Clinical Characteristics and Functional Outcomes of Postoperative Myocardial Injury: A Prospective Cohort Study - Troponin Elevation After Major Noncardiac Surgery 2
Conditions: Perioperative Myocardial Infarction, Disability, Perioperative/Postoperative Complications
Sponsor: UMC Utrecht

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RESEARCH PROTOCOL 
 
Troponin Elevation After Major noncardiac Surgery (TEAMS) 
 
Department of Anesthesiology, University Medical Center Utrecht, Utrecht, the Netherlands 
L.M. Vernooij, MSc; W.A. van Klei, MD, PhD; L.M. Peelen, PhD 
 
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical 
Center Utrecht, Utrecht, the Netherlands 
L.M. Vernooij, MSc; L.M. Peelen, PhD 
 
Department of Anesthesia and Pain Management, University Health Network Toronto, Toronto, 
Ontario, Canada 
W.S. Beattie, MD, PhD, FRCPR  
 
Correspondence to: 
 L.M. Vernooij, PhD candidate UMC Utrecht, Department of Anesthesiology 
and department of Epidemiology 
 
 
Postal address:  UMCU Str 6.101 
 
 
 
 
 
P.O. Box 85500 
 
 
 
 
 
3508 GA Utrecht 
 
 
E-mail: l.m.vernooij@umcutrecht.nl 
 
 
Telephone: 06-46919498 
 
 
 
 
 
 
 
 

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PROTOCOL TITLE: 
 
TEAMS: Troponin Elevation After Major noncardiac Surgery 
 
Protocol ID 
TEAMS 
Short title 
TEAMS 
Version 
2 
Date 
07-11-2017 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
University Medical Center Utrecht: prof. dr. W.A. van 
Klei 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
University Medical Center Utrecht  
Independent expert (s) 
Dr. J.M. Dieleman, anesthesiologist at UMC Utrecht 
s.dieleman@umcutrecht.nl   
Laboratory sites 
Clinical laboratory University Medical Center Utrecht 
 
 
 

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TABLE OF CONTENTS 
 
INTRODUCTION AND RATIONALE .................................................................................................. 11 
1.
 
OBJECTIVES .................................................................................................................................... 13 
2.
2.1 
Primary objective................................................................................................................... 13 
2.2 
Secondary objectives ............................................................................................................. 13 
 
STUDY DESIGN ............................................................................................................................... 14 
3.
 
STUDY POPULATION ...................................................................................................................... 16 
4.
4.1 
Population (base) .................................................................................................................. 16 
4.2 
Inclusion criteria .................................................................................................................... 16 
4.3 
Exclusion criteria ................................................................................................................... 16 
4.4 
Sample size calculation .......................................................................................................... 16 
 
METHODS ...................................................................................................................................... 18 
5.
5.1 
Study parameters/endpoints ................................................................................................ 18 
5.1.1 
Main study parameter/endpoint................................................................................... 18 
5.1.2 
Secondary study parameters/endpoints ....................................................................... 18 
5.1.3 
Other study parameters ................................................................................................ 19 
5.2 
Randomization, blinding and treatment allocation .............................................................. 20 
5.3 
Study procedures .................................................................................................................. 20 
5.4 
Withdrawal of individual subjects ......................................................................................... 23 
5.5 
Replacement of individual subjects after withdrawal ........................................................... 23 
5.6 
Follow-up of subjects withdrawn from treatment ................................................................ 23 
5.7 
Premature termination of the study ..................................................................................... 23 
 
SAFETY REPORTING ....................................................................................................................... 24 
6.
6.1 
Temporary halt for reasons of subject safety ....................................................................... 24 
6.2 
AEs, SAEs and SUSARs ........................................................................................................... 24 
6.2.1 
Adverse events (AEs) ..................................................................................................... 24 
6.2.2 
Serious adverse events (SAEs) ....................................................................................... 24 
6.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ......................................... 25 
6.3 
Annual safety report .............................................................................................................. 25 
6.4 
Follow-up of adverse events ................................................................................................. 25 
 
STATISTICAL ANALYSIS ................................................................................................................... 26 
7.
7.1 
Data description .................................................................................................................... 26 
7.2 
Primary study parameter(s) .................................................................................................. 26 
7.3 
Secondary study parameter(s) .............................................................................................. 26 
 
ETHICAL CONSIDERATIONS ........................................................................................................... 28 
8.
8.1 
Regulation statement ............................................................................................................ 28 
8.2 
Recruitment and consent ...................................................................................................... 28 
8.3 
Benefits and risks assessment, group relatedness ................................................................ 28 
8.4 
Compensation for injury ........................................................................................................ 28 
8.5 
Incentives .............................................................................................................................. 29 
 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .................................................... 30 
9.
9.1 
Handling and storage of data and documents ...................................................................... 30 

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9.2 
Monitoring and Quality Assurance ........................................................................................ 30 
9.3 
Amendments ......................................................................................................................... 30 
9.4 
Annual progress report ......................................................................................................... 30 
9.5 
Temporary halt and (prematurely) end of study report ....................................................... 30 
9.6 
Public disclosure and publication policy................................................................................ 31 
 
REFERENCES .............................................................................................................................. 32 
10.

