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Early Diagnosis of Myocardial Infarction Using Absolute and Relative Changes in Cardiac Troponin Concentrations

      Abstract

      Background

      Absolute changes in high-sensitivity cardiac troponin T (hs-cTnT) seem to have higher diagnostic accuracy in the early diagnosis of acute myocardial infarction compared with relative changes. It is unknown whether the same applies to high-sensitivity cardiac troponin I (hs-cTnI) assays and whether the combination of absolute and relative change might further increase accuracy.

      Methods

      In a prospective, international multicenter study, high-sensitivity cardiac troponin (hs-cTn) was measured with 3 novel assays (hs-cTnT, Roche Diagnostics Corp, Indianapolis, Ind; hs-cTnI, Beckman Coulter Inc, Brea, Calif; hs-cTnI, Siemens, Munich, Germany) in a blinded fashion at presentation and after 1 and 2 hours in a blinded fashion in 830 unselected patients with suspected acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists.

      Results

      The area under the receiver operating characteristic curve for diagnosing acute myocardial infarction was significantly higher for 1- and 2-hour absolute versus relative hs-cTn changes for all 3 assays (P < .001). The area under the receiver operating characteristic curve of the combination of 2-hour absolute and relative change (hs-cTnT 0.98 [95% confidence interval {CI}, 0.97-0.99]; hs-cTnI, Beckman Coulter Inc, 0.97 [95% CI, 0.96-0.99]; hs-cTnI, Siemens, 0.96 [95% CI, 0.93-0.99]) were high and provided some benefit compared with the use of absolute change alone for hs-cTnT, but not for the hs-cTnI assays. Reclassification analysis confirmed the superiority of absolute changes versus relative changes.

      Conclusions

      Absolute changes seem to be the preferred metrics for both hs-cTnT and hs-cTnI in the early diagnosis of acute myocardial infarction. The combination of absolute and relative changes provides a small added value for hs-cTnT, but not for hs-cTnI.

