Systematic review, meta-analysis and economic modelling of ...

Background2. investigation of the cost-effectiveness of multislice CTCA as a first-line test for ruling out obstructiveCAD in patients with suspected troponin-negative acute coronary syndromes.Description of technology under assessmentHigh-sensitivity troponin and alternative biomarkersThe cardiac troponins form part of the cardiac contractile apparatus, the troponin–tropomyosin complex,and comprise three troponins [troponin C (TnC), troponin I (TnI) and troponin T (TnT)] plus tropomyosin.As they have unique structures, immunoassays to measure TnT and TnI were developed, and preliminarystudies demonstrated that the measurement of cardiac troponin was both more sensitive and morespecific for myocardial injury than previously used biomarkers [creatine kinase (CK) and creatine kinase MBisoenzyme (CK-MB)]. TnT or TnI is now the recommended biomarker for MI. 7The original redefinition of acute MI suggested that the analytical imprecision of the assay should allowmeasurement with a low analytical imprecision within the reference interval of the assay. This qualityspecification was not met by the assays available at the time and resulted in progressive improvement inassay quality to produce the current generation of sensitive troponin assays. Sensitive troponin assays arecapable of measuring troponin in healthy individuals with a high degree of analytical imprecision, typically< 10% imprecision at the 99th percentile of a reference population.In addition to meeting the quality specification stipulated in the universal definition of acute MI, the newsensitive assays can detect myocardial injury substantially earlier than the previous generation of assays.Progressive improvement in the analytical performance of troponin assays demonstrated that the analyticalperformance of second- and third-generation assays was already beginning to outstrip that of othermarkers of myocardial injury, such as myoglobin and CK-MB, 17,18 and studies of new high-sensitivity assayssuggest that they are superior to all of the conventional markers of myocardial injury. 19,20Systematic reviews have established the diagnostic 10 and prognostic 8 accuracy of troponin testingin suspected ACS, and a systematic review of the diagnostic accuracy of troponin, CK, CK-MB andmyoglobin 21 established that troponin has the highest accuracy for MI. Measurement of troponin levelsat 10–12 hours after symptom onset is now standard diagnostic practice for suspected ACS. 11 Thereis effectively no potential for alternative biomarkers to improve on the diagnostic accuracy of a 10- to12-hour troponin assay for MI, as this forms the reference standard. 7 However, alternative biomarkersmay have a role in addressing two limitations of troponin measurement. First, the limited early sensitivityof troponin means that there is the potential for biomarkers with better early sensitivity for MI to improvecare. Second, although a negative 10- to 12-hour troponin assay stratifies patients to a low risk of adverseoutcome, this does not equate to a negligible risk. Thus alternative biomarkers may have a useful role infurther risk stratifying patients with a negative 10- to 12-hour troponin assay result.The relative insensitivity of the early generation of cardiac troponin assays led to the suggestion that smallcytoplasmic proteins that would leak earlier through the ischaemic myocardial cell membrane wouldprovide early sensitive diagnostic information in patients presenting with acute chest pain. Myoglobin isa single-chain globular protein containing a haem prosthetic group and is the primary oxygen storageprotein of muscle tissues that could be an early marker for MI.An alternative approach was to find markers that would be released when myocardial ischaemia occurred.Ischaemia-modified albumin (IMA) is a form of human serum albumin in which the N-terminal amino acidshave been affected by ischaemia so as to be unable to bind transition metals. Fatty acid-binding proteinsare relatively small proteins, of 126–137 amino acids in length, present in tissues with an active fattyacid metabolism, such as heart, liver and intestine. The myocardial isoform, heart-type fatty acid-bindingprotein (H-FABP), is present predominantly in the heart, but is also found in other tissues including skeletalmuscle and the distal tubal cells in the kidney.4NIHR Journals Library