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
AR 
ASA 
BNP 
Adverse Reaction 
American Society of Anesthesiologists class 
Brain natriuretic peptide 
CCMO 
 
CRP 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
C-reactive protein 
CV 
ENIGMA II 
Curriculum Vitae 
Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia  
ECG 
eGFR 
Electrocardiogram 
Estimated glomerular filtration rate 
GCP 
GP 
Hb 
Good Clinical Practice 
General practitioner 
Hemoglobin 
IC 
ICU 
NITE 
NoCAE 
MACE 
MAPE 
Informed Consent 
Intensive care unit 
Non-infarct troponin elevation 
Noncardiac adverse event 
Major adverse cardiovascular event 
Major adverse postoperative event 
METC 
 
MINS 
PMI 
RCRI  
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
Myocardial injury after noncardiac surgery 
Postoperative myocardial injury 
Revised Cardiac Risk Index 
(S)AE 
SIRS 
(Serious) Adverse Event  
Systemic inflammatory response syndrome 
Sponsor 
The sponsor is the party that commissions the organization or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organization or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidizing party. 
TTE 
UHNT 
UMCU 
VISION 
Transthoracic echo 
University Health Network Toronto 
University Medical Center Utrecht 
Vascular Events in Noncardiac Surgery Patients Cohort Evaluation 
Wbp 
WHODAS 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
World Health Organisation Disability Assessment Score 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
Rationale:  
Patients undergoing major noncardiac surgery may experience major adverse postoperative events 
(MAPE), which lead to mortality and morbidity. Such complications are hard to diagnose, as typical 
symptoms are often not present in most often postoperative patients (e.g., chest pain may be 
masked by pain medication).  
Routinely measuring cardiac troponins during the perioperative period is an accurate method to 
confirm diagnosis of postoperative myocardial injury (PMI). In patients aged > 60 years undergoing 
intermediate or high risk noncardiac surgery, PMI occurs in 15% of the patients.  Approximately one 
third of them develops an often symptomless myocardial infarction. However, PMI is also associated 
with other cardiac and noncardiac pathologies including heart failure, arrhythmias, pulmonary 
embolism, sepsis and renal failure. Therefore, we consider PMI as either myocardial infarction or  
noninfarct troponin elevation (NITE). Currently, the etiology and long term effects of PMI on 
disability are unknown. Differentiation of patients with PMI in the appropriate disease entity will 
hopefully contribute to more suitable treatment and prevention of major complications.  
The aim of this study is to investigate and compare the independent prognostic effects of the 
different PMI phenotypes (myocardial infarction and NITE) and noncardiac MAPE on disability. We 
will be diagnosing the differing PMI phenotypes using clinical evaluation and biomarkers.  
 
Objective:  
Primary objective  
To investigate and compare the independent prognostic effects of the different PMI phenotypes 
(myocardial infarction and NITE) and noncardiac MAPE on disability in patients undergoing elective 
noncardiac surgery. 
 
Secondary objectives 
1. To investigate and compare the independent prognostic effect of the different PMI 
phenotypes (myocardial infarction and NITE) and noncardiac MAPE on disability free survival 
in patients undergoing elective noncardiac surgery. 
2. To examine whether (combinations of) perioperatively measured biomarkers are associated 
with in-hospital MAPE in patients undergoing elective noncardiac surgery. MAPE are divided 
in different subtypes, including: 
a. MACE, which is defined as the composite endpoint of cardiovascular death, non-fatal 
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ventricular hemodynamic compromise, atrial fibrillation requiring cardioversion, 
pulmonary embolism and stroke.  
b. Noncardiac MAPE including sepsis, renal failure, unexpected intensive care unit (ICU) 
admission and respiratory disorders. 
c. All-cause mortality 
3. To examine whether (combinations of) perioperatively measured biomarkers are associated 
with 6-month MACE and all-cause mortality in patients undergoing elective noncardiac 
surgery.  
4. To assess the added value of the perioperatively measured biomarkers on top of the 
currently used Revised Cardiac Risk Index (RCRI) to predict MACE after noncardiac surgery. 
 
Study design  
This prospective observational cohort study includes patients, aged 60 years and older, undergoing 
elective intermediate or high risk noncardiac surgery under spinal or general anesthesia with an 
expected postoperative hospital admittance of at least 24h. All patients are required to visit the 
preanesthesia outpatient clinic for preoperative consultation. In addition to care as usual, extra 
blood samples will be taken preoperatively and postoperatively up to three days after surgery to 
determine the following biomarkers: high sensitive troponin, brain natriuretic protein, C-reactive 
protein, creatinine and hemoglobin. At postoperative day 2, extra to routine care noninvasive 
imaging (i.e. electrocardiography and transthoracic echography) will be performed.  Preoperatively 
measured biomarkers are considered baseline measurements. Biomarker values will be blinded from 
treating physicians in case this particular biomarker was not measured in routine care. In-hospital 
MAPE will be monitored including cardiac events, respiratory failure, pulmonary embolism, sepsis, 
renal failure and mortality. In addition, patients will be asked to fill out the WHODAS 2.0 
questionnaire preoperatively and 6 months after their surgery to assess disability. Their general 
practitioners (GPs) will be approached to determine whether MACE and/or mortality have occurred 
during the 6 months follow up after surgery. 
 
