Multi-marker Strategy of Natriuretic Peptide for ACS
In this low-to-intermediate risk cohort of acute chest pain patients in the ED with no previous history of coronary artery disease (CAD) and initial negative cTn, we found that there was considerable incremental value for ACS and UAP diagnosis by using a dual marker strategy of combining established and emerging biomarkers of myocardial injury (either cTnT or hsTnT) with myocyte stress (NT-proBNP or MR-proANP) from a single blood draw after ED presentation (median 4.2 hours). Importantly, even in the context of superior sensitivity provided by hsTnT, the addition of a natriuretic peptide (particularly NT-proBNP) improved diagnostic accuracy, and increased NPV for excluding an ACS.
Cardiac troponins have become the biomarker of choice for the detection of myocardial injury and are central to the diagnosis of MI. The development of hsTn assays has allowed for the detection of much smaller concentrations of the biomarker, but the diagnostic and prognostic implications of this enhanced sensitivity are still under investigation, and the ramifications of reduced specificity of the biomarker for ACS are undefined. The additive diagnostic value of natriuretic peptides to hsTnT in this cohort is intriguing given the enhanced sensitivity of the latter biomarker. Given this, it is not surprising that there was value from adding NT-proBNP to cTnT as well. Because our analyses include both cTnT and hsTnT, our study is applicable independent of what type of troponin assay may be used in the future.
Given the reduced specificity of hsTn methods, adding a second biomarker may enhance diagnostic performance. The natriuretic peptides are a natural choice, given their tight association with structural heart disease, including ischemic heart disease. Indeed, while concentrations of natriuretic peptides have taken on special meaning relative to the presence and severity of heart failure, their release is not limited to this diagnosis. Early in the course of myocardial ischemia, natriuretic peptide levels have been shown to rise, correlate with extent of myocardial damage, and have prognostic implications after MI. As the combination of adding NT-proBNP to cTNT has already provided complementary information for prognosis in those with ACS as well as further risk stratification even in patients with negative cTnT results, strategies employing multiple cardiac markers will likely improve the diagnostic ability in ACS beyond single marker strategy alone, and may negate the need for serial blood sampling and prolonged hospitalization, particularly when both markers are low. It is of note and interest that while NT-proBNP and MR-proANP delivered relatively comparable diagnostic information, there were differences in their overall performance, perhaps favoring NT-proBNP. As these 2 natriuretic peptides are biologically distinct and released from different areas in the heart, there may be subtle differences in their clinical behavior. Notably, in this cohort, we previously showed that another candidate chest pain marker, copeptin, had no added value to hsTnT. Our findings extend to the understanding of which biomarkers can be used synergistically to optimally evaluate patients with acute chest pain.
When assessed individually, all 4 biomarkers levels were higher in patients with ACS and those with UAP compared to those without. Reflecting their role as a clinical mainstay for diagnosis of ACS, both troponins had excellent specificity (90%-99%) for adjudicated ACS and UAP diagnoses; however, sensitivity was low for cTnT (19%-38%) and improved but still modest sensitivity (48-59%) was noted for hsTnT. Given its high specificity, a positive troponin value could not be overlooked clinically because of a negative natriuretic peptide result. Therefore, we incorporated natriuretic peptides with troponins in a dual-negative marker strategy, whereby only patients with negative values for both assays were considered negative. In a dual-negative marker approach with the natriuretic peptides, we found enhanced sensitivities to 81% to 90% with corresponding near perfect NPV of 97% to 98% for ACS and UAP detection, thus identifying a cohort at a very low risk of ACS. This is of particular importance in our study population of patients presenting to the ED, as this approach can give clinicians, particularly ED physicians, more confidence to manage patients with dual-negative result in a lesser aggressive manner.
