how low can we go? the high-sensitivity cardiac troponin debate

4
CARDIOLOGY/EDITORIAL How Low Can We Go? The High-Sensitivity Cardiac Troponin Debate Alan B. Storrow, MD; Thomas A. Lardaro, MD, MPH; Pauline T. Alexander, MLIS, MPH; Fred S. Apple, PhD 0196-0644/$-see front matter Copyright © 2013 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2013.03.021 A podcast for this article is available at www.annemergmed.com. [Ann Emerg Med. 2013;62:580-583.] Recently published investigations using high-sensitivity cardiac troponin assays highlight many challenges we will encounter as these tests are deployed. 1-8 Cardiac troponin’s analytic sensitivity has decreased into the nanograms per liter (picograms per milliliter) range and is now measurable in the serum and plasma of healthy individuals with normal levels. A test once simply considered a dichotomous yes or no for the diagnosis of acute myocardial infarction has become considerably more complex and detectable in a wide range of clinical conditions. 9-11 Our discipline would benefit from a deeper understanding of these analytically improved, evolving tests and related clinical implications. Better insight into the debate surrounding high-sensitivity cardiac troponin assays will act as an essential driver to promote collaboration with laboratory medicine, primary care physicians, and cardiology, as well as encourage a unified approach to their use at the institutional level. This begins with defining high sensitivity, discussing how our clinical approach must adapt, and understanding that cardiac troponin levels represent a continuum of cardiac myocardial necrosis, rather than simply a dichotomous biomarker for acute myocardial infarction. HIGH SENSITIVITY A number of recent reports detailed increased diagnostic and prognostic accuracy of high-sensitivity cardiac troponin across a spectrum of cardiovascular diseases, including acute coronary syndrome. 12-14 Although a consistent definition of high sensitivity seems essential for both clinical and analytic purposes, it has unfortunately not reached consensus. Analytically, high sensitivity is defined as the ability to detect low level values for a given substance, more commonly reported as a test’s ability to determine whether the majority of healthy subjects in a given population have a measured value above that assay’s limit of detection, as well as the ability of the assay to have a coefficient of variation (CV) percentage of less than 10% at the 99th percentile reference value (Table). 15,16 The term “sensitivity” reflects an assay’s analytic characteristics and not the cardiac troponin type (cardiac troponin I or T) measured. 17 Clinically, high sensitivity refers to an increased and early ability to detect both acute myocardial infarction and structural cardiac injury, with concurrent increased morbidity, at the expense of decreased clinical specificity for acute myocardial infarction detection. Although determining high-sensitivity cardiac troponin changes over time ( change) has been shown to improve specificity, the cornerstone of the clinical debate is concern that lower specificity will cause harm through increased false-positive results (clinical for myocardial infarction, not analytic false-positive results) and unnecessary interventions. Expert guidelines have provided a universal definition of myocardial infarction and established ideal diagnostic parameters for cardiac troponin assays. 18 The Joint ESC/ACCF/ AHA/WHF Task Force for the Third Universal Definition of Myocardial Infarction endorses the use of a 99th percentile value for a healthy population, as long as the assay delivers acceptable precision at this level. 17 Consensus defines optimal precision as 10% CV at the 99th percentile value, although a CV of less than 20% is considered clinically acceptable. 18 Most contemporary cardiac troponin assays lack the ability to deliver precise measurements below the 99th percentile (% CV 20%) or the ability to measure cardiac troponin below the 99th percentile. 19 High-sensitivity assays, however, detect cardiac troponin concentrations at or below guideline-recommended 99th percentile threshold in greater than 50% of healthy subjects. 19 Cardiac troponin (I or T) values that exceed the 99th percentile threshold and continue to increase over time are the criterion standard biomarker for MI diagnosis. 20 Use of high- sensitivity cardiac troponin assays (currently not approved by the Food and Drug Administration for US use) will identify more at-risk patients who meet the definition of acute myocardial infarction at earlier intervals. 21-23 Conversely, high- sensitivity assay advances also decrease specificity and raise concerns surrounding therapeutic choices for clinicians who may incorrectly equate any abnormal cardiac troponin value with an acute myocardial infarction. 24,25 Observations do suggest that increases caused by almost any mechanism of cardiac injury are associated with worse outcomes. 23,25 However, identification of worse prognosis, generally demonstrated in populations, is sometimes difficult in translation to prognostic value related to clinical effects and actionable maneuvers on individual patients. 26 Apple and Collinson 17 further define high sensitivity by using a scorecard concept 15 that involves 2 criteria: “1) the total 580 Annals of Emergency Medicine Volume , . : December