Study population  
Patients aged >60 years undergoing elective intermediate (e.g. hip replacement) or high risk (e.g. 
liver resection) noncardiac surgery under general or spinal anesthesia with a postoperative hospital 
stay of at least 24 hours are eligible for participation in this study. We aim to include 500 patients in 
this study. Approximately 1,200 patients undergo elective major noncardiac surgery each year in the 
UMC Utrecht. Taking into account nonparticipation and potential lower inclusion rates at the 

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beginning of the study, the estimated inclusion time is one year with six months follow-up resulting 
in a total study time of 18 months.  
 
Main study parameters/endpoints:  
Primary end points: 
Disability is expressed in terms of the WHODAS 2.0 which is based on different functional domains, 
including cognition, mobility, self-care, getting along, life activities and participation. 
 
Secondary endpoints: 
- 
Disability free survival is defined as being alive with a WHODAS 2.0 score ≤ 25% and no 
increase of the preoperative score ≥ 25% at 6 months after surgery.  
- 
An in-hospital major adverse postoperative events (MAPE), which could be distinguished in: 
o Major adverse cardiac event (MACE), which is defined as the composite endpoint of 
cardiovascular death, non-fatal myocardial infarction, non-fatal cardiac arrest, non-
fatal ventricular fibrillation, non-fatal ventricular hemodynamic compromise and 
atrial fibrillation requiring cardioversion.  
o Noncardiac MAPE, which is defined as a composite outcome consisting of respiratory 
disorders (including pneumonia and respiratory failure), pulmonary embolism, sepsis 
and/or systemic inflammatory response syndrome (SIRS), renal failure, reoperation 
and unplanned ICU admission.  
- 
In hospital all-cause mortality 
- 
Length of hospital stay 
- 
6-month MACE 
- 
6-month all-cause mortality 
 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  
In addition to routine care, patients will be asked to fill out the WHODAS 2.0 before surgery and 
additional blood will be drawn (7 cc in total) before induction of anesthesia. Postoperatively, extra 
blood will be taken up to three days after surgery (7 cc in total each time) during routine blood 
draws.  At postoperative day 2, an electrocardiogram (ECG) and transthoracic echo (TTE) will be 
performed. Six months after surgery, patients will be asked to fill out the WHODAS 2.0 for the second 
time and their GPs will be approached to assess whether clinically relevant events have occurred. The 
study is associated with a negligible risk as only noninvasive imaging procedures will be performed 

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and blood will be drawn. The treating physician will be notified in case any unexpected findings from 
the ECG and TTE are observed meaning that participation to this study could lead to early recognition 
of heart disease.  

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 INTRODUCTION AND RATIONALE 
1.
Worldwide, over 300 million patients undergo major noncardiac surgery every year1 and this number 
has been increasing continuously2. Despite the beneficial aspects of surgery, approximately 19% of 
these patients will suffer an in-hospital major adverse postoperative event (MAPE)3. The most 
common MAPE had an infectious (33%) or cardiovascular origin (19%) with highest mortality rates 
observed in patients with a major adverse cardiac event (7.0%)3. Major adverse cardiac events 
(MACE) are a leading cause of postoperative morbidity and mortality4–7 and is associated with 
prolonged hospitalization and increased medical costs8.  
 
Several new guidelines regarding perioperative cardiac risk assessment in patients undergoing 
noncardiac surgery recommend routine postoperative surveillance of troponin to improve early 
recognition of postoperative myocardial injury (PMI)4. Cardiac troponin is a highly sensitive, specific 
biomarker for myocardial injury and has been found to be independently associated with mortality4,9.  
PMI is defined as an elevation in cardiac troponin I above the 99th percentile with a 10% variation10. 
Reported incidences of PMI in patients undergoing major noncardiac surgery are between 11 and 
19%4,6, depending on the study population and emergency status of the surgery. However, the 
etiology and long term effects of PMI are largely unknown. The most common phenotype of PMI is a 
myocardial infarction, which occurs in approximately one third of the patients with PMI. Diagnosis of 
myocardial infarction in patients with PMI is hard as only 10-15% of the patients experience typical 
ischemic symptoms due to the analgesic and sedative effects of anesthetics7,9. However, PMI is also 
seen in other cardiac pathologies including heart failure, arrhythmias and pulmonary embolism, but 
is also associated with noncardiac adverse events, such sepsis, respiratory and renal failure11.  
Therefore, we consider PMI as either myocardial infarction (by the third universal definition10) or as 
noninfarct troponin elevation (NITE). Higher mortality rates are observed in patients with myocardial 
infarction compared to patients suffering NITE (adjusted hazard ratio (HR) 3.4, 95% CI 2.6-4.5 and 
adjusted HR 1.9 95% CI 1.4-2.5, respectively)12. However, the risk of death in patients with NITE is still 
significantly higher compared to patients without PMI meaning that identification of these patients in 
appropriate disease entities is essential.  
 
