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Requiem for a Heavyweight

2008; Lippincott Williams & Wilkins; Volume: 118; Issue: 21 Linguagem: Inglês

10.1161/circulationaha.108.773218

1524-4539

Amy K. Saenger, Allan S. Jaffe,

Coronary Interventions and Diagnostics

HomeCirculationVol. 118, No. 21Requiem for a Heavyweight Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBRequiem for a HeavyweightThe Demise of Creatine Kinase-MB Amy K. Saenger, PhD and Allan S. Jaffe, MD Amy K. SaengerAmy K. Saenger From the Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology (A.K.S., A.S.J.), and the Cardiovascular Division, Department of Medicine (A.S.J.), Mayo Clinic and Mayo Clinic Medical School, Rochester, Minn. and Allan S. JaffeAllan S. Jaffe From the Division of Laboratory Medicine, Department of Laboratory Medicine and Pathology (A.K.S., A.S.J.), and the Cardiovascular Division, Department of Medicine (A.S.J.), Mayo Clinic and Mayo Clinic Medical School, Rochester, Minn. Originally published18 Nov 2008https://doi.org/10.1161/CIRCULATIONAHA.108.773218Circulation. 2008;118:2200–2206The development of rapid, automated, and accurate laboratory testing for creatine kinase MB (CK-MB) revolutionized the treatment of patients with acute cardiac events in the 1970s and 1980s.1 To clinicians, CK-MB values augmented a thorough history, physical, and ECG findings, and elevations rapidly became the gold standard for identifying cardiac injury.1 CK-MB allowed earlier diagnosis of acute myocardial infarction (AMI), and detection of reinfarction, and measurements could be used to provide a facile clinical estimate of infarct size. Elevations of CK-MB were never intended to be synonymous with myocardial infarction, only indicative of cardiac injury.1 However, because of the relative insensitivity of measurements, increased concentrations occurred predominantly with larger insults such those associated with acute ischemic heart disease. For that reason, AMI was rarely diagnosed, assuming appropriate timing of the samples, in the absence of a CK-MB elevation.2,3CK-MB assays initially relied on the measurement of enzyme activity, but over time, improved accuracy and ease of use were established by the use of mass assays. Mass assays allowed earlier detection of abnormal values and improved both clinical sensitivity and specificity. However, mass assays unmasked an increased frequency of CK-MB elevations due primarily to skeletal muscle injury because of their increased sensitivity.4–6 Clinical use of the percent relative index was then initiated. This approach improved the specificity of elevations for cardiac muscle injury but was insensitive when concurrent cardiac injury and skeletal muscle injury were present because elevations from skeletal muscle often are of a large magnitude.7–10 A large number of analytical confounds such as macrokinases and interfering substances also were substantial problems with these assays.10,11 Attempts to standardize assays12 have been partially successful, but differences still exist between manufacturers and even between the same testing antibodies used on different analytical platforms (ie, small versus large automated instruments). A frequency of up to 20% "false-positive" levels, thought to be due to skeletal muscle injury, was reported in patients with renal failure.13,14 This was only one of many conditions such as noncardiac surgery, chest trauma, asthma, pulmonary embolism, chronic and acute muscle disease, head trauma, hyperventilation, and hypothyroidism in which CK-MB was elevated in the absence of cardiac injury.11 In some ways, analytical tribulations and the lack of cardiac specificity provided clinicians with more flexibility in their decision-making processes. Enough analytical and physiological reasons not related to cardiac injury were available that elevations of CK-MB in any given patient could be considered false positives if the physician did not believe the assay results fit the clinical presentation. It was clear that cardiac biomarkers with better specificity and sensitivity were needed.Transformations Caused by the Advent of TroponinThe development of cardiac troponin I and T assays has revolutionized this arena. Troponin elevations are nearly totally specific for cardiac injury15,16 except for infrequent analytical false positives caused by fibrin interference and/or cross-reacting antibodies, interferences that are far less frequent with contemporary assays and are inherent to any immunoassay testing. In high-quality clinical laboratories, these issues are recognized and easily dealt with by repeat centrifugation, testing on alternative platforms, dilution studies, and/or the use of heterophile blocking agents. In addition, troponin is substantially more sensitive than CK-MB,8,17 related to the fact that more troponin is found in the heart per gram of myocardium and that a greater percentage depleted from the heart by cardiac injury arrives in the blood.9,18–21 It is now clear that minor cardiac injury occurs in many situations, and in most circumstances, the associated increases in troponin values correlate with adverse short- and long-term outcomes.22–30 This fact demonstrates that cardiac injury is a component of many nonischemic syndromes, but it also makes it difficult for physicians to disregard any elevated troponin values. Clinicians are forced to deal with new and at times undefined causes of the discernible elevations for which little practical guidance is available on how to proceed with patient care. This phenomenon is likely to continue as analytical detection limits, accuracy, and precision of troponin immunoassays constantly improve. It suggests the need for more research in these important areas.Use of Troponin in 2008Diagnosis of AMIWhen troponin assays were first introduced clinically, it was unclear how to properly interpret values. In addition, a surfeit of data existed on the estimation of infarct size, diagnosis of reinfarction, and use of troponin after interventional procedures. Extensive data now indicate that troponin, because of its better sensitivity and specificity, provides at least comparable and often superior information than can be gleaned from CK-MB once it is appreciated how to use the marker (the Table). Troponin is the preferred marker of both the clinical (American College of Cardiology/European Society of Cardiology/American Heart Association [ACC/ESC/AHA])31 and biochemical (National Academy of Clinical Biochemistry) guidelines groups.32,33 With the use of contemporary high-sensitivity troponin assays and the 99th percentile cutoff values advocated by these groups,31–33 it has been observed that