The PROMISE Trial: The Functional Imaging Perspective
The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial was presented at ACC.15 and concurrently published in The New England Journal of Medicine. Briefly, PROMISE was a multicenter randomized control trial of 10,003 patients in whom functional testing was ordered (exercise treadmill testing [ETT], stress echocardiography, or stress nuclear imaging). The patients enrolled were then randomly assigned to either coronary computed tomography angiography (CTA) evaluation or the original test ordered as an initial strategy for outpatients with chest pain syndrome. The study design was to test the hypothesis that clinical outcomes in patients undergoing CTA would be superior to functional testing. Statistically, the study was designed with a 90% power to detect a 20% difference in the primary endpoint in the CTA group, as compared with the functional testing group, assuming an event rate of 8%. The composite primary endpoint was death, myocardial infarction (MI), hospitalization for unstable angina, or major procedural complications. The secondary endpoints included invasive cardiac catheterization that did not show obstructive coronary artery disease (CAD) and radiation exposure. The composite primary endpoint occurred in only 3.3% of the CTA group and 3.0% of the functional-testing group (P = 0.75). The CTA group was associated with fewer catheterizations showing obstructive CAD than the functional testing group, (3.4% vs. 4.3%, p = 0.02). However, statistically significantly more patients in the CTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%, p <0.01) and significantly more revascularizations (CTA 388, 6.2%; functional testing 158, 3.2%, p <0.0001) than the functional testing group, without a change in outcomes. The mean radiation exposure of CTA was significantly higher than in the functional imaging group, although 32% of patients in the functional testing group had no radiation exposure (mean, 12.0 mSv for CTA vs. 10.1 mSv for functional group; P <0.001). The authors concluded that in symptomatic patients suggestive of CAD an initial strategy of initial CTA did not improve outcomes over functional testing.
This study is rare in the literature in that its design was to randomize patients to the functional versus CTA strategy to provide an objective evaluation of the testing modalities within a large number of enrolled patients. There were two limitations in the conduct and results of the study that may have affected the results and conclusions. The original objective was for every patient to have a two-year follow-up. However, due to financial constraints, the follow-up was limited to one year in patients enrolled after April 30, 2013. This may have affected overall event rates. Secondly, and more importantly, while the projected cumulative event rate was 8%, the actual event rate was considerably less at 3.3% in the CTA group and 3% in the functional group. Thus, the study was almost certainly underpowered to test for superiority, and this important limitation also applies to a secondary analysis for non-significant differences between the two approaches. The much lower observed versus predicted event rates also raise concerns as to the composition of the study group.
What is a noninvasive cardiologist's take on this study? First, it is by far the largest evaluation to date and demonstrates relative equivalence between testing strategies. The authors should be congratulated on an enormous effort. The study clearly demonstrated that noninvasive strategies can adequately evaluate outpatients with chest pain with a low cardiac catherization rate and favorable outcomes with any of the included procedures. With the low cardiac event rate in the aggregate, this confirms the value of noninvasive testing as a safe and efficacious approach to symptomatic patients with a suspicion of CAD. Effectiveness of a noninvasive test can also be measured by cardiac catherization and revascularization rates following the testing procedure being assessed. While the percentage of these procedures were not endpoints in this trial, it is concerning that the study demonstrated significantly higher catheterization and revascularization rates for the CTA group than the functional testing group with no effect upon outcomes. These findings could imply that following the CTA strategy as the noninvasive test could result in an increased cost due to downstream testing and procedures, higher radiation exposure, and unnecessary revascularizations in such patients; a step in the wrong direction. Cost data showing an increased cost of CTA were reported at ACC.15, but results have not been published.
In the current world, decisions as to which functional test is ordered are generally based upon the physician or health care worker's suspicion for disease, as well as meeting appropriate use criteria, the latter not being a part of this trial. It has been suggested that patients with a pre-test low likelihood are referred for ETT alone; those with low-to-intermediate likelihood are more likely to be referred for stress echocardiography; and finally that patients with intermediate-to-high pre-test likelihood are more likely to be referred for stress nuclear imaging. The pre-test probability in the PROMISE Trial was 53.4%, indicating a wide spectrum. How CTA fits into this decision process based upon these categories is unknown, but the high negative predictive value of CTA would suggest low likelihood CAD patients to be the ideal candidates. In order for CTA to be accepted as an alternative to ETT or stress echocardiography in which radiation exposure is zero, it would need to be demonstrated to be significantly better for patient care, which was not shown in the PROMISE trial. In the intermediate-to-high risk patients in which stress nuclear imaging would likely be ordered, the possibility of some evidence of soft or hard plaque with the CTA strategy would increase, even if subsequent testing demonstrated non-obstructive disease. Thus, it would be anticipated that the cardiac catheterization and revascularization rate would be higher, as demonstrated in the overall results of this trial. Again, in order to show CTA to be beneficial, a significant improvement in outcomes would be desirable.
With regard to radiation exposure, we agree that it is a complex issue as some modalities had no radiation exposure (echocardiography, ETT) while both CTA and stress nuclear imaging did. For both of these procedures, new advances in technologies have substantially reduced patient radiation exposure and using this new instrumentation should be much lower than reported in the PROMISE trial. Thus, these results may not reflect the reality of radiation exposure for either CT or cardiac nuclear imaging in the current era.
While this trial certainly contributes to our knowledge of noninvasive testing for suspected CAD, many questions remain, particularly with regard to cases in which CTA would be preferred to ETT, stress echocardiography, or stress nuclear imaging. Thus, given all of these factors, it is clear that the CTA approach is not superior to functional evaluation; whether it is equivalent to and should replace current functional testing, based upon many factors elucidated in this commentary, remains unknown.
- Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 2015;372:1291-300.
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