Myocardial injury in noncardiac surgery in Sweden

Editor, A significant proportion of patients suffer from myocardial injury after noncardiac surgery (MINS). The majority of these patients neither fulfil the universal definition of myocardial infarction (MI) nor experience ischaemic symptoms yet MINS independently increases the risk of mortality.1 Therefore, despite the fact that an effective intervention for MINS is yet to be found, routine screening for MINS postoperatively has been recommended for high-risk patients.2 MINS is detected by the measurement of cardiac Troponins (cTns). However, several gaps in knowledge exist regarding the prognostic value of cTns in peri-operative care. First, most previous studies have focused on postoperative measurements. Yet, elevations in pre-operative Troponins have been shown to occur commonly and may act as an early warning signal for significant postoperative morbidity. Second, it is important to establish the timing of myocardial injury as it may indicate different outcomes and differences in peri-operative management. Finally, with the introduction of the high-sensitivity cardiac troponin T (hsTnT) assay into daily clinical practise, it has been proposed that the prognostic value of hsTnT should be further investigated.2,3 Current guidelines recommend the use of validated pre-operative cardiac risk scores to identify patients at high risk of peri-operative cardiac complications.3 Pre-operative biomarkers are notably not included in any risk score. The Revised Cardiac Risk Index (RCRI) is the most well established cardiac risk score however its discriminative ability has been questioned.4 This reinforces the need to find a more optimal risk stratification tool for patients undergoing noncardiac surgery. In recent years, interest in biomarkers as potential predictors of postoperative cardiac morbidity and mortality has increased. hsTnT, brain natriuretic peptide (BNP), copeptin, adrenomedullin (ADM) and endothelin-1 (ET-1) are all biomarkers connected to the cardiovascular system. cTns are cardiac-specific proteins released by cardiomyocytes into the blood as a response to myocardial injury and/or necrosis. Although robust data are available regarding the prognostic value of postoperative TnT,1–3 pre-operative investigations are still lacking. BNP is a hormone that together with its inactive cleavage product pro-N-terminal BNP (NT-proBNP), is secreted into the blood from cardiomyocytes in response to stretching of the atrial or ventricular wall. Pre-operative BNP independently predicts 30-day cardiovascular events after noncardiac, and in particular, vascular surgery.5 However, studies are still lacking in other high-risk surgical populations. Copeptin is a novel biomarker that reliably rules out acute MI in patients with acute chest pain when used in combination with troponin.6 However, very little is known about copeptin within peri-operative care. ADM and ET-1 are hormones with opposing effects on the cardiovascular system. ADM acts as a vasodilator and increases cardiac output, and is measured as the mid-regional portion of the precursor peptide pro-ADM (MR-proADM) in clinical practice.7 ET-1 is a vasoconstrictor and has been linked to decreased cardiac performance. In clinical practice, it is measured as C-terminal pro-ET-1 (CT-proET1). These novel biomarkers are sparsely investigated in the peri-operative population and there are no studies investigating the combination of hsTnT, NT-proBNP, copeptin, MR-proADM and CT-proET1. Our hypothesis is that peri-operative elevation of biomarkers, alone or combined in a biomarker panel, independently predict mortality and major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing major abdominal surgery. We also hypothesise that the addition of a biomarker or biomarker panel improves peri-operative risk stratification compared with the RCRI. Study protocol Inclusion Adults at least 50 years old undergoing elective, major or major/complex abdominal surgery defined according to the Surgical Outcome Risk Tool (www.sortsurgery.com), requiring general anaesthesia and at least one overnight stay. Exclusion Patients with acute coronary syndromes, new or decompensated heart failure at presentation, documented severe aortic stenosis, severely reduced ejection fraction (<40%) and inability to follow the procedures of the study or lack of capacity to give informed consent. Transplantation, trauma, endocrine, vascular and endovascular surgical procedures will also be excluded due to their distinct risk profiles compared with the intended population. Outcome The coprimary endpoints are all-cause mortality at 30 days and MACCE, the latter defined as nonfatal cardiac arrest, acute MI, congestive heart failure, new cardiac arrhythmia, angina and stroke. Secondary endpoints are 365-day all-cause mortality and MACCE. Data collection Relevant clinical and peri-operative data for example comorbidities, RCRI, ASA-PS score, type and length of surgery, blood loss and intra-operative lowest blood pressure will be collected. Plasma levels of hsTnT, NT-proBNP, copeptin, MR-proADM and CT-proET1 will be measured at five sampling points: pre-operatively, immediately postoperatively, and on Days 1 to 3 postoperatively or until discharge. Data on MACCE will be obtained from patient records and structured telephone interviews at 30 and 365 days by assessors blinded to the results of the biomarker analyses (see also NCT03436238). Statistics Based on an assumed incidence of MINS of 10%1 and 365-day mortality in the non-MINS group of 11% (estimate based on current data from the Swedish Perioperative Registry), the required sample size to detect an effect size of 10% is 1142. To account for drop-outs and missing data, we will recruit up to 1600 patients. Receiver operating curve analysis will be used to determine the optimal threshold of each biomarker in predicting mortality/MACCE. The net reclassification index will be used to assess if biomarkers confer added value to the RCRI for the classification of MACCE. A multivariable Cox proportional hazard models will be used to test the independent prognostic value of biomarkers. The sample size allows for adjustment of the following prespecified variables, selected on the basis of clinical plausibility and prior evidence: age, sex, ASA-PS class, RCRI, Charlson Comorbidity Index, length and type of surgery, presence of intra-operative hypotension, pre-operative creatinine and haemoglobin, biomarkers (alone and in combination). An independent statistical analysis will be conducted after recruitment of 600 patients to assess the frequency of outcomes and missing data, after which the sample size may be adjusted. Acknowledgements relating to this article Assistance with the study: The authors thank the MINSS study group investigators: Linköping University Hospital: Helén Didriksson, Rasmus Nordström, Michael Linhardt, Lina De Geer, Eva Fremner; Ryhov County Hospital Jönköping: Fredrik Hammarskjöld; Central Hospital Kristianstad: Malin Kollind, Monir Jawad; Vrinnevi Hospital Norrköping: Louise Elander, Jakob Zeuchner; Malarsjukhuset, Eskilstuna County Hospital Sara Lyckner, Jesper Sperber; Skane University Hospital Lund and Malmo: Ulrika Andersson, Patrik Johnsson. The authors thank all staff in the participating hospitals for their dedicated support of the MINSS study. We are also grateful to Gunilla Gagnö, Lena Sundin, Elisabeth Aardal, Ewa Lönn Karlsson, Anneli Reinholdsson, Dzeneta Dernroth, Lena Thunell, Gunilla Bergström and Gunilla Davour for their contribution to setting up the database, biomarker analyses including certification and quality control, biobank and study coordination. Financial support and sponsorship: supported by research grants from the European Society of Anaesthesiology, Region Ostergotland County Council ALF Grant, Medical Research Council of Southeast Sweden, Swedish Research Council. The sponsor is Region Ostergotland County Council and has no role in study design, execution, data synthesis and reporting of results. Conflicts of interest: none.