- Email: [email protected]
Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery
Accepted Manuscript Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery
Danielle M Gualandro, Christian Puelacher, Giovanna LuratiBuse, Andreas Lampart, Celia Strunz, Francisco A Cardozo, Pai C Yu, Allan S Jaffe, Sanela Barac, Lukas Bock, Patrick Badertscher, Jeanne du Fay de Lavallaz, Stella Marbot, Lorraine Sazgary, Daniel Bolliger, Katharina Rentsch, Raphael Twerenbold, Angelika Hammerer-Lercher, Edielle S Melo, Daniela Calderaro, Alberto JS Duarte, Nelson de Luccia, Bruno Caramelli, Christian Mueller, TropoVasc and BASEL-PMI Investigators PII: DOI: Reference:
S0002-8703(18)30201-1 doi:10.1016/j.ahj.2018.06.012 YMHJ 5720
To appear in:
American Heart Journal
Received date: Accepted date:
13 December 2017 30 June 2018
Please cite this article as: Danielle M Gualandro, Christian Puelacher, Giovanna LuratiBuse, Andreas Lampart, Celia Strunz, Francisco A Cardozo, Pai C Yu, Allan S Jaffe, Sanela Barac, Lukas Bock, Patrick Badertscher, Jeanne du Fay de Lavallaz, Stella Marbot, Lorraine Sazgary, Daniel Bolliger, Katharina Rentsch, Raphael Twerenbold, Angelika Hammerer-Lercher, Edielle S Melo, Daniela Calderaro, Alberto JS Duarte, Nelson de Luccia, Bruno Caramelli, Christian Mueller, TropoVasc and BASEL-PMI Investigators , Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery. Ymhj (2018), doi:10.1016/j.ahj.2018.06.012
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Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery Danielle M Gualandro*1,2, Christian Puelacher*2, Giovanna LuratiBuse3,4, Andreas Lampart,4 Celia Strunz5, Francisco A Cardozo1, Pai C Yu1, Allan S Jaffe6, Sanela
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Barac2, Lukas Bock2, Patrick Badertscher2, Jeanne du Fay de Lavallaz2, Stella Marbot2, Lorraine Sazgary2, Daniel Bolliger4, Katharina Rentsch7, Raphael
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Twerenbold2,8, Angelika Hammerer-Lercher9, Edielle S Melo1, Daniela Calderaro1,
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Alberto JS Duarte10, Nelson de Luccia11, Bruno Caramelli1, Christian Mueller2 , for
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the TropoVasc and BASEL-PMI Investigators. *both authors have contributed equally and should be considered first author 1
Interdisciplinary Medicine in Cardiology Unit, Cardiology Department, Heart Institute (InCor),
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University of Sao Paulo Medical School, Brazil; 2Department of Cardiology, University Hospital Basel, University of Basel, Switzerland; 3 Department of Anaesthesiology, University Hospital Düsseldorf, Germany; 4 Department of Anaesthesiology, University Hospital Basel,
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University of Basel, Switzerland; 5 Heart Institute (InCor), University of Sao Paulo Medical
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School, Brazil; 6Department of Cardiology and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA; 7Department of Laboratory Medicine, University Hospital Basel, Switzerland; 8 Department of General and Interventional Cardiology,
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Hamburg University Heart Center, Hamburg, Germany; 9 Department of Laboratory Medicine, Cantonal Hospital Aarau, Switzerland; 10Laboratory of Immunogenetics and Experimental Transplantation, University of Sao Paulo Medical School, Brazil; 11 Vascular and
Brazil
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Endovascular Surgery Clinic of the Clinics Hospital, University of São Paulo Medical School,
Corresponding author: Danielle M Gualandro Address: Av.Dr.Eneas de Carvalho Aguiar, 44 andar AB, São Paulo, SP Brazil ZIP CODE: 05403-000. Phone: +55 11 26615376 Fax: +55 11 26615535 Email: [email protected]
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Abstract Background: We aimed to directly compare preoperative high-sensitivity cardiac troponin (hs-cTn) I and T concentration for the prediction of major cardiac complications after non-cardiac surgery.
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Methods: We measured hs-cTnI and hs-cTnT preoperatively in a blinded fashion in 1022 patients undergoing non-cardiac surgery. The primary endpoint was a
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composite of major cardiac complications including cardiac death, cardiac arrest,
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myocardial infarction, clinically relevant arrhythmias, and acute heart failure within 30 days. We hypothesized that the type of surgery may impact on the predictive
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accuracy of hs-cTnI/T and stratified all analyses according to the type of surgery.
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Results: Major cardiac complications occurred in 108 (11%) patients, 58/243 (24%) patients undergoing vascular surgery and 50/779 (6%, p<0.001) patients undergoing
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non-vascular surgery. Using regulatory-approved 99th percentile cut-off
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concentrations, preoperative hs-cTnI elevations were less than one-fifth as common as preoperative hs-cTnT elevations (p<0.001). Among patients undergoing vascular
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surgery, preoperative hs-cTnI concentrations, but not hs-cTnT, was an independent predictor of cardiac complications (adjusted odds ratio (aOR) 1.5, 95% confidence
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interval (95%CI) 1.0-2.1). The area under the receiver-operating characteristics curve (AUC) was 0.67 (95%CI, 0.59-0.75) for hs-cTnI versus 0.59 (95%CI 0.51-0.67, p=0.012) for hs-cTnT. In contrast, among patients undergoing non-vascular surgery both preoperative hs-cTnI and hs-cTnT were independent predictors of the primary endpoint (aOR 1.6, 95%CI 1.3-2.0, and aOR 3.0, 95%CI 2.0-4.6, respectively) and showed higher predictive accuracy (AUC 0.77, 95%CI, 0.71-0.83, and 0.79, 95%CI 0.73-0.85, p=ns).
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Conclusions: Preoperative hs-cTnI and hs-cTnT concentrations predict major cardiac complications after non-vascular surgery, while, in patients undergoing vascular surgery, hs-cTnI may have better accuracy.
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Keywords: troponin; preoperative care; cardiac complications; non-cardiac surgery
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Introduction More than 300 million surgeries are performed annually worldwide.1 Despite advances in surgery and anaesthesia, 30-day mortality after non-cardiac surgery remains substantial.2, 3 Cardiac complications, including perioperative myocardial infarction (MI), are important contributors to 30-day mortality.4, 5 Because cardiac
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complications, particularly MI, maybe silent and ECGs at one point in time can miss
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important changes, accurate detection mandates active surveillance.5 Predicting
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cardiac complications after non-cardiac surgery is difficult and inaccurate, as both patient and surgery related factors seem to matter. A recent multicentre study
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suggested that the current clinical standard of care using multivariate risk scores has poor prognostic accuracy, particularly in patients undergoing vascular surgery. 6 Thus,
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the central task of preoperative assessment and patient counselling, the quantification of the risk-benefit ratio of planned operations, remains elusive. In
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addition, targeting interventions that might be preventative or therapeutic to high-risk
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populations is hardly possible as the reliable preoperative detection of patients at high-risk of developing major cardiac complications would be a requisite.
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The use of cardiac biomarkers could improve the prediction of cardiac complications
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after non-cardiac surgery. Pilot studies by several groups including ours have suggested that preoperative high-sensitivity cardiac troponin T (hs-cTnT) blood concentrations seem to improve risk prediction in non-cardiac surgery.7, 8 The role of high-sensitivity cardiac troponin I (hs-cTnI) in predicting cardiac complications after non-cardiac surgery remains largely unknown. It is also unknown, whether one cardiac troponin signal is more accurate than the other, and/or whether the type of surgery may impact on the relative accuracy of hs-cTnT versus hs-cTnI.
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The aim of our study was to compare the accuracy of preoperative hs-cTnI and hs-
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cTnT for the prediction of major cardiac complications after non-cardiac surgery.
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Methods Patients Between May 2014 and March 2016, patients undergoing non-cardiac surgery (vascular and non-vascular) were studied in two University hospitals, including consecutive adult patients scheduled for planned or urgent, open or endovascular
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arterial vascular surgery at the Clinics Hospital, University of Sao Paulo Medical
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School, Brazil, and consecutive patients undergoing major non-cardiac surgery
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(vascular and non-vascular) from April to December 2015, at the University Hospital Basel, Switzerland. Inclusion criteria were age above 65 years OR and history of
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coronary artery disease, peripheral artery disease, or cerebrovascular disease.
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For this analysis, we excluded patients with acute MI, stroke, or pulmonary embolism in the week preceding the operation because these events substantially influence
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both the risk of cardiac complications and blood concentration of hs-cTnI and hs-
values were excluded.
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cTnT. For the main analysis, patients with missing hs-cTnI or hs-cTnT preoperative
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Local ethics committees approved the protocol (EKNZ 2015/301 in Basel and
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CAPPESQ 610608 in Sao Paulo) and written informed consent was provided.