The effect of the phenotypic diversity of PMI on MAPE, including cardiac and noncardiac events, has 
not been fully investigated. A pilot study found that measuring additional biomarkers (i.e. high 
sensitive troponin, brain natriuretic peptide, C-reactive protein, hemoglobin, creatinine, 
electrocardiography and transthoracic echocardiography) could easily discern the varied etiologies of 
PMI. Perioperative measuring of these biomarkers could potentially uncover the underlying disease 
entities, including ischemia (myocardial infarction), cardiac function (heart failure) and renal 

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function, in patients with PMI and thereby, patients will be treated more appropriately and major 
complications could (hopefully) be prevented. 
 
Nowadays, the Revised Cardiac Risk index (RCRI) is commonly used as a predictive tool to estimate 
the probability of MACE or mortality13. The RCRI includes six predictors, which are high risk surgery, 
history of myocardial infarction (MI), history of cerebrovascular disease, chronic heart failure, 
elevated creatinine and insulin dependent diabetes. Ford et al. performed a review on the 
performance of the RCRI in several validation studies and found that this cardiac index only 
moderately predicts, does not predict events in vascular surgery, and has not been prospectively 
validated using troponin or other biomarkers to predict MI or other cardiac events14. Since this 
publication, several studies reported the added predictive value to the RCRI of one (or more) 
biomarker(s), including (high sensitive) troponin 15–17, (NT-pro)BNP 15,16,18–20, eGFR21,22, CRP18,20, ECG 
23,24and transthoracic echocardiography19,25. Addition of (high sensitive) troponin, (NT-pro)BNP 
and/or CRP to the RCRI seems promising for the prediction of MACE as the predictive performance 
significantly improves compared to the RCRI by itself. To our knowledge, different combinations of 
several biomarkers together in addition to the RCRI have not been reported yet.  
 
Our primary objective is to investigate and compare the independent prognostic effect of the 
different PMI phenotypes (myocardial infarction and NITE) and noncardiac MAPE on disability. We 
will be diagnosing the differing PMI phenotypes using clinical evaluation and biomarkers. The primary 
endpoint is disability. Disability is assessed using the World Health Organization Disability Assessment 
Score 2.0 (WHODAS 2.0) 26. Our primary hypothesis is that any postoperative troponin elevation 
regardless of its association with MACE or noncardiac MAPE is independently associated with an 
increased risk of death and disability. 
 
 
 

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 OBJECTIVES 
2.
2.1 Primary objective  
To investigate and compare the independent prognostic effect of the different PMI phenotypes 
(myocardial infarction and NITE) and noncardiac MAPE on disability in patients undergoing elective 
noncardiac surgery. 
 
2.2 Secondary objectives 
1. To investigate and compare the independent prognostic effect of the different PMI 
phenotypes (myocardial infarction and NITE) and noncardiac MAPE on disability free survival 
in patients undergoing elective noncardiac surgery. 
2. To examine whether (combinations of) perioperatively measured cardiac biomarkers are 
associated with in-hospital major adverse postoperative events (MAPE) in patients 
undergoing elective noncardiac surgery. MAPE are divided in different subtypes, including: 
a. Major adverse cardiovascular events (MACE), which is defined as the composite endpoint 
of cardiovascular death, non-fatal myocardial infarction, non-fatal cardiac arrest, non-
fatal ventricular fibrillation, ventricular hemodynamic compromise, atrial fibrillation 
requiring cardioversion, pulmonary embolism and stroke.  
b. Noncardiac major adverse postoperative events (MAPE) including sepsis, renal failure, 
unexpected ICU admission and respiratory failure. 
c. All-cause mortality 
3. To examine whether (combinations of) perioperatively measured cardiac biomarkers are 
associated with 6-month MACE and all-cause mortality in patients undergoing elective 
noncardiac surgery.  
4. To assess the added value of the perioperatively measured biomarkers on top of the 
currently used Revised Cardiac Risk Index (RCRI) to predict major adverse cardiac events 
(MACE) after noncardiac surgery. 
 
 

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 STUDY DESIGN 
3.
This prospective observational cohort study includes patients undergoing major elective noncardiac 
surgery. Major elective noncardiac surgery is defined as all surgical procedures under spinal or 
general anesthesia with a postoperative hospital admittance of at least 24 hours that have been 
preceded by a preoperative consultation at the preanesthesia outpatient clinic. Patients are treated 
at the University Medical Center Utrecht (UMCU). 
 