      Keywords

      Patients with acute chest pain, angina pectoris, or other symptoms suggestive of acute myocardial infarction account for approximately 10% of all emergency department consultations.
      • Nawar E.W.
      • Niska R.W.
      • Xu J.
      National Hospital Ambulatory Medical Care Survey: 2005 Emergency Department Summary.
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      Universal definition of myocardial infarction.
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      Electrocardiography (ECG) and cardiac troponin (cTn) form the diagnostic cornerstones and complement clinical assessment.
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      Recommendations for the use of cardiac troponin measurement in acute cardiac care.
      A limitation of conventional cTn assays is a delayed increase of circulating levels in peripheral blood, mandating serial sampling for 6 to 12 hours.
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      • Alpert J.S.
      • White H.D.
      • et al.
      Universal definition of myocardial infarction.
      • Bassand J.P.
      • Hamm C.W.
      • Ardissino D.
      • et al.
      Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes.
      • Macrae A.R.
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      • et al.
      Assessing the requirement for the 6-hour interval between specimens in the American Heart Association Classification of Myocardial Infarction in Epidemiology and Clinical Research Studies.
      This sensitivity deficit in the diagnosis of acute myocardial infarction at presentation to the emergency department is substantially reduced with the use of sensitive and high-sensitivity cardiac troponin (hs-cTn) assays.
      • Reichlin T.
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      • et al.
      Early diagnosis of myocardial infarction with sensitive cardiac troponin assays.
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      Sensitive troponin I assay in early diagnosis of acute myocardial infarction.
      • Haaf P.
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      High sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac non-coronary artery disease.
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      • et al.
      Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.
      • Wu A.H.
      • Jaffe A.S.
      The clinical need for high-sensitivity cardiac troponin assays for acute coronary syndromes and the role for serial testing.
      hs-cTn assays also significantly increase the detection of cardiomyocyte damage in various acute and chronic conditions with cardiac involvement other than acute myocardial infarction, including acute heart failure, tachyarrhythmias, hypertensive emergency, and even stable coronary artery disease.
      • Reichlin T.
      • Hochholzer W.
      • Bassetti S.
      • et al.
      Early diagnosis of myocardial infarction with sensitive cardiac troponin assays.
      • Keller T.
      • Zeller T.
      • Peetz D.
      • et al.
      Sensitive troponin I assay in early diagnosis of acute myocardial infarction.
      • Haaf P.
      • Drexler B.
      • Reichlin T.
      • et al.
      High sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac non-coronary artery disease.
      • Keller T.
      • Zeller T.
      • Ojeda F.
      • et al.
      Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.
      • Wu A.H.
      • Jaffe A.S.
      The clinical need for high-sensitivity cardiac troponin assays for acute coronary syndromes and the role for serial testing.
      • Omland T.
      • de Lemos J.A.
      • Sabatine M.S.
      • et al.
      A sensitive cardiac troponin T assay in stable coronary artery disease.
      • Reiter M.
      • Twerenbold R.
      • Reichlin T.
      • et al.
      Early diagnosis of acute myocardial infarction in the elderly using more sensitive cardiac troponin assays.
      As a consequence, the “increase or decrease” criteria for acute myocardial infarction have become increasingly important to differentiate acute myocardial infarction from alternative causes of acute chest pain that may be associated with mostly mild elevations in hs-cTn.
      • Thygesen K.
      • Alpert J.S.
      • White H.D.
      • et al.
      Universal definition of myocardial infarction.
      • Thygesen K.
      • Mair J.
      • Katus H.
      • et al.
      Recommendations for the use of cardiac troponin measurement in acute cardiac care.
      • Twerenbold R.
      • Jaffe A.
      • Reichlin T.
      • Reiter M.
      • Mueller C.
      High-sensitive troponin T measurements: what do we gain and what are the challenges?.
      Both the Joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation task force for the universal definition of myocardial infarction and the National Academy of Clinical Biochemistry recommend a 20% change from an elevated cTn value as indicative of additional myocardial necrosis.
      • Thygesen K.
      • Alpert J.S.
      • White H.D.
      • et al.
      Universal definition of myocardial infarction.
      • Morrow D.A.
      • Cannon C.P.
      • Jesse R.L.
      • et al.
      National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: clinical characteristics and utilization of biochemical markers in acute coronary syndromes.
      • Thygesen K.
      • Mair J.
      • Giannitsis E.
      • et al.
      How to use high-sensitivity cardiac troponins in acute cardiac care.
      This 20% change represents a significant (>3 standard deviations of the variation associated with an elevated baseline concentration) change in cTn based on a 5% to 7% analytic total coefficient of variation. Because this criterion was derived from the use of conventional cTn assays, recent research has reexamined the best metrics for change.
      • Reichlin T.
      • Irfan A.
      • Twerenbold R.
      • et al.
      Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction.
      • Mueller M.
      • Biener M.
      • Vafaie M.
      • et al.
      Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome.
      Of note, evidence from 2 independent large observational studies has suggested that absolute changes in high-sensitivity cardiac troponin T (hs-cTnT) may have significantly higher diagnostic accuracy for acute myocardial infarction than relative changes,
      • Reichlin T.
      • Irfan A.
      • Twerenbold R.
      • et al.
      Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction.
      • Mueller M.
      • Biener M.
      • Vafaie M.
      • et al.
      Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome.
      whereas other experts have suggested using a combination of absolute and relative changes.
      • Reichlin T.
      • Irfan A.
      • Twerenbold R.
      • et al.
      Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction.
      • Mueller M.
      • Biener M.
      • Vafaie M.
      • et al.
      Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome.
      • Kavsak P.A.
      • MacRae A.R.
      Letter by Kavsak and MacRae regarding article, “Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction”.
      A recent position paper by the Study Group on Biomarkers in Cardiology of the European Society of Cardiology Working Group on Acute Cardiac Care recommended using an absolute change for baseline levels below the 99th percentile and a relative change of 20% for baseline levels above the 99th percentile.
      • Mueller M.
      • Biener M.
      • Vafaie M.
      • et al.
      Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome.
      Obviously, solving this issue could help physicians apply hs-cTn levels in clinical practice and thereby improve patient care.
      • Absolute changes have significantly higher diagnostic accuracy compared with relative changes in diagnosing acute myocardial infarction among patients with chest pain for all 3 high-sensitivity cardiac troponin (hs-cTn) assays.
      • Absolute changes also are superior in the subgroup of patients with elevated baseline levels of hs-cTn.
      • The combination of absolute and relative changes compared with the use of absolute values alone provided a small added value for hs-cTn T assays but not for hs-cTn I assays.

      Materials and Methods

      Study Design and Population

      The Advantageous Predictors of Acute Coronary Syndromes Evaluation study is an ongoing prospective, international, multicenter study designed and coordinated by the University Hospital Basel. From April 2006 to June 2009, 1247 consecutive patients who presented to the emergency department with symptoms suggestive of acute myocardial infarction, such as chest pain and angina pectoris with onset or peak of symptoms within the last 12 hours, were recruited. Patients were eligible for this analysis if they had blood samples taken at presentation and at least 1 serial blood sample at 1 or 2 hours. Patients with acute trauma and with terminal kidney failure requiring dialysis were excluded. The study was conducted according to the principles of the Declaration of Helsinki and approved by the local ethics committee at each participating institution. Written informed consent was obtained from all patients.