Perioperative assessment Before surgery, clinical evaluation and an electrocardiogram (ECG) were performed. Patients’ cardiac risk was classified based on the Revised Cardiac Risk Index (RCRI).9 Additional cardiac tests, such as echocardiogram or myocardial perfusion imaging tests, were performed at the discretion of the attending physician. Previous coronary artery disease (CAD) was considered in the presence of history of MI, chronic typical exercise-induced angina pectoris, previous coronary revascularization
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(coronary artery bypass graft or percutaneous coronary intervention), or evidence of CAD in myocardial perfusion imaging (presence of fixed or reversible perfusion defects) or in coronary angiography. Preoperative chronic heart failure (CHF) was considered if there were: clinical symptoms consistent with CHF, left ventricle ejection fraction (LVEF) lower than 50% assessed by echocardiography or LVEF
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lower than 45% assessed by GATED SPECT obtained during myocardial perfusion
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imaging. In cases with diagnostic uncertainty, B-type natriuretic peptide (BNP) or NTproBNP were measured. Anaemia was diagnosed according to WHO criteria as
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haemoglobin levels below 130g/L in men and 120g/L in women. 10, 11
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As recommended by our Institution and international guidelines, we used active surveillance in the detection of major cardiac complications after non-cardiac
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surgery.5, 12, 13 Hs-cTnT blood concentrations were measured preoperatively, on the first and second postoperative day, and whenever symptoms suggestive of MI
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occurred. Routine 12-lead ECG was performed daily until the third postoperative day in Sao Paulo, in case of a relevant absolute increase in hs-cTnT (absolute change of 14ng/L or more) in Basel, and in both cohorts whenever symptoms suggestive of MI
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or arrhythmias occurred. Patients were followed-up for 30 days after surgery.
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Troponin measurements
Blood samples for the determination of hs-cTnI (ARCHITECT High Sensitive STAT Troponin I assay, Abbott Laboratories) and hs-cTnT (Elecsys, Roche diagnostics, Mannheim, Germany) were collected once before surgery (within 30 days) and on the first and second postoperative days. After blood collection, one aliquot of the blood sample was immediately processed, from which hs-cTnT was measured. In Basel, hs-cTnI was also measured from this sample; in Sao Paulo hs-cTnI was measured from serum that was frozen at -80°C in a batch. Prior the analysis,
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samples were homogenized by inversion and centrifuged at 3,000g for 10 minutes in order to remove particulate matter. The hs-cTnT assay has a limit of blank (LoB) of 3ng/L, a limit of detection (LoD) of 5ng/L and a 99th percentile upper reference limit (URL) of 14ng/L.14 The hs-cTnI assay has a LoB between 0.7-1.3ng/L, a LoD between 1.1-1.9ng/L and a 99th
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percentile URL recommended by the manufacturer of 26ng/L.15 As recent studies
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have suggested that a lower 99th percentile cut-off of 13ng/L would also be bio-
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equivalent to the 99th percentile of hs-cTnT (14ng/L), this cut-off was used for a
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secondary analysis.16-18 Additional secondary analyses included sex-specific cut-offs. In the cohort of vascular surgery patients, sensitive cardiac Troponin I (s-cTnI,
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Siemens Ultra, Advia Centaur immunoassay system) was also obtained. The s-cTnI assay has a LoD of 6ng/L and a 99th percentile of 40ng/L.
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Clinical endpoints
The primary endpoint was a composite of major cardiac complications including cardiac death, cardiac arrest, perioperative MI, clinically relevant arrhythmias, and
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acute heart failure (AHF) within 30 days. Two independent physicians adjudicated all MI cases according to the criteria defined in the Third Universal Definition of
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Myocardial Infarction for spontaneous MI.12 Accordingly, MI was diagnosed in patients with acute cardiomyocyte necrosis exceeding the 99th percentile of the hscTn assay used in clinical practice in both centres (hs-cTnT), accompanied by either ischemic symptoms, new ECG changes or imaging evidence of loss of viable myocardium.12, 19, 20 Arrhythmia (atrial fibrillation/flutter, supraventricular tachycardia, ventricular tachycardia) was considered clinically significant if requiring drug therapy or electrical cardioversion. The attending cardiologist diagnosed AHF using clinical symptoms, physical examination, chest x-ray, BNP or NT-proBNP blood
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concentrations, and echocardiography.10, 21, 22 Deaths were considered cardiovascular in the absence of a clear non-cardiac cause, as suggested in recent recommendations.23 The secondary endpoint was all-cause mortality within 30 days of surgery. Patients were followed-up in outpatient clinic consultations, by phone, or by contacting their primary care physician. Additionally, study personnel requested
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reports from the general practitioners, treating facilities or death registries.
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Statistical analysis
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Categorical variables are shown as numbers and percentages and were compared by Fisher’s exact test. Continuous variables are presented as medians and
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interquartile range (IQR) and were compared by Mann-Whitney-U test.
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Based on our recent finding of very high cardiac event rate in patients undergoing vascular surgery and poor accuracy of existing risk prediction tools in these patients 6,
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we prospectively decided to stratify the analysis according to the type of surgery
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(vascular versus non-vascular). We calculated the interaction p-value for the prognostic value of hs-cTn with the type of surgery for the combined endpoint using a
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binary logistic regression model. We did multivariable binary logistic regression analysis for each available cTn assay adjusted for predefined covariables (age, sex,
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CAD, CHF, stroke, diabetes mellitus, hypertension, dialysis, and anaemia), with one covariable per 10 events. Receiver operating characteristic curves (ROC) were constructed to assess accuracy of the troponin assays for prediction of the primary endpoint, and compared by de Long method. Troponin values were log-transformed for this analysis and for the models. We calculated sensitivity, specificity and positive/negative Likelihood ratio with confidence intervals for the RCRI, hs-cTnT and I assays, and the combination of RCRI and hs-cTn assays, for prediction of cardiac complications after surgery, for
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vascular and non-vascular groups. We also performed correlation analysis of preoperative hs-cTnI, hs-cTnT, haemoglobin, and estimated glomerular filtration rate (eGFR, calculated by CKD-EPI formula) values by Spearman’s test. ROC analyses were repeated for the secondary endpoint all-cause death.
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To further test the different behaviour of hs-cTnT in vascular and non-vascular patients, we performed a post-hoc analysis comparing AUC of hs-cTnT in vascular
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versus non-vascular patients, including all patients for whom preoperative hs-cTnT
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was available, irrespective of missing hs-cTnI values. P-values of <0.05 were considered to indicate statistical significance. Analyses were performed using SPSS
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22 (IBM Co, NY, USA) and R software (version 3.1.3, “pROC”).24
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The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.
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Funding
Funding for this research was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil [FAPESP grant number 2015/ 23731-6]; the Swiss Heart
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Foundation; the Cardiovascular Research Foundation Basel, Basel University;
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Abbott; Roche; the University Hospital Basel, Clinical Research Program of the University of Basel, Spezialprogramm Nachwuchsförderung Klinische Forschung, Förderung exzellenter junger Forschender. The funding source had no role in the study design, collection, analysis and interpretation of data or in the writing of the report.
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Results Baseline characteristics The patient flow is shown in Supplement Figure 1. Baseline characteristics of the 1022 patients included in the main analysis are shown in Table 1. Detailed surgical characteristics are shown in Supplement Table 1. In brief, 243 patients underwent
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vascular surgeries (mainly open or endovascular aortic aneurysm repair, lower
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extremity bypass, or carotid surgery) and 779 patients underwent non-vascular
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surgeries (mainly orthopaedic/trauma, urologic, spinal, or visceral surgery). 807 (79%) surgeries were planned, and the remaining 215 (21%) were urgent or
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emergent.
