PROspective Multicenter Imaging Study
for Evaluation of Chest Pain
Udo Hoffmann MD
MGH
ACRIN CardioVascular Committee
October 2nd, 2010
What is PROMISE??
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A pragmatic randomized controlled trial
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Comparing noninvasive testing strategies for
patients with suspected CAD
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10,000 subjects at >200 sites
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Funded by NHLBI
Study Timeline
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Grant Awarded October 2009
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Targeted First Subject Enrolled June 2010
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First Investigator Meeting Summer 2010
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Last Subject Enrolled Summer 2012
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Database Lock Fall 2014
Background and Rationale
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Evaluation of Chest Pain Syndrome is the most
common clinical cardiology problem
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Large and growing costs ($14.1 billion for imaging)
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Differing ACC/AHA guideline recommendations
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Lack of trial data on effect of imaging care
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Calls for studies showing improved health outcomes by
patients / physicians / insurers / policy makers
Imaging for CAD: Wow vs Value?
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Imaging: Improved assessment of cardiac function,
anatomy, and pathology
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Does this translate into improved diagnostic
accuracy or assessment of risk?
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How about improved outcomes? Lower cost?
Critical Questions for NI Testing
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What is the population being tested today?
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Do current tests perform well for
 Diagnosis (yield)?
 Prognosis (events)?
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What about new technology like CTA?
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What is the right way to evaluate NI testing
for CAD diagnosis?
Current Use of Stress Testing in Stable CP:
Low Test Yield and Few Clinical Events
UHC Claims Data:
84,656 pts w/o CAD; M 45-64 yo; W 50-64 yo
CP visit + stress test w/in 30 days
Kaplan Meier plots: 1 year test yield and event rates
Obstructive CAD at Cath: NCDR 2005-2007
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376,430 pts without CAD/MI or prior PCI/CABG
Undergoing diagnostic cath to R/O CAD
59% of patients with positive stress tests had no obstructive CAD
on invasive angio (False positive)
NEJM. 2010 362:886-95
What is the Population Currently Being
Tested for Suspected CAD?
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Very large numbers of pts being tested
 Most are low risk for CAD and for MACE
 Bayesian principles preclude high accuracy
Multiple testing choices
 Exercise ECG, Stress Echo, Stress Nuclear
 All provide functional assessments
Large numbers of pts undergoing cath
 Most do not have obstructive CAD
Current practice: Imperfect NI testing strategies and
clinical diagnostic/prognostic assessments
PROMISE Will Address 3 Fundamental Questions
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Which is the right noninvasive test for a patient with
new CAD symptoms?
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What is the correct role of CTA in the evaluation of
stable chest pain?
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Should new imaging tests be required to prove that they
improve outcomes?
The PROMISE Hypothesis
Question: Is functional or anatomic testing the best initial
testing strategy for diagnosis of stable symptoms
concerning for CAD?
Hypothesis: Information derived from an initial anatomic
strategy (CTA) will drive superior health outcomes
compared to a functional strategy (ischemia testing)
Why a CTA-Superior Hypothesis?
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Anticipate population with low disease prevalence
 15% CAD, 40% Non-Obstructive CAD, 45% Normal
Superior test performance
  false negative test results/untreated CAD
 coronary events (death, MI, unstable angina)
  false positive test results/unnecessary caths
 invasive procedures with complications
Better detection of non-obstructive CAD
Improved preventive treatment and adherence
More confidence in CTA results over functional test results
Longer ‘warranty’ period with fewer repeat tests
 hospitalizations during follow up
Trial Design Philosophy
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General principles of a pragmatic trial
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Effectiveness, not efficacy
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Large, simple study with real world care
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Maximize generalizability
New paradigm for imaging research
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Prospective and randomized
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Clinical endpoints
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Goal: Change care; require demo of clinical superiority
Balancing efficacy and effectiveness
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Site certification and testing quality control - Dx Testing Core
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Optimal medical therapy - 1 and 2 prevention sheets
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Assure ‘Best practices; Usual care’
PROMISE Trial Design
Symptoms suspicious for significant CAD,
Requiring non-emergent noninvasive testing
Randomization
Anatomic strategy
64+ slice CTA
Functional strategy
Pharmacologic
Stress imaging
Exercise ECG or
Exercise Imaging
Clinical results immediately available to care team
Subsequent testing/mgmt per care team + guideline care
Average f/u 30 months
1º = 30 mo death, MI, Complications, UA hosp
2º = MACE components, Costs, QOL
Safety: Radiation exposure
PROMISE Trial – Inclusion Criteria
Stable symptoms suspicious for significant CAD,
Requiring non-emergent noninvasive testing
No prior W/U for this episode of CP
Planned non-invasive evaluation
