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Economic Outcomes With Anatomical Versus Functional Diagnostic Testing for Coronary Artery DiseaseEconomic Outcomes With Anatomical vs. Functional Diagnostic Testing for CAD

Daniel B. Mark, MD, MPH; Jerome J. Federspiel, MD; Patricia A. Cowper, PhD; Kevin J. Anstrom, PhD; Udo Hoffmann, MD, MPH; Manesh R. Patel, MD; Linda Davidson-Ray, MA; Melanie R. Daniels, BA; Lawton S. Cooper, MD; J. David Knight, MS; Kerry L. Lee, PhD; Pamela S. Douglas, MD, for the PROMISE Investigators*
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 24 May 2016.

* For a list of the PROMISE investigators, see the Appendix.


From the Outcomes Research Group, Duke Clinical Research Institute, Duke University Medical Center, and Duke University, Durham, North Carolina; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the National Heart, Lung, and Blood Institute, Bethesda, Maryland.

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

Acknowledgment: The authors thank the coordinators at the PROMISE sites who enrolled the study participants and collected the study data (see the Appendix) and the patients who agreed to participate in this trial.

Grant Support: By grants R01HL098237, R01HL098236, R01HL098305, and R01HL098235 from the National Heart, Lung, and Blood Institute.

Disclosures: Dr. Mark reports grants from the National Institutes of Health during the conduct of the study; grants from Eli Lilly and Company, Gilead Sciences, Bristol-Myers Squibb, AGA Medical Corporation, Merck, Oxygen Therapeutics, AstraZeneca, and Medtronic outside the submitted work; and personal fees from Medtronic, CardioDx, St. Jude Medical, and Milestone outside the submitted work. Dr. Federspiel reports grants from the National Institutes of Health during the conduct of the study. Dr. Cowper reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study and grants from GE Healthcare, Bristol-Myers Squibb, Pfizer, Eli Lilly and Company, Tenax Therapeutics, Gilead Sciences, AGA Medical Corporation, and AstraZeneca outside the submitted work. Dr. Anstrom reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr. Hoffmann reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; grants from HeartFlow, Siemens Healthcare, the Radiological Society of North America, Genentech, Kowa Company, and the American College of Radiology Imaging Network outside the submitted work; and personal fees from the American Heart Association outside the submitted work. Dr. Patel reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; grants from Janssen Pharmaceutica, AstraZeneca, Maquet, and the Patient-Centered Outcomes Research Institute outside the submitted work; and personal fees from Genzyme, Bayer, and Janssen Pharmaceutica outside the submitted work. Mr. Knight reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr. Douglas reports grants from HeartFlow and GE Healthcare outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2639.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Reproducible Research Statement:Study protocol: See the Supplement. Statistical code: Not available. Data set: Available according to National Institutes of Health requirements.

Requests for Single Reprints: Daniel B. Mark, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715.

Current Author Addresses: Drs. Mark, Federspiel, Cowper, Anstrom, Patel, Lee, and Douglas; Ms. Davidson-Ray; Ms. Daniels; and Mr. Knight: Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715.

Dr. Hoffmann: Radiological Associates, 55 Fruit Street, Boston, MA 02114-2696.

Dr. Cooper: National Heart, Lung, and Blood Institute, RKL2 BG RM 10108, 6701 Rockledge Drive, Bethesda, MD 20817.

Author Contributions: Conception and design: D.B. Mark, J.J. Federspiel, P.A. Cowper, M.R. Patel, L.S. Cooper, K.L. Lee.

Analysis and interpretation of the data: D.B. Mark, J.J. Federspiel, P.A. Cowper, K.J. Anstrom, M.R. Daniels, L.S. Cooper, K.L. Lee, P.S. Douglas.

Drafting of the article: D.B. Mark.

Critical revision of the article for important intellectual content: D.B. Mark, J.J. Federspiel, P.A. Cowper, K.J. Anstrom, M.R. Patel, M.R. Daniels, L.S. Cooper, K.L. Lee, P.S. Douglas.

Final approval of the article: D.B. Mark, J.J. Federspiel, P.A. Cowper, K.J. Anstrom, U. Hoffmann, M.R. Patel, L. Davidson-Ray, M.R. Daniels, L.S. Cooper, J.D. Knight, K.L. Lee, P.S. Douglas.

Provision of study materials or patients: P.S. Douglas.

Statistical expertise: D.B. Mark, J.J. Federspiel, K.J. Anstrom, K.L. Lee.

Obtaining of funding: D.B. Mark, M.R. Daniels, K.L. Lee, P.S. Douglas.

Administrative, technical, or logistic support: L. Davidson-Ray, M.R. Daniels, P.S. Douglas.

Collection and assembly of data: D.B. Mark, J.J. Federspiel, P.A. Cowper, M.R. Patel, L. Davidson-Ray, J.D. Knight, K.L. Lee, P.S. Douglas.