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Page 1: How Low Can We Go? The High-Sensitivity Cardiac Troponin Debate

CARDIOLOGY/EDITORIAL

How Low Can We Go? The High-Sensitivity CardiacTroponin Debate

Alan B. Storrow, MD; Thomas A. Lardaro, MD, MPH; Pauline T. Alexander, MLIS, MPH; Fred S. Apple, PhD

0196-0644/$-see front matterCopyright © 2013 by the American College of Emergency Physicians.http://dx.doi.org/10.1016/j.annemergmed.2013.03.021

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A podcast for this article is available at www.annemergmed.com.

[Ann Emerg Med. 2013;62:580-583.]

Recently published investigations using high-sensitivitycardiac troponin assays highlight many challenges we willencounter as these tests are deployed.1-8 Cardiac troponin’sanalytic sensitivity has decreased into the nanograms per liter(picograms per milliliter) range and is now measurable in theserum and plasma of healthy individuals with normal levels. Atest once simply considered a dichotomous yes or no for thediagnosis of acute myocardial infarction has becomeconsiderably more complex and detectable in a wide range ofclinical conditions.9-11 Our discipline would benefit from adeeper understanding of these analytically improved, evolvingtests and related clinical implications. Better insight into thedebate surrounding high-sensitivity cardiac troponin assays willact as an essential driver to promote collaboration withlaboratory medicine, primary care physicians, and cardiology, aswell as encourage a unified approach to their use at theinstitutional level. This begins with defining high sensitivity,discussing how our clinical approach must adapt, andunderstanding that cardiac troponin levels represent acontinuum of cardiac myocardial necrosis, rather than simply adichotomous biomarker for acute myocardial infarction.

HIGH SENSITIVITYA number of recent reports detailed increased diagnostic and

prognostic accuracy of high-sensitivity cardiac troponin across aspectrum of cardiovascular diseases, including acute coronarysyndrome.12-14 Although a consistent definition of highsensitivity seems essential for both clinical and analyticpurposes, it has unfortunately not reached consensus.Analytically, high sensitivity is defined as the ability to detectlow level values for a given substance, more commonly reportedas a test’s ability to determine whether the majority of healthysubjects in a given population have a measured value above thatassay’s limit of detection, as well as the ability of the assay tohave a coefficient of variation (CV) percentage of less than 10%at the 99th percentile reference value (Table).15,16 The term“sensitivity” reflects an assay’s analytic characteristics and notthe cardiac troponin type (cardiac troponin I or T) measured.17

Clinically, high sensitivity refers to an increased and early ability

to detect both acute myocardial infarction and structural cardiac u

580 Annals of Emergency Medicine

njury, with concurrent increased morbidity, at the expense ofecreased clinical specificity for acute myocardial infarctionetection. Although determining high-sensitivity cardiacroponin changes over time (� change) has been shown tomprove specificity, the cornerstone of the clinical debate isoncern that lower specificity will cause harm through increasedalse-positive results (clinical for myocardial infarction, notnalytic false-positive results) and unnecessary interventions.

Expert guidelines have provided a universal definition ofyocardial infarction and established ideal diagnostic

arameters for cardiac troponin assays.18 The Joint ESC/ACCF/HA/WHF Task Force for the Third Universal Definition ofyocardial Infarction endorses the use of a 99th percentile

alue for a healthy population, as long as the assay deliverscceptable precision at this level. 17 Consensus defines optimalrecision as 10% CV at the 99th percentile value, although aV of less than 20% is considered clinically acceptable.18 Most

ontemporary cardiac troponin assays lack the ability to deliverrecise measurements below the 99th percentile (% CV �20%)r the ability to measure cardiac troponin below the 99thercentile.19 High-sensitivity assays, however, detect cardiacroponin concentrations at or below guideline-recommended9th percentile threshold in greater than 50% of healthyubjects.19

