1. PROspective Multicenter Imaging Study for Evaluation of Chest Pain Udo Hoffmann MD MGH ACRIN CardioVascular Committee October 2nd, 2010

2. What is PROMISE?? n n A pragmatic randomized controlled trial n n Comparing noninvasive testing strategies for patients with suspected CAD n n 10,000 subjects at >200 sites n n Funded by NHLBI

3. Study Timeline n Grant Awarded October 2009 n Targeted First Subject Enrolled June 2010 n First Investigator Meeting Summer 2010 n Last Subject Enrolled Summer 2012 n Database Lock Fall 2014

4. Background and Rationale n Evaluation of Chest Pain Syndrome is the most common clinical cardiology problem n Large and growing costs ($14.1 billion for imaging) n Differing ACC/AHA guideline recommendations n Lack of trial data on effect of imaging care n Calls for studies showing improved health outcomes by patients / physicians / insurers / policy makers

5. Imaging for CAD: Wow vs Value? n Imaging: Improved assessment of cardiac function, anatomy, and pathology n Does this translate into improved diagnostic accuracy or assessment of risk? n How about improved outcomes? Lower cost?

6. Critical Questions for NI Testing n What is the population being tested today? n n Do current tests perform well for l l Diagnosis (yield)? l l Prognosis (events)? n What about new technology like CTA? n What is the right way to evaluate NI testing for CAD diagnosis?

7. 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 Kaplan Meier plots: 1 year test yield and event rates

8. Obstructive CAD at Cath: NCDR 2005-2007 n 376,430 pts without CAD/MI or prior PCI/CABG n Undergoing diagnostic cath to R/O CAD n 59% of patients with positive stress tests had no obstructive CAD on invasive angio (False positive ) NEJM. 2010 362:886-95

9. What is the Population Currently Being Tested for Suspected CAD? n Very large numbers of pts being tested l Most are low risk for CAD and for MACE l Bayesian principles preclude high accuracy n Multiple testing choices l Exercise ECG, Stress Echo, Stress Nuclear l All provide functional assessments n Large numbers of pts undergoing cath l Most do not have obstructive CAD n Current practice: Imperfect NI testing strategies and clinical diagnostic/prognostic assessments

10. PROMISE Will Address 3 Fundamental Questions n Which is the right noninvasive test for a patient with new CAD symptoms? n What is the correct role of CTA in the evaluation of stable chest pain? n Should new imaging tests be required to prove that they improve outcomes?

11. 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) The PROMISE Hypothesis

12. n Anticipate population with low disease prevalence l 15% CAD, 40% Non-Obstructive CAD, 45% Normal n Superior test performance l  false negative test results/untreated CAD  coronary events (death, MI, unstable angina) l  false positive test results/unnecessary caths  invasive procedures with complications n Better detection of non-obstructive CAD Improved preventive treatment and adherence n More confidence in CTA results over functional test results Longer ‘warranty’ period with fewer repeat tests  hospitalizations during follow up Why a CTA-Superior Hypothesis?

13. Trial Design Philosophy n General principles of a pragmatic trial l Effectiveness, not efficacy l Large, simple study with real world care l Maximize generalizability n New paradigm for imaging research l Prospective and randomized l Clinical endpoints l Goal: Change care; require demo of clinical superiority n Balancing efficacy and effectiveness l Site certification and testing quality control - Dx Testing Core l Optimal medical therapy - 1  and 2  prevention sheets l Assure ‘Best practices; Usual care’

14. Symptoms suspicious for significant CAD, Requiring non-emergent noninvasive testing Randomization 1º = 30 mo death, MI, Complications, UA hosp 2º = MACE components, Costs, QOL Safety: Radiation exposure 64+ slice CTA Anatomic strategyFunctional strategy Exercise ECG or Exercise Imaging Pharmacologic Stress imaging Clinical results immediately available to care team Subsequent testing/mgmt per care team + guideline care Average f/u 30 months PROMISE Trial Design

15. Randomize Stable symptoms suspicious for significant CAD, Requiring non-emergent noninvasive testing No prior W/U for this episode of CP Planned non-invasive evaluation No prior W/U for this episode of CP Planned non-invasive evaluation Men: 45- 54 years Women: 50- 64 years + One risk factor Men: 45- 54 years Women: 50- 64 years + One risk factor Men: > 55 years Women: > 65 years Men: > 55 years Women: > 65 years PROMISE Trial – Inclusion Criteria

