Advertisement

Single High-Sensitivity Cardiac Troponin I to Rule Out Acute Myocardial Infarction

      Abstract

      Background

      This study examined the performance of single high-sensitivity cardiac troponin I (hs-cTnI) measurement strategies to rule out acute myocardial infarction.

      Methods

      This was a prospective, observational study of consecutive patients presenting to the emergency department (n = 1631) in whom cTnI measurements were obtained using an investigational hs-cTnI assay. The goals of the study were to determine 1) negative predictive value (NPV) and sensitivity for the diagnosis of acute myocardial infarction, type 1 myocardial infarction, and type 2 myocardial infarction; and 2) safety outcome of acute myocardial infarction or cardiac death at 30 days using hs-cTnI less than the limit of detection (LoD) (<1.9 ng/L) or the High-STEACS threshold (<5 ng/L) alone and in combination with normal electrocardiogram (ECG).

      Results

      Acute myocardial infarction occurred in 170 patients (10.4%), including 68 (4.2%) type 1 myocardial infarction and 102 (6.3%) type 2 myocardial infarction. For hs-cTnI<LoD (27%), the NPV and sensitivity for acute myocardial infarction were 99.6% (95% confidence interval 98.9%-100%) and 98.8 (97.2%-100%). For hs-cTnI<5 ng/L (50%), the NPV and sensitivity for acute myocardial infarction were 98.9% (98.2%-99.6%) and 94.7% (91.3%-98.1%). In combination with a normal ECG, 1) hs-cTnI<LoD had an NPV of 99.6% (98.9%-100%) and sensitivity of 99.4% (98.3%-100%); and 2) hs-cTnI<5 ng/L had an NPV of 99.5% (98.8%-100%) and sensitivity of 98.8% (97.2%-100%). The NPV and sensitivity for the safety outcome were excellent for hs-cTnI<LoD alone or in combination with a normal ECG, and for hs-cTnI<5 ng/L in combination with a normal ECG.

      Conclusion

      Strategies using a single hs-cTnI alone or in combination with a normal ECG allow the immediate identification of patients unlikely to have acute myocardial infarction and who are at very low risk for adverse events at 30 days.