Vascular n = 243
Non-vascular n = 779
p-value
640 (63)
178 (73)
462 (59)
<0.001
72 [68-78]
68 [62-74]
74 [69-79]
<0.001
282 (28)
89 (37)
193 (25)
<0.001
718 (70)
204 (84)
514 (66)
<0.001
310 (30)
95 (39)
215 (28)
0.001
183 (18)
52 (21)
131 (17)
0.104
349 (34)
243 (100)
106 (13)
<0.001
148 (14)
39 (16)
109 (14)
0.465
Stroke/transient ischemic attack, n (%)
136 (13)
60 (25)
76 (10)
<0.001
COPD, n (%)
126 (12)
11 (5)
115 (15)
<0.001
14 (1)
8 (3)
6 (1)
0.007
456 (45)
86 (36)
370 (48)
<0.001
Acetylsalacylic acid, n (%)
438 (43)
208 (86)
230 (30)
<0.001
Statins n (%)
552 (54)
221 (91)
331 (42)
<0.001
Betablockers, n (%)
431 (42)
125 (51)
306 (39)
0.001
ACEI or ARB, n (%)
552 (54)
150 (62)
402 (52)
0.006
I
361 (35)
25 (10)
336 (43)
II
352 (34)
86 (35)
266 (34)
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All Patients n = 1022 Male gender, n (%) Age (years), median (IQR) Hypertension, n (%) Coronary artery disease, n (%) CABG/PCI, n (%)
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Chronic heart failure, n (%)
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Peripheral artery disease, n (%)
Renal failure in dialysis, n (%) *
Anaemia , n (%)
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Diabetes mellitus, n (%)
Preoperative medications
Revised cardiac risk index <0.001
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208 (20)
84 (35)
124 (16)
IV
101 (10)
48 (20)
53 (7)
0.94 [0.76-1.23]
1.14 [0.92-1.36]
0.9 [0.72-1.14]
<0.001
73 [54-88]
64 [49-80]
77 [56-88]
<0.001
12.8 [11.2-14]
13.3 [12.1-14.2]
12.6 [10.9-13.9]
<0.001
Laboratory assessment Creatinine (mg/dL), median (IQR) eGFR (ml/min) *
Haemoglobin (g/dL), median (IQR) *
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n=1020; CABG = coronary artery bypass graft surgery; PCI = percutaneous coronary intervention; COPD = chronic obstructive pulmonary disease; ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blockers; eGFR = estimated glomerular filtration rate
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Table 1. Baseline characteristics, shown for the whole cohort and split according to
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surgery type. Data shown as counts (n) with percentage (%) or median with
Preoperative levels of cardiac troponin
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interquartile range (IQR)
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Preoperatively, hs-cTnI plasma concentrations were detectable in 100%, hs-cTnT plasma concentrations in 98%, and s-cTnI in 60% of patients. The prevalence of
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preoperative cTn plasma concentrations above the regulatory-approved 99th
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percentile was significantly lower for hs-cTnI than for hs-cTnT assay: 7% for hs-cTnI in vascular and 8% for non-vascular patients versus 36% and 47% for hs-cTnT,
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respectively (Figure 1). Using biological-equivalent 99th percentiles, 17% of patients had hs-cTnI above the 99th percentile (Table 2). Overall, correlation between hs-cTnI
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and hs-cTnT plasma concentrations was moderate-to-good (r=0.64 in vascular and 0.68 in non-vascular patients) and comparable in vascular and non-vascular patients. Both hs-cTnI and hs-cTnT plasma concentrations were also negatively correlated with eGFR and haemoglobin (Supplement Table 2).
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Figure 1. Prevalence of cardiac troponin (cTn) levels above the 99th percentile
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before vascular and non-vascular surgery, shown for high-sensitivity cTn (hs-cTn) I
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and T as well as sensitive-cTnI in for vascular surgery patients
Vascular n = 243
Non-vascular n = 779
Preoperative level, median (IQR), ng/L
5 (3-9.4)
5 (3-10)
4 (3-9)
Above cut-off (>13ng/L), n (%)
171 (17)
40 (17)
131 (17)
Above cut-off (>26ng/L), n (%)
84 (8)
18 (7)
66 (8)
0.689
119 (12)
23 (10)
96 (12)
0.253
Preoperative level, median (IQR),ng/L
13 (7-22)
11 (7-18)
13 (8-24)
0.002
Above cut-off (>14ng/L), n (%)
450 (44)
87 (36)
363 (47)
0.003
Preoperative level, median (IQR),ng/L
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8 (6-16)*
-
-
Above cut-off (>40ng/L), n (%)
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17 (8)*
-
-
Preoperative measurements
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High-sensitivity cTn I
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All Patients n = 1022
Above sex specific (>34/16ng/L), n (%)
p-value
0.038 1
High-sensitivity cTn T
Sensitive cTn I
IQR=interquartile range; *n=224
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Table 2. Blood concentration of cardiac troponin (cTn) measured by different assays and absolute number of patients above the 99th-percentile cut-off, shown for the whole cohort and according to surgery type
Clinical outcomes
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The primary combined endpoint of major cardiac complications occurred in 108/1022 (10.6%, 95%CI 8.8-12.7) patients, with events occurring four-times more often after
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vascular surgery with an incidence of 58/243 (24%, 95%CI 19.0-29.9) versus 50/779
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(6.4%, 95%CI 4.9-8.4, p<0.001) after non-vascular surgery (Table 3). All-cause mortality occurred in 33/1022 (2.9%) of all patients within 30-days, and similarly was
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four-times higher in patients undergoing vascular surgery as compared to non-
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vascular surgery (8% versus 2%).
Cardiac arrest Myocardial infarction
Arrhythmia All-cause mortality
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Acute heart failure
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Cardiovascular death
Vascular surgery n = 243
Non-vascular n = 779
p-value
108 (11%)
58 (24%)
50 (6%)
<0.001
11 (1%)
4 (2%)
7 (1%)
0.302
8 (1%)
3 (1%)
5 (1%)
0.404
57 (6%)
32 (13%)
25 (3%)
<0.001
37 (4%)
23 (9%)
14 (2%)
<0.001
24 (3%)
18 (7%)
6 (1%)
<0.001
33 (3%)
19 (8%)
14 (2%)
<0.001
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Major cardiac complication
All patients n = 1022
Comparison done with Fisher’s exact test; multiple events possible in one patient
Table 3. Clinical outcomes within 30 days, shown for all patients and stratified according to the type of surgery
Prediction of the primary endpoint: major cardiac complications
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Patients with major cardiac complications had significantly higher preoperative hscTnI and hs-cTnT plasma concentrations than patients without complications. In vascular surgery patients, median hs-cTnI was 8ng/L (IQR 4-15) vs. 5ng/L (IQR 3-8; p<0.001), median hs-cTnT was 14ng/L (IQR 9-19) vs. 10ng/L (IQR 6-17; p=0.039) and median s-cTnI was 11ng/L (IQR 6-23) vs. 7ng/L (IQR 6-14; p=0.002),
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respectively for patients with versus without cardiac complications.
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In non-vascular surgery patients, median preoperative hs-cTnI was 12ng/L (IQR 7-
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29) vs. 4ng/L (IQR 2-8; p<0.001) and median hs-cTnT was 40ng/L (IQR 15-64) vs. 13ng/L (IQR 7-22; p<0.001), respectively for patients with versus without cardiac
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complications.
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In vascular surgery patients, the prognostic accuracy for major cardiac complications of hs-cTnI was significantly higher than that of hs-cTnT (AUC 0.67 (95%CI 0.59-0.75)
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versus 0.59 (95%CI 0.51-0.67, p=0.012, Figure 2A). In non-vascular surgery
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patients, the both hs-cTn AUCs overall were higher than in vascular surgery patients and hs-cTnI and hs-cTnT showed comparable AUCs of 0.77 (95%CI 0.71-0.83)
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versus 0.79 (95%CI 0.73-0.85, p=ns, Figure 2B). We found a significant interaction for both hs-cTnI (p=0.011) and hs-cTnT (p<0.001) with the type of surgery in the
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prediction of major cardiac complications. In vascular surgery patients, the presence of hs-cTnI above the cut-offs of 13ng/L and 26 ng/L had high specificity for cardiac events (88% and 96%, respectively), but low sensitivity (31% and 17%,respectively), whereas hs-cTnT had specificity of only 67% and sensitivity of 45%. In non-vascular patients, the hs-cTnI assay had also high specificity (85% and 93%), but hs-cTnT had a better sensitivity (76%), in spite of also low specificity (55%) (Supplement Table 3).
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Figure 2 Area under the receiver operating characteristics curves (AUC) of the
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different troponin assays measured preoperatively for prediction of cardiac complications following vascular surgery (Panel A) and non-vascular surgery (Panel B), shown with 95% confidence intervals. In multivariable analysis, in vascular surgery patients, preoperative hs-cTnI, but not hs-cTnT, remained an independent predictor of the primary endpoint (aOR 1.5, 95%CI 1.0-2.1;Supplement Table 4), while in non-vascular surgery patients, preoperative hs-cTnI and hs-cTnT were independent predictors of major cardiac
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complications (aOR 1.6, 95%CI 1.3-2.0, and OR 3.0, 95%CI 2.0-4.6, respectively; Supplement Table 5). In the ancillary analysis of the extended cohort of patients with available hs-cTnT plasma concentrations (n=2495, Supplement Figure 1), we found an AUC for hs-
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0.70–0.79; p <0.001) in non-vascular surgery patients.
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cTnT of 0.55 (95%CI 0.48-0.62) in vascular surgery patients versus 0.75 (95%CI
Prediction of the secondary endpoint: all-cause mortality
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Preoperative hs-cTnI, hs-cTnT, and s-cTnI plasma concentrations provided
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comparable and modest discrimination (AUC 0.64-0.70) in the prediction of all-cause mortality in vascular surgery patients. In non-vascular surgery, AUCs for the
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prediction of all-cause death were higher for both hs-cTnI and hs-cTnT. In addition, hs-cTnT plasma concentrations provided higher diagnostic accuracy than hs-cTnI
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(AUC 0.8 and 0.67, respectively, p=0.05; Supplement Figure 2).
Discussion
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To the best of our knowledge, this is the first large prospective diagnostic study directly comparing preoperative hs-cTnI and hs-cTnT plasma concentrations in the
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prediction of major cardiac complications after non-cardiac surgery. We report four major findings. First, using regulatory-approved 99th percentile cut-off concentrations in current clinical use, preoperative hs-cTnI elevations were less than one-fifth as common as preoperative hs-cTnT elevations. Using biological equivalent 99th percentile cut-off concentration for hs-cTnI and hs-cTnT,16, 17 preoperative hs-cTnI elevations were still less than half as common as preoperative hs-cTnT elevations. This finding emerged irrespective of the type of surgery. Second, patients undergoing vascular surgery had four-fold more major cardiac complications and all-cause
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mortality rates in comparison to patients undergoing non-vascular surgery. Third, among patients undergoing vascular surgery, preoperative hs-cTnI concentrations provided higher prognostic accuracy for major cardiac complications as compared to hs-cTnT concentrations. Similarly, hs-cTnI, but not hs-cTnT, was an independent predictor of major cardiac complications. Fourth, among patients undergoing non-
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vascular surgery, both preoperative hs-cTnI and hs-cTnT plasma concentrations
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were independent predictors of major cardiac complications after non-cardiac
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surgery.
