Discussion
The optimal assessment of suspected ACS remains controversial despite decades of research. The current standard of care uses stress testing,8 36–38 in which the patient who has ruled out for MI undergoes a protocolised stressor and is assessed via imaging modalities such as echocardiography. The current paradigm remains inefficient, and many question the utility of routine stress testing in ED patients with symptoms of ACS.21 39–42 Based on the event rate in the reported literature (eg, <1% in Sandhu et al
42), it appears that stress testing is currently overused. However, there remains concern for adverse cardiac outcomes following serial cardiac troponin testing, even with high-sensitivity assays.7 30
In this context, we sought to determine whether a biomarker-based stress test could improve the current paradigm. Currently, biomarkers are only serially measured in resting patients as a test for MI, heart failure or as a predictor of cardiac complications following major non-cardiac surgery.43 44 Measuring dynamic changes in biomarker levels during stress testing is a novel application of cardiac biomarkers in ED patients. If a biomarker-based stress test could be developed, it would have several advantages. Since laboratory testing is routinely available 24 hours a day to ED patients, a biomarker stress test could serve as a triage test in the ED to determine which patients need further work-up. If it could provide equivalent predictive value, it might represent a cost-effective and time-effective alternative to standard stress testing that does not require special equipment nor specialists to obtain or interpret the images. Based on prior literature,45 46 it would appear that using two serial NT-proBNP tests compared with an echocardiogram would be approximately 30% the cost of using echocardiography with stress testing. However, for biomarkers to replace the use of stress echocardiography, considerably higher sensitivities than our current results would likely be needed. Alternatively, it could be used as an adjunct to aid in disposition of patients with indeterminate results on standard stress tests.
In this study, we assessed the feasibility of a biomarker-based stress test using NT-proBNP. We found that NT-proBNP concentrations differed significantly according to patients’ stress test imaging results. Our study is one of the largest to examine this biomarker-based stress test concept with NT-proBNP. Prior authors found that patients with ischaemia had a differential stress-delta response,22 25–29 while others did not.23 24 Our patient sample of recently symptomatic ED patients makes our study unique. Obtaining a baseline measurement of NT-proBNP just prior to stress testing limits any potential impact that the patients’ recent symptoms may have had on results.
NT-proBNP is the prohormone of BNP released first in the bloodstream and has a shorter half-life, which could potentially lead to differences in results between these two markers. However, others have studied BNP in this paradigm and found a similar range of response in patients with inducible ischaemia.47–54
Prior studies used the stress test imaging component as their gold standard for outcome. We built on these by considering a broader range of downstream outcomes, although these occurred infrequently in our population. Our study did not find significantly different stress-delta results in this comparison, a finding that we attribute to underpowered analyses.
We also found that baseline NT-proBNP levels were significantly higher among patients who ultimately had myocardial ischaemia. This was not our primary intent in this study so these findings should be considered preliminary. However, NT-proBNP has long been noted to have high independent prognostic capability as a traditional ACS biomarker.55–57 Although professional society guidelines acknowledge their potential use for ED risk stratification of ACS,58 they have not entered into common use for this purpose. These findings suggest a potential role for NT-proBNP in ED ACS risk stratification that should be further explored.
Study limitations
Our study has some important limitations. It was performed at a single institution and in a population that had been selected for relatively low risk for ACS. During this time, our unit did not have objective criteria for entry in the ACS pathway. However, it has been shown that clinician gestalt can effectively risk-stratify patients to lower risk groups,59 and our unit’s prevalence of ischaemia is similar to that described in other settings.60 Furthermore, during the time of this study, high-sensitivity troponin assays were not available in our setting. The introduction of these assays will likely alter the prevalence of disease in the population being referred for observation unit care in the future. Although we attempted to approach consecutive patients, we did not have the ability to reach all patients on weekends.
This was an observational study that is subject to ascertainment bias of downstream outcomes, although all patients had the reference standard test as an inclusion criterion. Furthermore, a small sample size with a low event rate led to underpowered analyses of downstream composite outcomes. We did not control for multiple other baseline risk factors other than NT-proBNP to avoid overfitting our small number of patients with ischaemia. We did use an admittedly surrogate outcome for patient-oriented adverse events; however, we felt that for this low-risk cohort, the stress test result is the key data point that determines further testing and thus a valid outcome. In the future, cardiac MRI or angiography could be considered as diagnostic standard, but this would require significant resources to conduct in a study and has less practical relevance for most ED practices. Nonetheless, our findings warrant further study in larger samples with higher risk of ACS. Although we conducted multiple comparisons between groups, the consistency of results at multiple time points and between static and stress-delta comparisons is compelling.
We were not able to obtain 4-hour post-stress samples on all patients in our biorepository. In almost all cases, this was because the patient had been discharged from the ED within 4 hours of completion of their stress test. Despite the smaller sample size for this comparison, we still noted results that were directionally the same as our 2-hour analyses and that were statistically significant in our adjusted analyses. It remains to be seen whether our proposed paradigm of biomarker-based stress testing would be clinically acceptable to clinicians and patients. Furthermore, a complete financial analysis of a biomarker-based stress test strategy is beyond the scope of this paper.
In conclusion, patients with ischaemia on stress testing demonstrated higher concentrations of NT-proBNP at baseline and all subsequent post-stress time points.
Relative and absolute stress-delta NT-proBNP differed significantly based on stress test imaging results at the 2-hour and 4-hour time points, although when adjusted for baseline NT-proBNP only the 4-hour time point remained significant. These findings warrant further study of this biomarker stress test paradigm in a larger number of patients.