      Keywords

      Clinical Significance
      • Strategies using a single high-sensitivity cardiac troponin I measurement at presentation in combination with a normal electrocardiogram allow the immediate identification of patients unlikely to have acute myocardial infarction and who are at very low risk for adverse events at 30 days.
      • The implementation of these approaches may reduce overcrowding, facilitate early discharge in selected patients, expedite triaging, and reduce costs.
      High-sensitivity (hs) cardiac troponin (cTn) I and T assays are analytically superior assays compared with contemporary cTn assays and are able to measure cTn at very low concentrations with excellent precision.
      • Apple F.S.
      • Sandoval Y.
      • Jaffe A.S.
      • Ordonez-Llanos J.
      for the IFCC Task Force on Clinical Applications of Cardiac Bio-Markers
      Cardiac troponin assays: guide to understanding analytical characteristics and their impact on clinical care.
      • Apple F.S.
      • Jaffe A.S.
      • Collinson P.
      • et al.
      IFCC educational materials on selected analytical and clinical applications of high sensitivity cardiac troponin assays.
      • Sandoval Y.
      • Smith S.W.
      • Apple F.S.
      Present and future of cardiac troponin in clinical practice: a paradigm shift to high-sensitivity assays.
      Both hs-cTnI and hs-cTnT assays are available and clinically used worldwide, with only the hs-cTnT assay recently cleared for use in the United States by the US Food and Drug Administration.
      • Sandoval Y.
      • Smith S.W.
      • Apple F.S.
      Present and future of cardiac troponin in clinical practice: a paradigm shift to high-sensitivity assays.
      • Korley F.K.
      • Jaffe A.S.
      Preparing the United States for high-sensitivity cardiac troponin assays.
      The ability to measure very low hs-cTn concentrations with clinically acceptable imprecision has allowed the development of new rule-out strategies, which have suggested that both acute myocardial infarction and/or myocardial injury can be safely excluded with a single measurement at presentation.
      • Body R.
      • Carley S.
      • McDowell G.
      • et al.
      Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay.
      • Bandstein N.
      • Ljung R.
      • Johansson M.
      • Holzmann M.J.
      Undetectable high-sensitivity cardiac troponin T level in the emergency department and risk of myocardial infarction.
      • Thelin J.
      • Melander O.
      • Ohlin B.
      Early rule-out of acute coronary syndrome using undetectable levels of high sensitivity troponin T.
      • Carlton E.W.
      • Cullen L.
      • Than M.
      • Gamble J.
      • Khattab A.
      • Greaves K.
      A novel diagnostic protocol to identify patients suitable for discharge after a single high-sensitivity troponin.
      • Body R.
      • Burrows G.
      • Carley S.
      • et al.
      High-sensitivity cardiac troponin T concentrations below the limit of detection to exclude acute myocardial infarction: a prospective evaluation.
      • Vafaie M.
      • Slagman A.
      • Möckel M.
      • et al.
      Prognostic value of undetectable hs troponin T in suspected acute coronary syndrome.
      • Rubini Giménez M.
      • Hoeller R.
      • Reichlin T.
      • et al.
      Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin.
      • Carlton E.
      • Greenslade J.
      • Cullen L.
      • et al.
      Evaluation of high-sensitivity cardiac troponin I levels in patients with suspected acute coronary syndrome.
      • Shah A.S.
      • Anand A.
      • Sandoval Y.
      • et al.
      High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study.
      • Sandoval Y.
      • Smith S.W.
      • Shah A.S.
      • et al.
      Rapid rule-out of acute myocardial injury using a single high-sensitivity cardiac troponin I measurement.
      Two particular strategies have gained attention. The first strategy is based on the use of an assay's limit of detection (LoD), an analytical threshold below the 99th percentile.
      • Sandoval Y.
      • Smith S.W.
      • Apple F.S.
      Present and future of cardiac troponin in clinical practice: a paradigm shift to high-sensitivity assays.
      • Sandoval Y.
      • Smith S.W.
      • Shah A.S.
      • et al.
      Rapid rule-out of acute myocardial injury using a single high-sensitivity cardiac troponin I measurement.
      The second strategy, the High-STEACS approach, consists of using a hs-cTnI concentration (assay dependent) threshold selected on the basis of a clinical need, rather than an analytical threshold.
      • Shah A.S.
      • Anand A.
      • Sandoval Y.
      • et al.
      High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study.
      This approach was derived and validated in the High-STEACS cohort study, in which a single hs-cTnI concentration <5 ng/L was shown to identify patients at very low risk for cardiac events.
      • Shah A.S.
      • Anand A.
      • Sandoval Y.
      • et al.
      High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study.
      Both approaches have been shown to have excellent negative predictive values (NPVs) for acute myocardial infarction.
      • Body R.
      • Carley S.
      • McDowell G.
      • et al.
      Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay.
      • Bandstein N.
      • Ljung R.
      • Johansson M.
      • Holzmann M.J.
      Undetectable high-sensitivity cardiac troponin T level in the emergency department and risk of myocardial infarction.
      • Thelin J.
      • Melander O.
      • Ohlin B.
      Early rule-out of acute coronary syndrome using undetectable levels of high sensitivity troponin T.
      • Carlton E.W.
      • Cullen L.
      • Than M.
      • Gamble J.
      • Khattab A.
      • Greaves K.
      A novel diagnostic protocol to identify patients suitable for discharge after a single high-sensitivity troponin.
      • Body R.
      • Burrows G.
      • Carley S.
      • et al.
      High-sensitivity cardiac troponin T concentrations below the limit of detection to exclude acute myocardial infarction: a prospective evaluation.
      • Vafaie M.
      • Slagman A.
      • Möckel M.
      • et al.
      Prognostic value of undetectable hs troponin T in suspected acute coronary syndrome.
      • Rubini Giménez M.
      • Hoeller R.
      • Reichlin T.
      • et al.
      Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin.
      • Carlton E.
      • Greenslade J.
      • Cullen L.
      • et al.
      Evaluation of high-sensitivity cardiac troponin I levels in patients with suspected acute coronary syndrome.
      • Shah A.S.
      • Anand A.
      • Sandoval Y.
      • et al.
      High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study.
      • Sandoval Y.
      • Smith S.W.
      • Shah A.S.
      • et al.
      Rapid rule-out of acute myocardial injury using a single high-sensitivity cardiac troponin I measurement.
      Studies examining the use of single measurements to rule out acute myocardial infarction have primarily been performed outside the United States, in select cohorts of patients with chest pain, with the intent to exclude type 1 myocardial infarction.
      • Body R.
      • Carley S.
      • McDowell G.
      • et al.
      Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay.
      • Bandstein N.
      • Ljung R.
      • Johansson M.
      • Holzmann M.J.
      Undetectable high-sensitivity cardiac troponin T level in the emergency department and risk of myocardial infarction.
      • Thelin J.
      • Melander O.
      • Ohlin B.
      Early rule-out of acute coronary syndrome using undetectable levels of high sensitivity troponin T.
      • Carlton E.
      • Greenslade J.
      • Cullen L.
      • et al.
      Evaluation of high-sensitivity cardiac troponin I levels in patients with suspected acute coronary syndrome.
      No large study has tested and compared the rule-out of acute myocardial infarction, including type 1 and 2 myocardial infarction, using the 1) LoD and 2) High-STEACS approaches using an hs-cTnI assay in a US population. The goals of the present study were to examine the diagnostic performance of these two approaches for 1) ruling out acute myocardial infarction, including type 1 and 2 myocardial infarction; and 2) examine the safety outcomes for acute myocardial infarction or cardiac death at 30 days.

      Methods

      Study Design and Population

      Following institutional review board approval, we prospectively included consecutive, unselected patients presenting from February 4, 2014 through May 9, 2014 in whom initial pre-set serial cTnI measurements at 0, 3, 6, and 9 hours were ordered on clinical indication at Hennepin County Medical Center (Minneapolis, MN) to rule in and rule out acute myocardial infarction (Use of TROPonin In Acute coronary syndromes [UTROPIA]; NCT02060760). For inclusion, patients needed a baseline cTnI measurement at presentation and at least one additional cTnI measured within 24 hours of presentation before discharge and at least one 12-lead electrocardiogram (ECG) performed. Exclusion criteria were age <18 years, ST-segment elevation myocardial infarction, pregnancy, trauma, declined to participate on research as documented on information disclosure, did not present through the emergency department, or were transferred from an outside hospital. For patients with more than one presentation during the study period, we included only the first.

      Cardiac Troponin I Assays

      Fresh ethylenediaminetetraacetic acid plasma samples were simultaneously measured with both the contemporary cTnI (clinically used) and hs-cTnI (investigational) assays on the ARCHITECT i1000SR or i2000SR analyzers (Abbott Diagnostics, Abbott Park, IL). Only the hs-cTnI assay data were used for the present study. Sex-specific 99th percentile upper reference limits (URL) for the hs-cTnI assay were 16 ng/L for females and 34 ng/L for males; % coefficients of variation were 5.3% at 15 ng/L and <20% at the LoD of 1.9 ng/L.
      • Sandoval Y.
      • Smith S.W.
      • Schulz K.M.
      • et al.
      Diagnosis of type 1 and type 2 myocardial infarction using a high-sensitivity cardiac troponin I assay with sex-specific 99th percentiles based on the third universal definition of myocardial infarction classification system.
      • Love S.A.
      • Sandoval Y.
      • Smith S.W.
      • et al.
      Incidence of undetectable, measurable, and increased cardiac troponin I concentrations above the 99th percentile using a high-sensitivity vs. a contemporary assay in patients presenting to the emergency department.