Each year, approximately 1,200 patients undergo major noncardiac surgery at the UMCU. We intend 
to include 500 patients in this study. Taking non-participation into account and lower inclusion rate 
at the initial study phase, the expected duration of inclusion will be one year with a 6 month follow 
up leading to a total study period of 18 months. 
 
In figure 1, an overview of the proposed study procedures is shown. In short, patients visit the 
preanesthesia outpatient clinic for preoperative consultation and will be asked to participate in our 
study. Standard diagnostic tests, such as ECG, will be performed based on local protocol or additional 
diagnostic tests or markers are requested at the discretion of the screening anesthesiologist. One 
week before surgery, patients will be approached by telephone and asked if they are interested in 
participation in our study. In case patients are willing to participate, the WHODAS 2.0 questionnaire 
is taken off by the researcher. Informed consent will be signed at the day of hospital admission 
before surgery . Extra blood will be drawn before induction of anesthesia and stored for biobanking. 
Postoperatively, blood samples will be drawn at postoperative days 1-3. At postoperative day 2, 
additional imaging (i.e. ECG and TTE) will be performed. In addition, in-hospital clinical relevant 
outcomes, including MACE and major noncardiac events, will be monitored. Patients are followed up 
until 6 months after surgery by sending them the WHODAS 2.0 and a questionnaire regarding the 
clinical relevant events (i.e. MACE and mortality) since the date of the surgery. Patients will be 
contacted by the researcher to take off the questionnaires by telephone. In addition, their general 
practitioners will be approached to ask similar questions regarding the patients’ clinically relevant 
events during these 6 months follow up to verify details of the events. 
 

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Figure 1. Flowchart of proposed study procedures
 
ECG: electrocardiography; creat: creatinine; Hb: hemoglobin, TTE: transthoracic echocardiography, WHODAS 2.0: 12-item World Health Organization Disability Assessment 
Score 2.0; hsTroponin: high sensitive troponin; BNP: brain natriuretic peptide; CRP: C-reactive protein; GP: general practitioner. 

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 STUDY POPULATION 
4.
4.1 Population (base)  
Patients aged 60 years or older, undergoing major elective non-cardiac surgery under general or 
spinal anesthesia are eligible for study participation. Major elective noncardiac surgery is defined as 
all noncardiac surgical procedures requiring an expected hospital admittance of ≥ 24 hours that have 
been preceded by a preoperative consultation at the anesthesia preoperative screening outpatient 
clinic. For patients who undergo surgery more than once, the first surgery will be included in the 
analysis. Reoperations will not be included. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
- 
≥ 60 years old; 
- 
Major noncardiac surgery defined as all noncardiac surgical procedures requiring an 
expected hospital stay of at least 24 hours; 
- 
Elective surgery, defined as surgery that that has been preceded by a preoperative 
consultation at the anesthesia preoperative screening outpatient clinic. 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation in 
this study: 
- 
Patients unable to fully comply to study needs (e.g. legally incapablepatients or patients 
unable to communicate in Dutch or English). 
- 
Patients with an American Society of Anesthesiologists (ASA) Physical status 5 
 
4.4 Sample size calculation 
For this study, we aim to include 500 patients at the UMCU in this study. A similar study will be 
conducted at the University Health Network Toronto (UHNT), Toronto, Canada and they will include 
500 patients with the same in- and exclusion criteria. After including all patients in both centers, we 
will combine the data resulting in a total study population of 1,000 patients. In a previous conducted 
pilot study by the UHNT (registered at ClinicalTrial.gov: NCT02146560), 300 patients undergoing 
major elective noncardiac surgery were included and disability was assessed by the WHODAS 2.0 
after 6 months. The incidence of troponin elevation in this pilot was 14.1%. We do however expect 
an incidence of 11.0% as patients included in the pilot were mainly vascular patients, who are more 

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prone to have postoperative troponin elevations4. The mean WHODAS 2.0 in patients with an 
elevation in troponin was 29% compared to 15% in patients without troponin elevation. Based on 
these results, and using a level of significance of 0.05 and a power of 0.8 we expect 104 patients with 
troponin elevation. As the ratio between troponin elevation and no troponin elevation is 0.89/0.11 = 
8, we need to include 832 patients. We expect a dropout of 20% (based on the number of patients 
who did not fill out the WHODAS 2.0 after 6 months in the pilot study), leading to a final sample size 
of approximately 1,000 patients.  
 
 
 
 
 

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 METHODS 
5.
5.1 Study parameters/endpoints 
5.1.1 
Main study parameter/endpoint 
Disability is expressed by the WHODAS 2.0, which is based on difficulties experienced by the 
respondent in different functional domains including, cognition, mobility, self-care, getting along, life 
activities and participation during the previous 30 days. Disability is defined as a decrement in each 
functioning domain corresponding to score between 0% and 100%, in which no disability stands for a 
score of 0% and full disability represents a score of 100%, including death. The WHODAS 2.0 is easy 
to use and patient centered (see F1 for the questionnaire). In a validation study including noncardiac 
surgical patients, the WHODAS 2.0 has been found to be a clinically acceptable, valid, reliable and 
responsive instrument for measuring postoperative disability27.  
 
