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High-Sensitivity Cardiac Troponin T Improves the Diagnosis of Perioperative MI

Brown, Jamie C. MD*; Samaha, Eslam MD*; Rao, Srikar MD*; Helwani, Mohammad A. MD, MSPH*; Duma, Andreas MD, MSc*; Brown, Frank BSc*; Gage, Brian F. MD, MSc; Miller, J. Philip AB†‡; Jaffe, Allan S. MD§; Apple, Fred S. PhD; Scott, Mitchell G. PhD; Nagele, Peter MD, MSc*

doi: 10.1213/ANE.0000000000002240
Cardiovascular Anesthesiology: Original Clinical Research Report
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BACKGROUND: The diagnosis of myocardial infarction (MI) after noncardiac surgery has traditionally relied on using relatively insensitive contemporary cardiac troponin (cTn) assays. We hypothesized that using a recently introduced novel high-sensitivity cTnT (hscTnT) assay would increase the detection rate of perioperative MI.

METHODS: In this ancillary study of the Vitamins in Nitrous Oxide trial, readjudicated incidence rates of myocardial injury (new isolated cTn elevation) and MI were compared when diagnosed by contemporary cTnI versus hscTnT. We probed various relative (eg, >50%) or absolute (eg, +5 ng/L) hscTnT change metrics. Inclusion criteria for this ancillary study were the presence of a baseline and at least 1 postoperative hscTnT value.

RESULTS: Among 605 patients, 70 patients (12%) had electrocardiogram changes consistent with myocardial ischemia; 82 patients (14%) had myocardial injury diagnosed by contemporary cTnI, 31 (5.1%) of which had an adjudicated MI. After readjudication, 67 patients (11%) were diagnosed with MI when using hscTnT, a 2-fold increase. Incidence rates of postoperative myocardial injury ranged from 12% (n = 73) to 65% (n = 393) depending on the hscTnT metric used. Incidence rates of MI using various hscTnT change metrics and the presence of ischemic electrocardiogram changes, but without event adjudication, ranged from 3.6% (n = 22) to 12% (n = 74), a >3-fold difference. New postoperative hscTnT elevation, either by absolute or relative hscTnT change metric, was associated with an up to 5-fold increase in 6-month mortality.

CONCLUSIONS: The use of hscTnT compared to contemporary cTnI increases the detection rate of perioperative MI by a factor of 2. Using different absolute or relative hscTnT change metrics may lead to under- or overdiagnosis of perioperative MI.

Published ahead of print July 14, 2017.

From the *Division of Clinical and Translational Research, Department of Anesthesiology, Department of Internal Medicine, and Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri; §Cardiovascular Division, Department of Internal Medicine and Division of Core Clinical Laboratory Services, Department of Laboratory Medicine and Pathology, Mayo Clinic and Medical School, Rochester, Minnesota; Department of Laboratory Medicine & Pathology, Hennepin County Medical Center and University of Minnesota School of Medicine, Minneapolis, Minnesota; and Department of Pathology & Immunology, Washington University School of Medicine, St Louis, Missouri.

Accepted for publication April 21, 2017.

Published ahead of print July 14, 2017.

Funding: The parent Vitamins in Nitrous Oxide trial was funded by a grant from the National Institute for General Medical Sciences (K23 GM087534) and a grant to Washington University Institute of Clinical and Translational Sciences (UL1RR024992), the Foundation for Anesthesia Education and Research (FAER), and the Division of Clinical and Translational Research, Department of Anesthesiology, Washington University. Roche Diagnostics (Indianapolis, IN) provided the hscTnT assays and covered the costs of running these assays. P. N. is currently funded by NIH/NHLBI (R01HL126892). P. N. was supported by Roche Diagnostics US and Abbott Diagnostics. M. G. S. was supported by Siemens Healthcare Diagnostic, Abbott Diagnostics, and Instrumentation Laboratories. F. S. A. was supported by Minneapolis Medical Research Foundation, but received no salary support for work related to cardiac troponin: Abbott Diagnostics, Siemens, Ortho-Clinical Diagnostics, Roche Diagnostics, Radiometer.