      Clinical Assessment

      All patients underwent an initial clinical assessment that included clinical history, physical examination, 12-lead ECG, continuous ECG monitoring, pulse oximetry, standard blood tests, and chest radiography. Cardiac troponin I (cTnI) or cTnT, creatine kinase-MB, and myoglobin were measured at presentation and after 6 to 9 hours or as long as clinically indicated. Timing and treatment of patients were left at the discretion of the attending physician.

      Adjudicated Final Diagnosis

      To determine the final diagnosis for each patient, 2 independent cardiologists reviewed all available medical records (including patient history, physical examination, results of laboratory testing including local cTn values, radiologic testing, ECG, echocardiography, cardiac exercise test, coronary angiography) pertaining to the patient from the time of emergency department presentation to 90-day follow-up. In situations of diagnostic disagreement, cases were reviewed and adjudicated in conjunction with a third cardiologist.
      Acute myocardial infarction was defined as recommended in current guidelines.
      • Thygesen K.
      • Alpert J.S.
      • White H.D.
      • et al.
      Universal definition of myocardial infarction.
      Cardiac necrosis was diagnosed by at least 1 value of the local standard cTn above the 99th percentile with an imprecision of less than 10%. A significant increase or decrease was defined as a change in local standard cTn of at least 30% of the 99th percentile or the 10% CV level, respectively, within 6 to 9 hours. The following cTn assays were used for the adjudication of the final diagnosis onsite: Abbott Laboratories (Abbott Park, Ill) Axsym cTnI ADV, Beckman Coulter Inc (Brea, Calif) Accu cTnI, and Roche Diagnostics Corporation (Indianapolis, Ind) cTnT fourth generation. All 3 are well-validated current standard cTn assays with comparable performance in the diagnosis of acute myocardial infarction.
      • Apple F.S.
      • Wu A.H.
      • Jaffe A.S.
      European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: how to use existing assays clinically and for clinical trials.
      • Apple F.S.
      • Jesse R.L.
      • Newby L.K.
      • Wu A.H.
      • Christenson R.H.
      National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes.
      Unstable angina was diagnosed in patients with normal cTn levels and typical angina at rest, in patients with a deterioration of a previously stable angina, in cases of positive cardiac exercise testing or cardiac catheterization with coronary arteries found to have a stenosis of 70% or greater, and in ambiguous cases in which follow-up information revealed acute myocardial infarction or a sudden, unexpected cardiac death within 60 days. Further predefined diagnostic categories included cardiac but not coronary symptoms (eg, perimyocarditis, tachyarrhythmias), noncardiac chest pain, and symptoms of unknown origin. If acute myocardial infarction was excluded in the emergency department, but no sufficient further diagnostic procedures were performed for conclusive diagnosis, symptoms were classified as to be of unknown origin.

      Biochemical Analysis

      Blood samples for the determination of all 3 sensitive assays (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman Coulter; hs-cTnI, Siemens, Munich, Germany) were collected at the time of the patient's presentation to the emergency department. Additional samples were obtained 1, 2, 3, and 6 hours after presentation. Serial sampling was discontinued when the diagnosis of acute myocardial infarction was certain and treatment required transferring the patient to the catheterization laboratory or coronary care unit. After centrifugation, samples were frozen at −80°C until they were assayed in a blinded fashion in a dedicated core laboratory. The patients who received ST-segment elevation myocardial infarction as the final adjudicated diagnosis were excluded from this analysis because cardiac markers are of little benefit in the diagnosis of these patients (n = 50). Of the 1197 patients, samples at presentation and after 1 hour were available in 830 patients and after 2 hours in 583 patients for measurement of cTn for all 3 assays.
      The hs-cTnT assay was performed with the use of the Elecsys 2010 system (Roche Diagnostics). The limit of detection has been determined to be 0.003 μg/L, an imprecision corresponding to a 10% coefficient of variation was reported at 0.013 μg/L, and the 99th percentile of a healthy reference population was reported at 0.014 μg/L.
      • Giannitsis E.
      • Kurz K.
      • Hallermayer K.
      • Jarausch J.
      • Jaffe A.S.
      • Katus H.A.
      Analytical validation of a high-sensitivity cardiac troponin T assay.
      Beckman Coulter hs-cTnI was measured on the Access 2 analyzer using an investigational prototype assay. According to the manufacturer, the limit of detection is 0.002 μg/L and the 99th percentile of a healthy reference population is 0.009 μg/L with a 10% coefficient of variation lower than the 99th percentile. For Siemens hs-cTnI, the limit of detection is 0.0005 μg/L, the imprecision level corresponding to a 10% coefficient of variation is found at 0.003 μg/L, and the 99th percentile of a healthy reference population is found at 0.009 μg/L (all data according to the manufacturer).

