Identification of Patients With Stable Chest Pain Deriving Minimal Value From Noninvasive Testing: The PROMISE Minimal-Risk Tool, A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Guidelines recommend noninvasive testing for patients with stable chest pain, although many subsequently have normal test results and no adverse clinical events.

Objective: To describe a risk tool developed to use only pretest clinical data to identify patients with chest pain with normal coronary arteries and no clinical events during follow-up (minimal-risk cohort).

Design, setting, and participants: This secondary analysis of a randomized, pragmatic comparative effectiveness trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]) includes stable, symptomatic outpatients without known coronary artery disease referred for noninvasive testing at 193 sites in North America.

Interventions: Patients were randomized to receive coronary computed tomography angiography (CCTA) vs functional testing.

Main outcomes and measures: A low-risk tool was developed and internally validated from July 27, 2010, to September 19, 2013, in 4631 patients receiving CCTA as their initial test, with a median follow-up of 25 months. Logistic regression analysis was used to evaluate pretest variables to determine factors associated with minimal risk using a two-thirds random sample for model derivation (n = 3087) and a one-third sample for testing and validation (n = 1544). The model was then applied to the CCTA and functional testing arms, and test results and event rates were ascertained.

Results: A total of 1243 of 4631 patients (26.8%) were in the minimal-risk cohort. The final minimal-risk model included 10 clinical variables that together were correlated with normal CCTA results and no clinical events (C statistic = 0.725 for the derivation and validation subsets; 95% CI, 0.705-0.746): younger age; female sex; racial or ethnic minority; no history of hypertension, diabetes, or dyslipidemia; family history of premature coronary artery disease; never smoking; symptoms unrelated to physical or mental stress; and higher high-density lipoprotein cholesterol level. Across the entire PROMISE cohort, this model was associated with the lowest rates of severely abnormal test results (1.3% for CCTA; 5.6% for functional) and cardiovascular death or myocardial infarction (0.5% for a median of 25 months) among patients at the highest probability (10th decile) of minimal risk.

Conclusions and relevance: In contemporary practice, more than 25% of patients with stable chest pain referred for noninvasive testing will have normal coronary arteries and no long-term clinical events. A clinical tool using readily available pretest variables discriminates such minimal-risk patients, for whom deferred testing may be considered.

Trial registration: clinicaltrials.gov Identifier: NCT01174550.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Fordyce reported receiving support from the Clinician Investigator Program, University of British Columbia. Dr Douglas reported serving on the data safety monitoring board for GE Healthcare and receiving research grants from HeartFlow. Dr Hoffmann reported receiving research grants from HeartFlow. Dr Patel reported receiving consultant fees or honoraria from Bayer Healthcare, Genzyme, Medscape – theheart.org, and Merck & Co and receiving research grants from Agency for Healthcare Research and Quality, AstraZeneca, Jansen, Johnson & Johnson, Maquet, National Heart, Lung, and Blood Institute, and Patient-Centered Outcomes Research Institute. Dr Granger reported receiving grants and consulting fees from GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Sanofi, The Medicines Company, Janssen, and Bayer; research grants from the National Institutes of Health, the US Food and Drug Administration, Medtronic Foundation, Merck & Co, Novartis, and Armetheon; and consulting fees from Hoffmann-La Roche, Lilly, AstraZeneca, Gilead, and Medtronic. Dr Kostis reported receiving consultant fees and honoraria from ACI Clinical-Janssen Pharmaceuticals, serving on the data safety monitoring board for Palatin, and receiving other support from St Jude Medical. Dr Mark reported receiving consultant fees and honoraria from Medtronic and research grants from AGA Medical, AstraZeneca, Bayer Healthcare Pharmaceuticals, BMS, Eli Lilly, Gilead, and Merck & Co. Dr Lee reported serving on the data safety monitoring board for Amgen, AstraZeneca, CardiaQ, Edwards, and Merck & Co and receiving research grants from Medtronic. Dr Udelson reported receiving consultant fees and honoraria from Lantheus Medical Imaging; serving on the data safety monitoring board for Gilead and GSK; serving as an officer, director, trustee, or in another fiduciary role for the Heart Failure Society of American Executive Council; receiving other support from Abbott Laboratories; serving as an association editor for Circulation (American Heart Association) and as an editor for Circulation Heart Failure, Pfizer/GSK, and Sunshine Heart; and receiving research grants from the National Heart, Lung, and Blood Institute and Otsuka. No other disclosures were reported.

Figures

Figure.. Cohort Derivation, Model Derivation, and Validation Populations

Of the 10 003 patients randomized in the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), 4633 who received coronary computed tomography angiography (CCTA) as an initial noninvasive test were used to derive the model cohorts. Patients with no clinical events (all-cause death, myocardial infarction, unstable angina hospitalization, or revascularization) and a normal CCTA result were included in the minimal-risk cohort; all other patients were included in the other cohort. Two patients with insufficient data to categorize them as minimal risk vs other were excluded. The final analysis population was then divided into derivation and validation subsets with a random 2:1 split. CAC indicates coronary artery calcium; ICA, invasive coronary angiography.