Conflicts of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Peter Nagele, MD, MSc, Department of Anesthesiology, Washington University School of Medicine, 660 S Euclid Ave, Box 8054, St Louis, MO 63110. Address e-mail to nagelep@wustl.edu.

Acute myocardial infarction (MI) is diagnosed according to the international consensus document “The Third Universal Definition of Myocardial Infarction.”1 To objectively diagnose acute MI, at minimum 2 of 3 elements need to be present: (1) clinical symptoms consistent with myocardial ischemia, such as chest pain; (2) electrocardiogram (ECG) changes consistent with myocardial ischemia, such as ST-segment elevation or depression; (3) a new rise (or fall) pattern of a cardiac biomarker, preferably cardiac troponin (cTn). Because myocardial ischemia after noncardiac surgery is often silent, the diagnosis of acute perioperative MI relies greatly on the detection of new cardiac biomarker elevation.2–4

Until recently, cTn assays were relatively insensitive from an analytical perspective and preoperative cTn values were mostly undetectable, thus making it impossible to measure actual cTn change values. However, the recent development and introduction of high-sensitivity cTn (hscTn) assays changed this: several studies have now shown that hscTn values can be measured before noncardiac surgery.5–7

We thus hypothesized that the increased sensitivity of novel hscTn assays would increase the detection of postoperative cTn elevation. It is however unknown, if this would also translate into an increased detection rate of acute postoperative MI.

To answer these questions, we performed a secondary analysis of data obtained in the Vitamins in Nitrous Oxide (VINO) trial.8 In the current study, we used adjudicated event rates of myocardial injury and MI as objective standard, which were diagnosed by a contemporary non–high-sensitivity cTnI assay according to the Third Universal Definition of MI. We then compared these event rates to event rates that were obtained after readjudicating events using a novel high-sensitivity cTnT (hscTnT) assay.

A secondary aim of this investigation was to compare various absolute and relative hscTnT change metrics, ie, comparing the difference between preoperative and peak postoperative hscTnT.9,10 The principal reason for investigating hscTn change metrics is their successful application in rapid rule-in/rule-out MI protocols in emergency department setting, where the introduction of hscTn has profoundly changed how acute MI is diagnosed in patients presenting with acute chest pain.11–15

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METHODS

Study Design and Population

Patients were originally enrolled in the VINO Trial (Clinicaltrials.gov number NCT00655980).8 In brief, the VINO trial was a double blind, randomized, placebo-controlled, single-center trial that evaluated if patients carrying the MTHFR C677T or A1298C gene variant had higher risk for perioperative myocardial injury and infarction after nitrous oxide anesthesia for major noncardiac surgery, and whether this risk could be mitigated by B vitamins. The original trial was negative for any effect on postoperative myocardial injury and infarction. The VINO trial enrolled 625 patients, with elevated cardiac risk, scheduled for major noncardiac surgery. For this ancillary study, 605 patients with baseline high-sensitivity cTnT (hscTnT) and at least 1 postoperative hscTnT measurement were included in the analysis. This study was approved by the institutional review board at Washington University in St. Louis.

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Measurements

Biomarker Assays.

HscTnT measurements were collected at predefined time points: baseline (within 2 hours before surgery), end of surgery (within 30 minutes after arrival in the postanesthesia care unit), postoperative days 1, 2, and 3, or until discharge. HscTnT was processed on the Roche Elecsys 2010 analyzer (limit of detection: 5.0 ng/L; 99th percentile: men: hscTnT ≥ 14.5 ng/L; women: hscTnT ≥10 ng/L; 10% coefficient of variation at 13 ng/L).16,17 All hscTnT cutoffs used sex-specific reference values for the 99th percentile. The preoperative value was the baseline value, and the postoperative hscTnT peak was defined as the highest postoperative hscTnT concentration on any follow-up day. cTnI concentrations were also collected over the same time points and were measured on a contemporary non–high-sensitivity assay (Siemens Dimension RxL analyzer [Siemens Medical Solutions, Malvern, PA]; limit of detection: 0.04 µg/L (=40 ng/L); 99th percentile: 0.07 µg/L; 10% coefficient of variation at 0.14 µg/L). The contemporary cTnI values were used for clinical care.