5.1.2 
Secondary study parameters/endpoints 
- 
Disability free survival is defined as being alive with a WHODAS score ≤ 25% and no increase 
of the pre-operative score ≥ 25% at 6 months after surgery.   
- 
An in-hospital major adverse postoperative events (MAPE), which could be distinguished in: 
o Major adverse cardiovascular event (MACE), which is defined as the composite 
endpoint of: 
 
Cardiovascular death, defined as death resulting from an acute myocardial 
infarction, sudden cardiac death, death due to heart failure, death due to 
stroke, and any acute death unconfirmed yet probably due to a 
cardiovascular cause. 
 
Non-fatal myocardial infarction, defined in accordance to the third universal 
definition of myocardial infarction10. 
 
Non-fatal cardiac arrest. 
 
Non-fatal ventricular fibrillation. 
 
Ventricular arrhythmia with hemodynamic compromise.  
 
Atrial fibrillation requiring cardioversion. 
 
Pulmonary embolism, defined as a new thrombus within the pulmonary 
arterial system confirmed on CTA 
 
Stroke confirmed on CT.  
o Noncardiac MAPE, which is a composite outcome consisting of: 
 
Respiratory failure including pneumonia and hypoxia or hypercapnia leading 
to ICU admission for respiratory support 

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 
Sepsis and/or systemic inflammatory response syndrome (SIRS), defined as 
life-threatening organ dysfunction caused by a dysregulated host response to 
infection28.  
 
Renal failure, defined as AKIN criteria or renal replacement therapy. 
 
Unplanned ICU admission 
 
Unplanned medium care admission 
 
Reoperation 
- 
Length of hospital stay, defined as the number of days from the end of surgery until day of 
discharge 
- 
In-hospital all-cause mortality 
- 
6-month all-cause mortality 
- 
6-month MACE 
5.1.3 
Other study parameters 
- 
Baseline characteristics including: 
o Demographics, i.e. age, gender, BMI, smoking status, American Society of 
Anesthesiologists class (ASA). 
o Comorbidities, including history of the following diseases: myocardial infarction, 
cerebrovascular disease, congestive heart failure and cancer. Currently diagnosed 
with: diabetes, coronary artery disease, chronic renal failure, cancer, chronic 
obstructive pulmonary disease, peripheral vascular disease, and hypertension. 
o Medication use, including beta blockers, angiotensin converting enzyme inhibitors, 
calcium blockers, diuretics, statins, insulin, oral antidiabetics. 
o Surgical history, including coronary revascularization, pacemaker or implantable 
cardioverter defibrillator (ICD). 
o Laboratory results of preoperatively measured blood biomarkers, i.e. hsTroponin, C-
reactive protein (CRP), brain natriuretic peptide (BNP), hemoglobin (Hb) and 
creatinine in blood. Imaging biomarkers are electrocardiogram (ECG) and 
transthoracic echocardiogram (TTE). 
o Referral of the screening anesthesiologist at the preanesthesia consultation clinic to 
a cardiologist or other specialist before surgery 
o Preoperative WHODAS 2.0 
- 
Intraoperative: 
o Anesthesia related including type of anesthesia (general or spinal), vital signs (i.e. 
blood pressure, heart rate, eCO2). 

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o Surgical related factors: surgical risk, surgical specialty, blood loss, number of blood 
transfusions and fluid balance. 
- 
Postoperative: 
o Troponin I monitoring at postoperative day 1-3 as being part of routine care. 
o Laboratory results of postoperative measured blood biomarkers, i.e. hsTroponin, 
CRP, BNP, Hb and creatinine in blood on postoperative day 1-3. Imaging biomarkers 
(ECG and TTE) on postoperative day 2. 
o Rehospitalization within 6 months after surgery. 
5.2 Randomization, blinding and treatment allocation 
Not applicable 
 
5.3 Study procedures 
Patient recruitment and preoperative clinical practice 
Study eligibility will be checked by study personnel working at the preanesthesia outpatient clinic. 
Patients will be approached during the preoperative consultation and will be informed about the 
proposed study. Patients will receive extra study information together with the WHODAS 2.0 
questionnaire, in case they are interested in participation in this study. Patients will be approached 
by telephone one week before surgery and asked if they would like to participate on this study. 
Hence, patients have the time between the preanesthesia visit and one week before surgery, which 
is more than 24 hours, to decide if they are willing to participate. If the patient is interested in 
participation, the WHODAS 2.0 survey will be taken by the researcher during this telephone call and 
patients will be assigned a study number. This number is used as a reference for storage of study 
data in the Case Report File (CRF). Access to study numbers correlating to patient names will only be 
available to the principal study investigator, research personnel involved in including patients and 
study monitors/auditors. Informed consent will be signed at hospital admission before surgery. If 
patients decline study participation, they will receive perioperative care as usual. Study material 
collected before signing informed consent (e.g. WHODAS 2.0 survey) will be deleted for patients who 
were interested during the telephone call but rejected participation at the moment of signing 
informed consent. 
 