      Event Adjudication

      All cases with at least one hs-cTnI concentration >99th percentile were adjudicated according to the Third Universal Definition of Myocardial Infarction consensus recommendations by two clinicians after review of all available medical records, including 12-lead ECG, echocardiography, angiography, hs-cTnI values, and clinical presentation.
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Third universal definition of myocardial infarction.
      Cases with an adjudication discrepancy were reviewed and adjudicated by a third senior clinician.
      To guide the adjudication of acute myocardial infarction in relation to the presence or absence of a significant rise and/or fall of cTnI, an algorithm was developed for the hs-cTnI assay on the basis of biological variation,
      • Sandoval Y.
      • Smith S.W.
      • Schulz K.M.
      • et al.
      Diagnosis of type 1 and type 2 myocardial infarction using a high-sensitivity cardiac troponin I assay with sex-specific 99th percentiles based on the third universal definition of myocardial infarction classification system.
      with the primary purpose of ensuring that changes within biological variation were not deemed abnormal. If the initial hs-cTnI value was below the sex-specific 99th percentile cutoff, then a rise of >69% and/or fall of >41% on serial sampling were used to suggest a significant dynamic rise and/or fall. Conversely, if the initial hs-cTnI value was above the 99th percentile, then a change of at least >20% was used.
      For the diagnosis of acute myocardial infarction, a rise and/or fall with at least one value above the 99th percentile occurring in appropriate clinical circumstances consistent with acute myocardial ischemia was required, plus at least one additional myocardial infarction criteria: 1) ischemic symptoms, 2) development of pathologic Q waves in the 12-lead ECG, 3) ECG changes indicative of new ischemia, 4) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, or 5) identification of an intracoronary thrombus by angiography or autopsy.
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Third universal definition of myocardial infarction.
      Patients adjudicated as myocardial infarction were further classified into myocardial infarction subtypes.
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Third universal definition of myocardial infarction.
      Type 1 myocardial infarction was defined as myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus.
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Third universal definition of myocardial infarction.
      Type 2 myocardial infarction was defined as myocardial infarction secondary to an ischemic imbalance between myocardial oxygen supply and/or demand not due to atherothrombosis.
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Third universal definition of myocardial infarction.
      • Sandoval Y.
      • Thygesen K.
      Myocardial infarction type 2 and myocardial injury.
      • Sandoval Y.
      • Smith S.W.
      • Thordsen S.E.
      • Apple F.S.
      Supply/demand type 2 myocardial infarction: should we be paying more attention?.
      For type 2 myocardial infarction to be adjudicated, cases were required to have a rise and/or fall of cTnI with at least 1 value above the 99th percentile plus at least 1 additional myocardial infarction criteria according to the Universal Definition of Myocardial Infarction, including the objective evidence or documentation of supply/demand imbalance.
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Third universal definition of myocardial infarction.
      • Sandoval Y.
      • Thygesen K.
      Myocardial infarction type 2 and myocardial injury.
      • Sandoval Y.
      • Smith S.W.
      • Thordsen S.E.
      • Apple F.S.
      Supply/demand type 2 myocardial infarction: should we be paying more attention?.

      Study Outcomes

      The diagnostic outcomes examined were 1) acute myocardial infarction, 2) type 1 myocardial infarction, and 3) type 2 myocardial infarction during the index hospitalization. The safety outcome was a composite of acute myocardial infarction or cardiac death at 30 days, including events occurring during the index hospitalization.

      Statistical Analyses

      Categorical variables are shown as percentages. Continuous variables are shown as mean values ± standard deviation. The diagnostic and safety outcomes were examined for 1) LoD (<1.9 ng/L) and 2) High-STEACS (<5 ng/L) threshold based on a single hs-cTnI at presentation alone and in combination with a normal ECG. The ECGs were categorized as normal according to previously described criteria
      • Sandoval Y.
      • Smith S.W.
      • Shah A.S.
      • et al.
      Rapid rule-out of acute myocardial injury using a single high-sensitivity cardiac troponin I measurement.
      (Supplementary Methods, available online). Diagnostic performance statistics were sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV); 95% confidence intervals (CIs) were ascertained using binomial proportions. Subgroup analyses were performed on early presenters, defined as individuals who had their first cTnI sample obtained ≤2 hours after symptom onset. All analysis was done using SAS version 9.4 (SAS Institute, Cary, NC).

