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PRO spective M ulticenter I maging S tudy for E valuation of Chest Pain

PRO spective M ulticenter I maging S tudy for E valuation of Chest Pain. Site Kick Off Call. May 4, 2010. Agenda for the Site Kick Off Call. Brief Introductions PROMISE Protocol Review Open Question Session Email promisetrial@notes.duke.edu in real time to ask questions Next Steps

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PRO spective M ulticenter I maging S tudy for E valuation of Chest Pain

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  1. PROspective Multicenter Imaging Studyfor Evaluation of Chest Pain Site Kick Off Call May 4, 2010

  2. Agenda for the Site Kick Off Call • Brief Introductions • PROMISE Protocol Review • Open Question Session • Email promisetrial@notes.duke.edu in real time to ask questions • Next Steps • Future Calls • Investigator Meetings • Contacts www.promisetrial.org

  3. 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 www.promisetrial.org

  4. Protocol Overview Structure and Timeline Background and Population Study Design Endpoints and Statistics Substudies www.promisetrial.org

  5. PROMISE Leadership: NHLBI Funding for 4 Linked RO-1s Clinical Coordinating Center Douglas, Dolor, Go, Patel, Velazquez Data and Statistical Coordinating Center Lee, Kosinski, Al-Khalidi Economics and Quality of Life Coordinating Center Mark, Anstrom Diagnostic Testing Coordinating Center Hoffmann, Krucoff, Picard, Udelson www.promisetrial.org

  6. Study Timeline Grant Awarded October 2009 Targeted First Subject Enrolled June 2010 First Investigator Meeting Summer 2010 Last Subject Enrolled June 2012 Database Lock October 2014 www.promisetrial.org

  7. Protocol Overview Structure and Timeline Background and Population Study Design Endpoints and Statistics Substudies www.promisetrial.org

  8. Background and Rationale Evaluation of Chest Pain Syndrome is the most common clinical cardiology problem Large and growing costs (GAO report – 14.1 billion dollars on imaging) Differing ACC/AHA guideline recommendations Lack of trial data on effect of imaging care Patients / physicians / insurers / policy makers want studies showing improved health outcomes www.promisetrial.org

  9. Imaging for CAD: WOW vs Value? Imaging: Improved assessment of cardiac function, anatomy, and pathology Does this translate into improved diagnosis or improved clinical outcomes? www.promisetrial.org

  10. Critical Questions for NI Testing What is the population being tested today? How do tests compare on: Diagnostic results (yield)? Prognostic results (events)? What about new technology like CTA? What is the right way to evaluate NI testing for CAD diagnosis and treatment? www.promisetrial.org

  11. 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 www.promisetrial.org

  12. Obstructive CAD at Cath: NCDR 2005-2007 376,430 pts without CAD/MI or prior PCI/CABG Undergoing diagnostic cath to R/O CAD Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis RG, Douglas PS. NEJM. 2010 Mar 11;362(10):886-95 www.promisetrial.org

  13. Is CTA a Disruptive Technology? Revolutionary vs evolutionary change Sensitivity/ Specificity: 85-90%; 83-99% Quick, robust, well tolerated, visual Limitations: Ca++, false + rate, radiation Clinical noninvasive testing strategy decisions Is CTA ever the preferred initial strategy in suspected CAD ? If so, when? First test can be functional or anatomic Are lesions or ischemia more important? www.promisetrial.org

  14. Why is the PROMISE Trial Important? Current testing strategies to evaluate suspected CP are not optimal Many low risk patients are tested Imaging costs are large and growing Limited data documenting value for $B spent/yr Strong $$ and admin pressure to do less testing CTA is a new, disruptive technology What is the value of anatomic vs functional data? Should new imaging tests be required to demonstrate improved outcomes? Can we do large scale pragmatic trials in imaging? www.promisetrial.org

  15. Protocol Overview Structure and Timeline Background and Population Study Design Endpoints and Statistics Substudies www.promisetrial.org

  16. 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 www.promisetrial.org

  17. 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? www.promisetrial.org

  18. Trial Design Philosophy General principlesof a pragmatic trial Large, simple 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’ www.promisetrial.org

  19. PROMISE Trial Design Symptoms suspicious for significant CAD, Requiring non-emergent noninvasive testing Randomization Anatomic strategy Functional strategy 64+ slice CTA Pharmacologic Stress imaging Exercise ECG or Exercise Imaging • Clinical results immediately available to care team • Subsequent testing/mgmt per care team + guideline care • Average follow-up 30 months 1º = Death, MI, Complications, UA hosp 2º = MACE components, Costs, QOL 2º Safety = Cumulative radiation exposure www.promisetrial.org

  20. PROMISE Trial – Inclusion Criteria Symptoms suspicious for significant CAD, Requiring non-emergent non-invasive testing No prior W/U for this episode of CP Planned Non-invasive Evaluation Serum Creatinine <1.5mg/dl within the past 90 days Men ≥ 55 years Women ≥ 65 years Men 45- 54 years Women 50- 64 years Randomize Check Risk Factors www.promisetrial.org

