unRaveling pErioperative MyocArdial INjury
Conditions: Myocardial Injury, Myocardial Injury After Non-Cardiac Surgery
Sponsor: Erasmus Medical Center

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 unRaveling pErioperative 
MyocArdial INjury (REMAIN) 
 
Department of Anesthesiology 
Erasmus MC, Rotterdam, The 
Netherlands 
 
 
non-WMO-applicable research 
 
 
 
 
 
 
 

Version number 2, 26-09-2024
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Full title of protocol
unRaveling pErioperative MyocArdial INjury 
Short title or Acronym
REMAIN 
Version
2 
Date
26-09-2024 
Coordinating investigator/ 
project leader 
Dr. F. van Lier 
Erasmus University Medical Center 
Department of Anesthesiology 
3000 CA Rotterdam, The Netherlands 
 
Principal investigator(s) 
 
 
Dr. F. van Lier en Dr. S.E Hoeks 
 
Sponsor (in Dutch:
verrichter/opdrachtgever) 
Erasmus MC, University Medical Center Rotterdam 
Department of Anesthesiology 
Postbus 2400 
3000 CA Rotterdam, The Netherlands 
Subsidising party
N.A. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
List of abbreviations and relevant definitions 
4 
Protocol summary 
5 
1. Introduction and rationale 
6 
2. Objective(s) 
6 
3. Study type 
6 
4. Study population 
7 
5. Methods 
7 
6. Unexpected discoveries 
8 
7. Exchange, sharing or transfer of data and/or human material and/or 
images outside the Erasmus MC 
8 
8. Statistical analysis 
8 
9. Recruitment and consent 
8 
10. Handling and storage of data and images 
9 
11. Handling and storage of human material 
9 
12. Amendments 
10 
13. Publication 
10 
14. References 
10 
15. Attachments 
10 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
 
 
DRE 
Digital Research Environment 
Exception consent Form Care for data Template, in Dutch: Formulier uitzondering toestemming 
GCP 
Good Clinical Practice 
IC 
Informed Consent 
KLEP 
Klinische Epidemiologie 
UAVG 
Dutch Act on Implementation of the General Data Protection 
Regulation; in Dutch: Uitvoeringswet Algemene Verordening 
Gegevensbescherming 
WMO 
Medical Research Involving Human Subjects Act, in Dutch: Wet 
Medisch- wetenschappelijk Onderzoek met Mensen 
 
 
 
 

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SUMMARY  
 
Rationale: Myocardial injury is an independent predictor for poor outcome after non-cardiac surgery. 
The causes for myocardial injury can be multifactorial. Knowing what the exact cause for myocardial 
injury is, is often unclear or mixed pathophysiology exist. However, in clinical practice doctors have an 
opinion on the most likely cause.  
 
Objective: The aim of this study is to gain insight into the etiology of myocardial injury after non cardiac 
surgery. Secondary we try to find what doctors think of the most logical explanation for myocardial injury, 
what phenotype is associated with the most likely cause, how this determines prognosis and what factors 
are associated with improved outcome. 
 
Study design: Retrospective cohort study 
  
Study population: Patients who underwent non-cardiac surgery in the Erasmus MC in the period 2017-
2023. 
 
Intervention: None  
 
Main study parameters/endpoints: The primary endpoint is a description of the main etiologies found 
within patients with an elevated troponin T after non cardiac surgery.  
 
Nature and extent of burden and risks associated with participation, benefit and group 
relatedness:  
There will not be a significant burden to patients. This study will use existing data from patients that have 
been operated in the time period 2017-2023 in the Erasmus MC. There is no additional intervention 
required.  
 
 
 

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1. Introduction and rationale 
 
 
Myocardial injury, a significant increase/or elevation of cardiac troponin after non-cardiac surgery, 
has proven to be a major contributor to perioperative mortality[1, 2]. It is estimated that myocardial 
injury contributes to 34-42% of all deaths following non-cardiac surgery within 30 days [3]. One 
major difference between non-surgical acute myocardial infarction and perioperative myocardial 
injury is that the vast majority of patients experiencing perioperative myocardial injury do not show 
any typical ischemic symptoms (chest pain and/or ischemic changes on the electrocardiogram). It is 
therefore difficult to diagnose myocardial injury, without knowing biomarker profiles. Due to the lack 
of typical symptoms, most patients with myocardial injury are currently not detected in routine clinical 
practice. Surprisingly, whether a patient fulfills the definition for acute myocardial infarction (i.e. has 
clinical symptoms, or ECG changes, or imaging evidence of new loss of viable myocardium), the 
prognosis is the same for all elevations, regardless of symptoms [3-5].  
 