      Results

      Baseline characteristics are shown in Table 1. Among the 1631 patients who met inclusion criteria, 444 patients (27%) had hs-cTnI<LoD at presentation. Using the High-STEACS threshold, 812 patients (50%) had hs-cTnI<5 ng/L at presentation. A total of 601 patients (37%) had a normal ECG. During the index hospitalization, acute myocardial infarction occurred in 170 patients (10.4%), including 68 (4.2%) type 1 and 102 (6.3%) type 2 myocardial infarctions.
      Table 1Baseline Characteristics
      CharacteristicValue
      Study cohort (n)1631
      Age (y), mean (SD)57 (15)
      Female gender720 (44)
      Hypertension1074 (66)
      Diabetes mellitus496 (43)
      Dyslipidemia696 (43)
      Coronary artery disease371 (23)
      Prior myocardial infarction190 (12)
      Prior percutaneous coronary intervention150 (9)
      Prior coronary artery bypass graft73 (4)
      Congestive heart failure231 (14)
      Atrial fibrillation129 (8)
      Peripheral vascular disease42 (3)
      Cerebrovascular disease153 (9)
      Renal insufficiency, nondialysis161 (10)
      End-stage renal disease on hemodialysis80 (5)
      History of tobacco use969 (59)
      Chest discomfort835 (51)
      Dyspnea680 (42)
      Arm and/or shoulder discomfort250 (15)
      Jaw and/or neck discomfort98 (6)
      Epigastric discomfort93 (6)
      Nausea and/or vomiting381 (23)
      Fatigue444 (27)
      Baseline hs-cTnI concentrations <1.9 ng/L444 (27)
      Baseline hs-cTnI concentrations <5 ng/L812 (50)
      Normal 12-lead ECG601 (37)
      Values are number (percentage) unless otherwise noted.
      ECG = electrocardiogram; SD = standard deviation.