Ann Intern Med. 2016;165(2):94-102. doi:10.7326/M15-2639
© 2016 American College of Physicians
Text Size: A A A

Background: PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) found that initial use of at least 64-slice multidetector computed tomography angiography (CTA) versus functional diagnostic testing strategies did not improve clinical outcomes in stable symptomatic patients with suspected coronary artery disease (CAD) requiring noninvasive testing.

Objective: To conduct an economic analysis for PROMISE (a major secondary aim of the study).

Design: Prospective economic study from the U.S. perspective. Comparisons were made according to the intention-to-treat principle, and CIs were calculated using bootstrap methods. (ClinicalTrials.gov: NCT01174550)

Setting: 190 U.S. centers.

Patients: 9649 U.S. patients enrolled in PROMISE between July 2010 and September 2013. Median follow-up was 25 months.

Measurements: Technical costs of the initial (outpatient) testing strategy were estimated from Premier Research Database data. Hospital-based costs were estimated using hospital bills and Medicare cost–charge ratios. Physician fees were taken from the Medicare Physician Fee Schedule. Costs were expressed in 2014 U.S. dollars, discounted at 3% annually, and estimated out to 3 years using inverse probability weighting methods.

Results: The mean initial testing costs were $174 for exercise electrocardiography; $404 for CTA; $501 to $514 for pharmacologic and exercise stress echocardiography, respectively; and $946 to $1132 for exercise and pharmacologic stress nuclear testing, respectively. Mean costs at 90 days were $2494 for the CTA strategy versus $2240 for the functional strategy (mean difference, $254 [95% CI, −$634 to $906]). The difference was associated with more revascularizations and catheterizations (4.25 per 100 patients) with CTA use. After 90 days, the mean cost difference between the groups out to 3 years remained small.

Limitation: Cost weights for test strategies were obtained from sources outside PROMISE.

Conclusion: Computed tomography angiography and functional diagnostic testing strategies in patients with suspected CAD have similar costs through 3 years of follow-up.

Primary Funding Source: National Heart, Lung, and Blood Institute.

Figures

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Figure 1.

Cumulative costs by random assignment (top) and mean cost differences with 95% CIs (CTA − functional) (bottom).

CTA = computed tomography angiography.

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Figure 2.

Mean cost differences, by cost category.

Values >0 indicate higher cost for CTA, and values <0 indicate higher cost for functional testing. Cath = cardiac catheterization; CTA = computed tomography angiography; CV = cardiovascular; Revasc = revascularization.

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Figure 3.

2-y cost threshold differences from bootstrap analysis.

The curve shows the cumulative distribution function of the mean cost difference (CTA − functional) from 1000 bootstrap replications out to 24 mo. CTA = computed tomography angiography.

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Appendix Figure 1.

2-y cost threshold differences from bootstrap analysis.

CTA = computed tomography angiography; RCC = cost–charge ratio.

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Figure 4.

Forest plots for mean differences and 95% CIs of 3-y costs (CTA  − functional testing) in prespecified subgroups.

CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiography; Echo = echocardiography.

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Appendix Figure 2.

Forest plots for mean differences and 95% CIs of costs (CTAfunctional testing) in prespecified subgroups.

CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiography; Echo = echocardiography; RCC = cost–charge ratio. Top. Using Medicare pricing. Bottom. Using RCC pricing.