This study corroborates and extends previous studies evaluating preoperative
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hs-cTnT measurements, and is the first to comprehensively evaluate the role of hscTnI mesurements.7, 8 The incidence of preoperative hs-cTnT plasma concentrations
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above the 99th percentile in this study (44%) was comparable to that observed in other recent cohorts (21-51%).5, 25-27 Our finding of a much lower incidence of
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preoperative hs-cTnI concentrations is in line with a recent pilot study evaluating the prevalence of hs-cTn elevations in patients admitted to the hospital without acute coronary syndromes (ACS), in which the authors reported that elevations of hs-cTnT
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above the 99th percentile were present in more than one third of non-ACS patients
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whereas hs-cTnI elevations were present in only one tenth.28 The pathophysiological mechanisms contributing to this major difference among the two commonly considered interchangeable biomarkers is incompletely understood. In the present study, hs-cTnT plasma concentrations seemed more strongly correlated to renal dysfunction and anaemia than hs-cTnI concentrations, confirming initial pilot findings in patients hospitalized without ACS.28 Although the origin of hscTnT elevations in patients with chronic kidney disease seems more complex than previously thought and only to a lesser degree determined by impaired renal
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elimination,29 cTnT plasma concentrations may suffer more interference from noncardiac comorbidities than cTnI, and elevated plasma concentrations of hs-cTnT may be related to severe systemic, non-coronary conditions. This could in part also explain the observation of a numerically higher prognostic performance for all-cause death observed in our study. CTnT exists in both cardiac and skeletal muscles of the
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foetus.30 In patients with inflammatory muscular diseases, silent genes that codify
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cTnT in skeletal muscles can be reactivated leading to elevated hs-cTnT plasma concentrations.31 Cardiac troponin I seems to be exclusively released by myocardial
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cells, so its release may be more specific for heart diseases.31 Our finding of high
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specificity values for the hs-cTnI assay in the prediction of cardiac events in both groups of patients corroborates with this hypothesis. Also, the mechanism
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responsible for the release of cTn from cardiomyocytes may be due to direct cardiomyocyte injury caused by systemic conditions, such as sepsis or
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inflammation,32 independent of the presence of CAD. Previous biochemical studies
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have showed that correlation between different hs-cTnI assays is better than between hs-cTnI and T, and that these differences cannot be explained by analytical
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imprecision alone, therefore, implying a biological difference in the release
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mechanism of cTnI and T.33 We have demonstrated that preoperative hs-cTnT values have different predictive value in patients undergoing vascular and non-vascular surgery. In vascular patients, although preoperative hs-cTnT is not a good predictor of major cardiac complications, it is good for predicting all-cause mortality. In contrast, in non-vascular surgery patients, both preoperative hs-cTnI and T are also good predictors for cardiac complications. We have confirmed these findings in an additional analysis of all patients for whom only hs-cTnT was available. One possible explanation is that the mechanism of perioperative MI may be different in vascular and non-vascular
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surgery patients. Vascular patients have more severe diffuse atherosclerotic disease and the procedure itself, including manipulation of the arterial bed, could trigger processes leading to plaque rupture and type 1 MI.34 Therefore, preoperative baseline hs-cTnT values (maybe a surrogate for patients with more severe systemic disease) are less useful predictors for cardiac complications after vascular surgery,
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and only hs-cTnI reached statistical significance in our cohort. On the other hand,
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patients submitted to non-vascular surgeries were older and had less previous coronary events but more severe systemic disease, which could lead to a type 2 MI,
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AHF, or arrhythmias.27, 35 Therefore, in non-vascular surgery patients, blood
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concentration of hs-cTnT can predict cardiac events as well as hs-cTnI.
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Overall, measurement of hs-cTn preoperatively improves the prediction of cardiac complications after non-vascular surgery, and should be implemented in clinical practice for patients with age above 65 years or with pre-existing
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atherosclerotic disease.5, 13, 36 In patients undergoing vascular surgery, hs-cTnI may be preferable than hs-cTnT. These biomarkers may be used not only to assess more accurately the risk-benefit of surgery, but also to recommend measures to reduce
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risk, such as giving statins, referring the patient to the intensive care unit after
events.
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surgery and performing surveillance for improving diagnosis and treatment of cardiac
Some limitations should be considered when interpreting our findings. First, the sample size of patients undergoing vascular surgery was only moderate and came from only one site. However, this seemed to have been compensated by the high event rate in these patients, and a possible site effect was mitigated by the additional analysis of hs-cTnT including vascular patients at both sites, which confirmed that hs-cTnT had better accuracy in the non-vascular patients. Second, in
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the non-vascular surgery cohort, only high-risk patients (age ≥65 years or preexisting atherosclerotic disease) were included. These results cannot be applied to low-risk patients. Third, we measured both currently clinically available hs-cTn assays. Further studies are necessary to examine additional hs-cTn that are in development. Fourth, it is possible that vascular patients were more closely
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monitored in routine clinical care as they are considered a high-risk cohort.36
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Therefore, the difference in event rate between vascular and non-vascular surgery
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may have been slightly overestimated. Additionally, the hs-cTnT assay was used for diagnosis of perioperative MI, what could have overestimated its accuracy, but that
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effect occurred in both subgroups, therefore not changing the fact, that there was a
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difference in behavior for vascular and non-vascular surgeries.
Conclusion
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In conclusion, preoperative hs-cTnI and hs-cTnT predict major cardiac events after
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non-vascular surgery, while, in patients undergoing vascular surgery, hs-cTnI may
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have better accuracy. Further studies are needed to validate this hypothesis.
include:
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Other BASEL-PMI Investigators and contributors to this manuscript
Lorenz Guerke, MD1; Thomas Wolff, MD1; Luzius Steiner, MD2; Karin Wildi, MD3; Thomas Nestelberger, MD3; Jasper Boeddinghaus, MD3; Maria Rubini Giménez, MD3; Desiree Wussler, MD3; Karin Wildi, MD3; Stefan Osswald, MD3. 1
Division of Vascular Surgery, University Hospital Basel, University of Basel, Switzerland;
2
Department of Anaesthesiology, University Hospital Basel, University of Basel, Switzerland;
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Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University
Hospital Basel, University Basel, Switzerland
Acknowledgments The authors would like to thank the team of nurses and physicians of the
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postoperative intensive care unit (UAC), Interdisciplinary Medicine in Cardiology Unit
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(UMIC) and vascular surgical ward of the Clinics Hospital, University of Sao Paulo
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Medical School for their help with patient care and blood sample collection.
Disclosures
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DM Gualandro has received research grants from FAPESP (Sao Paulo Research Foundation) for the submitted work, and speaker or consulting honoraria from
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Servier, Sanofi, EMS and Roche, outside the submitted work. C Puelacher has
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received research grants from PPHS (PhD Educational Platform Health Sciences) Basel, outside the submitted work. D Calderaro has received research grants from
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FAPESP and speaker or consulting honoraria from Bayer, outside the submitted work. Dr. Twerenbold received research support from the Swiss National Science
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Foundation (P300PB-167803/1) and speaker honoraria/consulting honoraria from Roche, Abbott, Siemens and Brahms, outside the submitted work. A HammererLercher has received speaker honoraria from Abbott, outside the submitted work. Professor Caramelli has received research grants from FAPESP, CNPq (National Counsel of Technological and Scientific Development, Brasil), as well as speaker or consulting honoraria from Bayer, Boehringer Ingelheim, Servier, and AbbVie, outside the submitted work. Dr. Jaffe has previously or presently consults for most of the major diagnostic companies, outside the submitted work. Professor Mueller has
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received research grants Swiss Heart Foundation, grants from Astra Zeneca, grants and non-financial support from University of Basel, and Abbott, during the conduct of the study, and from the European Union, 8sense, Abbott, ALERE, Beckman Coulter, Biomerieux, Brahms, Critical Diagnostics, Nanosphere, Roche, Siemens, Singulex, Sphingotec and the University Hospital Basel, as well as speaker or consulting
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honoraria from Abbott, ALERE, Astra Zeneca, Biomerieux, BMS, Boehringer
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Ingelheim, Brahms, Cardiorentis, Novartis, Roche, Sanofi-Aventis, Siemens and
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Singulex, outside the submitted work.
1.
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Highlights
Predicting cardiac complications after non-cardiac surgery is challenging;
Preoperative hs-cTn concentrations can be used for the prediction of complications; Hs-cTn I and T may have different behavior, according to type of surgery;
In non-vascular surgeries, hs-cTnT and I are predictors of complications
In vascular surgeries, hs-cTnI may have better accuracy for risk prediction.