      Rule-Out Using the LoD Alone and in Combination with a Normal ECG

      In patients with hs-cTnI<LoD at presentation (27% of patients), independent of ECG findings, the NPV and sensitivity for acute myocardial infarction were 99.6% (95% CI, 98.9%-100%) and 98.8% (95% CI, 97.2%-100%), respectively (Table 2). Using hs-cTnI<LoD alone, 2 of 170 patients with acute myocardial infarction were missed, corresponding to a miss rate of 1.2% (or 2 of 444 patients with an hs-cTnI<LoD, 0.5%). In comparison with hs-cTnI<LoD alone, the addition of a normal ECG (16% of patients) offered a NPV of 99.6% (95% CI, 98.9%-100%) and sensitivity of 99.4% (95% CI, 98.3%-100%) for acute myocardial infarction. Using hs-cTnI<LoD with a normal ECG, only 1 of 170 patients with acute myocardial infarction was missed, corresponding to a miss rate of 0.6% (or 1 of 254 patients with an hs-cTnI<LoD and a normal ECG, 0.4%).
      Table 2Use of a Single hs-cTnI at Presentation Alone and in Combination with a Normal 12-lead ECG for the Diagnosis of Acute Myocardial Infarction (Type 1 and 2 Myocardial Infarction), Type 1 Myocardial Infarction Alone, and Type 2 Myocardial Infarction Alone
      ParameterLoD (1.9 ng/L)High-STEACS (<5 ng/L)
      Baseline hs-cTnI<LoDBaseline hs-cTnI<LoD and Normal ECGBaseline hs-cTnI<5 ng/LBaseline hs-cTnI<5 ng/L and Normal ECG
      Acute myocardial infarction
       Proportion qualifying444/1631 (27)254/1631 (16)812/1631 (50)406/1631 (25)
       Proportion of missed MIs2/170 (1.2)1/170 (0.6)9/170 (5.3)2/170 (1.2)
       NPV99.6 (98.9-100)99.6 (98.8-100)98.9 (98.2-99.6)99.5 (98.8-100)
       Sensitivity98.8 (97.2-100)99.4 (98.3-100)94.7 (91.3-98.1)98.8 (97.2-100)
       PPV14.2 (12.2-16.1)12.3 (10.5-14.0)19.7 (16.9-22.4)13.7 (11.8-15.6)
       Specificity30.3 (27.9-32.6)17.3 (15.4-19.3)55.0 (52.4-57.5)27.7 (25.4-30.0)
      Type 1 myocardial infarction
       Proportion qualifying443/1529 (29)254/1529 (17)807/1529 (53)405/1529 (27)
       Proportion of missed MIs1/68 (1.5)1/68 (1.5)4/68 (5.9)1/68 (1.5)
       NPV99.8 (99.3-100)99.6 (98.8-100)99.5 (99.0-100)99.8 (99.3-100)
       Sensitivity98.5 (95.7-100)98.5 (95.7-100)94.1 (88.5-99.7)98.5 (95.7-100)
       PPV6.2 (4.7-7.6)5.3 (4.0-6.5)8.9 (6.8-10.9)6.0 (4.6-7.3)
       Specificity30.3 (27.9-32.6)17.3 (15.4-19.3)5.5 (5.2-5.8)27.7 (25.4-30.0)
      Type 2 myocardial infarction
       Proportion qualifying443/1563 (28)253/1563 (16)808/1563 (52)405/1563 (26)
       Proportion of missed MIs1/102 (0.98)0/102 (0)5/102 (4.9)1/102 (0.98)
       NPV99.8 (99.3-100)100 (100-100)99.4 (98.8-99.9)99.8 (99.3-100)
       Sensitivity99.0 (97.1-100)100 (100-100)95.1 (90.9-99.3)99.0 (97.1-100)
       PPV9.0 (7.3-10.7)7.8 (6.3-9.2)12.9 (10.5-15.2)8.7 (7.1-10.4)
       Specificity30.3 (27.8-32.6)17.3 (15.4-19.3)55.0 (52.4-57.5)27.7 (25.4-30.0)
      Values are number (percentage) or percentage (95% confidence interval).
      ECG = electrocardiogram; LoD = limit of detection; MI = myocardial infarction; NPV = negative predictive value; PPV = positive predictive value.
      At 30 days, the NPV and sensitivity for acute myocardial infarction or cardiac death were 99.6% (95% CI, 98.9%-100%) and 98.8% (95% CI, 97.2%-100%) for hs-cTnI<LoD alone, and 99.6% (95% CI, 98.8%-100%) and 99.4% (95% CI, 98.3%-100%) for hs-cTnI<LoD with a normal ECG (Figure, Table 3). Using hs-cTnI<LoD alone, 2 of 171 events (1.2%) were missed (or 2 of 444 patients with an hs-cTnI<LoD, 0.5%); whereas using hs-cTnI<LoD with a normal ECG only 1 of 171 events (0.6%) was missed (or 1 of 254 patients with a hs-cTnI<LoD and a normal ECG, 0.4%).
      Figure thumbnail gr1
      FigureSafety outcome: risk stratification at 30 days for acute myocardial infarction and cardiac death. Columns for proportion of patients qualifying for each approach (limit of detection, <1.9 ng/L, and High-STEACS, <5 ng/L) with and without a normal result on electrocardiogram (ECG), and corresponding sensitivities for the safety outcome.
      Table 3Safety Outcome: Risk Stratification at 30 Days for Acute Myocardial Infarction and Cardiac Death (Including Events During Index Hospitalization) Using a Single hs-cTnI at Presentation Alone and in Combination with a Normal 12-Lead ECG
      ParameterLoD (1.9 ng/L)High-STEACS (<5 ng/L)
      Baseline hs-cTnI<LoDBaseline hs-cTnI<LoD and Normal ECGBaseline hs-cTnI<5 ng/LBaseline hs-cTnI<5 ng/L and Normal ECG
      Acute myocardial infarction
       Proportion of missed events2/171 (1.2)1/171 (0.6)9/171 (5.3)2/171 (1.2)
       NPV99.6 (98.9-100)99.6 (98.8-100)98.9 (98.2-99.6)99.5 (98.8-100)
       Sensitivity98.8 (97.2-100)99.4 (98.3-100)94.7 (91.4-98.1)98.8 (97.2-100)
      Type 1 myocardial infarction
       Proportion of missed events1/70 (1.4)1/70 (1.4)4/70 (5.7)1/70 (1.4)
       NPV99.8 (99.3-100)99.6 (98.8-100)99.5 (99.0-100)99.8 (99.3-100)
       Sensitivity98.6 (95.8-100)98.6 (95.8-100)94.3 (88.9-99.7)98.6 (95.8-100)
      Type 2 myocardial infarction
       Proportion of missed events1/108 (0.9)0/108 (0)5/103 (4.6)1/108 (0.9)
       NPV99.8 (99.3-100)100 (100-100)99.4 (98.8-99.9)99.8 (99.3-100)
       Sensitivity99.1 (97.3-100)100 (100-100)95.4 (91.4-99.3)99.1 (97.3-100)
      Values are number (percentage) or percentage (95% confidence interval).
      ECG = electrocardiogram; LoD = limit of detection; NPV = negative predictive value.
      For ruling out type 1 myocardial infarction alone, baseline hs-cTnI<LoD alone resulted in a NPV of 99.8% (95% CI, 99.3%-100%) and sensitivity of 98.5% (95% CI, 95.7%-100%). In combination with a normal ECG, hs-cTnI<LoD resulted in an NPV of 99.6% (95% CI, 98.8%-100%) and sensitivity of 98.5% (95% CI, 95.7%-100%). For type 1 myocardial infarction, the sensitivity for the safety outcome was 98.6% (95% CI, 95.8%-100%) using either hs-cTnI<LoD alone or in combination with a normal ECG.
      For ruling out type 2 myocardial infarction alone, baseline hs-cTnI<LoD alone resulted in an NPV of 99.8 (95% CI, 99.3%-100%) and sensitivity of 99.0% (95% CI, 97.1%-100%). In combination with a normal ECG, hs-cTnI<LoD resulted in an NPV and sensitivity of 100% (95% CI, 100%-100%). For type 2 myocardial infarction, the sensitivity for the safety outcome was 99.1% (95% CI, 97.3%-100%) using hs-cTnI<LoD alone and 100% (95% CI, 100%-100%) in combination with a normal ECG.
      In early presenters the NPV and sensitivity for the diagnostic and safety outcomes was 100% (95% CI, 100%-100%) using hs-cTnI<LoD alone or in combination with a normal ECG (Table 4).
      Table 4Use of a Single hs-cTnI at Presentation Alone and in Combination with a Normal 12-Lead ECG for 1) Diagnosis of Acute Myocardial Infarction and 2) 30-Day Risk Stratification for Acute Myocardial Infarction or Cardiac Death in Early Presenters
      Early Presenters (n = 262)LoD (1.9 ng/L)High-STEACS (<5 ng/L)
      Baseline hs-cTnI<LoDBaseline hs-cTnI<LoD and Normal ECGBaseline hs-cTnI<5 ng/LBaseline hs-cTnI<5 ng/L and Normal ECG
      Diagnostic outcome, acute myocardial infarction
       Proportion qualifying78/262 (30)41/262 (16)137/262 (52)63/262 (24)
       Proportion of missed MIs0/39 (0)0/39 (0)2/39 (5.1)0/39 (0)
       NPV100 (100-100)100 (100-100)98.5 (96.5-100)100 (100-100)
       Sensitivity100 (100-100)100 (100-100)94.9 (88.0-100)100 (100-100)
       PPV21.2 (15.3-27.1)17.7 (12.6-22.7)29.6 (21.6-37.6)19.6 (14.1-25.1)
       Specificity35.0 (28.7-41.2)18.4 (13.3-23.5)60.5 (54.1-67.0)28.3 (22.3-34.2)
      Safety outcome, 30-day acute myocardial infarction or cardiac death
       Proportion of missed events0/40 (0)0/40 (0)2/40 (5)0/40 (0)
       NPV100 (100-100)100 (100-100)98.5 (96.5-100)100 (100-100)
       Sensitivity100 (100-100)100 (100-100)95.0 (88.3-100)100 (100-100)
      Values are number (percentage) or percentage (95% confidence interval).
      ECG = electrocardiogram; LoD = limit of detection; MI = myocardial infarction; NPV = negative predictive value; PPV = positive predictive value.