 
In the last decade, extensive efforts have been made to determine the etiology of myocardial injury, 
in order to discover a pathophysiology that is leading and may guide us to treatment options. One of 
the published definition is MINS (Myocardial Injury after Noncardiac Surgery) [4, 6-8]. This definition 
evaluates all elevations for any other cause that may be causing the elevation (i.e. sepsis, heart 
failure, tachyarrhythmias, renal failure, chronic elevations). If any of these other causes are unlikely, 
a diagnosis of MINS can be made; MINS therefore covers the spectrum of ischemic heart disease 
(acute coronary syndromes and type 2 ischemia). Unfortunately, it is not known which criteria are 
used to rule out other causes, the individual contribution on mortality of the other phenotypes or how 
often mixed etiologies are possible. 
 
 
A second strategy has recently been published by another research group (Figure 1) [9]. Here an 
increase in troponin in the first steps is analyzed for a cause other than type 2 ischemia. If there is, 
treatment may be started appropriate to the most likely cause. Thus, by definition, if no other cause 
found likely, type 2 ischemia becomes the most logical cause. The prognosis varies greatly 
depending on what researchers found the most likely cause [9, 10]. These results call for an 
replication in our hospital, since we have been measuring myocardial injury for more than a decade.  
Furthermore, it is unclear anesthesiologists in different phases of training, agree with regard to the 
most likely cause of the myocardial injury. In this study we would like to search for more clarity 
regarding these questions, which are better elaborated below. 
 

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Figure 1: Evaluating scheme for patients with perioperative myocardial injury 
2. Objective(s) 
 

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The aim of this study is multiple: 
 
Primary aim: 
-  The primary aim is to determine the etiology of myocardial injury after non cardiac surgery.  
 
Secondary aims: 
- Do phenotypes, with regard to blood pressure, heart rate, of ST-segment analysis, differ between 
the different etiologies? 
- How often do health care providers from different levels of training differ in opinion on the most 
likely diagnosis? 
- What were clinical features present for selecting the most the likely etiology? 
 
3. Study type 
 
3.1 Study type: 
 
X Retrospective 
☐ Prospective 
☐ Combination Retrospective/Prospective 
 
3.2 Check all the applicable boxes: 
 
X   Medical records (re-use of data from healthcare, including AI) Case report 
☐ Re-use data from research 
X   Evaluations of quality of healthcare (retrospective) 
☐ Research with additional use of residual material from regular healthcare 
☐ Research with re-use of human materials from research or existing biobank 
☐ Research with human materials without biobank 
☐ De novo biobank (human material obtained without burdensome or invasive procedures) 
☐ Post marketing survey research with medical devices 
☐ Phase IV research 
☐ Healthcare evaluation research (prospective) Medical devices 
☐ In Vitro Diagnostic Tests Other research, describe 
 
4. Study population 
 
4.1 Population (base) 

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The population to be studied consists of all non-cardiac surgical patients who 
underwent surgery at Erasmus MC in the period 2017-2023.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
- 
 
Age > 18 year of age 
- 
 
Undergoing non-cardiac surgery in the Erasmus MC, with (high-sensitive) Troponin T > 50  
 
ng/L measured in any of the first three days after surgery. 
 
4.3 Exclusion criteria 
The following types of operations are excluded from the analysis: 
-  
Re-operations within the study period. 
- 
Daycare surgery 
 
4.4 Sample size calculation 
The sample size is based on convenience sampling of the cohort of routine postoperative 
troponin measurements in the Erasmus MC since 2017 (MEC-2017-062). A total of 100 patients 
per year with a (high-sensitive) Troponin T > 50 ng/L are estimated [11] which would result in 
roughly 700 patients. 
 
4.5 (Planned) start date 
Baseline and in hospital data extraction can be started as soon as approval by the ethics 
committee is given. We plan to start as soon as we receive permission to collect the necessary 
data. Expected start date is October 2023. 
 
