Insights from the PROMISE Trial Neha J. Pagidipati, MD MPH; Kshipra Hemal; Adrian Coles, PhD; Daniel B. Mark, MD MPH; Rowena J. Dolor, MD MHS; Patricia Pellikka, MD; Udo Hoffmann, MD; Sheldon E. Litwin, MD; Melissa A Daubert, MD; Svati H. Shah, MD; Kerry L. Lee, PhD; Pamela S. Douglas, MD On behalf of the PROMISE Investigators Duke Clinical Research Institute, Massachusetts General Hospital, and the National Heart, Lung, and Blood Institute Sex Differences in Functional Stress Test vs CT Angiography Results and Prognosis in Symptomatic Patients with Suspected Coronary Artery Disease

Disclosures Neha J. Pagidipati, MD MPH: ownership of Freedom Health, Inc., Physician Partners, LLC, RXAdvance, LLC, Florida Medical Associates, LLC Dan Mark, MD MPH: personal fees from Medtronic, CardioDx, and St. Jude Medical; grant support from Eli Lilly, Bristol-Myers Squibb, Gilead Sciences, AGA Medical, Merck, Oxygen Biotherapeutics, and AstraZeneca Udo Hoffmann, MD MPH: grant support from Siemens Healthcare and HeartFlow Pamela S. Douglas, MD: grant support from HeartFlow; serves on a data and safety monitoring board for GE Healthcare. This project was supported by grants R01HL098237, R01HL098236, R01HL98305, and R01HL from the National Heart, Lung, and Blood Institute (NHLBI).

Background  While the diagnosis of CAD is a primary goal of non-invasive testing, risk stratification is also important in guiding clinical care  Patient sex influences the presentation, pathophysiology, and outcomes of CAD  Few data exist on sex-specific prognostic value of stress testing vs CTA  The PROMISE trial provides an opportunity to compare the relative prognostic performances of stress testing vs CTA within each sex to inform optimal test selection for women and men

Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE): Design and Primary Results  10,003 adults (53% women) with stable symptoms suggestive of CAD  Randomized to initial CTA vs. stress testing Stratified by intended stress test  All tests interpreted locally  Median follow-up 25 months  Primary endpoint (death, MI, unstable angina, or major complication)  Similar outcomes between CTA and stress testing arms overall and by sex Douglas PS et al. NEJM 2015; 372: 1291–1300 Adjusted Event Curves CTA : Functional Hazard Ratio: 1.04 (95% CI: 0.83, 1.29) P = 0.750

Objectives 1.To perform the following sex-specific analyses: In women, compare: Likelihood of a positive CTA vs stress test Prognostic information derived from CTA vs stress test In men, compare: Likelihood of a positive CTA vs stress test Prognostic information derived from CTA vs stress test 2.To determine the interactions between sex, test type and test results in predicting events in patients with suspected CAD

Methods and Statistical Analyses Study Population: All PROMISE patients who were tested as randomized and who had interpretable test results Primary Endpoint: All-cause death, myocardial infarction (MI), or unstable angina hospitalization Statistical Analyses:  Comparing CTA with stress testing within each sex: Test results and event rates  Comparing CTA with stress testing in both sexes: Likelihood of test positivity — Interaction of sex and test type Prognostic value of a positive vs negative test — Interaction of sex, test type, and test result Models adjusted for 15 clinical characteristics

Testing in Women and Men Patients randomized (N=10,003) Tested as randomized with interpretable results (N=8966; 90%) Stress Nuclear (N=1704; 71%) Stress Echo (N=505; 21%) Exercise ECG (N=179; 8%) Stress Nuclear (N=1362; 66%) Stress Echo (N=465; 22%) Exercise ECG (N=251; 12%) Women (N=4720; 53%) Men (N=4246; 47%) CTA (N=2332; 49%) Stress (N=2388; 51%) CTA (N=2168; 51%) Stress (N=2078; 49%) Exclusions: N=1037 (10%) Not tested as randomized: N=366 (35%) Indeterminate test result: N=661 (65%)

Baseline Characteristics of Women CTA (N=2332) Stress (N=2388) P-value Age (years, mean)6263 non-significant for all characteristics Racial / ethnic minority (%)2421 BMI (mean)30 Hypertension (%)6667 Dyslipidemia (%)7069 Family history (%)3533 Ever-smoker (%)46 Sedentary behavior (%)53 CAD equivalent (%)2627 Typical chest pain (%)11 Framingham Risk Score (% risk of 10-yr event)15 Pretest likelihood of obstructive CAD (Diamond and Forrester, %)2829 High likelihood (>70%) of significant stenosis per MD (%)34

Test Results and Event Rates in Women n = n = P = P < 0.001

Baseline Characteristics of Men CTA (N=2168) Stress (N=2078) P-value Age (years, mean)59 significant only for ever-smoker and Framingham Risk Score Racial / ethnic minority (%)2221 BMI (mean)3031 Hypertension (%)63 Dyslipidemia (%)6568 Family history (%)3029 Ever-smoker (%)5758 Sedentary behavior (%)4443 CAD equivalent (%)2325 Typical chest pain (%)12 Framingham Risk Score (% risk of 10-yr event)2829 Pretest likelihood of obstructive CAD (Diamond and Forrester, %)6061 High likelihood (>70%) of significant stenosis per MD (%)66

Test Results and Event Rates in Men n = n = P = P = 0.047

Adjusted Associations Between Noninvasive Test Type and Test Result, by Sex Interaction between test type and sex on test positivity: Adjusted p < 0.001

Adjusted Event Curves of Clinical Endpoint by Sex, Test Type, and Test Results HR 5.86HR 2.27 HR 2.80HR 4.42 Interaction between test result, test type, and sex on events: Adjusted p < Adj p=0.028 Adj p=0.168

 Both positive CTAs and stress tests are associated with events in women and in men  The relative prognostic values of each test type varies by sex In women, a positive CTA is less likely than a positive stress, and a positive CTA is more predictive of outcomes In men, a positive CTA is more likely than a positive stress, and positive results were similarly predictive for both types of tests  Although overall trial outcomes comparing testing strategies were similar in men and women, women may derive greater positive prognostic value from CTA than from stress testing, while men may derive similar value Summary and Conclusions

Simultaneous Online Publication

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