All patients are required to visit the preanesthesia outpatient clinic for preoperative consultation as 
part of usual care (i.e. non-study related). The following procedures will be performed: 
- 
Patient characteristics regarding demographics, comorbidities, medication use, surgical and 
anesthetic factors will be collected by the anesthesiologist.  

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- 
If requested by the screening anesthesiologist, venous blood will be sampled for additional 
diagnostic testing as part of routine care. Data regarding information about preoperative 
biomarker determination will be collected. This means that not all patients require 
preoperative venous sampling, only if indicated.  
- 
An ECG will be performed and assessed by the screening anesthesiologist. 
All data collected at the preoperative consultation clinic, including biomarker determination (i.e. ECG 
and blood biomarkers) will be interpreted as baseline measurements. 
 
Hospital admittance and intraoperative data collection 
For patients who agreed on study participation during the telephone call one week before surgery, 
informed consent will be signed by the patient and study investigator. If a patient decides to decline 
study participation at this point, this patient will receive routine care as usual. The treating 
anesthesiologist will be informed about participation and 7 cc blood will be drawn at the operation 
theatre immediately before induction of anesthesia. Blood will be collected, processed and stored at 
the Centrale Biobank (CBB) with corresponding study number. Blood biomarkers will be considered 
preoperative baseline values. During surgery, the following data will be collected: 
- 
Vital signs, i.e. blood pressure, heart rate and ET-CO2.  
- 
Blood loss and number of blood transfusions 
- 
Duration of surgery 
Collection of intraoperative data is part of routine clinical care; no study related procedures will be 
conducted. 
 
Postoperative in hospital stay 
At postoperative day 1-3, the following procedures will be performed: 
- 
Extra blood (7 cc each time) will be drawn during the standard blood sampling rounds in the 
morning. Blood will be processed and stored at the CBB.  
- 
At postoperative day 2, an ECG and TTE will be performed by certified study personnel and 
uploaded at the local electronic health record (EHR) and a digital databank. 
- 
In-hospital MAPE, such as MACE, unplanned ICU admission, respiratory disorders, renal 
failure, sepsis and/or SIRS and mortality will be monitored.  
At the UMCU, troponin-I is routinely monitored in all patients, aged ≥ 60 years, undergoing major 
noncardiac surgery. In case troponin-I is elevated, routine (i.e. non-study related) hospital protocol 
procedures involve an ECG and consultation by an anesthesiologist. The anesthesiologist could 
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based on the cardiologist’s discretion which is done in deliberation with the treating physician. 
Patients without troponin elevation only undergo cardiac assessment if deemed necessary by the 
ward physician. The treating physician will be blinded from the extra study related biomarker values 
except they request determination of (one or more) biomarkers as being part of usual care.  
The imaging biomarkers (i.e. ECG and TTE) will be uploaded in the EHR and on a digital databank. Due 
to logistical reasons, blinding of the imaging results is hardly feasible as all these results are uploaded 
to our local EHR automatically. By nature of the procedure, it might happen that an unexpected 
finding which could compromise the patient’s health will be observed by the study personnel 
performing the ECG or TTE. In that occasion, the treating physician will be notified and the treatment 
strategy will be adapted if deemed necessary.  
 
Hospital discharge of last patient 
All blood samples stored at the CBB will be analyzed for the previous mentioned biomarkers in one 
batch after hospital discharge of the last patient, meaning that this information will not be available 
to the treating physician. High sensitive troponin will be determined in addition to the routinely 
measured troponin I as recent  studies concluded that the detection rate of myocardial infarction is 
increased by factor 2 when using the high sensitive troponin compared to the contemporary assay29. 
Only if the physician requested determination of (one or more) biomarkers as part of clinical care, 
the biomarker value is known as being part of routine clinical practice. Availability of these 
biomarkers to the treating physician will also be registered as these biomarkers could influence 
clinical care of these patients, and hence patient outcomes. Imaging biomarkers, i.e. ECG and TTE, 
will be assessed by an independent cardiologist who was unaware of any patient related clinical 
factors. All preoperative patient data will be merged to the biomarker results using the 
corresponding study number and hospital identifier. 
 
