Detecting cardiac events – state-of-the-art

Abstract

Cardiac biomarker measurement currently addresses two key questions in patient management: the differential diagnosis of chest pain and the differential diagnosis of the patient with breathlessness. There are currently three major themes in the strategies for the differential diagnosis of chest pain. The first is to undertake troponin measurement in patients selected to be at lower risk, hence to have a low prior probability of disease. The second is the introduction of high-sensitivity cardiac troponin (hs cTn) assays into routine clinical use with measurement at 0 and 3 h from admission. Two other approaches that utilize the diagnostic characteristics of these assays have also been suggested. The first is to use the limit of detection or limit of blank of the assay as the diagnostic discriminant. The second approach is to use the low imprecision of the assay within the reference interval and combine a discriminant value with an absolute rate of change (delta value). The third is the use of additional biomarkers to allow early discharge from the emergency department. The concept is to measure high-sensitivity cardiac troponin plus the extra marker on admission. The role of measurement of B-type natriuretic peptide or its N-terminal prohormone, N-terminal pro-B-type natriuretic peptide, has been accepted and incorporated into guidelines for chronic heart failure for some time. More recently, guidelines for acute heart failure can also recommend a single measurement of B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide in people presenting with new suspected acute heart failure.

Introduction

Cardiac biomarker measurement currently addresses two key questions in patient management. The first question is the differential diagnosis of chest pain, in particular, is the chest pain caused by an acute myocardial infarction (AMI)? The second question is the differential diagnosis of the patient with breathlessness, specifically, does the patient have heart failure?

Cardiac biomarkers and the differential diagnosis of chest pain

There are currently three major themes in the strategies for the differential diagnosis of chest pain: (1) use of patient selection, (2) high-sensitivity troponin measurements and (3) the measurement of additional biomarkers.

Where troponin measurement is used in patients selected to be at lower risk, hence to have a low prior probability of disease, the objective is to combine the diagnostic sensitivity of rule out based on cardiac troponin (cTn) with the good prognosis of low-risk populations. Two approaches have been taken. The first is to use shorter time intervals (troponin measurement at 0 and 2–3 h from admission) with populations selected on clinical criteria such as normal electrocardiogram (ECG) and atypical clinical features. In the second, a more rigorous approach is to use a systematic scoring system to assign risk and only use low-risk patients. This approach has been pioneered and developed by emergency department physicians in Australasia. ¹

The second theme has been the introduction of high-sensitivity cardiac troponin (hs cTn) assays into routine clinical use. A high-sensitivity assay is pragmatically defined as one where the 10% coefficient of variation is less than the 99th percentile of the reference population, which will also detect (above the limit of detection of the assay) at least 50% of the reference population. The use of hs cTn assays and measurement at 0 and 3 h from admission rather than 6 or 10–12 h from admission has recently been supported by the National Institute for Health and Clinical Excellence (NICE). ² Two other approaches that utilize the diagnostic characteristics of these assays have also been suggested. The first is to use the limit of detection (LOD) or limit of blank (LOB) of the assay as the diagnostic discriminant. It has been suggested that an hs cTn value below the LOD/LOB identifies a low-risk group with a very high negative predictive value. The second approach is to use the low imprecision of the assay within the reference interval and combine a discriminant value with an absolute rate of change (delta value). A study of 1282 patients with chest pain measured high-sensitivity cardiac troponin T (hs cTnT) on admission and 1 h from admission. Patients were divided into one of three diagnostic groups. The first (rule out group) had 0 h hs cTnT < 12 ng/L and 1 h delta < 3 ng/L. This comprised 813 patients and had a negative predictive value of 99.1%. The second (rule in group) had a 0 h hs cTnT > 52 ng/L and a 1 h delta > 5 ng/L. This comprised 184 patients and had a positive predictive value of 77.2%. Patients who fell in the intermediary group (n = 285) had an AMI prevalence of 22.5%. Hence, within 1 h 63.4% of patients could be ruled out, 14.4% ruled in with only 22.2% requiring further emergency department assessment. ³

Measurement of hs cTn and the use of gender-specific discriminants allow better case detection in women. ⁴ Ischaemic heart disease is underdiagnosed and undertreated in women. The use of hs cTn assays allows the problem of under diagnosis to be overcome. Finally, comparison of conventional and high-sensitivity assays shows that high-sensitivity assays detect prognostically significant disease missed by conventional sensitive assays. ⁵

The third theme is the use of additional biomarkers to allow early discharge from the emergency department. The concept is to measure hs cTn plus the extra marker on admission. An hs cTn value below the 99th percentile plus the second marker value being below an appropriate discriminant point would allow immediate discharge. Here, the idea is that the other marker measures myocardial injury or dysfunction or alternatively provides additive prognostic value. The key questions then are: has this marker been measured with an appropriate method and shown to be additive to an hs cTn method? Is there appropriate clinical evidence, ideally from a randomized controlled trial? And finally, Can the marker be measured in a clinical laboratory without additional equipment and staff? At the moment, the only significant candidate marker is co-peptin but further evidence is required.

Cardiac biomarkers for the differential diagnosis of breathlessness

The role of measurement of B-type natriuretic peptide (BNP) or its N-terminal prohormone, NT pro-BNP has been accepted and incorporated into guidelines for chronic heart failure for some time. ⁶ More recently, guidelines for acute heart failure have also recommended a single measurement of BNP or NT pro-BNP in people presenting with new suspected acute heart failure followed by echocardiography if BNP or NT pro-BNP concentrations are increased. ⁷ The role of serial measurement of BNP or NT pro-BNP for treatment monitoring remains controversial. ⁸ One potential problem is the arrival of a new class of drugs, neutral endopeptidase inhibitors. These drugs work by inhibiting the breakdown of BNP and hence have a profound effect on BNP concentrations in the circulation. If these drugs achieve widespread clinical use they may have a significant impact on the diagnostic utility of BNP measurement in patients who are already treated, although measurement will still be useful in treatment naive individuals. It would appear from preliminary evidence that NT pro-BNP measurement may be useful, however, including potentially in treatment monitoring.