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Electrocardiograms.

Twelve-lead electrocardiograms (ECGs) were collected at the same time points to correlate with troponin concentrations at baseline, end of surgery, postoperative days 1, 2, and 3, or until discharge. The ECGs were read and analyzed by 2 investigators blinded to biomarker results for signs of myocardial ischemia: Q-waves, ST elevation ≥0.2 mV, ST depression or T-wave inversion ≥0.1 mV in at least 2 contiguous leads. Patients with at least 1 positive ECG finding, at any time in the 72 hours after surgery, were considered positive for myocardial ischemia. Ambiguous cases were resolved by consensus opinion that included the principal investigator.

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Outcomes

The primary outcome of this study was acute MI within the first 3 postoperative days, diagnosed according to the Third Universal Definition of MI. The diagnosis required a new postoperative cTn elevation >99th percentile plus simultaneous ischemic changes on a 12-lead ECG and/or clinical symptoms consistent with acute myocardial ischemia, such as chest pain.1 New postoperative cTn elevation was either determined by a contemporary cTnI assay or hscTnT. If baseline hscTnT was already elevated >99th percentile, a >50% hscTnT rise was used. All patients who developed new postoperative hscTnT elevation were readjudicated for missed cardiac events. MI was also diagnosed when cardiology consultants diagnosed acute MI, and/or by cardiac imaging or coronary angiography. Readjudication included a review of patient records, charts, clinical data to identify missed cardiac events.

Myocardial injury was diagnosed when an isolated new cTn elevation above the 99th% URL (either by cTnI or hscTnT) without evidence of myocardial ischemia on ECG or echo was present. Mortality was assessed at 6 months, 1 year, and 3 years from date of surgery.

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Statistical Methods

Adjudicated incidence rates of perioperative MI and myocardial injury were compared between events diagnosed using the contemporary cTnI assay and hscTnT.18 These incidence rates were then compared to unadjudicated incidence rates obtained using 11 absolute and relative hscTnT change metrics to determine if and by how much incidence rates would differ if only made with biomarker and ECG data (but without clinical adjudication), as most postoperative events of myocardial ischemia are silent.

The following absolute and relative hscTnT change metrics were used: (1) postoperative hscTnT >99th percentile; (2) postoperative hscTnT >99th percentile if baseline <99th percentile; (3) postoperative hscTnT increase >50% from baseline; (4) postoperative hscTnT increase >50% from baseline and 1 postoperative value >99th percentile; (5) postoperative hscTnT increase >100% from baseline; (6) postoperative hscTnT increase >100% from baseline and 1 postoperative value >99th percentile; (7) postoperative hscTnT increase by >100% if baseline <99th percentile, or increased by >50% if baseline hscTnT >99th percentile; (8) postoperative hscTnT increase >5 ng/L from baseline; (9) postoperative hscTnT increase >5 ng/L from baseline and 1 postoperative value >99th percentile; (10) postoperative hscTnT increase >10 ng/L from baseline; and (11) postoperative increase >10 ng/L from baseline hscTnT and 1 postoperative value >99th percentile.

Survival analysis was performed for each hscTnT metric at 6 months, 1 year, and 3 years. For all hscTnT metrics and the contemporary cTnI definition for diagnosis of MI, we used Kaplan–Meier curves and log rank tests to compare patients who had a MI and patients who did not have a MI. A Cox proportional hazards model was used to calculate the hazard ratios for each definition of myocardial injury and infarction by cTnI and hscTnT change metrics. The Cox proportional hazards models were then adjusted for potential confounders of age, sex, race, history of chronic kidney disease, and coronary artery disease (CAD). History of CAD or its equivalent (history of percutaneous coronary intervention or coronary artery bypass grafting) were combined into 1 dichotomous variable to reduce collinearity in the regression analyses. All Cox models were tested using Schoenfeld residuals to assure proportional hazard assumptions were not violated. Statistical methods were performed using Stata Version 14.0 (StataCorp, College Station, TX). All tests were 2 sided; results were not adjusted for multiple comparisons and a P value <.05 was considered statistically significant.