Men: > 55 years
Women: > 65 years
Men: 45- 54 years
Women: 50- 64 years
+ One risk factor
Randomize
Exclusion Criteria
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Diagnosed or suspected ACS; Unstable
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Known CAD, recent CV eval or known heart disease
 MI, PCI, CABG or CAD ≥50% lesion
 Cath or NI CV test for CAD <12 months
 Other causes of sxs: HCM, heart failure, etc
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Contraindication to radiation exposure, beta
blockers or contrast agents
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Unable to participate in long term follow up
Patient Flow and Follow Up
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Screening, enrollment, randomization
 Blood biomarker and Omics repository
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Randomized test performed w/in 30 days
 Images, ECGs and cath films repository
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Subsequent care per site MD
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Site f/u visit or phone - 60 days
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DCRI F/U mail and phone – q 6 mos for 2-4y
 Assessments of symptoms, interval events, IF
f/u, medications, CV risk Rx, QOL, costs
An Imaging Research Paradigm Shift
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New paradigm for imaging research
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Prospective and randomized
Clinical endpoints
Goal: Change care Requires demo of clinical superiority
Balancing efficacy and effectiveness
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Diagnostic Testing quality control
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Optimal medical therapy - 1 and 2 prevention sheets
Assure ‘Best practices; Usual care’
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Qualification of Testing Sites
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Equipment, protocol and report template review
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Upload 1- 2 test images to ACRIN; reports to DCRI
 Meet 100% completeness and quality
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Test case review
 Functional testing – COCATS II or equivalent
 Cardiac CT – COCATS III or review test series
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Ongoing QC
 100% technical for completeness and quality
 20% MD over-read for interpretation
Primary Endpoint
Time to first event in major cardiovascular events including:
 Death
 Myocardial infarction (MI)
 Unstable angina requiring hospitalization
 Major complications from CV procedures & testing:
 Stroke
 Major bleeding
 Anaphylaxis – requiring circulatory support
 Renal failure - defined as requiring dialysis
Secondary Endpoints
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Death or MI or unstable angina hospitalization
Death or MI
Major complications from CV procedures & testing (stroke,
bleeding, renal failure)
Medical costs, resource use, and incremental cost
effectiveness
Health related quality of life
Secondary Safety Endpoint
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Cumulative radiation exposure
Statistical Analysis Plan
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10,000 subjects
Usual care arm: Estimated rate of death / MI /
USA Hospitalization/ Major procedural
complication over 30 mo: 9.0%
CTA arm: Estimated relative reduction of 20%,
or rate of 7.2%
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Primary analysis is CTA superiority
 Power > 90% even if event rate  to 8%
 Power = 87% if effect magnitude  to 17.5%
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Threshold for superiority at p=0.05 level is an
effect magnitude of 13.5%
Statistical Analysis Plan: Non-Inferiority
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Non-inferiority: The results will be evaluated to test
the hypothesis that CTA is not worse than
standard of care by a clinically meaningful amount
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Additional pre-specified analyses
 Non-inferiority analysis if superiority not met;
Power > 80% for margin 1.10 (HR)
 Precision of risk/benefit estimates
 Test performance characteristics: dx, px
Why a Secondary Non-Inferiority Hypothesis?
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Without prior outcome trials in NI testing, we do not know:
 The true effect of standard of care
 The acceptable non-inferiority margin
 The margin needed to inform clinical care
 The margin needed for reimbursement
A primary hypothesis of non inferiority (margin of 47 vs 53%)
would require >15,000 patients
If one test is NOT found to be clinically superior, then calculating
cost effectiveness is impossible:
 effectiveness /  cost
Clinical choice would be based on cost and safety only…
Costs for cardiovascular procedures are changing rapidly, so
cant calculate an enduring true effect
Substudies
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Radiation exposure
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Incidental findings
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Site vs Core lab test interpretation
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Test diagnostic and prognostic accuracy
 Performance vs Cath and Event prediction
 All modalities
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Blood biomarker repository
 CV Risk- lipids hsCRP, etc
 Myocardial injury- hsTn
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‘Omics repository: RNA, DNA, Proteomics
PROMISE Sites
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212 overall
 164 cardiology, 39 primary care, 6 radiology, 3
ER, 1 anesthesia
Summary
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Large, pragmatic RCT evaluating diagnostic
strategies in stable CAD symptoms
 10,000 patients; >200 US sites; Up to 4 year FU
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Functional (usual care) vs anatomic (CTA) testing
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Subsequent usual dx and tx care up to local MD
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Uses 1 clinical and 2 economic outcomes
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Studies real world effectiveness of testing and
medical care, in multiple specialty settings
Highly experienced investigative team and advisors
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You are a part of it!
https://www.promisetrial.org