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Figure 1
Figure 2
Danielle M Gualandro, Christian Puelacher, Giovanna LuratiBuse, Andreas Lampart, Celia Strunz, Francisco A Cardozo, Pai C Yu, Allan S Jaffe, Sanela Barac, Lukas Bock, Patrick Badertscher, Jeanne du Fay de Lavallaz, Stella Marbot, Lorraine Sazgary, Daniel Bolliger, Katharina Rentsch, Raphael Twerenbold, Angelika Hammerer-Lercher, Edielle S Melo, Daniela Calderaro, Alberto JS Duarte, Nelson de Luccia, Bruno Caramelli, Christian Mueller, TropoVasc and BASEL-PMI Investigators PII: DOI: Reference:
S0002-8703(18)30201-1 doi:10.1016/j.ahj.2018.06.012 YMHJ 5720
To appear in:
American Heart Journal
Received date: Accepted date:
13 December 2017 30 June 2018
Please cite this article as: Danielle M Gualandro, Christian Puelacher, Giovanna LuratiBuse, Andreas Lampart, Celia Strunz, Francisco A Cardozo, Pai C Yu, Allan S Jaffe, Sanela Barac, Lukas Bock, Patrick Badertscher, Jeanne du Fay de Lavallaz, Stella Marbot, Lorraine Sazgary, Daniel Bolliger, Katharina Rentsch, Raphael Twerenbold, Angelika Hammerer-Lercher, Edielle S Melo, Daniela Calderaro, Alberto JS Duarte, Nelson de Luccia, Bruno Caramelli, Christian Mueller, TropoVasc and BASEL-PMI Investigators , Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery. Ymhj (2018), doi:10.1016/j.ahj.2018.06.012
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Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery Danielle M Gualandro*1,2, Christian Puelacher*2, Giovanna LuratiBuse3,4, Andreas Lampart,4 Celia Strunz5, Francisco A Cardozo1, Pai C Yu1, Allan S Jaffe6, Sanela
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Barac2, Lukas Bock2, Patrick Badertscher2, Jeanne du Fay de Lavallaz2, Stella Marbot2, Lorraine Sazgary2, Daniel Bolliger4, Katharina Rentsch7, Raphael
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Twerenbold2,8, Angelika Hammerer-Lercher9, Edielle S Melo1, Daniela Calderaro1,
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Alberto JS Duarte10, Nelson de Luccia11, Bruno Caramelli1, Christian Mueller2 , for
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the TropoVasc and BASEL-PMI Investigators. *both authors have contributed equally and should be considered first author 1
Interdisciplinary Medicine in Cardiology Unit, Cardiology Department, Heart Institute (InCor),
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University of Sao Paulo Medical School, Brazil; 2Department of Cardiology, University Hospital Basel, University of Basel, Switzerland; 3 Department of Anaesthesiology, University Hospital Düsseldorf, Germany; 4 Department of Anaesthesiology, University Hospital Basel,
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University of Basel, Switzerland; 5 Heart Institute (InCor), University of Sao Paulo Medical
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School, Brazil; 6Department of Cardiology and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA; 7Department of Laboratory Medicine, University Hospital Basel, Switzerland; 8 Department of General and Interventional Cardiology,
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Hamburg University Heart Center, Hamburg, Germany; 9 Department of Laboratory Medicine, Cantonal Hospital Aarau, Switzerland; 10Laboratory of Immunogenetics and Experimental Transplantation, University of Sao Paulo Medical School, Brazil; 11 Vascular and
Brazil
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Endovascular Surgery Clinic of the Clinics Hospital, University of São Paulo Medical School,
Corresponding author: Danielle M Gualandro Address: Av.Dr.Eneas de Carvalho Aguiar, 44 andar AB, São Paulo, SP Brazil ZIP CODE: 05403-000. Phone: +55 11 26615376 Fax: +55 11 26615535 Email: [email protected]
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Abstract Background: We aimed to directly compare preoperative high-sensitivity cardiac troponin (hs-cTn) I and T concentration for the prediction of major cardiac complications after non-cardiac surgery.
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Methods: We measured hs-cTnI and hs-cTnT preoperatively in a blinded fashion in 1022 patients undergoing non-cardiac surgery. The primary endpoint was a
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composite of major cardiac complications including cardiac death, cardiac arrest,
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myocardial infarction, clinically relevant arrhythmias, and acute heart failure within 30 days. We hypothesized that the type of surgery may impact on the predictive
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accuracy of hs-cTnI/T and stratified all analyses according to the type of surgery.
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Results: Major cardiac complications occurred in 108 (11%) patients, 58/243 (24%) patients undergoing vascular surgery and 50/779 (6%, p<0.001) patients undergoing
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non-vascular surgery. Using regulatory-approved 99th percentile cut-off
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concentrations, preoperative hs-cTnI elevations were less than one-fifth as common as preoperative hs-cTnT elevations (p<0.001). Among patients undergoing vascular
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surgery, preoperative hs-cTnI concentrations, but not hs-cTnT, was an independent predictor of cardiac complications (adjusted odds ratio (aOR) 1.5, 95% confidence
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interval (95%CI) 1.0-2.1). The area under the receiver-operating characteristics curve (AUC) was 0.67 (95%CI, 0.59-0.75) for hs-cTnI versus 0.59 (95%CI 0.51-0.67, p=0.012) for hs-cTnT. In contrast, among patients undergoing non-vascular surgery both preoperative hs-cTnI and hs-cTnT were independent predictors of the primary endpoint (aOR 1.6, 95%CI 1.3-2.0, and aOR 3.0, 95%CI 2.0-4.6, respectively) and showed higher predictive accuracy (AUC 0.77, 95%CI, 0.71-0.83, and 0.79, 95%CI 0.73-0.85, p=ns).
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Conclusions: Preoperative hs-cTnI and hs-cTnT concentrations predict major cardiac complications after non-vascular surgery, while, in patients undergoing vascular surgery, hs-cTnI may have better accuracy.
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Keywords: troponin; preoperative care; cardiac complications; non-cardiac surgery
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Introduction More than 300 million surgeries are performed annually worldwide.1 Despite advances in surgery and anaesthesia, 30-day mortality after non-cardiac surgery remains substantial.2, 3 Cardiac complications, including perioperative myocardial infarction (MI), are important contributors to 30-day mortality.4, 5 Because cardiac
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complications, particularly MI, maybe silent and ECGs at one point in time can miss
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important changes, accurate detection mandates active surveillance.5 Predicting
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cardiac complications after non-cardiac surgery is difficult and inaccurate, as both patient and surgery related factors seem to matter. A recent multicentre study
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suggested that the current clinical standard of care using multivariate risk scores has poor prognostic accuracy, particularly in patients undergoing vascular surgery. 6 Thus,
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the central task of preoperative assessment and patient counselling, the quantification of the risk-benefit ratio of planned operations, remains elusive. In
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addition, targeting interventions that might be preventative or therapeutic to high-risk
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populations is hardly possible as the reliable preoperative detection of patients at high-risk of developing major cardiac complications would be a requisite.
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The use of cardiac biomarkers could improve the prediction of cardiac complications
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after non-cardiac surgery. Pilot studies by several groups including ours have suggested that preoperative high-sensitivity cardiac troponin T (hs-cTnT) blood concentrations seem to improve risk prediction in non-cardiac surgery.7, 8 The role of high-sensitivity cardiac troponin I (hs-cTnI) in predicting cardiac complications after non-cardiac surgery remains largely unknown. It is also unknown, whether one cardiac troponin signal is more accurate than the other, and/or whether the type of surgery may impact on the relative accuracy of hs-cTnT versus hs-cTnI.
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The aim of our study was to compare the accuracy of preoperative hs-cTnI and hs-
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cTnT for the prediction of major cardiac complications after non-cardiac surgery.
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Methods Patients Between May 2014 and March 2016, patients undergoing non-cardiac surgery (vascular and non-vascular) were studied in two University hospitals, including consecutive adult patients scheduled for planned or urgent, open or endovascular
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arterial vascular surgery at the Clinics Hospital, University of Sao Paulo Medical
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School, Brazil, and consecutive patients undergoing major non-cardiac surgery
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(vascular and non-vascular) from April to December 2015, at the University Hospital Basel, Switzerland. Inclusion criteria were age above 65 years OR and history of
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coronary artery disease, peripheral artery disease, or cerebrovascular disease.
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For this analysis, we excluded patients with acute MI, stroke, or pulmonary embolism in the week preceding the operation because these events substantially influence
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both the risk of cardiac complications and blood concentration of hs-cTnI and hs-
values were excluded.
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cTnT. For the main analysis, patients with missing hs-cTnI or hs-cTnT preoperative
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Local ethics committees approved the protocol (EKNZ 2015/301 in Basel and
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CAPPESQ 610608 in Sao Paulo) and written informed consent was provided.
