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Appendix 9Clinical diagnosis of NSTEMI, according to the universal definition of MI [5], is based upon an elevation ofcardiac biomarkers (preferably troponin) above the 99th percentile of the upper reference limit. Patientswith an elevated troponin have an increased risk of adverse outcome and can benefit from hospitaladmission and treatment. However, troponin does not achieve optimal sensitivity for MI until several hoursafter the symptoms of MI [6] so guidelines typically recommend delaying sampling until 10–12 h aftersymptom onset. Most patients with suspected ACS present to hospital within a few hours of symptomonset, so delaying blood sampling usually incurs costs of hospital observation and/or admission. Earlierblood sampling is cheaper but may miss cases of MI, so the timing of sampling and tests used involve atrade-off between cost and accuracy.Diagnosis of underlying CADMany patients with suspected ACS are known to have CAD and are receiving secondary preventativetreatment. However, a substantial proportion of patients have not previously been investigated forCAD. Once MI has been ruled out these patients may be investigated for underlying CAD by eitherprovocative cardiac testing to identify symptoms of CAD induced by exertional or pharmacological stressor anatomical imaging of the coronary arteries. Identification of CAD allows treatment with aspirin,statins and angiotensin converting enzyme inhibitors to be commenced and consideration of coronaryrevascularisation for high-risk cases.Unstable anginaInvestigation of suspected ACS also involves identification and treatment of patients with unstable angina.These patients have CAD and worsening symptoms but no evidence of cardiac damage. Previously theyconstituted the majority of patients with suspected ACS. However, the increasing sensitivity of biochemicaltests for myocardial damage, and the redefinition of MI to include all patients with evidence of myocardialdamage, means that patients with unstable angina and no myocardial damage are fewer in numberand have a relatively low risk of adverse outcome. Furthermore, in the absence of ECG changes there aresubstantial difficulties defining which patients have unstable angina, since the diagnosis is based uponunreliable clinical features. These factors make it difficult to define the population with unstable anginaand estimate any benefits from treatment, beyond secondary prevention for underlying CAD.Uncertainties in the investigation of suspected ACSThere have been many published guidelines for the investigation of suspected ACS. Most recently theNational Institute for Health and Clinical Excellence (NICE) has issued draft guidance for the managementof patients with acute chest pain due to possible ACS [1]. These guidelines have identified areas ofuncertainty where further research is required. These are:1. Evaluation of new, high sensitivity troponin assay methods in low, medium and high-risk groups withacute chest pain, and evaluation of other putative biomarkers in comparison with the diagnostic andprognostic performance of the most clinically effective and cost-effective troponin assays.2. Investigation of the cost-effectiveness of multislice CT coronary angiography as a first-line test forruling out obstructive CAD in patients with suspected troponin-negative acute coronary syndromes.Evaluation of new troponin assays and other biomarkersThe draft NICE guidelines recommend measurement of troponin levels at 10–12 h after the onset ofsymptoms to accurately identify cases of MI. This is based upon evidence that troponin levels predictsubsequent risk of adverse outcome [7] and response to treatment [8], but do not achieve optimalsensitivity until 10–12 h after symptom onset [6]. However, delaying blood testing until 10–12 h aftersymptom onset is inconvenient for patients and often incurs additional health-care costs associatedwith hospital admission and/or observation. Various alternative strategies have been proposed for earlierdiagnosis of MI using combinations of biomarkers, measuring biomarker gradients and using newer, moresensitive troponin assays.178NIHR Journals Library
DOI: 10.3310/hta17010 Health Technology Assessment 2013 Vol. 17 No. 1Systematic reviews have established the diagnostic [6] and prognostic [7] accuracy of troponin testingin suspected ACS. A systematic review of the diagnostic accuracy of troponin, creatinine kinase, CK-MBand myoglobin [9] established that troponin has the highest accuracy for MI. Sensitivity and specificity ofother markers were more modest but could be improved by serial testing, measurement of the gradientrise and using combinations of biomarkers. A systematic review of 22 novel biomarkers, includingC-reactive protein, myeloperoxidase, B-type natriuretic peptide and heart-type fatty acid-binding protein[10], concluded that there was insufficient evidence to support the use of these biomarkers in emergencydepartment assessment of suspected ACS. However, more data have emerged since these reviews werepublished suggesting that early biomarker testing with combinations of troponin, CK-MB and