As reflected in differential patterns of sensitivity and specificity, we found significantly improved C-statistics and NRI for ACS and UAP diagnosis when combining troponin with a natriuretic peptide, largely driven by correctly reclassifying events. As confirmed in our subgroup analysis of patients without MI, these ACS events that are reclassified are essentially UAP. All combinations of natriuretic peptides and troponins showed significant improvement in C-statistics over the relevant troponin assay alone for both ACS and UAP, in addition to improved NRI with impressive reclassification when natriuretic peptides were added to troponins. Specifically, adding NT-proBNP to either troponin correctly reclassified 62% to 66% of patients for ACS and UAP diagnosis, while adding MR-proANP to either troponins correctly reclassified 38% to 52% of patients. Moreover, NT-proBNP performed much better than MR-proANP for the diagnosis of ACS but both natriuretic peptides performed comparably well when used in combination with the troponins for the diagnosis of UAP. Notably, neither dual-marker strategies resulted in significant degrees of incorrect reclassification, an important point in this patient population with low rates of diagnoses likely to affect natriuretic peptide values.
Interestingly, in a higher-risk ED multicenter cohort of acute chest pain patients, NT-proBNP was incremental to cTnT but did not reclassify patients beyond that of hsTnI. While our findings of the incremental of NT-proBNP to cTnT for ACS diagnosis were consistent despite different cut-points for NT-proBNP (50 ng/L in this analysis, 100 ng/L in the IMAGINE study, and 402 ng/L in the study by Haaf et al), several reasons could explain our conflicting findings with high-sensitivity troponin. First, we used different assays for high-sensitivity troponin in the two studies (hsTnT [Roche] vshsTnI [Singulex]). Probably most important is the use of category-free NRI instead of categorical NRI in this analysis. The use of the category-free NRI provides a more stable result when lack of optimal risk categories exist (such as in this ED cohort) and is less prone to changes of the pre-test categories. Lastly, this ROMICAT cohort includes low-intermediate risk patients for suspected ACS and more strict criteria including normal renal function and no prior history of CAD. The IMAGINE cohort consisted of patients with a generally higher-risk presentation, with a mixture of diagnoses typical of such a population, including heart failure, as well as impaired renal function. While adding NT-proBNP to hsTnI correctly reclassified ACS events by 15%, it incorrectly reclassified 32% of non-ACS cardiac events due to the majority (78%) being acutely decompensated heart failure patients. Of note, while the study by Haaf et al. included more heterogeneous patients such as those with known CAD, NT-proBNP was examined only with cTnT and not high-sensitivity troponin. Our study specifically targets the low risk patients with acute chest pain and excludes coexisting diagnosis that causes abnormal natriuretic peptide values (eg, heart failure, pulmonary thromboembolism, impaired renal function). In aggregate, the multi-marker approach of troponin plus natriuretic peptide adds considerable diagnostic value for ACS.
We had the unique opportunity to describe the relationship between cardiac CT with respect to the dual marker strategy since both were performed at the same time and measured or interpreted in a blinded fashion, without the clinical history or each other results. Using anatomic imaging with cardiac CT to explain the etiology of our dual marker results, we found elevated biomarker levels for all 4 markers in relation to CT abnormalities (plaque, stenosis, and RWMA). Moreover, we observe a gradient effect with the lowest proportion of patients with CT coronary plaque, stenosis, or RWMA having dual-negative result, followed by those with negative troponin but positive natriuretic peptide, and the highest prevalence of CT abnormalities in those with positive troponin (either cTnT or hsTnT). Thus, above and beyond delivering important diagnostic value for ACS, the patterns of biomarker release in this context are supported by the underlying cardiac structural and functional findings.
Our cohort is limited to symptomatic patients at low to intermediate risk of ACS and, so, is not applicable to medically complex patients or those with heart failure. Our study population also excluded patients with known CAD, making this different from an overall ED population. Nevertheless, our findings are appropriate in the large population of patients that present to the ED in whom troponin assays are of clinical importance. Also, the blood samples measured for cTnT and hsTnT were drawn at the time of the CT scan, which was a median of 4.2 hours after presentation. We could not use the first draw troponin blood sample on ED presentation since it was used to determine study eligibility. Since an earlier hsTnT draw of <3 hours from symptom onset have been reported to have less sensitivity as compared to that drawn at >3 hours, the initial reduced sensitivity from an earlier draw of troponin may lead to even more profound results when used in combination with the natriuretic peptides. Further prospective studies examining these biomarkers in combination at initial ED presentation would be of great utility for this ED cohort and help facilitate triage decision.