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Tables

References

Letters

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Comments to "Economic Outcomes with Anatomical versus Functional Diagnostic Testing for Coronary Artery Disease" 24 May 2016
Posted on June 6, 2016
Wade H. Martin III, M.D., F.A.C.P., F.A.C.C.
Washington University School of Medicine and the St. Louis Veterans Administration Healthcare System
Conflict of Interest: None Declared
Cost analysis of the PROMISE trial data suggested little or no difference in cost or outcomes with cardiac computed tomographic angiography (CTA) versus “functional” stress testing for assessment of chest pain or other symptoms of coronary artery disease in relatively low risk patients being evaluated in Emergency Departments.1 However, there are several important caveats to this trial and its conclusions. First, it is highly debatable whether pharmacologic stress testing legitimately can be termed “functional”. Truly functional and relevant clinical information such as exercise capacity, recovery heart rate, and exercise-induced symptoms, dysrhythmias, heart rate, blood pressure, and ischemic ST segment changes were not obtainable in the 29% of patients in this cohort who underwent pharmacologic stress testing. Exercise information is well-known to be a robust predictor of cardiovascular and all-cause mortality.2,3 Second, an alternative trial design could have compared exercise electrocardiographic (ECG) testing alone (which comprised only 10% of the “functional” testing group in this trial) with cardiac CTA. As shown by the data in Fig 4, treadmill ECG testing was $1731 less expensive than cardiac CTA from baseline to 3 years of follow-up with no apparent difference in outcome as stated by PROMISE trial authors in their response to my letter to the editor of the New England Journal of Medicine.4 Thus, value (outcome/cost) is highly likely to be greater for exercise ECG than for cardiac CTA evaluation of low risk patients with symptoms of coronary artery disease. Third, there are likely to be substantial additional benefits not entirely captured by the PROMISE trial results for patients who undergo exercise ECG testing alone rather than nuclear imaging or CTA evaluations. These include avoidance of radiation exposure and potential nephrotoxicity as well as fewer downstream diagnostic and therapeutic procedures such as invasive coronary arteriography and coronary revascularization, for which mortality reduction or prevention of myocardial infarction is unlikely and risks of mortality and other adverse outcomes are non-trivial. Technology is often blamed for the high cost of healthcare in the United States, which confers no apparent longevity advantage.5 The main evaluation strategies employed in the PROMISE trial provide an excellent example of technology run amok in the United States healthcare system with no obvious clinical benefit.
1. Mark DB, Federspiel JJ, Cowper PA, Anstrom KJ, Hoffman H, Patel MR, et al. for the PROMISE Investigators. Economic outcomes with anatomical versus functional diagnostic testing for coronary artery disease. Ann Intern Med 24 May 2016 doi: 10.7326/M15-2639.
2. Mark DB, Shaw L, Harrell FE Jr., Hlatky MA, Lee KL, Bengtson JR, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. New Eng J Med 1991; 325:849-853.
3. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart rate recovery immediately after exercise as a predictor of mortality. New Eng J Med 1999; 341: 1351-1357.
4. Douglas PS, Hoffman U. Correspondence for Anatomical versus functional testing for coronary artery disease. New Eng J Med 2016:373:91.
5. Squires D, Anderson C. U. S. health care from a global perspective: spending, use of services, prices, and health in 13 countries. The Commonwealth Fund 8 Oct 2015.
Author's Response
Posted on August 31, 2016
Daniel B. Mark, MD, MPH, Pamela S. Douglas, MD, Melanie R. Daniels, BA
Duke University Medical Center
Conflict of Interest: None Declared
Dr. Martin makes several interesting points in his letter. The PROMISE trial was a pragmatic randomized trial designed to assess the outcomes of two different diagnostic strategies in symptomatic patients: initial use of coronary computed tomographic angiography (CTA), or initial use of functional testing (a composite of exercise ECG, stress nuclear or stress echo with the choice of test left up to the managing physician).1, 2 The study was not designed or powered to compare each functional testing option individually against CTA. Exercise ECG testing without imaging is clearly less expensive than CTA but PROMISE was not designed to prove that it was clinically equivalent or better. The lack of evidence of a difference in this case is not evidence of a lack of a difference. The recent SCOT-HEART trial reported that after 1.7 years, CTA was associated with a 38% reduction in fatal and non-fatal myocardial infarction compared with a usual care strategy based primarily on exercise ECG testing.3 Thus, we are not in a position to conclude that had treadmill testing been used in all patients in the PROMISE trial, the clinical outcomes would be unchanged or would favor treadmill testing alone.

The Commonwealth Fund analysis4 provides a very low power view of country level health care spending and outcomes that does not permit any conclusions about cause and effect. We do agree with Dr. Martin’s argument that the value of medical technology cannot be assumed and must be demonstrated, which is why we conducted the PROMISE trial.



1. Douglas PS, Hoffmann U, Lee KL, Mark DB, Al-Khalidi HR, Anstrom K, Dolor RJ, Kosinski A, Krucoff MW, Mudrick DW, Patel MR, Picard MH, Udelson JE, Velazquez EJ, Cooper L, the PROMISE Investigators. PROspective Multicenter Imaging Study for Evaluation of chest pain: rationale and design of the PROMISE trial. Am Heart J. 2014;167(6):796-803 e1. doi: 10.1016/j.ahj.2014.03.003. PubMed PMID: 24890527; PMCID: 4044617.
2. Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalidi HR, Cavanaugh B, Cole J, Dolor RJ, Fordyce CB, Huang M, Khan MA, Kosinski AS, Krucoff MW, Malhotra V, Picard MH, Udelson JE, Velazquez EJ, Yow E, Cooper LS, Lee KL, PROMISE Investigators. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med. 2015;372(14):1291-300. doi: 10.1056/NEJMoa1415516. PubMed PMID: 25773919; PMCID: PMC4473773.
3. SCOT-HEART Investigators. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. Lancet. 2015;385(9985):2383-91. doi: 10.1016/S0140-6736(15)60291-4. PubMed PMID: 25788230.
4. Squires D, Anderson C. U. S. health care from a global perspective: spending, use of services, prices, and health in 13 countries. The Commonwealth Fund 8 Oct 2015.
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