myoglobinmay have comparable sensitivity to delayed troponin testing, and some novel biomarkers may provideadditional prognostic information in patients with troponin negative suspected ACS. In addition, newertroponin assays capable of detecting changes within the reference interval and capable of significantlyearlier detection have been developed and are entering, or have entered, routine clinical use.Two economic analyses have examined the cost-effectiveness of biomarker strategies in the NHS. Goodacre[11] used a decision analysis model to compare five strategies for patients with undifferentiated chest painand showed that rapid biomarker testing was most likely to be cost-effective in the NHS while hospitaladmission was unlikely to be cost-effective. This analysis only evaluated five potential strategies and didnot explore uncertainty in estimates. Mant [12] used modelling to compare four strategies for identifyingST-elevation MI and to compare three models of care for patients presenting to primary care with possibleangina. The modelling did not therefore evaluate the cost-effectiveness of biomarkers in patients withsuspected ACS. Two studies from outside the UK have suggested that the use of troponin T is cost-effectivecompared with CK-MB [13,14], but neither evaluated other biomarker strategies in suspected ACS.In summary, there is not yet convincing evidence that alternative biomarker strategies can match thediagnostic accuracy of a 10–12 h troponin. However, there are several reasons why a 10–12 h troponinmay not be the optimal approach for the NHS:1. Diagnostic data for alternative biomarker strategies have not to date been comprehensively andsystematically summarised.2. Alternative biomarkers may provide additional prognostic information beyond that provided by a10–12 h troponin.3. Selection of an optimal strategy is fundamentally an issue of cost-effectiveness. A 10–12 h troponinmay not be cost-effective compared with earlier strategies, even if it is more accurate, if the benefit ofmore accurate diagnosis does not justify the additional costs associated with delayed testing.Systematic reviews of potential biomarker strategies for suspected ACS need to be updated and includeanalysis of the additional prognostic value provided by these tests. Cost-effectiveness analysis is required tocompare potential biomarker strategies in suspected ACS from the perspective of the NHS. This will allowus to determine what is the optimal strategy for the NHS on the basis of currently available data. It willalso allow us to identify the most promising biomarker strategies for future evaluation and the key areas ofuncertainty for primary research.Multislice CT coronary angiography for troponin negative suspected ACSOnce MI has been ruled out by a negative 10–12 hour troponin (or alternative biomarker strategy) currentEuropean Society of Cardiology guidelines recommend using a stress test (typically exercise ECG) to selectpatients for further investigation with coronary angiography [15]. Most studies of the diagnostic accuracyof exercise ECG have been undertaken in patients with stable symptoms rather than suspected ACS.The most recent meta-analysis [12] of the diagnostic accuracy of exercise ECG reported that the maindiagnostic criterion (ST depression) performed only moderately well, with a positive likelihood ratio of2.79 for a 1-mm cutoff and 3.85 for a 2-mm cutoff. The negative likelihood ratios were 0.44 and 0.72© Queen’s Printer and Controller of HMSO 2013. This work was produced by Goodacre et al. under the terms of a commissioning contract issued by the Secretary of Statefor Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journalsprovided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should beaddressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton SciencePark, Southampton SO16 7NS, UK.179
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DOI: 10.3310/hta17010 Health Techno
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ContentsAppendix 5 Expected discoun
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BackgroundTABLE 1 Hospital admissio
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Background2. investigation of the c
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BackgroundComputed tomographic coro
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Research questionsiii. the diagnost
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Assessment of diagnostic and progno
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Discussionspecificity were 62% (95%
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Discussionneed for revascularisatio
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Discussionchanges in sensitivity an
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Discussionuncertainty about these p
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Discussiontroponin assays have bett
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ConclusionsSuggested research prior
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Page 156 and 157: Appendix 1135. interleukin 33.mp. (
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