      Rule-Out Using the High-STEACS Threshold Alone and in Combination with a Normal ECG

      In patients with hs-cTnI<5 ng/L at presentation (50% of patients), independent of ECG findings, the NPV and sensitivity for acute myocardial infarction were 98.9% (95% CI, 98.2%-99.6%) and 94.7% (95% CI, 91.3%-98.1%), respectively. Using hs-cTnI<5 ng/L alone, 9 of 170 patients with acute myocardial infarction were missed, corresponding to a miss rate of 5.3% (or 9 of 812 patients with hs-cTnI<5 ng/L, 1.1%). The addition of a normal ECG to a hs-cTnI<5 ng/L (25% of patients) showed a NPV of 99.5% (95% CI, 98.8%-100%) and a sensitivity of 98.8% (95% CI, 97.2%-100%) for acute myocardial infarction (Table 2). Using hs-cTnI<5 ng/L with a normal ECG, 2 of 170 patients with acute myocardial infarction were missed, corresponding to a miss rate of 1.2% (or 2 of 406 patients with hs-cTnI<5 ng/L and a normal ECG, 0.5%).
      At 30 days, the NPV and sensitivity for acute myocardial infarction or cardiac death was 98.9% (95% CI, 98.2%-99.6%) and 94.7% (95% CI, 91.4%-98.1%) for hs-cTnI<5 ng/L alone, and 99.5% (95% CI, 98.8%-100%) and 98.8% (95% CI, 97.2%-100%) for hs-cTnI<5 ng/L with a normal ECG (Table 3). Using hs-cTnI<5 ng/L alone, 9 of 171 events (5.3%) were missed (or 9 of 812 patients with hs-cTnI<LoD, 1.1%), whereas when using hs-cTnI<5 ng/L with a normal ECG, only 2 of 171 (1.2%) were missed (or 2 of 406 patients with hs-cTnI<5 ng/L and a normal ECG, 0.5%).
      For ruling out type 1 myocardial infarction alone, baseline hs-cTnI<5 ng/L alone resulted in an NPV of 99.5% (95% CI, 99.0%-100%) and sensitivity of 94.1% (95% CI, 88.5%-99.7%). In combination with a normal ECG, hs-cTnI<5 ng/L resulted in a NPV of 99.8% (95% CI, 99.3%-100%) and sensitivity of 98.5% (95% CI, 95.7%-100%). For type 1 myocardial infarction, the sensitivities for the safety outcome were 94.3% (95% CI, 88.9%-99.7%) using hs-cTnI<5 ng/L alone and 98.6% (95% CI, 95.8%-100%) in combination with a normal ECG.
      For ruling out type 2 myocardial infarction alone, baseline hs-cTnI<5 ng/L alone resulted in a NPV of 99.4% (95% CI, 98.8%-99.9%) and sensitivity of 95.1% (95% CI, 90.9%-99.3%). In combination with a normal ECG, hs-cTnI<5 ng/L alone resulted in a NPV of 99.8% (95% CI, 99.3%-100%) and sensitivity of 99.0% (95% CI, 97.1%-100%). For type 2 myocardial infarction, the sensitivities for the safety outcome were 95.4% (95% CI, 91.4%-99.3%) using hs-cTnI<5 ng/L alone and 99.1% (95% CI, 97.3%-100%) in combination with a normal ECG.
      In early presenters, hs-cTnI<5 ng/L alone resulted in an NPV of 98.5% (95% CI, 96.5%-100%) and sensitivity of 94.9% (95% CI, 88.0%-100%) for acute myocardial infarction, whereas in combination with a normal ECG, hs-cTnI<5 ng/L had a NPV and sensitivity of 100% (95% CI, 100%-100%) (Table 4). Similarly, hs-cTnI<5 ng/L alone had an NPV 98.5% (95% CI, 96.5%-100%) and sensitivity of 95.0% (95% CI, 88.3%-100%) for the safety outcome of acute myocardial infarction or cardiac death at 30 days, whereas in combination with a normal ECG, both the NPV and sensitivity were 100% (95% CI, 100%-100%).