4.6 (Planned) end data 
March 1st 2027 
 
 
5. Methods 
 
5.1 Procedures 
The baseline population will consist of all patients who underwent a form of non-cardiac surgery, 
regardless of the type of anesthesia in the time period 2017-2023 in the Erasmus MC. For 
patients who have undergone multiple operations, only the first operation will be included for 
analysis. There are no restrictions to the type of anesthesia: local, locoregional and general 

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anesthesia will be included. The same applies for the type of surgery: emergency as well as 
elective surgery will be included. Baseline variables, medication use, type of surgery and 
perioperative hemodynamic and laboratory variables will be extracted from the hospital 
information system. Myocardial injury will be defined as a peak high-sensitive troponin T > 50 
ng/L, measured on one of the first three postoperative days. One year mortality is registered, as 
well as major vascular events. This is in line with previous publications from our group. The 
adjudication strategy used for patients with myocardial injury will follow a similar pattern 
compared to scheme in Figure 1. For the adjudication process anesthesiologists in various 
forms of training (resident and attending) will be invited. The total panel will have a maximum of 
6-10 members. Two members will receive a sample of patients to adjudicate. Together the entire 
panel will adjudicate all patients. In case of non-agreement between raters, a third rater will 
make a final decision. The goal to investigate the differences between the raters.  
 
5.2 Standard clinical care versus extra for research 
N.A. 
 
5.3 Please describe the burden and risks associated with participation, e.g. the amount and number 
of blood samples, biopsies, liquor, hair, urine, nails, saliva etc., the number of site visits, physical 
examinations or other tests, questionnaires or diaries that have to be filled out, physical and 
psychological discomfort associated with participation 
 
N.A. 
 
5.4 A risk-benefit analysis must be given, if applicable. 
 
N.A. 
 
5.5 Medical device(s)/In vitro diagnostic tests 
 
N.A. 
6. Unexpected discoveries 
 
6.1 Is there a chance of unexpected discoveries? 
☐ Yes 
X  No 
6.2 If yes, describe the procedures, who will be notified, how the subjects are notified. 

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N.A. 
 
7. Exchange, sharing or transfer of data and/or human material and/or images 
outside Erasmus MC 
 
N.A 
 
8. Statistical analysis 
 
8.1 Main study parameter/endpoint 
 
 The primary endpoint is a description of the main etiologies found within patients with an 
elevated troponin T after non cardiac surgery.  
 
8.2 Secondary study parameters/endpoints 
 
Differences in the adjudication process between different doctors will be assessed according to 
intraclass coeficients and Fleisch Kappa[12].  
 
8.3 Other study parameters:  
 
N.A. 
 
9. Recruitment and consent 
 
9.1 Will the subjects be asked for informed consent? 
 
☐ Yes (Upload Patient Information Letter and Informed Consent) 
☐ No, only anonymous data is used, i.e. the data can never be traced back to an individual 
subject 
X No, this research will be performed under the exception consent 
(Upload form Care for data Template, in Dutch: Formulier uitzondering toestemming) 
☐ Other (e.g. partly, indirectly) Please describe the situation. 
 
9.2 If yes, please give a description of the recruitment and informed consent procedures.  
 
N.A. 
 

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9.3 If no, exception consent: describe how it is safeguarded that subjects are excluded 
who have objected against the re-use of their data, human material, images. 
Since the primary endpoint is 1-year mortality, asking for informed consent is 
virtually impossible.  
 
10. Handling and storage of data and images 
 
10.1 Describe how subject’s privacy is protected. Describe how, when and by 
whom data is coded, and how the key table is safeguarded. 
 
All study patients will be given an anonymous study ID, untraceable to the 
 
patient.  
 
 
Baseline and outcome data, hemodynamic and laboratory data will be 
 
entered in the Clint/DRE database of the Erasmus MC or directly extracted 
 
from the hospital information system and stored on the DRE. After the 
 
adjudication process has finished, all research data will be anonymized so  
 
that cannot be traced to individual persons and can only be viewed by 
 
authorized personnel. These persons are the principal investigators of this 
 
study, members of the health care inspection and members of the Medical 
 
Research Ethics Committee. 
 
  
 For this, a separate file containing the code for unblinding will be kept in the 
 Erasmus MC environment and will only be accessible to those directly 
 involved in the study. 
 