Perioperative assessment Before surgery, clinical evaluation and an electrocardiogram (ECG) were performed. Patients’ cardiac risk was classified based on the Revised Cardiac Risk Index (RCRI).9 Additional cardiac tests, such as echocardiogram or myocardial perfusion imaging tests, were performed at the discretion of the attending physician. Previous coronary artery disease (CAD) was considered in the presence of history of MI, chronic typical exercise-induced angina pectoris, previous coronary revascularization
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(coronary artery bypass graft or percutaneous coronary intervention), or evidence of CAD in myocardial perfusion imaging (presence of fixed or reversible perfusion defects) or in coronary angiography. Preoperative chronic heart failure (CHF) was considered if there were: clinical symptoms consistent with CHF, left ventricle ejection fraction (LVEF) lower than 50% assessed by echocardiography or LVEF
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lower than 45% assessed by GATED SPECT obtained during myocardial perfusion
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imaging. In cases with diagnostic uncertainty, B-type natriuretic peptide (BNP) or NTproBNP were measured. Anaemia was diagnosed according to WHO criteria as
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haemoglobin levels below 130g/L in men and 120g/L in women. 10, 11
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As recommended by our Institution and international guidelines, we used active surveillance in the detection of major cardiac complications after non-cardiac
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surgery.5, 12, 13 Hs-cTnT blood concentrations were measured preoperatively, on the first and second postoperative day, and whenever symptoms suggestive of MI
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occurred. Routine 12-lead ECG was performed daily until the third postoperative day in Sao Paulo, in case of a relevant absolute increase in hs-cTnT (absolute change of 14ng/L or more) in Basel, and in both cohorts whenever symptoms suggestive of MI
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or arrhythmias occurred. Patients were followed-up for 30 days after surgery.
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Troponin measurements
Blood samples for the determination of hs-cTnI (ARCHITECT High Sensitive STAT Troponin I assay, Abbott Laboratories) and hs-cTnT (Elecsys, Roche diagnostics, Mannheim, Germany) were collected once before surgery (within 30 days) and on the first and second postoperative days. After blood collection, one aliquot of the blood sample was immediately processed, from which hs-cTnT was measured. In Basel, hs-cTnI was also measured from this sample; in Sao Paulo hs-cTnI was measured from serum that was frozen at -80°C in a batch. Prior the analysis,
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samples were homogenized by inversion and centrifuged at 3,000g for 10 minutes in order to remove particulate matter. The hs-cTnT assay has a limit of blank (LoB) of 3ng/L, a limit of detection (LoD) of 5ng/L and a 99th percentile upper reference limit (URL) of 14ng/L.14 The hs-cTnI assay has a LoB between 0.7-1.3ng/L, a LoD between 1.1-1.9ng/L and a 99th
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percentile URL recommended by the manufacturer of 26ng/L.15 As recent studies
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have suggested that a lower 99th percentile cut-off of 13ng/L would also be bio-
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equivalent to the 99th percentile of hs-cTnT (14ng/L), this cut-off was used for a
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secondary analysis.16-18 Additional secondary analyses included sex-specific cut-offs. In the cohort of vascular surgery patients, sensitive cardiac Troponin I (s-cTnI,
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Siemens Ultra, Advia Centaur immunoassay system) was also obtained. The s-cTnI assay has a LoD of 6ng/L and a 99th percentile of 40ng/L.
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Clinical endpoints
The primary endpoint was a composite of major cardiac complications including cardiac death, cardiac arrest, perioperative MI, clinically relevant arrhythmias, and
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acute heart failure (AHF) within 30 days. Two independent physicians adjudicated all MI cases according to the criteria defined in the Third Universal Definition of
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Myocardial Infarction for spontaneous MI.12 Accordingly, MI was diagnosed in patients with acute cardiomyocyte necrosis exceeding the 99th percentile of the hscTn assay used in clinical practice in both centres (hs-cTnT), accompanied by either ischemic symptoms, new ECG changes or imaging evidence of loss of viable myocardium.12, 19, 20 Arrhythmia (atrial fibrillation/flutter, supraventricular tachycardia, ventricular tachycardia) was considered clinically significant if requiring drug therapy or electrical cardioversion. The attending cardiologist diagnosed AHF using clinical symptoms, physical examination, chest x-ray, BNP or NT-proBNP blood
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concentrations, and echocardiography.10, 21, 22 Deaths were considered cardiovascular in the absence of a clear non-cardiac cause, as suggested in recent recommendations.23 The secondary endpoint was all-cause mortality within 30 days of surgery. Patients were followed-up in outpatient clinic consultations, by phone, or by contacting their primary care physician. Additionally, study personnel requested
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reports from the general practitioners, treating facilities or death registries.
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Statistical analysis
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Categorical variables are shown as numbers and percentages and were compared by Fisher’s exact test. Continuous variables are presented as medians and
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interquartile range (IQR) and were compared by Mann-Whitney-U test.
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Based on our recent finding of very high cardiac event rate in patients undergoing vascular surgery and poor accuracy of existing risk prediction tools in these patients 6,
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we prospectively decided to stratify the analysis according to the type of surgery
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(vascular versus non-vascular). We calculated the interaction p-value for the prognostic value of hs-cTn with the type of surgery for the combined endpoint using a
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binary logistic regression model. We did multivariable binary logistic regression analysis for each available cTn assay adjusted for predefined covariables (age, sex,
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CAD, CHF, stroke, diabetes mellitus, hypertension, dialysis, and anaemia), with one covariable per 10 events. Receiver operating characteristic curves (ROC) were constructed to assess accuracy of the troponin assays for prediction of the primary endpoint, and compared by de Long method. Troponin values were log-transformed for this analysis and for the models. We calculated sensitivity, specificity and positive/negative Likelihood ratio with confidence intervals for the RCRI, hs-cTnT and I assays, and the combination of RCRI and hs-cTn assays, for prediction of cardiac complications after surgery, for
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vascular and non-vascular groups. We also performed correlation analysis of preoperative hs-cTnI, hs-cTnT, haemoglobin, and estimated glomerular filtration rate (eGFR, calculated by CKD-EPI formula) values by Spearman’s test. ROC analyses were repeated for the secondary endpoint all-cause death.
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To further test the different behaviour of hs-cTnT in vascular and non-vascular patients, we performed a post-hoc analysis comparing AUC of hs-cTnT in vascular
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versus non-vascular patients, including all patients for whom preoperative hs-cTnT
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was available, irrespective of missing hs-cTnI values. P-values of <0.05 were considered to indicate statistical significance. Analyses were performed using SPSS
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22 (IBM Co, NY, USA) and R software (version 3.1.3, “pROC”).24
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The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.
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Funding
Funding for this research was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil [FAPESP grant number 2015/ 23731-6]; the Swiss Heart
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Foundation; the Cardiovascular Research Foundation Basel, Basel University;
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Abbott; Roche; the University Hospital Basel, Clinical Research Program of the University of Basel, Spezialprogramm Nachwuchsförderung Klinische Forschung, Förderung exzellenter junger Forschender. The funding source had no role in the study design, collection, analysis and interpretation of data or in the writing of the report.
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Results Baseline characteristics The patient flow is shown in Supplement Figure 1. Baseline characteristics of the 1022 patients included in the main analysis are shown in Table 1. Detailed surgical characteristics are shown in Supplement Table 1. In brief, 243 patients underwent
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vascular surgeries (mainly open or endovascular aortic aneurysm repair, lower
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extremity bypass, or carotid surgery) and 779 patients underwent non-vascular
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surgeries (mainly orthopaedic/trauma, urologic, spinal, or visceral surgery). 807 (79%) surgeries were planned, and the remaining 215 (21%) were urgent or
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emergent.
Vascular n = 243
Non-vascular n = 779
p-value
640 (63)
178 (73)
462 (59)
<0.001
72 [68-78]
68 [62-74]
74 [69-79]
<0.001
282 (28)
89 (37)
193 (25)
<0.001
718 (70)
204 (84)
514 (66)
<0.001
310 (30)
95 (39)
215 (28)
0.001
183 (18)
52 (21)
131 (17)
0.104
349 (34)
243 (100)
106 (13)
<0.001
148 (14)
39 (16)
109 (14)
0.465
Stroke/transient ischemic attack, n (%)
136 (13)
60 (25)
76 (10)
<0.001
COPD, n (%)
126 (12)
11 (5)
115 (15)
<0.001
14 (1)
8 (3)
6 (1)
0.007
456 (45)
86 (36)
370 (48)
<0.001
Acetylsalacylic acid, n (%)
438 (43)
208 (86)
230 (30)
<0.001
Statins n (%)
552 (54)
221 (91)
331 (42)
<0.001
Betablockers, n (%)
431 (42)
125 (51)
306 (39)
0.001
ACEI or ARB, n (%)
552 (54)
150 (62)
402 (52)
0.006
I
361 (35)
25 (10)
336 (43)
II
352 (34)
86 (35)
266 (34)
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All Patients n = 1022 Male gender, n (%) Age (years), median (IQR) Hypertension, n (%) Coronary artery disease, n (%) CABG/PCI, n (%)
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Chronic heart failure, n (%)
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Peripheral artery disease, n (%)
Renal failure in dialysis, n (%) *
Anaemia , n (%)
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Diabetes mellitus, n (%)
Preoperative medications
Revised cardiac risk index <0.001
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208 (20)
84 (35)
124 (16)
IV
101 (10)
48 (20)
53 (7)
0.94 [0.76-1.23]
1.14 [0.92-1.36]
0.9 [0.72-1.14]
<0.001
73 [54-88]
64 [49-80]
77 [56-88]
<0.001
12.8 [11.2-14]
13.3 [12.1-14.2]
12.6 [10.9-13.9]
<0.001
Laboratory assessment Creatinine (mg/dL), median (IQR) eGFR (ml/min) *
Haemoglobin (g/dL), median (IQR) *
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n=1020; CABG = coronary artery bypass graft surgery; PCI = percutaneous coronary intervention; COPD = chronic obstructive pulmonary disease; ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blockers; eGFR = estimated glomerular filtration rate
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Table 1. Baseline characteristics, shown for the whole cohort and split according to
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surgery type. Data shown as counts (n) with percentage (%) or median with
Preoperative levels of cardiac troponin
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interquartile range (IQR)
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Preoperatively, hs-cTnI plasma concentrations were detectable in 100%, hs-cTnT plasma concentrations in 98%, and s-cTnI in 60% of patients. The prevalence of
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preoperative cTn plasma concentrations above the regulatory-approved 99th
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percentile was significantly lower for hs-cTnI than for hs-cTnT assay: 7% for hs-cTnI in vascular and 8% for non-vascular patients versus 36% and 47% for hs-cTnT,
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respectively (Figure 1). Using biological-equivalent 99th percentiles, 17% of patients had hs-cTnI above the 99th percentile (Table 2). Overall, correlation between hs-cTnI
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and hs-cTnT plasma concentrations was moderate-to-good (r=0.64 in vascular and 0.68 in non-vascular patients) and comparable in vascular and non-vascular patients. Both hs-cTnI and hs-cTnT plasma concentrations were also negatively correlated with eGFR and haemoglobin (Supplement Table 2).
