PRO spective M ulticenter I maging S tudy for E valuation of Chest Pain Udo Hoffmann MD MGH

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

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

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

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

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

6. Critical Questions for NI Testing What is the population being tested today? Do current tests perform well for Diagnosis (yield)? Prognosis (events)? What about new technology like CTA? 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

8. Obstructive CAD at Cath: NCDR 2005-2007 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

9. What is the Population Currently Being Tested for Suspected CAD? 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 strategiesand clinical diagnostic/prognostic assessments

10. PROMISE Will Address 3 Fundamental Questions Which is the right noninvasive test for a patient with new CAD symptoms? What is the correct role of CTA in the evaluation of stable chest pain? 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. 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 Why a CTA-Superior Hypothesis?

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

14. PROMISE Trial Design Symptoms suspicious for significant CAD, Requiring non-emergent noninvasive testing Randomization Anatomic strategy Functional strategy Pharmacologic Stress imaging Exercise ECG or Exercise Imaging 64+ slice CTA 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

15. 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: 45- 54 years Women: 50- 64 years + One risk factor Men: > 55 years Women: > 65 years Randomize

16. Exclusion Criteria • Diagnosed or suspected ACS; Unstable • 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 • Contraindication to radiation exposure, beta blockers or contrast agents • Unable to participate in long term follow up

17. Patient Flow and Follow Up • Screening, enrollment, randomization • Blood biomarker and Omics repository • Randomized test performed w/in 30 days • Images, ECGs and cath films repository • Subsequent care per site MD • Site f/u visit or phone - 60 days • 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

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

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

20. 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 Primary Endpoint

21. 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 Cumulative radiation exposure Secondary Endpoints

22. Statistical Analysis Plan • 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 of7.2% • Primary analysis is CTA superiority • Power > 90% even if event rate  to 8% • Power = 87% if effect magnitude  to 17.5% • Threshold for superiority at p=0.05 level is an effect magnitude of 13.5%

23. Statistical Analysis Plan: Non-Inferiority • 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 • 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

24. 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 Why a Secondary Non-Inferiority Hypothesis?

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

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

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

28. https://www.promisetrial.org