      Statistical Analysis

      The data are presented as proportions, means (± standard deviation) and in case of non-normal distribution as median with interquartile range. Comparisons were made using the t test for normally distributed continuous variables, Mann-Whitney U test for non-normally distributed continuous variables, Fisher exact test for categoric variables with any field including less than 6 patients, and chi-square test for the other categoric variables. The Kolmogorov-Smirnov test was used to test for normality. The absolute values were used because we were interested in the magnitude of the change, as also recommended by current guidelines. Receiver operating characteristic (ROC) curves were constructed to assess the diagnostic accuracy for the diagnosis of acute myocardial infarction for absolute values of the log-transformed values of absolute (Δ) and relative (Δ%) changes within the first hour and within the first 2 hours after presentation alone and in combinations with each other. The comparison of areas under the ROC curve (AUC) was performed as recommended by DeLong et al.
      • DeLong E.R.
      • DeLong D.M.
      • Clarke-Pearson D.L.
      Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
      Optimal cutoff values were derived from ROC curves as described by Youden.
      • Youden W.J.
      Index for rating diagnostic tests.
      All hypothesis testing was 2-tailed, and a P value of <0.05 was considered statistically significant.
      Net reclassification improvement focuses on reclassification tables constructed separately for participants with and without events, and quantifies the correct movement in categories.
      • Pencina M.J.
      • D'Agostino Sr., R.B.
      • D'Agostino Jr., R.B.
      • Vasan R.S.
      Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.
      Net reclassification improvement was used to assess the yield of the additional use of the absolute and relative changes. Predefined subgroup analyses also were carried out among patients with hs-cTns above the 99th percentile as measured by the 3 assays because a recent position paper suggested continuing to use relative change in patients with elevated baseline levels. All statistical analyses were performed using SPSS for Windows 19.0 (SPSS Inc, Chicago, Ill) and MedCalc 9.6.4.0 (MedCalc Software, Ostend, Belgium).