Discussion
In this low-to-intermediate risk cohort of acute chest pain patients in the ED with no previous history of coronary artery disease (CAD) and initial negative cTn, we found that there was considerable incremental value for ACS and UAP diagnosis by using a dual marker strategy of combining established and emerging biomarkers of myocardial injury (either cTnT or hsTnT) with myocyte stress (NT-proBNP or MR-proANP) from a single blood draw after ED presentation (median 4.2 hours). Importantly, even in the context of superior sensitivity provided by hsTnT, the addition of a natriuretic peptide (particularly NT-proBNP) improved diagnostic accuracy, and increased NPV for excluding an ACS.
Cardiac troponins have become the biomarker of choice for the detection of myocardial injury and are central to the diagnosis of MI. The development of hsTn assays has allowed for the detection of much smaller concentrations of the biomarker, but the diagnostic and prognostic implications of this enhanced sensitivity are still under investigation, and the ramifications of reduced specificity of the biomarker for ACS are undefined. The additive diagnostic value of natriuretic peptides to hsTnT in this cohort is intriguing given the enhanced sensitivity of the latter biomarker. Given this, it is not surprising that there was value from adding NT-proBNP to cTnT as well. Because our analyses include both cTnT and hsTnT, our study is applicable independent of what type of troponin assay may be used in the future.
Given the reduced specificity of hsTn methods, adding a second biomarker may enhance diagnostic performance. The natriuretic peptides are a natural choice, given their tight association with structural heart disease, including ischemic heart disease. Indeed, while concentrations of natriuretic peptides have taken on special meaning relative to the presence and severity of heart failure, their release is not limited to this diagnosis. Early in the course of myocardial ischemia, natriuretic peptide levels have been shown to rise, correlate with extent of myocardial damage, and have prognostic implications after MI. As the combination of adding NT-proBNP to cTNT has already provided complementary information for prognosis in those with ACS as well as further risk stratification even in patients with negative cTnT results, strategies employing multiple cardiac markers will likely improve the diagnostic ability in ACS beyond single marker strategy alone, and may negate the need for serial blood sampling and prolonged hospitalization, particularly when both markers are low. It is of note and interest that while NT-proBNP and MR-proANP delivered relatively comparable diagnostic information, there were differences in their overall performance, perhaps favoring NT-proBNP. As these 2 natriuretic peptides are biologically distinct and released from different areas in the heart, there may be subtle differences in their clinical behavior. Notably, in this cohort, we previously showed that another candidate chest pain marker, copeptin, had no added value to hsTnT. Our findings extend to the understanding of which biomarkers can be used synergistically to optimally evaluate patients with acute chest pain.
When assessed individually, all 4 biomarkers levels were higher in patients with ACS and those with UAP compared to those without. Reflecting their role as a clinical mainstay for diagnosis of ACS, both troponins had excellent specificity (90%-99%) for adjudicated ACS and UAP diagnoses; however, sensitivity was low for cTnT (19%-38%) and improved but still modest sensitivity (48-59%) was noted for hsTnT. Given its high specificity, a positive troponin value could not be overlooked clinically because of a negative natriuretic peptide result. Therefore, we incorporated natriuretic peptides with troponins in a dual-negative marker strategy, whereby only patients with negative values for both assays were considered negative. In a dual-negative marker approach with the natriuretic peptides, we found enhanced sensitivities to 81% to 90% with corresponding near perfect NPV of 97% to 98% for ACS and UAP detection, thus identifying a cohort at a very low risk of ACS. This is of particular importance in our study population of patients presenting to the ED, as this approach can give clinicians, particularly ED physicians, more confidence to manage patients with dual-negative result in a lesser aggressive manner.
