The PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Trial: Economic Outcomes Daniel B. Mark, MD, MPH Professor of Medicine Vice Chief for Academic Affairs, Cardiology Division Duke University Medical Center Director, Outcomes Research Duke Clinical Research Institute Co-Investigators/Econ Team Kevin Anstrom Patricia Cowper Linda Davidson Ray Udo Hoffmann Manesh Patel Lawton Cooper Kerry Lee Pamela Douglas Jeff Federspiel Melanie Daniels Financial Disclosures Consulting Milestone Medtronic CardioDx St Jude Medical Research Grants NIH Eli Lilly & Company AstraZeneca Gilead AGA Medical Bristol Myers Squibb March 15, 2015

PROMISE Trial Background: Moving From Controversy to Evidence Noninvasive ability to directly visualize the coronary arteries of patients with chest pain has long been on Cardiology’s Wish List As coronary CT angiography evolved into a test that might actually be able to fulfill this wish, controversy broke out The PRO side: CTA would allow precision care - only the patients who needed revascularization would actually go to cath and the rest would avoid it –  invasive testing,  unneeded revascularization,  false positives,  $$ The CON side: CTA would:  non-invasive and invasive testing to clarify ambiguous findings,  radiation exposure,  $$

PROMISE: Design Overview 10,003 patients with symptoms of CAD New or worsening chest pain or symptoms w/out known CAD Low to intermediate risk Planned noninvasive testing for diagnosis 193 sites (US, CA) 1:1 Randomization Stratified by site and intended functional test Intervention Arm Anatomic Testing 64-slice CTA Usual Care Arm Pre-selected Functional Testing Median study follow-up 25.2 months 1° endpoint: composite of death, MI, UA hosp, or major procedural complication 2° aims incl.: cost and cost effectiveness

PROMISE Trial: CTA Patient Outcomes Not Superior to Functional Testing “Strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years.” Douglas PS et al NEJM 2015

PROMISE Primary Endpoint Results: Death, MI, Unstable Angina, Major Procedural Complications Douglas PS et al NEJM 2015

PROMISE Economic Substudy: Primary Objectives Measure and compare cumulative total costs as randomized If CTA outcomes superior, estimate cost effectiveness of anatomic strategy

PROMISE Economic Substudy: Calculation of Medical Costs 96% (9649) of PROMISE cohort in Economic Substudy Initial diagnostic test technical fees Bottom up estimate (resource-based cost accounting methods) from large proprietary registry (Premier Research Database) Hospital-based facility costs UB 04 bill forms provide hospital charges by department Department-specific ratios of costs to charges (RCCs) used to convert charges to estimates of cost MD professional fees for testing and hospital services Medicare Fee Schedule

PROMISE Economic Substudy: Analysis Methods Comparisons by intention to treat principle Costs to 3 years estimated, accounting for censoring using inverse probability weighting methods Bootstrapped confidence intervals: 1000 replications (500 in subgroup analyses), 95% confidence intervals

PROMISE Economic Substudy: Baseline Characteristics Functional Anatomic (N=4,818) (N=4,831) Demographics   Age, mean 60.9 ± 8.3 60.7 ± 8.3 Female 54% 52% Cardiac risk factors BMI, mean 30.6 ± 6.2 Hypertension 66% Diabetes 22% Dyslipidemia 68% 67% Family history premature CAD 32% 33% Current or past smoking 51% Primary symptom chest pain or DOE  88% Typical or atypical angina 89% Pretest probability of CAD 53%

PROMISE Economic Substudy: Estimation of Initial Diagnostic Testing Costs Dx Test CTA Echo w/ exercise stress Echo w/ pharmacologic stress ECG-only Stress Nuclear w/ exercise stress Nuclear w/ pharmacologic stress Mean Cost* $285 $428 $415 $137 $829 $1015 MD Fees** $119 $86 $37 $117 Total $404 $514 $501 $174 $946 $1132 *based on costs in Premier database **based on Medicare Fee Schedule

(Anatomic – Functional) PROMISE Economic Substudy: Cumulative Total Costs by ITT and Mean Cost Difference (95%CI) Difference in Cost (Anatomic – Functional) Cumulative Cost $694 $358 $388 $279

PROMISE Secondary Endpoints: 90-Day Catheterization and Revascularization Rates Invasive cath Revascularization No CAD on cath CTA (n=4996) 609 (12.2%) 311 (6.2%) (51% of cath patients) 170 (3.4%) (28% of cath patients) Functional (n=5007) 406 (8.1%) 158 (3.2%) (39% of cath patients) 213 (4.3%) (52% of cath patients)

PROMISE Economic Substudy: Cost Differences by Categories 0-3 and 4-12 Months -$378 $68 $357 $203 $17 $12 $279 -$17 $49 $43 -$10 $8 $8 $81

PROMISE Economic Substudy: Cost Differences by Categories Years 2 and 3 $10 $20 -$35 -$97 $311 $97 $306 $35 -$12 -$69 $7 $15 $53 $29

PROMISE Economic Substudy: 2-Year Cost Difference Thresholds From Bootstrap Analysis Cumulative distribution of mean cost difference [CTA-FXN] from 1000 bootstrap replications out to 24 months Cost difference: < $500 – 62% of samples < $750 – 81% of samples < $1000 – 93% of samples

PROMISE Economic Substudy: Pre-Randomization MD Choice of Functional Test Subgroups Months 0-3 Months 0-36 Overall (N= 9,649) ECG-Only (N= 858) Echo (N= 2,204) Nuclear (N= 6,587) Mean Cost Difference

PROMISE Economic Substudy: Caveats Costs of initial testing from external data source Significant deviations by centers from testing costs used in this analysis might alter relative cost positions of the two strategies Outpatient medications not counted QOL and employment status still being analyzed

PROMISE Economic Substudy: Summary In stable patients with new chest pain, CTA strategy improved efficiency of use of invasive cath (fewer normal caths, higher proportion of caths also getting revasc) But despite lower testing costs for CTA compared with stress echo (~$100 less) and stress nuclear (~$630 less), net effect was to drive a small (<$500), statistically non- significant increase in cost After 90 days, very little test strategy-related differences in costs out to 3 years Coronary CTA may not be the “holy grail” of diagnostic testing once hoped for, but its more liberal use following PROMISE standards will improve some aspects of care without causing a major new economic burden on the health care system