
n=99
n=3
n=11
Abnormal
LV Function
n=8
n=2
CT Scan
n=28
n=33
Normal LV
Function
Inconclusive
CT
n=26
n=3
n=5
Abnormal
LV Function
n=2
n=2
n=14
n=33
Normal LV
Function
Stenosis
n=12
n=17
n=19
Abnormal
LV Function
n=2
Distribution of CT results and association with clinical outcomes within the study
population – observed from ROMICAT I and predicted 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
Powers to Detect Estimated Differences in Mean LOS depending on accuracy of
assumptions
ED LOS
Accuracy
Rate
Assumption
6
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%
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
• Overview Data Collection
• Update Enrollment/Patient population
• Update Secondary Data Collection
8
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
ROMICAT II: Actual vs. Expected Enrollment
300
Total Enrollment
265
280
235
250 219
205
220 191 209
175
169 182
190
145
160 136 150
115
130 113
200
100
0
90
80
70
60 64 10087 99
50
40
57 73 80
48
30
20 29 31 44
0 10 19
0
0
Expected
Actual
10
20
Week
10
Start of Enrollment: April 23rd 2010
30
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
Figure 1: Percent of Targeted Enrollment by Month
(Expected Enrollment of 1000 Patients)
100
88.8
% Targeted Enrollment
83.2
77.1
80
70.9
64.8
58.9
60
53.1
47.2
41.3
35.5
40
20
0
11
100
94.4
0
0
MAR10
29.6
23.7 22
17.9 17.9
12
7.9
4 4.68
12.6
1.4
JUN10
SEP10
Enrolled
Expected
DEC10
Month
MAR11
JUN11
SEP11
Enrollment and Screening by Site and Week
Average
Weekly
Enrollment
Screened &
Enrolled Total
# of Subjects % Enrolled
Site
# Enrolled
# Weeks Since
1st Enrollment
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
Ethnicity
Age
Male
Female
Total
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%
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
* This AI/AN subject is also counted as White
13
Activities for Enrollment
• PI/SC visit all sites – Grand Rounds
• Weekly PI/CRC calls
• Website/Newsletter
• Monitoring Visits (MGH, Baystate)
14
Secondary Aims - Data Collection
• Cost Data
• CT Reader Certification
• CT Core Lab Over Reads
• Discharge Diagnosis
• Blood Biomarker Study
15
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
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
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 ?
21
Site
BIDMC
Baystate
MGH
UMM
Wash U
Total
No
3
25.00
5
15.63
14
37.84
30
100.00
16
51.61
68
Yes
9
75.00
27
84.38
23
62.16
0
0.00
15
48.39
74
12
32
37
30
31
142
Total
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
Next Steps/Timeline
• Add sites (October/November 2010)
• Supplement for one year follow-up
• Common CT database with other large studies
(PROMISE, RESCUE, ISCHEMIA)
•
23
DSMB meeting – review of mid enrollment
period - 04/2011
3nd
Thank you!!