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Figure 1. Prevalence of cardiac troponin (cTn) levels above the 99th percentile
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before vascular and non-vascular surgery, shown for high-sensitivity cTn (hs-cTn) I
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and T as well as sensitive-cTnI in for vascular surgery patients
Vascular n = 243
Non-vascular n = 779
Preoperative level, median (IQR), ng/L
5 (3-9.4)
5 (3-10)
4 (3-9)
Above cut-off (>13ng/L), n (%)
171 (17)
40 (17)
131 (17)
Above cut-off (>26ng/L), n (%)
84 (8)
18 (7)
66 (8)
0.689
119 (12)
23 (10)
96 (12)
0.253
Preoperative level, median (IQR),ng/L
13 (7-22)
11 (7-18)
13 (8-24)
0.002
Above cut-off (>14ng/L), n (%)
450 (44)
87 (36)
363 (47)
0.003
Preoperative level, median (IQR),ng/L
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8 (6-16)*
-
-
Above cut-off (>40ng/L), n (%)
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17 (8)*
-
-
Preoperative measurements
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High-sensitivity cTn I
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All Patients n = 1022
Above sex specific (>34/16ng/L), n (%)
p-value
0.038 1
High-sensitivity cTn T
Sensitive cTn I
IQR=interquartile range; *n=224
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Table 2. Blood concentration of cardiac troponin (cTn) measured by different assays and absolute number of patients above the 99th-percentile cut-off, shown for the whole cohort and according to surgery type
Clinical outcomes
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The primary combined endpoint of major cardiac complications occurred in 108/1022 (10.6%, 95%CI 8.8-12.7) patients, with events occurring four-times more often after
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vascular surgery with an incidence of 58/243 (24%, 95%CI 19.0-29.9) versus 50/779
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(6.4%, 95%CI 4.9-8.4, p<0.001) after non-vascular surgery (Table 3). All-cause mortality occurred in 33/1022 (2.9%) of all patients within 30-days, and similarly was
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four-times higher in patients undergoing vascular surgery as compared to non-
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vascular surgery (8% versus 2%).
Cardiac arrest Myocardial infarction
Arrhythmia All-cause mortality
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Acute heart failure
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Cardiovascular death
Vascular surgery n = 243
Non-vascular n = 779
p-value
108 (11%)
58 (24%)
50 (6%)
<0.001
11 (1%)
4 (2%)
7 (1%)
0.302
8 (1%)
3 (1%)
5 (1%)
0.404
57 (6%)
32 (13%)
25 (3%)
<0.001
37 (4%)
23 (9%)
14 (2%)
<0.001
24 (3%)
18 (7%)
6 (1%)
<0.001
33 (3%)
19 (8%)
14 (2%)
<0.001
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Major cardiac complication
All patients n = 1022
Comparison done with Fisher’s exact test; multiple events possible in one patient
Table 3. Clinical outcomes within 30 days, shown for all patients and stratified according to the type of surgery
Prediction of the primary endpoint: major cardiac complications
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Patients with major cardiac complications had significantly higher preoperative hscTnI and hs-cTnT plasma concentrations than patients without complications. In vascular surgery patients, median hs-cTnI was 8ng/L (IQR 4-15) vs. 5ng/L (IQR 3-8; p<0.001), median hs-cTnT was 14ng/L (IQR 9-19) vs. 10ng/L (IQR 6-17; p=0.039) and median s-cTnI was 11ng/L (IQR 6-23) vs. 7ng/L (IQR 6-14; p=0.002),
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respectively for patients with versus without cardiac complications.
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In non-vascular surgery patients, median preoperative hs-cTnI was 12ng/L (IQR 7-
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29) vs. 4ng/L (IQR 2-8; p<0.001) and median hs-cTnT was 40ng/L (IQR 15-64) vs. 13ng/L (IQR 7-22; p<0.001), respectively for patients with versus without cardiac
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complications.
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In vascular surgery patients, the prognostic accuracy for major cardiac complications of hs-cTnI was significantly higher than that of hs-cTnT (AUC 0.67 (95%CI 0.59-0.75)
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versus 0.59 (95%CI 0.51-0.67, p=0.012, Figure 2A). In non-vascular surgery
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patients, the both hs-cTn AUCs overall were higher than in vascular surgery patients and hs-cTnI and hs-cTnT showed comparable AUCs of 0.77 (95%CI 0.71-0.83)
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versus 0.79 (95%CI 0.73-0.85, p=ns, Figure 2B). We found a significant interaction for both hs-cTnI (p=0.011) and hs-cTnT (p<0.001) with the type of surgery in the
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prediction of major cardiac complications. In vascular surgery patients, the presence of hs-cTnI above the cut-offs of 13ng/L and 26 ng/L had high specificity for cardiac events (88% and 96%, respectively), but low sensitivity (31% and 17%,respectively), whereas hs-cTnT had specificity of only 67% and sensitivity of 45%. In non-vascular patients, the hs-cTnI assay had also high specificity (85% and 93%), but hs-cTnT had a better sensitivity (76%), in spite of also low specificity (55%) (Supplement Table 3).
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Figure 2 Area under the receiver operating characteristics curves (AUC) of the
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different troponin assays measured preoperatively for prediction of cardiac complications following vascular surgery (Panel A) and non-vascular surgery (Panel B), shown with 95% confidence intervals. In multivariable analysis, in vascular surgery patients, preoperative hs-cTnI, but not hs-cTnT, remained an independent predictor of the primary endpoint (aOR 1.5, 95%CI 1.0-2.1;Supplement Table 4), while in non-vascular surgery patients, preoperative hs-cTnI and hs-cTnT were independent predictors of major cardiac
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complications (aOR 1.6, 95%CI 1.3-2.0, and OR 3.0, 95%CI 2.0-4.6, respectively; Supplement Table 5). In the ancillary analysis of the extended cohort of patients with available hs-cTnT plasma concentrations (n=2495, Supplement Figure 1), we found an AUC for hs-
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0.70–0.79; p <0.001) in non-vascular surgery patients.
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cTnT of 0.55 (95%CI 0.48-0.62) in vascular surgery patients versus 0.75 (95%CI
Prediction of the secondary endpoint: all-cause mortality
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Preoperative hs-cTnI, hs-cTnT, and s-cTnI plasma concentrations provided
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comparable and modest discrimination (AUC 0.64-0.70) in the prediction of all-cause mortality in vascular surgery patients. In non-vascular surgery, AUCs for the
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prediction of all-cause death were higher for both hs-cTnI and hs-cTnT. In addition, hs-cTnT plasma concentrations provided higher diagnostic accuracy than hs-cTnI
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(AUC 0.8 and 0.67, respectively, p=0.05; Supplement Figure 2).
Discussion
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To the best of our knowledge, this is the first large prospective diagnostic study directly comparing preoperative hs-cTnI and hs-cTnT plasma concentrations in the
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prediction of major cardiac complications after non-cardiac surgery. We report four major findings. First, using regulatory-approved 99th percentile cut-off concentrations in current clinical use, preoperative hs-cTnI elevations were less than one-fifth as common as preoperative hs-cTnT elevations. Using biological equivalent 99th percentile cut-off concentration for hs-cTnI and hs-cTnT,16, 17 preoperative hs-cTnI elevations were still less than half as common as preoperative hs-cTnT elevations. This finding emerged irrespective of the type of surgery. Second, patients undergoing vascular surgery had four-fold more major cardiac complications and all-cause
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mortality rates in comparison to patients undergoing non-vascular surgery. Third, among patients undergoing vascular surgery, preoperative hs-cTnI concentrations provided higher prognostic accuracy for major cardiac complications as compared to hs-cTnT concentrations. Similarly, hs-cTnI, but not hs-cTnT, was an independent predictor of major cardiac complications. Fourth, among patients undergoing non-
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vascular surgery, both preoperative hs-cTnI and hs-cTnT plasma concentrations
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were independent predictors of major cardiac complications after non-cardiac
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surgery.