Cardiac troponin (I or T) values that exceed the 99thercentile threshold and continue to increase over time are theriterion standard biomarker for MI diagnosis.20 Use of high-ensitivity cardiac troponin assays (currently not approved byhe Food and Drug Administration for US use) will identifyore at-risk patients who meet the definition of acuteyocardial infarction at earlier intervals.21-23 Conversely, high-

ensitivity assay advances also decrease specificity and raiseoncerns surrounding therapeutic choices for clinicians whoay incorrectly equate any abnormal cardiac troponin valueith an acute myocardial infarction.24,25 Observations do

uggest that increases caused by almost any mechanism ofardiac injury are associated with worse outcomes.23,25

owever, identification of worse prognosis, generallyemonstrated in populations, is sometimes difficult inranslation to prognostic value related to clinical effects andctionable maneuvers on individual patients.26

Apple and Collinson17 further define high sensitivity by

sing a scorecard concept15 that involves 2 criteria: “1) the total

Volume , . : December

Page 2: How Low Can We Go? The High-Sensitivity Cardiac Troponin Debate

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Storrow et al High-Sensitivity Cardiac Troponin Debate

imprecision (CV) at the 99th percentile value should be �10%, and 2) measurable concentrations below the 99thpercentile should be attainable with an assay at a concentrationvalue above the assay’s limit of detection for at least 50% (andideally � 95%) of healthy individuals to attain the highestsensitivity level of scorecard designation.”14

Obtaining measurable concentrations in a high percentage ofhealthy subjects is troublesome to the emergency physician27;some would suggest that contemporary assays, from a clinicalstandpoint, are sufficient and perhaps preferable. Furthermore,high-sensitivity cardiac troponin assays will identify more true-positive results but conversely detect more positive results notindicative of acute coronary syndrome but of nonvascular heartdisease or even noncardiac disease.6,28 Therefore,recommendations indicating that any detectable abnormalcardiac troponin level implies a higher risk for MI are a coreemergency department (ED) challenge. An elevated cardiactroponin level by itself does not indicate MI; rather, it is asensitive and specific determinant of cardiac myocardial necrosisand is nonspecific relative to cause.28

CLINICAL USEThe negative predictive value of undetectable or normal

levels,8 as well as earlier diagnosis, is a significant advantage tohigh-sensitivity cardiac troponin assays. The diagnostic dilemmalies in separating patients with acute coronary syndrome andinitially elevated cardiac troponin levels from those who mayhave a positive test result for non–acute coronary syndromereasons.29,30 Troponins are biomarkers of cardiac myocardialnecrosis and are not solely markers of acute myocardialinfarction. This singular issue accounts for most of the angstsurrounding cardiac troponin use, whether high-sensitivityassays or not. Numerous conditions, such as renal failure, heartfailure, and myocarditis, may lead to increased cardiac troponinlevels at baseline.6

Given the many non–acute coronary syndrome causes forelevated cardiac troponin levels, a 1-time elevated high-sensitivity cardiac troponin result is not sufficient to make thediagnosis of acute myocardial infarction; serial tests will improvethe ability (specificity) to rule out any chronic conditions thatmay affect levels. Although a single baseline level has predictivevalue,31 changing cardiac troponin levels are crucial in

Table. Definitions for concepts related to high-sensitivity tropon

Term

99th percentile reference value The recommended decisionmyocardial infarction.17,1

%CV A numeric representation fas the SD divided by thepercentage).45 Guidelinereference value of �10%

Limit of detection (LOD) The lowest quantity of a suthat can be detected wit

evaluating a patient for acute or chronic myocardial injury; an m

Volume , . : December

ncrease in assay values during the first 2 to 3 hours with high-ensitivity cardiac troponin assays shows an increased likelihoodf acute myocardial infarction.23 Thus, initial values alone,ithout documented imaging or ECG information, shouldsually not be interpreted as “rule in/out” but rather on aontinuum, as a risk-stratification tool, and always with clinicalontext. Because high-sensitivity assays can detect cardiacroponin values in healthy individuals, it is tempting to look forthreshold value that would differentiate acute pathology from

hronic or “normal.” Unfortunately, the true utility of high-ensitivity cardiac troponin assays lies in comparing a patient’sresenting value with a subsequent value. Although therecision of these assays is excellent, baseline high-sensitivityardiac troponin assays vary markedly,19 especially in patientsith comorbidities.3,32 In addition, a stable increased cardiac

roponin value does have prognostic value in many conditionsithout an associated acute coronary syndrome, such as heart

ailure,33-35 kidney disease,36 and sepsis,37 and in the criticallyll.38-40 Therefore, physicians should consider the change or �n cardiac troponin levels over time to separate acute myocardialnjury, characterized by an acute increase in assay values, from ahronic process that would likely maintain constant levels.41