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RESULTS

Demographics

Table 1.

Table 1.

The final study population included 605 patients with both baseline and at least 1 postoperative hscTnT value. Surgical procedures included predominantly vascular and orthopedic surgery.8Table 1 shows a summary of patient characteristics for the study population based on the clinical diagnosis of acute MI using the contemporary non–high-sensitivity cTnI assay. At baseline, 290 of 605 (48%) study participants had elevated hscTnT above the sex-specific 99th percentile.

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Diagnostic Criteria for MI by High-Sensitivity cTnT

In the parent trial, and used as comparator group, 82 of 605 (14%) patients had myocardial injury diagnosed with a contemporary non–high-sensitivity cTnI assay within the first 3 days after surgery, 31 (5.1%) of whom had an adjudicated MI. Seventy patients (12%) had ECG changes consistent with myocardial ischemia.

After readjudication of all patients who developed a new hscTnT elevation above the 99th percentile or a >50% increase compared to baseline if the baseline was already >99th percentile (using the high-sensitivity cTnT assay), 67 patients (11%) were diagnosed with MI, a >2-fold increase in call rate (Table 2). Among the 67 patients, 1 patient had a ST-elevation MI (1.5%), 57 patients a non-ST-elevation MI (85%), and 9 had unspecific ECG changes (13%); 20 patients (30%) had clinical symptoms consistent with myocardial ischemia and 47 had no symptoms (70%); 8 patients (12%) were referred to coronary angiography and 4 (6%) received a percutaneous coronary intervention and stent.

Based on the absolute or relative hscTnT change metric used, which compared the change between baseline and peak hscTnT, the incidence rate of myocardial injury (isolated hscTnT elevation without evidence of myocardial ischemia) ranged from 12% (n = 73) to 65% (n = 393), a >5-fold difference (Table 2). Nearly all hscTnT change metrics captured more myocardial injury events than with the contemporary non–high-sensitivity cTnI assay.

Table 2.

Table 2.

Figure 1.

Figure 1.

Incidence rates of perioperative MI ranged from 3.6% (n = 22) to 12% (n = 74) by absolute and relative hscTnT change metric, when diagnosed in combination with ischemic ECG changes, but without event adjudication, a >3-fold difference. Figure 1 shows Venn diagrams comparing readjudicated MI call rates by hscTnT to the call rates obtained by using absolute and relative hscTnT change metric.

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Short-term and Long-term Mortality

Table 3.

Table 3.

Figure 2.

Figure 2.

Among the 605 study patients, there were 21 (3.5%) deaths at 6 months, 42 (7.0%) deaths at 1 year, and 96 (16%) deaths at 3 years. Table 3 compares hazard ratios for each cTnI and hscTnT change metric, and Figure 2 shows Kaplan–Meier survival curves for MIs adjudicated by either contemporary cTnI assays versus hscTnT. Patients with new postoperative hscTnT elevation above the 99th percentile, either by absolute or relative hscTnT change metric, experienced up to 5-fold increase in 6-month mortality. This finding was consistent with the 3.4-fold increased risk of short-term mortality seen in MI diagnosed by the contemporary TnI (P = .047, 95% confidence interval, 1.0–12). The association of preoperative and postoperative hscTnT elevation with increased rate of mortality decreased over the 1- and 3-year follow-up periods (Table 3).

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DISCUSSION

High-sensitivity cTn assays have profoundly changed how acute MI is diagnosed.11,19–21 When clinicians rely on contemporary non–high-sensitivity cTn assays, the only available standard in the United States until very recently, the recommendation is to obtain a cTn value at the time of presentation and a second one 6–9 hours later due to the relative insensitivity of the assay. In contrast, hscTn can detect a rising or falling cTn pattern in less than 2 hours with a high degree of sensitivity and specificity to rule-in/ rule-out acute MI. Over the past 5 years, significant progress has been made in the clarification of rule-in/rule-out protocols for acute MI in patients presenting with clinical symptoms consistent with acute coronary syndrome in the emergency department using hscTn assays.11,20–28 However, scant if any data are currently available for perioperative patients using the hscTn assays. Thus, the goal of this study was to fill the knowledge gap and to determine if the introduction of hscTnT versus contemporary non–high-sensitivity cTn assays would change the incidence rates of detected perioperative myocardial injury and infarction.