As reflected in differential patterns of sensitivity and specificity, we found significantly improved C-statistics and NRI for ACS and UAP diagnosis when combining troponin with a natriuretic peptide, largely driven by correctly reclassifying events. As confirmed in our subgroup analysis of patients without MI, these ACS events that are reclassified are essentially UAP. All combinations of natriuretic peptides and troponins showed significant improvement in C-statistics over the relevant troponin assay alone for both ACS and UAP, in addition to improved NRI with impressive reclassification when natriuretic peptides were added to troponins. Specifically, adding NT-proBNP to either troponin correctly reclassified 62% to 66% of patients for ACS and UAP diagnosis, while adding MR-proANP to either troponins correctly reclassified 38% to 52% of patients. Moreover, NT-proBNP performed much better than MR-proANP for the diagnosis of ACS but both natriuretic peptides performed comparably well when used in combination with the troponins for the diagnosis of UAP. Notably, neither dual-marker strategies resulted in significant degrees of incorrect reclassification, an important point in this patient population with low rates of diagnoses likely to affect natriuretic peptide values.
Interestingly, in a higher-risk ED multicenter cohort of acute chest pain patients, NT-proBNP was incremental to cTnT but did not reclassify patients beyond that of hsTnI. While our findings of the incremental of NT-proBNP to cTnT for ACS diagnosis were consistent despite different cut-points for NT-proBNP (50 ng/L in this analysis, 100 ng/L in the IMAGINE study, and 402 ng/L in the study by Haaf et al), several reasons could explain our conflicting findings with high-sensitivity troponin. First, we used different assays for high-sensitivity troponin in the two studies (hsTnT [Roche] vshsTnI [Singulex]). Probably most important is the use of category-free NRI instead of categorical NRI in this analysis. The use of the category-free NRI provides a more stable result when lack of optimal risk categories exist (such as in this ED cohort) and is less prone to changes of the pre-test categories. Lastly, this ROMICAT cohort includes low-intermediate risk patients for suspected ACS and more strict criteria including normal renal function and no prior history of CAD. The IMAGINE cohort consisted of patients with a generally higher-risk presentation, with a mixture of diagnoses typical of such a population, including heart failure, as well as impaired renal function. While adding NT-proBNP to hsTnI correctly reclassified ACS events by 15%, it incorrectly reclassified 32% of non-ACS cardiac events due to the majority (78%) being acutely decompensated heart failure patients. Of note, while the study by Haaf et al. included more heterogeneous patients such as those with known CAD, NT-proBNP was examined only with cTnT and not high-sensitivity troponin. Our study specifically targets the low risk patients with acute chest pain and excludes coexisting diagnosis that causes abnormal natriuretic peptide values (eg, heart failure, pulmonary thromboembolism, impaired renal function). In aggregate, the multi-marker approach of troponin plus natriuretic peptide adds considerable diagnostic value for ACS.
We had the unique opportunity to describe the relationship between cardiac CT with respect to the dual marker strategy since both were performed at the same time and measured or interpreted in a blinded fashion, without the clinical history or each other results. Using anatomic imaging with cardiac CT to explain the etiology of our dual marker results, we found elevated biomarker levels for all 4 markers in relation to CT abnormalities (plaque, stenosis, and RWMA). Moreover, we observe a gradient effect with the lowest proportion of patients with CT coronary plaque, stenosis, or RWMA having dual-negative result, followed by those with negative troponin but positive natriuretic peptide, and the highest prevalence of CT abnormalities in those with positive troponin (either cTnT or hsTnT). Thus, above and beyond delivering important diagnostic value for ACS, the patterns of biomarker release in this context are supported by the underlying cardiac structural and functional findings.
Limitations
Our cohort is limited to symptomatic patients at low to intermediate risk of ACS and, so, is not applicable to medically complex patients or those with heart failure. Our study population also excluded patients with known CAD, making this different from an overall ED population. Nevertheless, our findings are appropriate in the large population of patients that present to the ED in whom troponin assays are of clinical importance. Also, the blood samples measured for cTnT and hsTnT were drawn at the time of the CT scan, which was a median of 4.2 hours after presentation. We could not use the first draw troponin blood sample on ED presentation since it was used to determine study eligibility. Since an earlier hsTnT draw of <3 hours from symptom onset have been reported to have less sensitivity as compared to that drawn at >3 hours, the initial reduced sensitivity from an earlier draw of troponin may lead to even more profound results when used in combination with the natriuretic peptides. Further prospective studies examining these biomarkers in combination at initial ED presentation would be of great utility for this ED cohort and help facilitate triage decision.