Absolute or relative change in high-sensitivity cardiacroponin levels during an interval has been recently described,ith improved diagnostic specificity for baseline and at 60, 90,20, or 180 minutes.1-7 However, each cardiac troponin assayill require a specific � determination for both absolute and

elative change, and caregivers should be cautious about �seported from a single center, particularly small ones.21 Studiessing the high-sensitivity cardiac troponin T assay comparingbsolute with relative change from baseline suggest that anbsolute increase of greater than 7 ng/L during 2 hours wasuperior to a percentage change.3,7 However, most patientsresented late after symptom onset and had higher baselinealues.7 Algorithms for incorporation of high-sensitivity cardiacroponin assays into ED management have been proposed42,43

ut await large prospective studies for widespread adoption.Last, it is the opinion of some that the emphasis on a cardiac

roponin biomarker standard for the definition of MI18 haserhaps eroded the importance of clinical findings, diminishedhe value of the ECG, and marginalized the value of serial

Definition

e (upper reference value, or URL) for the confirmation or exclusion of

relative spread, total imprecision, or variation of a test. It is definedn of a population multiplied by 100 (thus expressed as ae endorsed a %CV of cardiac troponin assays at their 99th percentileough imprecision up to 20% may be used.18,46

ce that can be distinguished from the absence of that substance orsonable certainty.47

ins.

valu8,44

or themea

s hav, althbstan

easurements.26 As cardiac troponin assays become more

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analytically sensitive and precise at very low measurableconcentrations, these issues will become increasingly important.

CONCLUSIONHigh-sensitivity cardiac troponin assays, likely to be cleared

by the Food and Drug Administration in 2014, representexciting promise for earlier diagnostic accuracy for acutemyocardial infarction detection and improved risk outcomesassessment, but will arrive in the ED with unique interpretivechallenges. It is hoped that, if used correctly, high-sensitivityassays may allow for earlier, efficient, and safe ED patientdischarge and free up limited resources. Optimal timing and �value cutoffs have been initially explored but await largerprospective studies and local determinations of specific �s,whether absolute concentration or percentage changes during 2to 3 hours, for each cardiac troponin assay and platform.Integration of clinical data, temporal changes, and experience inbroader populations will become increasingly important indeciding whom to test and what diagnosis results.

Supervising editor: Deborah B. Diercks, MD

Author affiliations: From the Department of EmergencyMedicine, Vanderbilt University Medical Center, Nashville, TN(Storrow, Lardaro, Alexander); and the Department ofLaboratory Medicine and Pathology, Hennepin County MedicalCenter and University of Minnesota School of Medicine,Minneapolis, MN (Apple).

Funding and support: By Annals policy, all authors are requiredto disclose any and all commercial, financial, and otherrelationships in any way related to the subject of this articleas per ICMJE conflict of interest guidelines (seewww.icmje.org). Dr. Storrow reports receiving grant supportfrom the National Institutes of Health, Abbott Diagnostics,Roche Diagnostics, Centers for Disease Control andPrevention, and Mylan Specialty and is a consultant forNovartis Pharmaceuticals and Roche Diagnostics. Dr. Applereports receiving industry grant/research support through theMinneapolis Medical Research Foundation (without salary),Abbott Diagnostics, Siemens, Ortho-Clinical Diagnostics,Roche Diagnostics, Radiometer, Arrkray, BioMerieux, Alere,and Beckman Coulter; is a paid consultant for InstrumentationLaboratories and T2 Biosystems; and is on thescientific/medical advisory boards of InstrumentationLaboratory, Beckman Coulter, and T2 Biosystems.

Address for correspondence: Alan B. Storrow, MD, [email protected].

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