In the United States, the current standard cTn assays do not have the analytic sensitivity of hscTn assays and were used in the parent VINO trial to diagnose myocardial injury and infarction. In this ancillary study, these incidence rates (14% and 5%, respectively) were used as main comparator. We then readjudicated all patients with a new postoperative hscTnT elevation >99th percentile, or—if they were already elevated >99th percentile at baseline—a >50% postoperative hscTnT rise for missed cardiac events. After readjudication, the “call rate” increased from 14% to 22% for myocardial injury and from 5% to 11% for MI, about a 2-fold increase.

To determine, how incidence rates of myocardial injury and infarction would differ when only using hscTnT change metric and ECG evidence of myocardial ischemia, but without adjudication, we then compared a total of 11 absolute and relative hscTnT change metrics. These absolute and relative hscTnT change metrics had been proposed in the literature as diagnostic cutoffs for acute MI in patients with acute chest pain presenting to the emergency department. Some hscTnT metrics were too stringent and resulted in lower call rate compared to the contemporary cTnI assay (eg, postoperative hscTnT >99th percentile if baseline <99th percentile), and some were overly broad, such as simply relying on a postoperative hscTnT elevation >99th percentile without comparison to the preoperative baseline value. Most hscTnT change metrics, however, resulted in a markedly higher call rate of postoperative myocardial injury and infarction. However, the call rate may even be higher if clinicians use different approaches.13

Short-term mortality (6-month) risk was increased 3- to 5-fold when patients experienced a postoperative hscTnT increase and this effect was rather consistent regardless of the hscTnT change metric used. Of note, as we have shown previously preoperatively elevated hscTnT above the 99th percentile, an indicator of elevated cardiovascular risk, was independently associated with both short- and long-term mortality.5 The multicenter vascular events in noncardiac surgery patients cohort evaluation study showed conclusively that isolated postoperative cTn elevations are associated with an increased risk for 30-day morbidity and mortality, yet vascular events in the noncardiac surgery patient cohort evaluation study did not collect preoperative blood samples and was thus unable to definitively determine if these cTn elevations were new or in a rising/falling pattern.9,29 Our study now provides definitive evidence that both myocardial injury and MI detected and quantified by comparing baseline and peak postoperative hscTnT samples markedly influence postoperative cardiovascular outcomes.

The definitive value of the 99th percentile for the hscTnT assay is currently under discussion: we used the published sex-specific values of 10 ng/L for women and 14.5 ng/L for men.16 However, others recommend higher values, 13 ng/L for women and 20 ng/L for men. Because this is an area of active investigation, reference values may change in the future and thus influence the validity of our results. Furthermore, comparisons to hscTnI assays have not been published and would be very informative, as many hospitals use hscTnI and not hscTnT.

At present, the mechanism underlying postoperative cTn release after noncardiac surgery is unclear, and there may be some pathophysiological differences between early and late increases. In some patients, the mechanism is likely due to supply-demand mismatch and ischemic imbalance in the setting of obstructive CAD resulting in myocardial ischemia. In other patients, however, it may involve mechanism that resembles more stress-induced cardiomyopathy or simple shear stress of cardiomyocytes without coronary flow limitation. In other patients, postoperative cTn may be due to secondary causes, such as pulmonary embolism or sepsis. We believe in our patient population, the majority of events were due to acute myocardial injury or non-ST elevation MI (type II MI), as the exact nature and nomenclature is currently under discussion.30

Evidence from this study suggests that: (1) it is helpful to obtain a preoperative hscTnT value to determine if a postoperatively elevated hscTnT value is new, and to be able to quantify the extent of myocardial injury; and (2) the use of hscTn assays will be markedly more sensitive in the diagnosis of postoperative myocardial injury and infarction. At present, it is unclear which particular hscTn absolute or relative change metric will be used in the future, but it appears that a >50% increase with at least 1 value >99th percentile may be a good starting point.