10.2 Describe how data is stored (i.e. which data management system/data capture 
system), who has access to the coded source data, how long data will be kept, 
which steps are taken to ensure data security, what happens with the data after the 
research has been completed. 
 
 
All collected data in this study will be stored in a secure environment inside the 
 
Erasmus MC and can only be accessed by those involved in data management and 
 
analysis for the study. The hemodynamic and laboratory data that will be extracted 
 
from the electronic medical record and will be stored in a secure environment in the 
 
DRE and are only accessible to study staff.  

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Both data sources will be stored for 15 years. 
 
10.3 Describe how images are stored, how the subject’s privacy is protected, what 
happens with images after the research has been completed. 
 
N.A. 
 
10.4 Describe how approval of re-use of data and/or images is obtained. 
 
N.A. 
 
11.  Handling and storage of human material 
 
 
  N.A. 
 
12. Amendments 
 
N.A. 
 
13. Publication 
Do you have the intention to submit the study results in a manuscript for publication in a journal: 
 
X Yes 
☐ No, please motivate 
 
14. References 
 
 
1. 
Thygesen, K., et al., Fourth universal definition of myocardial infarction (2018). European Heart 
Journal, 2018. 40(3): p. 237-269. 
2. 
Borja Ibanez, S.J., Stefan Agewall, Manuel J Antunes, Chiara Bucciarelli-Ducci, Héctor Bueno, 
Alida L P Caforio, Filippo Crea, John A Goudevenos, Sigrun Halvorsen, Gerhard Hindricks, 
Adnan Kastrati, Mattie J Lenzen, Eva Prescott, Marco Roffi, Marco Valgimigli, Christoph 
Varenhorst, Pascal Vranckx, Petr Widimský, ESC Scientific Document Group, 2017 ESC 
Guidelines for the management of acute myocardial infarction in patients presenting with ST-
segment elevation: The Task Force for the management of acute myocardial infarction in patients 
presenting with ST-segment elevation of the European Society of Cardiology (ESC). European 
Heart Journal, 2017. 39(2): p. 119-177. 
3. 
Botto, F., et al., Myocardial injury after noncardiac surgery: a large, international, prospective 
cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. 
Anesthesiology, 2014. 120(3): p. 564-78. 
4. 
Devereaux PJ, B.B., Sigamani A, Xavier D, Chan MTV, Srinathan SK,, et al., Association of 
Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality 
Among Patients Undergoing Noncardiac Surgery. Jama, 2017. 317(16): p. 1642-1651. 
5. 
Puelacher, C., et al., Perioperative Myocardial Injury After Noncardiac Surgery: Incidence, 
Mortality, and Characterization. Circulation, 2018. 137(12): p. 1221-1232. 
6. 
Biccard, B.M., et al., Myocardial Injury After Noncardiac Surgery (MINS) in Vascular Surgical 

Short title or Acronym 
 
Version number 1, 27-01-2023  
 
Patients: A Prospective Observational Cohort Study. Annals of Surgery, 2018. 268(2): p. 357-
363. 
7. 
Biccard, B.M., et al., Effect of aspirin in vascular surgery in patients from a randomized clinical 
trial (POISE-2). Br J Surg, 2018. 105(12): p. 1591-1597. 
8. 
Devereaux, P.J. and W. Szczeklik, Myocardial injury after non-cardiac surgery: diagnosis and 
management. European Heart Journal, 2019. 41(32): p. 3083-3091. 
9. 
Puelacher, C., et al., Long-term outcomes of perioperative myocardial infarction/injury after non-
cardiac surgery. European Heart Journal, 2023. 
10. 
Puelacher, C., et al., Etiology of Peri-Operative Myocardial Infarction/Injury After Noncardiac 
Surgery and Associated Outcome. Journal of the American College of Cardiology, 2020. 76(16): 
p. 1910-1912. 
11. 
Mol, K.H.J.M., et al., Postoperative troponin release is associated with major adverse 
cardiovascular events in the first year after noncardiac surgery. Int J Cardiol, 2019. 280: p. 8-13. 
12. 
Koo, T.K. and M.Y. Li, A Guideline of Selecting and Reporting Intraclass Correlation Coefficients 
for Reliability Research. J Chiropr Med, 2016. 15(2): p. 155-63. 
 
 
15. Attachments 
 
 
 
N.A.