troponin levels rise by 2 to 3 hours after the onset of chest discomfort. Thus, in upwards of 80% of patients, a definitive rule-in diagnosis can be made in 2 to 3 hours with troponin.34 A definitive rule-out diagnosis takes longer, and the most recent guidelines suggest that samples be obtained at baseline, at 6 hours, and again at 12 hours in occasional patients in whom suspicion is very high.31,33 For those who wish to facilitate the movement of patients from an emergency department setting, a 2- or 3-hour sample may be considered.34 No evidence exists that CK-MB adds to the accuracy and/or rapidity of this serial sampling approach. Approximately 10% of an acute coronary syndrome population is made up of individuals with normal troponin values and increased CK-MB,35 and these patients have excellent outcomes,36 confirming the lack of specificity of CK-MB in this situation. Thus, CK-MB adds only increased cost. Furthermore, because of the ability to make an early diagnosis with troponin, several studies suggest that the previously touted "rapidly rising" markers that lack specificity such as myoglobin, CK-MB, and fatty acid binding protein are no longer needed.37–40 Patients who have an elevated troponin but not an elevated CK-MB have an increased risk for developing future cardiac events, morbidity, and mortality.25,34 Several studies suggest that the use of these more sensitive assays and cutoff values identifies many more (30% to 130%, depending on the study) patients who meet the criteria for AMI and are at risk.35,41–48 Prognostic studies suggest that this group is very similar to those with non–ST-segment elevation myocardial infarction identified by CK-MB. In some studies, these patients have been shown to have a worse prognosis,49 but that finding may be due to differences in treatment before the potent prognostic effects of troponin were recognized. Other studies have shown slightly lower event rates after non–ST-segment elevation myocardial infarction defined by troponin concentrations alone,50 but in each study, the time course of events has been similar between groups. Of equal importance is the fact that troponin elevations in patients with acute coronary syndrome have been shown to predict benefit from specific anticoagulant, antiplatelet, and invasive therapies in multiple large randomized clinical trials.31,33Table. Use of TroponinSituationCriteriaPCI indicates percutaneous coronary intervention; cTn, cardiac troponin; and CABG, coronary artery bypass graft surgery.AMIRising or falling values with at least 1 value above the 99th percentile of the reference rangeReinfarctionAn increase of values >20% over a 6-h periodPost-PCINormal baseline cTn; increases >3-fold (by convention) above the reference rangeBaseline cTn elevated but stable; use criteria for reinfarctionBaseline cTn elevated but changing; no criteria can distinguish injury related to the index event from that potentially caused by PCIPost-CABG AMIA 5-fold increase in cTn with other clinical evidence (eg, ECG or imaging)Infarct sizeCorrelation best with 72- to 96-h troponin concentrationRenal failureAll elevations of cTn are highly prognosticPatients with acute events have changing values despite the elevated baselineChronic elevation not associated with renal failureAll elevations of cTn are highly prognosticPatients with acute events have changing values despite the elevated baselineCritically illElevations predict short- and long-term outcomes; therapy if AMI is not present is usually oriented toward the underlying diseaseExtreme exerciseElevations are transient (24 h) and are not associated with an increased incidence of short-term cardiac eventsDespite the fact that CK-MB values are no longer necessary to make the primary diagnosis of AMI, clinicians continue to use it. One reason is that tests that have assisted us for many years are hard to give up. A second reason is that clinicians, despite nearly 15 years of experience with troponin measurements, are still not comfortable with how to use the data in certain clinical situations. Thus, many do not make the diagnosis of AMI even when criteria with troponin have been met.50 Some of this is appropriate because it is integral to the diagnosis of AMI for biomarker elevations to occur in the appropriate clinical context; ie, the clinical circumstances and ECG are key to the diagnosis of AMI.31,33 If the clinical situation is not one in which acute ischemia is suggested clinically, another explanation for the troponin elevation should be sought.51 We would contend that investing in learning how to use troponin concentrations properly will result in better clinical care and a reduction in cost owing to the elimination of the need for other biomarkers, including CK-MB.Estimation of Infarct SizePrognosis after AMI is closely related to the extent of myocardial damage. Calculations based on the analysis of serial levels of total CK or CK-MB have provided this estimate for many years since the pioneering work of Geltman et al,52 Roberts et al,53,54 and Marmor et al.55 For clinicians, peak values provide a reasonable clinical estimate if sufficient samples are present56 and if factors such as reperfusion (which changes the kinetics and magnitude of CK-MB release) are considered. For some, this has been a rationale for retaining the use of CK-MB. Recent data comparing cardiac troponin concentrations with imaging suggest that troponin values provide similar, and indeed often superior, estimates of infarct size. Ingkanisorn et al57 published the first work investigating the association between early troponin values and infarct size in patients with acute coronary syndromes. They reported that peak troponin I correlated with acute infarct mass in patients undergoing acute primary percutaneous coronary intervention (r=0.83, P 10 years of experience using troponin in the clinical arena, it is time for clinicians to learn how to use cardiac troponin properly and, in doing so, let our old friend CK-MB rest.We thank Drs Raymond Gibbons and Bernard Gersh for their astute review of this manuscript.DisclosuresDr Jaffe is or has been a consultant to most of the major diagnostic companies that make troponin and CK-MB assays. Dr Saenger has received grant funding from Roche Diagnostics.FootnotesCorrespondence to Allan S. Jaffe, MD, Cardiovascular Division, Gonda 5, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail [email protected] References 1 Jaffe AS. Biochemical detection of acute myocardial infarction. In: Gersh B, Rahimtoola S, eds. Acute Myocardial Infarction. New York, NY: Elsevier; 1991: 110–127.Google Scholar2 Roberts R. 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