This study had several limitations. The patient population and surgical procedures were high risk. Thus, the results of this study may not be applicable to an unselected adult patient population. As one of the most recent guidelines states, recommendations pertain only to patients: (1) 45 years of age and older; or (2) patients 18–44 years of age with known significant cardiovascular disease who undergo surgeries that require at least an overnight stay in the hospital after surgery.31

In conclusion, this study showed that the use of a novel hscTnT assay—regardless of change metric—will likely lead to an increased incidence rate of diagnosed perioperative MI. Both absolute and relative hscTnT rising patterns have prognostic implications for short-term mortality after noncardiac surgery.

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DISCLOSURES

Name: Jamie C. Brown, MD.

Contribution: This author helped in study conception, data acquisition, data analysis, data interpretation, initial drafting the manuscript, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

Name: Eslam Samaha, MD.

Contribution: This author helped in data interpretation and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

Name: Srikar Rao, MD.

Contribution: This author helped in data interpretation and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

Name: Mohammad A. Helwani, MD, MSPH.

Contribution: This author helped in study conception, data interpretation, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

Name: Andreas Duma, MD, MSc.

Contribution: This author helped in data interpretation and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

Name: Frank Brown, BSc.

Contribution: This author helped in study conception, data acquisition, data interpretation, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

Name: Brian F. Gage, MD, MSc.

Contribution: This author helped in study conception, data interpretation, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

Name: J. Philip Miller, AB.

Contribution: This author helped in study conception, data analysis, data interpretation, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

Name: Allan S. Jaffe, MD.

Contribution: This author helped in study conception, data interpretation, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: Dr Jaffe discloses consultant work for Beckman, Ortho, Abbott, Alere, Critical Diagnostics, Roche, Radiometer, Amgen, and theHeart.org.

Name: Fred S. Apple, PhD.

Contribution: This author helped in study conception, data interpretation, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: Dr Apple is a paid consultant for Instrumentation Laboratories, Alere, T2 Biosystems.

Name: Mitchell G. Scott, PhD.

Contribution: This author helped in study conception, data interpretation, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: Dr Scott is a consultant for Instrumentation Laboratories; Becton-Dickinson, Alere; Speaker fees: Abbott. Support from Roche Diagnostics and Abbott.

Name: Peter Nagele, MD, MSc.

Contribution: This author helped in study conception, data acquisition, data interpretation, initial drafting of the manuscript, and critically revising the manuscript for important intellectual content.

Conflicts of Interest: None.

This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.