16. Exclusion Criteria n n Diagnosed or suspected ACS; Unstable n n Known CAD, recent CV eval or known heart disease l l MI, PCI, CABG or CAD ≥50% lesion l l Cath or NI CV test for CAD <12 months l l Other causes of sxs: HCM, heart failure, etc n n Contraindication to radiation exposure, beta blockers or contrast agents n n Unable to participate in long term follow up

17. Patient Flow and Follow Up n n Screening, enrollment, randomization l l Blood biomarker and Omics repository n n Randomized test performed w/in 30 days l l Images, ECGs and cath films repository n n Subsequent care per site MD n n Site f/u visit or phone - 60 days n n DCRI F/U mail and phone – q 6 mos for 2-4y l l Assessments of symptoms, interval events, IF f/u, medications, CV risk Rx, QOL, costs

18. An Imaging Research Paradigm Shift n n New paradigm for imaging research l l Prospective and randomized l l Clinical endpoints l l Goal: Change care  Requires demo of clinical superiority n n Balancing efficacy and effectiveness l l Diagnostic Testing quality control l l Optimal medical therapy - 1  and 2  prevention sheets l l Assure ‘Best practices; Usual care’

19. n Equipment, protocol and report template review n Upload 1- 2 test images to ACRIN; reports to DCRI l Meet 100% completeness and quality n Test case review l Functional testing – COCATS II or equivalent l Cardiac CT – COCATS III or review test series n Ongoing QC l 100% technical for completeness and quality l 20% MD over-read for interpretation Qualification of Testing Sites

20. Time to first event in major cardiovascular events including: n Death n Myocardial infarction (MI) n Unstable angina requiring hospitalization n Major complications from CV procedures & testing: l Stroke l Major bleeding l Anaphylaxis – requiring circulatory support l Renal failure - defined as requiring dialysis Primary Endpoint

21. n Death or MI or unstable angina hospitalization n Death or MI n Major complications from CV procedures & testing (stroke, bleeding, renal failure) n Medical costs, resource use, and incremental cost effectiveness n Health related quality of life Secondary Safety Endpoint n Cumulative radiation exposure Secondary Endpoints

22. Statistical Analysis Plan n n 10,000 subjects n Usual care arm: Estimated rate of death / MI / USA Hospitalization/ Major procedural complication over 30 mo: 9.0% n CTA arm: Estimated relative reduction of 20%, or rate of 7.2% n n Primary analysis is CTA superiority l l Power > 90% even if event rate  to 8% l l Power = 87% if effect magnitude  to 17.5% n n Threshold for superiority at p=0.05 level is an effect magnitude of 13.5%

23. Statistical Analysis Plan: Non-Inferiority n 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 n Additional pre-specified analyses l Non-inferiority analysis if superiority not met; Power > 80% for margin 1.10 (HR) l Precision of risk/benefit estimates l Test performance characteristics: dx, px

24. n Without prior outcome trials in NI testing, we do not know: l The true effect of standard of care l The acceptable non-inferiority margin l The margin needed to inform clinical care l The margin needed for reimbursement n A primary hypothesis of non inferiority (margin of 47 vs 53%) would require >15,000 patients n If one test is NOT found to be clinically superior, then calculating cost effectiveness is impossible:  effectiveness /  cost n Clinical choice would be based on cost and safety only… n Costs for cardiovascular procedures are changing rapidly, so cant calculate an enduring true effect Why a Secondary Non-Inferiority Hypothesis?

25. Substudies n Radiation exposure n Incidental findings n Site vs Core lab test interpretation n Test diagnostic and prognostic accuracy l Performance vs Cath and Event prediction l All modalities n Blood biomarker repository l CV Risk- lipids hsCRP, etc l Myocardial injury- hsTn n ‘Omics repository: RNA, DNA, Proteomics

26. PROMISE Sites n n 212 overall l l 164 cardiology, 39 primary care, 6 radiology, 3 ER, 1 anesthesia

27. Summary n Large, pragmatic RCT evaluating diagnostic strategies in stable CAD symptoms l 10,000 patients; >200 US sites; Up to 4 year FU n Functional (usual care) vs anatomic (CTA) testing n Subsequent usual dx and tx care up to local MD n Uses 1  clinical and 2  economic outcomes n Studies real world effectiveness of testing and medical care, in multiple specialty settings n Highly experienced investigative team and advisors n You are a part of it!

28. https://www.promisetrial.org