      Results

      The baseline characteristics of all 830 patients are shown in Table 1. Non–ST-segment elevation myocardial infarction was the adjudicated final diagnosis in 108 patients (13%). The other adjudicated final diagnoses were unstable angina in 115 patients (14%), cardiac symptoms from causes other than coronary artery disease in 120 patients (15%), noncardiac causes in 415 patients (50%), and symptoms of unknown origin in 72 patients (9%). The baseline levels and absolute and relative changes between cTn levels at presentation and after 1 hour and 2 hours were significantly higher in patients diagnosed with acute myocardial infarction than in the rest of the patients among all 3 investigational assays (P < .001).
      Table 1Baseline Characteristics of 830 Patients
      All PatientsMyocardial Infarction
      YesNo
      Male gender559 (67)72 (68)487 (68)
      Age, y64 (51-75)74 (63-82)63 (50-74)
      BMI26 (24-30)26 (24-29)26 (24-30)
      Medical history
       Coronary artery disease295 (36)47 (44)248 (34)
       Previous myocardial infarction205 (25)34 (32)171 (24)
       Arterial hypertension532 (64)80 (74)452 (63)
       Hypercholesterolemia388 (47)55 (51)333 (46)
       Previous pulmonary embolism18 (2)2 (2)16 (2)
       Previous stroke50 (6)17 (16)33 (5)
       Peripheral artery disease51 (6)12 (11)39 (5)
       Renal insufficiency87 (11)22 (20)65 (9)
       Diabetes167 (20)28 (26)139 (19)
      Renal function
       eGFR – MDRD89 (71-106)75 (59-100)90 (73-107)
      Medications
       Aspirin323 (39)51 (47)272 (37)
       Beta-blocker318 (38)45 (42)273 (38)
       ACE inhibitor198 (24)32 (30)166 (23)
       Angiotensin receptor blocker153 (18)18 (18)135 (19)
       Calcium antagonist135 (16)21 (19)114 (16)
       Statin303 (37)39 (36)264 (37)
      ACE = angiotensin-converting enzyme; BMI = body mass index; eGFR = estimated glomerular filtration rate; MDRD = Modification of Diet in Renal Disease.
      The AUCs of the baseline values for all 3 assays to diagnose acute myocardial infarction were similar: 0.94 (95% confidence interval, 0.92-0.97). Among all patients, 35% (n = 286), 38% (n = 311), and 38% (n = 318) had hs-cTn elevated above the 99th percentile at baseline as measured by assays hs-cTnT Roche, hs-cTnI Beckman Coulter, and hs-cTnI Siemens, respectively; of these patients with elevated cTn, 35%, 33%, and 33%, respectively, were finally diagnosed with acute myocardial infarction. Figure 1 shows the proportion of patients according to the amount of absolute, relative, and their combination 2-hour changes in the 3 investigational assays stratified to acute myocardial infarction or other diagnoses of chest pain.
      Figure thumbnail gr1
      Figure 1Two-hour absolute (A, D, G), relative (B, E, H), and the combination of both (C, F, I) changes in hs-cTnT: Roche Diagnostics Corporation (Indianapolis, Ind) (top); hs-cTnI: Beckman Coulter Inc (Brea, Calif) (middle); hs-cTnI: Siemens (Munich, Germany) (bottom). Patients with acute myocardial infarction are shown on the right in green, and patients with other causes of chest pain are shown on the left in blue. hs-cTnI = high-sensitivity cardiac troponin I; hs-cTnT = high-sensitivity cardiac troponin T.
      Table 2 and Figure 2 show the AUCs for absolute and relative changes, and their combination to diagnose acute myocardial infarction in all patients. Supplementary Table 1 (available online) shows the subgroup of patients who had cTn >99th percentile as measured by the assays. The ROC-derived cutoff value for absolute changes after 1 hour was 0.005 μg/L for all 3 assays, whereas it was 0.007 μg/L for hs-cTnT and 0.010 μg/L for both hs-cTnI assays at 2 hours. The ROC-derived cutoff values for relative changes after 1 and 2 hours are 17% and 30% for hs-cTnT, respectively, and approximately 30% and 80% for both hs-cTnI assays, respectively.
      Table 2Area Under the Receiver Operating Characteristic Curves for the Diagnosis of Acute Myocardial Infarction for Absolute and Relative Changes in Cardiac Troponin 1 and 2 Hours After Presentation
      AUC (95% CI)ROC-Derived Optimal Cutoff ValuesSensitivitySpecificityPPVNPV
      hs-cTnT1 h
      Absolute change (Δ)0.93 (0.91-0.95)0.00584936698
      Relative change (Δ%)0.67 (0.64-0.70)1760722592
      Absolute and relative change0.97 (0.95-0.98)91957399
      2 h
      Absolute change (Δ)0.95 (0.93-0.97)0.00787936198
      Relative change (Δ%)0.75 (0.71-0.78)3064833294
      Absolute and relative change0.98 (0.96-0.99)94926099
      hs-cTnI Beckman Coulter Inc (Brea, Calif)1 h
      Absolute change (Δ)0.93 (0.91-0.95)0.00591885499
      Relative change (Δ%)0.65 (0.62-0.68)2763662292
      Absolute and relative change0.95 (0.93-0.96)92905899
      2 h
      Absolute change (Δ)0.97 (0.95-0.98)0.0194926099
      Relative change (Δ%)0.75 (0.71-0.78)8860894395
      Absolute and relative change0.97 (0.96-0.98)96925899
      hs-cTnI Siemens (Munich, Germany)1 h
      Absolute change (Δ)0.95 (0.93-0.97)0.00594885499
      Relative change (Δ%)0.67 (0.64- 0.70)3759742592
      Absolute and relative change0.95 (0.94-0.97)89936698
      2 h
      Absolute change (Δ)0.96 (0.94-0.97)0.0193905599
      Relative change (Δ%)0.73 (0.70-0.77)8059823094
      Absolute and relative change0.96 (0.94-0.98)96925899
      AUC = area under the curve; hs-cTnI = high-sensitivity cardiac troponin I; hs-cTnT = high-sensitivity cardiac troponin T; NPV = negative predictive value; PPV = positive predictive value; ROC = receiver operating characteristic.
      Figure thumbnail gr2
      Figure 2AUC of the 2-hour absolute changes, relative changes alone, and the combination of both changes in all patients for hs-cTnT, Roche (A); hs-cTnI, Beckman Coulter (B); hs-cTnI, Siemens (C); and in subgroup of patients with an elevated baseline hs-cTn level (with the relative change >20% shown on the graph) (D, E, F).
      Table 3 shows the P values for comparison between the AUC of absolute, relative, and their combination changes. The combinations of (a) baseline and absolute, (b) baseline and relative, and (c) absolute and relative achieved similar AUC for all 3 assays among all patients for 1- and 2-hour changes: hs-cTnT Roche 0.97 and 0.98; hs-cTnI 0.96 and 0.97 (similar results were obtained even among the subgroup of patients with elevated cTn, data not shown).
      Table 3P Values Between Area Under the Receiver Operating Characteristic Curves of Absolute and Relative Changes Alone and in Combination for the Diagnosis of Acute Myocardial Infarction in All Patients and Subgroup of Patients with an Elevated Baseline High-Sensitivity Cardiac Troponin Level
      hs-cTnBeckman Coulter

      hs-cTnI
      Siemens

      hs-cTnI
      1 h2 h1 h2 h1 h2 h
      All patientsAbsoluteRelative<0.01<0.01<0.01<0.01<0.01<0.01
      AbsoluteAbsolute and relative<0.010.050.050.060.610.18
      RelativeAbsolute and relative<0.01<0.01<0.01<0.01<0.01<0.01
      Patients >99th percentile of cTn at baselineAbsoluteRelative<0.01<0.01<0.01<0.01<0.01<0.01
      AbsoluteAbsolute and relative<0.01<0.010.770.380.880.97
      RelativeAbsolute and relative<0.01<0.01<0.01<0.01<0.01<0.01
      cTn = cardiac troponin; hs-cTn = high-sensitivity cardiac troponin; hs-cTnI = high-sensitivity cardiac troponin I.