      Discussion

      Several findings are unique to our study evaluating the LoD and High-STEACS threshold rule-out strategies using a single hs-cTnI at presentation, alone and in combination with a normal ECG. First, we demonstrate that both strategies are excellent in safely ruling out acute myocardial infarction when used in combination with a normal ECG, as demonstrated by the very high NPV and sensitivity achieved for both the diagnostic and safety outcomes, including an excellent performance in early presenters. The use of these strategies allows the immediate identification of patients in whom the clinical presentation is unlikely to be due to an acute myocardial infarction (type 1 and 2 myocardial infarction) and who are at very low risk for adverse events at 30 days. The implementation of these approaches may reduce overcrowding, facilitate early discharge in selected patients, expedite triaging and reduce costs.
      Second, our study provides novel insights into the performance of single measurement rule-out strategies across myocardial infarction subtypes, including both type 1 and 2 myocardial infarctions. Our findings suggest that both the LoD and High-STEACS approaches in combination with a normal ECG are excellent in safely ruling out both type 1 and 2 myocardial infarction. Our study uniquely demonstrates that these rule-out approaches have an excellent clinical performance in a heterogeneous, all-comers cohort of patients undergoing hs-cTnI measurements on clinical indication, regardless of the presence or absence of chest pain, reflective of US practice. In contrast, most studies assessing rule-out strategies (outside the United States) often based their findings on select cohorts of patients with chest pain (5-7, 12) without providing detailed insights as to whether the rule-out strategies are applicable across the spectrum of patients with acute myocardial infarction, including both type 1 and 2 myocardial infarction.
      Third, among patients with a normal ECG, the High-STEACS approach seems more efficient because it applies to a larger proportion of patients than the LoD. In our study, we demonstrate that a single hs-cTnI<LoD, regardless of ECG findings, offers an excellent NPV and sensitivity for both the diagnostic and safety outcome, an approach applying to a similar proportion of patients than the one seen when combining a baseline hs-cTnI<5 ng/L and a normal ECG. The highest proportion of patients qualifying for rule-out was seen with the High-STEACS approach using hs-cTnI alone, which applied to 50% of patients. However, although the High-STEACS approach using hs-cTnI alone offered a very high NPV, the achieved sensitivity (approximately 95%) for both the diagnostic and safety outcome may not meet the desired acceptable event miss rate (approximately ≤1% miss rate or ≥99% sensitivity),
      • Than M.
      • Herbert M.
      • Flaws D.
      • et al.
      What is an acceptable risk of major adverse cardiac event in chest pain patients soon after discharge from the Emergency Department? A clinical survey.
      a matter of recent debate.
      • Carlton E.
      • Cullen L.
      • Body R.
      Appropriate use of high-sensitivity cardiac troponin levels in patients with suspected acute myocardial infarction-reply.
      • Chapman A.R.
      • Shah A.S.
      • Mills N.L.
      Appropriate use of high-sensitivity cardiac troponin levels in patients with suspected acute myocardial infarction.
      However, when combined with a normal ECG, the High-STEACS approach offered an excellent NPV and sensitivity for the diagnostic and safety outcomes.
      Prior non-US studies examining single measurement rule-out strategies have mostly examined hs-cTnT, with few non-US studies assessing the Abbott hs-cTnI assay. Similar to our findings, the Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) investigators (Switzerland) also examined the Abbott hs-cTnI assay using the <1.9 ng/L threshold for their calculations in 1567 patients and reported both a sensitivity and NPV of 100%.
      • Rubini Giménez M.
      • Hoeller R.
      • Reichlin T.
      • et al.
      Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin.
      Similarly, Carlton et al
      • Carlton E.
      • Greenslade J.
      • Cullen L.
      • et al.
      Evaluation of high-sensitivity cardiac troponin I levels in patients with suspected acute coronary syndrome.
      (England) examined hs-cTnI <1.2 ng/L with a nonischemic ECG and reported a sensitivity of 99.0% and NPV of 99.5%.
      Contrary to our findings, using hs-cTnI<2 ng/L with a nonischemic ECG, Carlton et al
      • Carlton E.
      • Greenslade J.
      • Cullen L.
      • et al.
      Evaluation of high-sensitivity cardiac troponin I levels in patients with suspected acute coronary syndrome.
      reported a sensitivity of 97.9% and an NPV of 99.3%. Additionally, using hs-cTnI<5 ng/L (High-STEACS threshold) with a nonischemic ECG, Carlton et al
      • Carlton E.
      • Greenslade J.
      • Cullen L.
      • et al.
      Evaluation of high-sensitivity cardiac troponin I levels in patients with suspected acute coronary syndrome.
      reported a sensitivity of 94.5% and an NPV of 99.2%. Whether differences in the ECG adjudication alone explain the difference in the achieved sensitivity is uncertain. These observations highlight that other factors not related to hs-cTnI concentrations alone may influence the diagnostic performance.
      Last, the present study complements our recent work using the LoD to rule out acute myocardial injury. An hs-cTnI<LoD demonstrates excellent a) sensitivity and NPV for ruling out acute myocardial injury
      • Sandoval Y.
      • Smith S.W.
      • Shah A.S.
      • et al.
      Rapid rule-out of acute myocardial injury using a single high-sensitivity cardiac troponin I measurement.
      and for ruling out type 1 and type 2 myocardial infarction, and b) risk stratification at 30 days for acute myocardial infarction or cardiac death. We note that our findings are limited to one hs-cTnI assay (Abbott Diagnostics) and emphasize that independent studies need to be carried out for other hs-cTn assays.
      • Apple F.S.
      • Sandoval Y.
      • Jaffe A.S.
      • Ordonez-Llanos J.
      for the IFCC Task Force on Clinical Applications of Cardiac Bio-Markers
      Cardiac troponin assays: guide to understanding analytical characteristics and their impact on clinical care.

      Conclusions

      Single measurement rule-out strategies using very low hs-cTnI concentrations such as the LoD and the High-STEACS approaches are excellent in safely ruling out acute myocardial infarction, including type 1 and 2, particularly when combined with a normal ECG. Both rule-out strategies quickly identify patients at low risk for acute myocardial infarction or cardiac death at 30 days, representing a potential opportunity to improve care and reduce costs.

      Supplementary Methods

      A normal 12-lead electrocardiogram (ECG) was defined as an entirely normal ECG (including those with normal variation ST elevation) or where there were nondiagnostic ST-T wave abnormalities. Sinus bradycardia, prolonged PR interval, low voltage, right or left atrial hypertrophy, right ventricular conduction delay, and occasional premature atrial beats were all within normal for the purpose of this study. All ECGs with atrial fibrillation, sinus tachycardia, high-degree atrioventricular block, premature ventricular contractions, bundle branch block, intraventricular conduction delay (>120 ms), paced rhythm, left ventricular hypertrophy, pathologic Q waves, ST segment depression ≥0.05 mV in 2 contiguous leads, T wave inversion (≥0.15 mV in 2 contiguous leads with prominent R wave or R/S ratio >1), or ST elevation were considered abnormal. Nonspecific ST-T wave abnormalities were slight variations in ST or T that were <1.5 mm of abnormal T wave inversion in 2 consecutive leads or up to 0.5 mm ST depression in 2 consecutive leads or both, or T wave flattening.