  21. PROMISE Trial – Inclusion Criteria Men 45- 54 years Women 50- 64 years CAD Equivalent: Diabetes Mellitus OR Peripheral Arterial Disease OR Cerebrovascular Disease One CV Risk Factor: - Ongoing tobacco use - Hypertension - Abnormal ABI < 0.9 - Dyslipidemia Randomize www.promisetrial.org

  22. Exclusion Criteria • Diagnosed or suspected ACS; Unstable • Known CAD, recent CV evaluation or other 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 consent or participate in follow up www.promisetrial.org

  23. Pragmatic Post-test Medical Care: ‘Usual Care; Best Practices’ Test Information sheets 1 and 2  Prevention Information sheets Post test care at discretion of local MD Monitor life style and medical RX for risk factor modification www.promisetrial.org

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

  25. Study Assessments Day 0/ Day 1: Screening / Randomization Days 1-30: Functional test or CTA performed Post test FU – 60 days post randomization- Site Q 6 months until end of trial – DCRI Follow-up assessments QOL q 12 mo www.promisetrial.org

  26. Medical history, medications, cardiac symptoms and chest pain descriptors, cardiac risk Determine eligibility Consent eligible subjects for study participation Pregnancy and creatinine tests, if applicable 12-lead baseline ECG, if not current within past 30 days Quality of Life Questionnaires Blood sample if participating in biomarker/genomic banking Randomized to the functional test of Investigator/MD choice or to CTA Study Procedures at Day 0/ Day 1 Screening/ Randomization www.promisetrial.org

  27. Perform functional diagnostic test or CTA test assigned by IVRS within 30 days of randomization Study Procedures for Days 1-30 www.promisetrial.org

  28. Relevant medical hx, including symptoms and con meds Interval resource consumption including hospitalizations Testing safety assessment May be performed via phone call or clinic visit Site documents data via InForm EDC system Upload images and ECGs of first NI test (and cath) to Dx Core Lab; Test reports faxed to DCRI Post Test Follow-up Assessment (60 days post-randomization) www.promisetrial.org

  29. Collect Medical Hx since last assessment, including con meds 1° and 2° Endpoint Assessments Interval resource consumption including hospitalizations CV risk modification QOL at 6, 12, 24, 36, 48 months only Follow-ups every 6 months from randomization = DCRI Follow-up and Outcomes Group (DOFG) www.promisetrial.org

  30. Executed CTA & Reg doc complete IVRS confirmed randomization of pt Query clean baseline eCRFs Q-clean 60-day FU & image upload CCTA* results entered & clean Core lab receipt of blood specimen Plus $1,000 per 10 pts randomized Site Budget Information (*CCTA pt) • $5,000 (start-up) • $200 • $300 • $250 • $500* • $100 Total: $1,350 per pt* www.promisetrial.org

  31. Protocol Overview Structure and Timeline Background and Population Study Design Endpoints and Statistics Substudies www.promisetrial.org

  32. Time to first major cardiovascular event including: Death Myocardial infarction (MI) Unstable angina requiring hospitalization Major complications from CV procedures & testing: Stroke Major bleeding Anaphylaxis Renal failure - defined as requiring dialysis Primary Endpoint www.promisetrial.org

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

  34. Statistical Analysis Plan • 10,000 subjects • Estimated rate of death / MI / USA Hospitalization/ Major procedural complication over 30 mo:9.0% • 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% www.promisetrial.org

  35. Statistical Analysis Plan: Non-Inferiority • Non-inferiority: If superiority of CTA compared to functional testing is not demonstrated, 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 www.promisetrial.org

  36. Protocol Overview Structure and Timeline Background and Population Study Design Endpoints and Statistics Substudies www.promisetrial.org

  37. 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 www.promisetrial.org

  38. 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 Be a part of it! www.promisetrial.org

  39. Why Participate in PROMISE? Help to develop the required critical evidence regarding benefits of non-invasive testing and CTA which are urgently needed to preserve reimbursement Be part of a ground breaking study Largest CV imaging trial ever performed First ever CV imaging trial with clinical endpoints State-of-the-art technology Cardiac CTA reimbursement available for areas that are not covered by insurance Potential referral patients It’s easy…the only trial intervention is the choice of first test www.promisetrial.org

  40. PROMISE – Next Steps • Additional Kick Off Call • 3rd call to be held week of May 3rd (date/time forthcoming) • Investigator Meeting/Study Coordinator Training • Dates: July 14-15, 2010 in Las Vegas* * more information to follow www.promisetrial.org

  41. PROMISE – Contacts for Sites • Clinical Coordinating Center • PROMISE Trial E-mail Box promisetrial@notes.duke.edu • Carrie Elliott, Lead CRA 919-668-8021 / carrie.elliott@duke.edu • Diagnostic Testing Coordinating Center • Nathan Sciortino, Project Manager 617-643-5308 / nsciortino@partners.org • ACRIN - Image Software and storage • Heather Polley, Project Manager 215-574-3245 / hpolley@acr-arrs.org www.promisetrial.org

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