      Net Reclassification Improvement

      The addition of ROC-derived absolute change to the cutoffs for baseline or ROC-derived relative change improved the reclassification of the patients with acute myocardial infarction (P < .01 for all 3 assays), except for 1-hour hs-cTnT change, but not vice versa. The nonimprovement of classification also was seen with the addition of relative change >20% to the 99th percentile at baseline (Table 4).
      Table 4Net Reclassification Index of Patients with and without Acute Myocardial Infarction by Cutoff Values of 99th Percentile for Baseline and the Receiver Operating Characteristic–Derived Absolute Change, Receiver Operating Characteristic–Derived Relative Change, and Relative Change Greater Than 20% in Cardiac Troponin Changes After 1 and 2 Hours
      Test 1Test 2hs-cTnTBeckman Coulter hs-cTnISiemens hs-cTnI
      1 h2 h1 h2 h1 h2 h
      NRIP ValueNRIP ValueNRIP ValueNRIP ValueNRIP ValueNRIP Value
      BaselineBaseline and absolute7.1210.0211<.00116<.00114<.00114<.001
      BaselineBaseline and relative−18NS−19NS−15NS−15NS−15NS−15NS
      BaselineBaseline and relative >20%
      Relative >20% reflects change in cardiac troponin concentration >20%. Rest of relative and absolute changes were ROC derived.
      −22NS−13NS−15NS−5NS−13NS−2NS
      AbsoluteAbsolute and relative−23NS−30NS−27NS−31NS−29NS−29NS
      RelativeAbsolute and relative22<.0019<.00124<.0014.0419<.00112<.001
      hs-cTnI = high-sensitivity cardiac troponin I; hs-cTnT = high-sensitivity cardiac troponin T; NRI = net reclassification improvement; NS = nonsignificant.
      Relative >20% reflects change in cardiac troponin concentration >20%. Rest of relative and absolute changes were ROC derived.