      References

        • Apple F.S.
        • Sandoval Y.
        • Jaffe A.S.
        • Ordonez-Llanos J.
        • for the IFCC Task Force on Clinical Applications of Cardiac Bio-Markers
        Cardiac troponin assays: guide to understanding analytical characteristics and their impact on clinical care.
        Clin Chem. 2017; 63: 73-81
        • Apple F.S.
        • Jaffe A.S.
        • Collinson P.
        • et al.
        IFCC educational materials on selected analytical and clinical applications of high sensitivity cardiac troponin assays.
        Clin Biochem. 2015; 48: 201-203
        • Sandoval Y.
        • Smith S.W.
        • Apple F.S.
        Present and future of cardiac troponin in clinical practice: a paradigm shift to high-sensitivity assays.
        Am J Med. 2016; 129: 354-365
        • Korley F.K.
        • Jaffe A.S.
        Preparing the United States for high-sensitivity cardiac troponin assays.
        J Am Coll Cardiol. 2013; 61: 1753-1758
        • Body R.
        • Carley S.
        • McDowell G.
        • et al.
        Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay.
        J Am Coll Cardiol. 2011; 58: 1332-1339
        • Bandstein N.
        • Ljung R.
        • Johansson M.
        • Holzmann M.J.
        Undetectable high-sensitivity cardiac troponin T level in the emergency department and risk of myocardial infarction.
        J Am Coll Cardiol. 2014; 63: 2569-2578
        • Thelin J.
        • Melander O.
        • Ohlin B.
        Early rule-out of acute coronary syndrome using undetectable levels of high sensitivity troponin T.
        Eur Heart J Acute Cardiovasc Care. 2015; 4: 403-409
        • Carlton E.W.
        • Cullen L.
        • Than M.
        • Gamble J.
        • Khattab A.
        • Greaves K.
        A novel diagnostic protocol to identify patients suitable for discharge after a single high-sensitivity troponin.
        Heart. 2015; 101: 1041-1046
        • Body R.
        • Burrows G.
        • Carley S.
        • et al.
        High-sensitivity cardiac troponin T concentrations below the limit of detection to exclude acute myocardial infarction: a prospective evaluation.
        Clin Chem. 2015; 61: 983-989
        • Vafaie M.
        • Slagman A.
        • Möckel M.
        • et al.
        Prognostic value of undetectable hs troponin T in suspected acute coronary syndrome.
        Am J Med. 2016; 129: 274-282
        • Rubini Giménez M.
        • Hoeller R.
        • Reichlin T.
        • et al.
        Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin.
        Int J Cardiol. 2013; 168: 3896-3901
        • Carlton E.
        • Greenslade J.
        • Cullen L.
        • et al.
        Evaluation of high-sensitivity cardiac troponin I levels in patients with suspected acute coronary syndrome.
        JAMA Cardiol. 2016; 1: 405-412
        • Shah A.S.
        • Anand A.
        • Sandoval Y.
        • et al.
        High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study.
        Lancet. 2015; 386: 2481-2488
        • Sandoval Y.
        • Smith S.W.
        • Shah A.S.
        • et al.
        Rapid rule-out of acute myocardial injury using a single high-sensitivity cardiac troponin I measurement.
        Clin Chem. 2017; 63: 369-376
        • Sandoval Y.
        • Smith S.W.
        • Schulz K.M.
        • et al.
        Diagnosis of type 1 and type 2 myocardial infarction using a high-sensitivity cardiac troponin I assay with sex-specific 99th percentiles based on the third universal definition of myocardial infarction classification system.
        Clin Chem. 2015; 61: 657-663
        • Love S.A.
        • Sandoval Y.
        • Smith S.W.
        • et al.
        Incidence of undetectable, measurable, and increased cardiac troponin I concentrations above the 99th percentile using a high-sensitivity vs. a contemporary assay in patients presenting to the emergency department.
        Clin Chem. 2016; 62: 1115-1119
        • Thygesen K.
        • Alpert J.S.
        • Jaffe A.S.
        • et al.
        Third universal definition of myocardial infarction.
        J Am Coll Cardiol. 2012; 60: 1581-1598
        • Sandoval Y.
        • Thygesen K.
        Myocardial infarction type 2 and myocardial injury.
        Clin Chem. 2017; 63: 101-107
        • Sandoval Y.
        • Smith S.W.
        • Thordsen S.E.
        • Apple F.S.
        Supply/demand type 2 myocardial infarction: should we be paying more attention?.
        J Am Coll Cardiol. 2014; 63: 2079-2087
        • Than M.
        • Herbert M.
        • Flaws D.
        • et al.
        What is an acceptable risk of major adverse cardiac event in chest pain patients soon after discharge from the Emergency Department? A clinical survey.
        Int J Cardiol. 2013; 166: 752-754
        • Carlton E.
        • Cullen L.
        • Body R.
        Appropriate use of high-sensitivity cardiac troponin levels in patients with suspected acute myocardial infarction-reply.
        JAMA Cardiol. 2017; 2: 229-230
        • Chapman A.R.
        • Shah A.S.
        • Mills N.L.
        Appropriate use of high-sensitivity cardiac troponin levels in patients with suspected acute myocardial infarction.
        JAMA Cardiol. 2017; 2: 228