This study corroborates and extends previous studies evaluating preoperative
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hs-cTnT measurements, and is the first to comprehensively evaluate the role of hscTnI mesurements.7, 8 The incidence of preoperative hs-cTnT plasma concentrations
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above the 99th percentile in this study (44%) was comparable to that observed in other recent cohorts (21-51%).5, 25-27 Our finding of a much lower incidence of
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preoperative hs-cTnI concentrations is in line with a recent pilot study evaluating the prevalence of hs-cTn elevations in patients admitted to the hospital without acute coronary syndromes (ACS), in which the authors reported that elevations of hs-cTnT
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above the 99th percentile were present in more than one third of non-ACS patients
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whereas hs-cTnI elevations were present in only one tenth.28 The pathophysiological mechanisms contributing to this major difference among the two commonly considered interchangeable biomarkers is incompletely understood. In the present study, hs-cTnT plasma concentrations seemed more strongly correlated to renal dysfunction and anaemia than hs-cTnI concentrations, confirming initial pilot findings in patients hospitalized without ACS.28 Although the origin of hscTnT elevations in patients with chronic kidney disease seems more complex than previously thought and only to a lesser degree determined by impaired renal
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elimination,29 cTnT plasma concentrations may suffer more interference from noncardiac comorbidities than cTnI, and elevated plasma concentrations of hs-cTnT may be related to severe systemic, non-coronary conditions. This could in part also explain the observation of a numerically higher prognostic performance for all-cause death observed in our study. CTnT exists in both cardiac and skeletal muscles of the
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foetus.30 In patients with inflammatory muscular diseases, silent genes that codify
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cTnT in skeletal muscles can be reactivated leading to elevated hs-cTnT plasma concentrations.31 Cardiac troponin I seems to be exclusively released by myocardial
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cells, so its release may be more specific for heart diseases.31 Our finding of high
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specificity values for the hs-cTnI assay in the prediction of cardiac events in both groups of patients corroborates with this hypothesis. Also, the mechanism
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responsible for the release of cTn from cardiomyocytes may be due to direct cardiomyocyte injury caused by systemic conditions, such as sepsis or
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inflammation,32 independent of the presence of CAD. Previous biochemical studies
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have showed that correlation between different hs-cTnI assays is better than between hs-cTnI and T, and that these differences cannot be explained by analytical
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imprecision alone, therefore, implying a biological difference in the release
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mechanism of cTnI and T.33 We have demonstrated that preoperative hs-cTnT values have different predictive value in patients undergoing vascular and non-vascular surgery. In vascular patients, although preoperative hs-cTnT is not a good predictor of major cardiac complications, it is good for predicting all-cause mortality. In contrast, in non-vascular surgery patients, both preoperative hs-cTnI and T are also good predictors for cardiac complications. We have confirmed these findings in an additional analysis of all patients for whom only hs-cTnT was available. One possible explanation is that the mechanism of perioperative MI may be different in vascular and non-vascular
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surgery patients. Vascular patients have more severe diffuse atherosclerotic disease and the procedure itself, including manipulation of the arterial bed, could trigger processes leading to plaque rupture and type 1 MI.34 Therefore, preoperative baseline hs-cTnT values (maybe a surrogate for patients with more severe systemic disease) are less useful predictors for cardiac complications after vascular surgery,
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and only hs-cTnI reached statistical significance in our cohort. On the other hand,
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patients submitted to non-vascular surgeries were older and had less previous coronary events but more severe systemic disease, which could lead to a type 2 MI,
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AHF, or arrhythmias.27, 35 Therefore, in non-vascular surgery patients, blood
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concentration of hs-cTnT can predict cardiac events as well as hs-cTnI.
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Overall, measurement of hs-cTn preoperatively improves the prediction of cardiac complications after non-vascular surgery, and should be implemented in clinical practice for patients with age above 65 years or with pre-existing
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atherosclerotic disease.5, 13, 36 In patients undergoing vascular surgery, hs-cTnI may be preferable than hs-cTnT. These biomarkers may be used not only to assess more accurately the risk-benefit of surgery, but also to recommend measures to reduce
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risk, such as giving statins, referring the patient to the intensive care unit after
events.
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surgery and performing surveillance for improving diagnosis and treatment of cardiac
Some limitations should be considered when interpreting our findings. First, the sample size of patients undergoing vascular surgery was only moderate and came from only one site. However, this seemed to have been compensated by the high event rate in these patients, and a possible site effect was mitigated by the additional analysis of hs-cTnT including vascular patients at both sites, which confirmed that hs-cTnT had better accuracy in the non-vascular patients. Second, in
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the non-vascular surgery cohort, only high-risk patients (age ≥65 years or preexisting atherosclerotic disease) were included. These results cannot be applied to low-risk patients. Third, we measured both currently clinically available hs-cTn assays. Further studies are necessary to examine additional hs-cTn that are in development. Fourth, it is possible that vascular patients were more closely
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monitored in routine clinical care as they are considered a high-risk cohort.36
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Therefore, the difference in event rate between vascular and non-vascular surgery
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may have been slightly overestimated. Additionally, the hs-cTnT assay was used for diagnosis of perioperative MI, what could have overestimated its accuracy, but that
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effect occurred in both subgroups, therefore not changing the fact, that there was a
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difference in behavior for vascular and non-vascular surgeries.
Conclusion
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In conclusion, preoperative hs-cTnI and hs-cTnT predict major cardiac events after
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non-vascular surgery, while, in patients undergoing vascular surgery, hs-cTnI may
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have better accuracy. Further studies are needed to validate this hypothesis.
include:
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Other BASEL-PMI Investigators and contributors to this manuscript
Lorenz Guerke, MD1; Thomas Wolff, MD1; Luzius Steiner, MD2; Karin Wildi, MD3; Thomas Nestelberger, MD3; Jasper Boeddinghaus, MD3; Maria Rubini Giménez, MD3; Desiree Wussler, MD3; Karin Wildi, MD3; Stefan Osswald, MD3. 1
Division of Vascular Surgery, University Hospital Basel, University of Basel, Switzerland;
2
Department of Anaesthesiology, University Hospital Basel, University of Basel, Switzerland;
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Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University
Hospital Basel, University Basel, Switzerland
Acknowledgments The authors would like to thank the team of nurses and physicians of the
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postoperative intensive care unit (UAC), Interdisciplinary Medicine in Cardiology Unit
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(UMIC) and vascular surgical ward of the Clinics Hospital, University of Sao Paulo
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Medical School for their help with patient care and blood sample collection.
Disclosures
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DM Gualandro has received research grants from FAPESP (Sao Paulo Research Foundation) for the submitted work, and speaker or consulting honoraria from
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Servier, Sanofi, EMS and Roche, outside the submitted work. C Puelacher has
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received research grants from PPHS (PhD Educational Platform Health Sciences) Basel, outside the submitted work. D Calderaro has received research grants from
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FAPESP and speaker or consulting honoraria from Bayer, outside the submitted work. Dr. Twerenbold received research support from the Swiss National Science
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Foundation (P300PB-167803/1) and speaker honoraria/consulting honoraria from Roche, Abbott, Siemens and Brahms, outside the submitted work. A HammererLercher has received speaker honoraria from Abbott, outside the submitted work. Professor Caramelli has received research grants from FAPESP, CNPq (National Counsel of Technological and Scientific Development, Brasil), as well as speaker or consulting honoraria from Bayer, Boehringer Ingelheim, Servier, and AbbVie, outside the submitted work. Dr. Jaffe has previously or presently consults for most of the major diagnostic companies, outside the submitted work. Professor Mueller has
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received research grants Swiss Heart Foundation, grants from Astra Zeneca, grants and non-financial support from University of Basel, and Abbott, during the conduct of the study, and from the European Union, 8sense, Abbott, ALERE, Beckman Coulter, Biomerieux, Brahms, Critical Diagnostics, Nanosphere, Roche, Siemens, Singulex, Sphingotec and the University Hospital Basel, as well as speaker or consulting
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honoraria from Abbott, ALERE, Astra Zeneca, Biomerieux, BMS, Boehringer
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Ingelheim, Brahms, Cardiorentis, Novartis, Roche, Sanofi-Aventis, Siemens and
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Singulex, outside the submitted work.
1.
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Highlights
Predicting cardiac complications after non-cardiac surgery is challenging;
Preoperative hs-cTn concentrations can be used for the prediction of complications; Hs-cTn I and T may have different behavior, according to type of surgery;
In non-vascular surgeries, hs-cTnT and I are predictors of complications
In vascular surgeries, hs-cTnI may have better accuracy for risk prediction.
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Figure 1
Figure 2