      Discussion

      The ongoing controversy regarding the specific metrics to be used to assess the increasing or decreasing criteria required in the universal definition of acute myocardial infarction has magnified the uncertainty and sometimes reluctance among clinicians when applying hs-cTn levels in the early diagnosis of acute myocardial infarction.
      • Thygesen K.
      • Mair J.
      • Giannitsis E.
      • et al.
      How to use high-sensitivity cardiac troponins in acute cardiac care.
      • Reichlin T.
      • Irfan A.
      • Twerenbold R.
      • et al.
      Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction.
      • Mueller M.
      • Biener M.
      • Vafaie M.
      • et al.
      Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome.
      • Kavsak P.A.
      • MacRae A.R.
      Letter by Kavsak and MacRae regarding article, “Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction”.
      This study tried to advance this debate by evaluating different change criteria in the early diagnosis of acute myocardial infarction with the use of 3 different hs-cTn assays. We report 6 major findings. First, as quantified by the AUC, absolute changes alone had significantly higher diagnostic accuracy compared with relative changes alone in diagnosing acute myocardial infarction among unselected patients with symptoms suggestive of acute myocardial infarction for hs-cTnT and hs-cTnI. Second, for all 3 assays absolute changes also were superior in the subgroup of patients with elevated baseline levels of hs-cTn. Third, reclassification analysis confirmed the superiority of absolute changes over relative changes. The addition of the ROC-derived absolute changes to the 99th percentile of baseline significantly improved the reclassification of patients with acute myocardial infarction, whereas relative changes did not provide additional benefit. Fourth, the ROC-derived cutoff value of 1-hour absolute change to diagnose acute myocardial infarction was similar for all 3 assays: 0.005 μg/L. Fifth, the ROC-derived cutoff value of 2-hour absolute change to diagnose acute myocardial infarction was twice the 1-hour value for both hs-cTnI assays: 0.010 μg/L. This finding suggests that cTn release may be linear in the early phase of acute myocardial infarction. Sixth, combining absolute and relative changes compared with the use of absolute values alone did provide a small added value for hs-cTnT, but not for hs-cTnI.
      These findings extend and corroborate previous research on the application of hs-cTn in the early diagnosis of acute myocardial infarction
      • Reichlin T.
      • Hochholzer W.
      • Bassetti S.
      • et al.
      Early diagnosis of myocardial infarction with sensitive cardiac troponin assays.
      • Keller T.
      • Zeller T.
      • Peetz D.
      • et al.
      Sensitive troponin I assay in early diagnosis of acute myocardial infarction.
      • Haaf P.
      • Drexler B.
      • Reichlin T.
      • et al.
      High sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac non-coronary artery disease.
      • Keller T.
      • Zeller T.
      • Ojeda F.
      • et al.
      Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.
      • Wu A.H.
      • Jaffe A.S.
      The clinical need for high-sensitivity cardiac troponin assays for acute coronary syndromes and the role for serial testing.
      and may thereby help physicians to apply these novel tools in clinical practice.
      Previous studies have reported remarkably consistent findings regarding the best metrics when using hs-cTnT: Absolute changes clearly outperformed relative changes, and a cutoff value of approximately half the 99th percentile at 2 hours seemed to work best.
      • Reichlin T.
      • Hochholzer W.
      • Bassetti S.
      • et al.
      Early diagnosis of myocardial infarction with sensitive cardiac troponin assays.
      • Keller T.
      • Zeller T.
      • Peetz D.
      • et al.
      Sensitive troponin I assay in early diagnosis of acute myocardial infarction.
      • Haaf P.
      • Drexler B.
      • Reichlin T.
      • et al.
      High sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac non-coronary artery disease.
      • Keller T.
      • Zeller T.
      • Ojeda F.
      • et al.
      Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.
      • Wu A.H.
      • Jaffe A.S.
      The clinical need for high-sensitivity cardiac troponin assays for acute coronary syndromes and the role for serial testing.
      The same was observed for the hs-cTnI assay.
      • Reichlin T.
      • Hochholzer W.
      • Bassetti S.
      • et al.
      Early diagnosis of myocardial infarction with sensitive cardiac troponin assays.
      • Keller T.
      • Zeller T.
      • Peetz D.
      • et al.
      Sensitive troponin I assay in early diagnosis of acute myocardial infarction.
      • Haaf P.
      • Drexler B.
      • Reichlin T.
      • et al.
      High sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac non-coronary artery disease.
      • Keller T.
      • Zeller T.
      • Ojeda F.
      • et al.
      Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.
      • Wu A.H.
      • Jaffe A.S.
      The clinical need for high-sensitivity cardiac troponin assays for acute coronary syndromes and the role for serial testing.
      Although this analysis confirmed the general superiority of absolute changes for 2 hs-cTnI assays and to patients with elevated baseline levels, it also endorsed the recommendation of the Study Group on Biomarkers in Cardiology of the European Society of Cardiology Working Group on Acute Cardiac Care that optimal cutoff values need to be defined for each assay. Of note, the best 1-hour absolute changes were identical for all 3 hs-cTn assays, whereas the best 2-hour absolute changes began to diverge with more pronounced changes necessary with the 2 hs-cTnI assays. Future studies need to clarify whether this pattern applies to all hs-cTnI assays.
      It is important to note that different findings may be obtained when one does not try to optimize accuracy but specificity. A high relative change (+250%) seemed to provide the most pronounced increase in specificity in a recent analysis from Germany.
      • Keller T.
      • Zeller T.
      • Ojeda F.
      • et al.
      Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.
      Although relative changes provided some added value on top of the baseline value in AUC analysis in our study, this was not evident once net reclassification improvement was used to quantify the difference.
      Although it is important to highlight the change criteria in the universal definition of acute myocardial infarction,
      • Thygesen K.
      • Mair J.
      • Giannitsis E.
      • et al.
      How to use high-sensitivity cardiac troponins in acute cardiac care.
      it is at least as critical to emphasize the wealth of diagnostic information already provided by the baseline level of hs-cTn in patients presenting with acute chest pain to the emergency department.
      • Thygesen K.
      • Mair J.
      • Giannitsis E.
      • et al.
      How to use high-sensitivity cardiac troponins in acute cardiac care.
      • Reichlin T.
      • Schindler C.
      • Drexler B.
      • et al.
      One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T.
      The higher the level of hs-cTn at presentation, the higher the positive predictive value for acute myocardial infarction. This explains why the change criteria clinically is of less importance in patients with markedly elevated baseline levels but of critical importance in patients with hs-cTn levels at presentation around the 99th percentile.

      Study Limitations

      The following limitations of our study merit consideration. First, we evaluated changes with 2 hs-cTnI assays. Future studies need to define whether our findings can be extrapolated to other novel hs-cTnI assays. Second, because this was a prospective observational study, we cannot quantify the potential clinical benefit associated with the application of the absolute or relative changes in cTn concentrations to diagnose acute myocardial infarction in patients with chest pain. Algorithms incorporating baseline cTn values and changes need to be developed retrospectively and validated prospectively.
      • Reichlin T.
      • Schindler C.
      • Drexler B.
      • et al.
      One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T.
      Third, we cannot comment on the accuracy of cTn changes among patients with terminal kidney failure requiring dialysis, because such patients were excluded from our study. Fourth, the blood samples after 1 and 2 hours were not available for measurement by all 3 investigational assays in the whole cohort of patients and can be a potential source of bias. However, there was no statistical difference in any of the baseline characteristics between those patients with missing values and those analyzed in this study (Supplementary Table 2, online).