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REFERENCES

1. Thygesen K, Alpert JS, Jaffe AS, et al.; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation. 2012;126:2020–2035.
2. Fleisher LA, Fleischmann KE, Auerbach AD, et al.; American College of Cardiology; American Heart Association. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64:e77–137.
3. Biccard BM, Rodseth RN. The pathophysiology of peri-operative myocardial infarction. Anaesthesia. 2010;65:733–741.
4. Landesberg G, Beattie WS, Mosseri M, Jaffe AS, Alpert JS. Perioperative myocardial infarction. Circulation. 2009;119:2936–2944.
5. Nagele P, Brown F, Gage BF, et al. High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery. Am Heart J. 2013;166:325–332.e1.
6. Weber M, Luchner A, Seeberger M, et al. Incremental value of high-sensitive troponin T in addition to the revised cardiac index for peri-operative risk stratification in non-cardiac surgery. Eur Heart J. 2013;34:853–862.
7. Kavsak PA, Walsh M, Srinathan S, et al. High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: a prospective cohort study. Clin Biochem. 2011;44:1021–1024.
8. Nagele P, Brown F, Francis A, Scott MG, Gage BF, Miller JP; VINO Study Team. Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial. Anesthesiology. 2013;119:19–28.
9. Botto F, Alonso-Coello P, Chan MT, et al.; Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Writing Group, on behalf of the Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Investigators; Appendix I. The Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Study Investigators Writing Group; Appendix II. The Vascular events In noncardiac Surgery patIents cOhort evaluatioN Operations Committee; Vascular events In noncardiac Surgery patIents cOhort evaluatioN VISION Study Investigators. Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology. 2014;120:564–578.
10. Biccard BM, Devereaux PJ, Rodseth RN. Cardiac biomarkers in the prediction of risk in the non-cardiac surgery setting. Anaesthesia. 2014;69:484–493.
11. Sandoval Y, Smith SW, Apple FS. Present and future of cardiac troponin in clinical practice: a paradigm shift to high-sensitivity assays. Am J Med. 2016;129:354–365.
12. Lipinski MJ, Baker NC, Escárcega RO, et al. Comparison of conventional and high-sensitivity troponin in patients with chest pain: a collaborative meta-analysis. Am Heart J. 2015;169:6–16.e6.
13. Thygesen K, Mair J, Giannitsis E, et al.; Study Group on Biomarkers in Cardiology of ESC Working Group on Acute Cardiac Care. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J. 2012;33:2252–2257.
14. Shah AS, Anand A, Sandoval Y, et al.; High-STEACS investigators. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet. 2015;386:2481–2488.
15. Reichlin T, Cullen L, Parsonage WA, et al. Two-hour algorithm for triage toward rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Am J Med. 2015;128:369–79.e4.
16. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56:254–261.
17. Giannitsis E, Becker M, Kurz K, Hess G, Zdunek D, Katus HA. High-sensitivity cardiac troponin T for early prediction of evolving non-ST-segment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission. Clin Chem. 2010;56:642–650.
18. Jaffe AS, Moeckel M, Giannitsis E, et al. In search for the Holy Grail: suggestions for studies to define delta changes to diagnose or exclude acute myocardial infarction: a position paper from the study group on biomarkers of the Acute Cardiovascular Care Association. Eur Heart J Acute Cardiovasc Care. 2014;3:313–316.
19. Nestelberger T, Wildi K, Boeddinghaus J, et al. Characterization of the observe zone of the ESC 2015 high-sensitivity cardiac troponin 0h/1h-algorithm for the early diagnosis of acute myocardial infarction. Int J Cardiol. 2016;207:238–245.
20. Jaeger C, Wildi K, Twerenbold R, et al. One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I. Am Heart J. 2016;171:92–102.e1.
21. Boeddinghaus J, Reichlin T, Cullen L, et al. Two-hour algorithm for triage toward rule-out and rule-in of acute myocardial infarction by use of high-sensitivity cardiac troponin I. Clin Chem. 2016;62:494–504.
22. Twerenbold R, Wildi K, Jaeger C, et al. Optimal cutoff levels of more sensitive cardiac troponin assays for the early diagnosis of myocardial infarction in patients with renal dysfunction. Circulation. 2015;131:2041–2050
23. Tanglay Y, Twerenbold R, Lee G, et al. Incremental value of a single high-sensitivity cardiac troponin I measurement to rule out myocardial ischemia. Am J Med. 2015;128:638–646.
24. Sara JD, Holmes DR Jr, Jaffe AS. Fundamental concepts of effective troponin use: important principles for internists. Am J Med. 2015;128:111–119.
25. Sanchis J, Abellán L, García-Blas S, et al. Usefulness of delta troponin for diagnosis and prognosis assessment of non-ST-segment elevation acute chest pain. Eur Heart J Acute Cardiovasc Care. 2016;5:399–406.
26. Rubini Gimenez M, Twerenbold R, Jaeger C, et al. One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I. Am J Med. 2015;128:861–870.e4.
27. Reichlin T, Twerenbold R, Wildi K, et al. Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay. CMAJ. 2015;187:E243–E252.
28. Neumann JT, Sörensen NA, Schwemer T, et al. Diagnosis of myocardial infarction using a high-sensitivity troponin I 1-hour algorithm. JAMA Cardiol. 2016;1:397–404.
29. Devereaux PJ, Chan MT, Alonso-Coello P, et al.; Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study I. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;307:2295–2304.
30. Nagele P. The case for a revised definition of myocardial infarction-resolving the ambiguity of type 2 myocardial infarction. JAMA Cardiol. 2016;1:247–248.
31. Duceppe E, Parlow J, MacDonald P, et al. Canadian Cardiovascular Society Guidelines on perioperative cardiac risk assessment and management for patients who undergo noncardiac surgery. Can J Cardiol. 2017;33:17–32.
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