      Conclusions

      Absolute changes seem to be the preferred metrics for both hs-cTnT and hs-cTnI in the early diagnosis of acute myocardial infarction. The combination of absolute and relative changes provides a small added value for hs-cTnT but not for hs-cTnI.

      Acknowledgments

      The authors thank the patients who participated in the study, the staff of the emergency department, the laboratory technicians, and particularly Michael Freese, Claudia Stelzig, Esther Garrido, Irina Klimmeck, Melanie Wieland, Kirsten Hochholzer, Beate Hartmann, and Fausta Chiaverio for valuable efforts, and Dr Christian Schindler for statistical advise.

      Appendix

      Supplementary Table 1Area Under the Receiver Operating Characteristic Curves for the Diagnosis of Acute Myocardial Infarction for Absolute and Relative Changes in Cardiac Troponin 1 and 2 Hours After Presentation in Subgroup of Patients with Elevated Baseline High-Sensitivity Cardiac Troponin Level
      AUC (95% CI)ROC-Derived Optimal Cutoff ValuesSensitivitySpecificityPPVNPV
      hs-cTnT1 h
      Absolute change (Δ)0.88 (0.84-0.93)0.00585867791
      Relative change (Δ%)0.72 (0.65-0.79)1758856879
      Absolute and relative change0.94 (0.90-0.96)96817397
      2 h
      Absolute change (Δ)0.89 (0.84-0.95)0.00888877694
      Relative change (Δ%)0.76 (0.68-0.84)1672816486
      Absolute and relative change0.94 (0.89-0.97)95847498
      hs-cTnI Beckman Coulter1 h
      Absolute change (Δ)0.88 (0.84-0.93)0.02477908089
      Relative change (Δ%)0.70 (0.63-0.76)2761795980
      Absolute and relative change0.88 (0.84-0.92)84847392
      2 h
      Absolute change (Δ)0.91 (0.87-0.95)0.01693796596
      Relative change (Δ%)0.77 (0.70-0.84)10056907083
      Absolute and relative change0.92 (0.87-0.95)92826896
      hs-cTnI Siemens1 h
      Absolute change (Δ)0.91 (0.88-0.95)0.01888857493
      Relative change (Δ%)0.71 (0.65- 0.78)3759846581
      Absolute and relative change0.91 (0.88-0.94)82908091
      2 h
      Absolute change (Δ)0.92 (0.88-0.96)0.0387857194
      Relative change (Δ%)0.77 (0.70-0.84)2378715289
      Absolute and relative change0.92 (0.88-0.95)94796497
      AUC = area under the curve; hs-cTnI = high-sensitivity cardiac troponin I; hs-cTnT = high-sensitivity cardiac troponin T; NPV = negative predictive value; PPV = positive predictive value; ROC = receiver operating characteristic.
      Supplementary Table 2Baseline Characteristics of Patients with 2-Hour Troponin Values and Patients with Missing 1- and 2-Hour Troponin Values
      2-h Values n = 583 (49)Missing Troponin Values
      1 h n = 367 (31)2 h n = 614 (51)
      Male gender193 (33)133 (36)211 (34)
      Age, y64 (51-75)60 (48-76)63 (50-75)
      BMI26 (24-30)26 (24-30)26 (24-30)
      Medical history
       Coronary artery disease211 (36)147 (40)231 (38)
       Previous myocardial infarction147 (25)90 (25)148 (24)
       Arterial hypertension370 (64)224 (61)386 (63)
       Hypercholesterolemia278 (48)150 (41)260 (42)
       Previous pulmonary embolism11 (2)12 (3)19 (3)
       Previous stroke31 (5)18 (5)37 (6)
       Peripheral artery disease39 (7)31 (8)43 (7)
       Renal insufficiency65 (11)35 (10)57 (9)
       Diabetes117 (20)56 (15)106 (17)
      Renal function
       eGFR – MDRD90 (72-105)90 (73-109)90 (71-108)
       Medications
       Aspirin228 (39)151 (41)246 (40)
       Beta-blocker223 (38)136 (37)231 (38)
       ACE inhibitor132 (23)83 (23)149 (24)
       Angiotensin receptor blocker120 (21)67 (18)100 (16)
       Calcium antagonist100 (17)64 (17)99 (16)
       Statin211 (36)132 (36)224 (37)
      ACE = angiotensin-converting enzyme; BMI = body mass index; eGFR = estimated glomerular filtration rate; MDRD = Modification of Diet in Renal Disease.

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