6 month follow up 
Patients will be followed up for 6 months after the day of surgery. Follow-up involves: 
- 
Answering the WHODAS 2.0 questionnaire and a questionnaire regarding patient’s health 
since the surgery (see F1. Vragenlijst 6 maanden follow up and F1. Vragenlijst WHODAS). 
Both questionnaires will be sent to the patient’s home address and in the accompanying 
letter, a date with time will be mentioned during which patients could expect a telephone 
call by the researcher. The questionnaires will be taken off by telephone. In case of 
nonresponse, the researcher will approach the patient at another time to keep the response 
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- 
Approaching the patient’s general practitioner to obtain information regarding postoperative 
events in the previous 6 months after surgery. This information will include clinically relevant 
events, such as MACE, hospital admission/consultation and change in medication 
prescription. In case patients are admitted or consulted at a hospital, the corresponding 
treating physician will be approached as well for clinically relevant information.   
Before sending the questionnaires to the patient’s home address, the GBA (Gemeentelijke 
Basisadministratie) will be used to find out whether the patient is still alive, to avoid sending 
questionnaires and calling patients who have deceased. Follow up will end after completion of both 
questionnaires. All results will be merged to the preoperative patient characteristics and biomarker 
data using the corresponding study number and hospital identifier.  
 
5.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent medical 
reasons. After withdrawal, subjects will be treated according standard of care. Subjects can withdraw 
informed consent for participation in ‘deelbiobank’ at any time for any reason. Samples and data 
already used for research, will not be destroyed, but stored in coded form after withdrawal from the 
‘deelbiobank’. 
 
5.5 Replacement of individual subjects after withdrawal 
Subjects who withdraw informed consent will not be replaced by new study participants. The time 
between signing informed consent and preoperative blood sampling is quite short (on average 30 
minutes), hence we assume that it is very unlikely that patients withdraw informed consent before 
surgery. The collected data up to withdrawal of informed consent is still valid and will therefore be 
included in the analysis.  
 
5.6 Follow-up of subjects withdrawn from treatment 
Not applicable 
 
5.7 Premature termination of the study 
Since this is an observational cohort study measuring the difference in pre- and postoperative 
disability status, premature termination due to futility is not applicable. 
 

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 SAFETY REPORTING 
6.
 
6.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardize subject health or safety.  
The sponsor will notify the accredited METC without undue delay of a temporary halt including 
the reason for such an action. The study will be suspended pending a further positive decision by 
the accredited METC. The investigator will take care that all subjects are kept informed.  
 
6.2 AEs, SAEs and SUSARs 
6.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
related to study procedures including venous blood sampling and noninvasive cardiac imaging. 
All blood draws for the current study are conducted during venous sampling for routine clinical 
care, hence potential undesirable experiences related to venous sampling (e.g., pain, bruising), 
are not to be attributed to the current study.  
 
Adverse events related to noninvasive cardiac imaging, i.e. ECG and TTE include: 
- 
Allergic reaction to the lubricating gel used during the TTE 
- 
Mild skin rash where the electrodes for the ECG were attached 
All adverse events reported spontaneously by the subject or observed by the investigator or his 
staff will be recorded. As these adverse events for both venous blood sampling and noninvasive 
cardiac imaging are very rare, the risk of participation in this study based on these procedures is 
low. 
6.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
results in persistent or significant disability or incapacity; 
- 
any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been based upon appropriate 
judgment by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 

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The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events. The sponsor will report the SAEs through the web portal ToetsingOnline 
to the accredited METC that approved the protocol, within 7 days of first knowledge for SAEs that 
result in death or are life threatening followed by a period of maximum of 8 days to complete the 
initial preliminary report. All other SAEs will be reported within a period of maximum 15 days 
after the sponsor has first knowledge of the serious adverse events. 
6.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable 
6.3 Annual safety report 
Not applicable 
 
6.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol.  
 
 
 
 

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 STATISTICAL ANALYSIS 
7.
 
7.1 Data description 
Baseline characteristics will be presented using percentages for categorical covariates, means 
with standard deviations and/or medians with interquartile ranges for continuous variables. 
Comparison between baseline characteristics will be done using the chi-square test for categorical 
variables and Student’s t-test or Mann Whitney-U test for continuous variables as appropriate. 
Based on a pilot study conducted at UHNT, we assume a patient dropout of 20%  at 6 months 
follow up (see Sample size calculation). Baseline characteristics of patients who did and did not 
respond at 6 months follow up will be compared to examine whether selective dropout occurred. 
Multiple imputation will be performed in case of any missing data. Throughout the analyses, a p-
value of 0.05 is considered statistically significant. 
 
7.2 Primary study parameter(s) 
The primary outcome, postoperative WHODAS 2.0 after 6 months, will be compared among 
patients with and without PMI, using Student’s t-test or a nonparametric Mann Whitney U test. 
In case of normality, the mean 6-months WHODAS 2.0 will be calculated together with the 
accompanying 95% confidence intervals. Otherwise, the median WHODAS 2.0 with interquartile 
range will be reported.  
With respect to the association between the different phenotypes of PMI (i.e. myocardial 
infarction, NITE and MAPE) and disability, the preoperative, postoperative and the change 
(meaning difference between pre- and postoperative measurements) in biomarkers are of 
particular interest. The biomarkers will be analyzed both as continuous variables and using 
predefined clinical thresholds to define when the each of the biomarkers are elevated. 
Combination(s) of different biomarkers and the biomarker by itself in association with 
postoperative WHODAS 2.0 will be performed. These combination(s) of biomarkers will be 
related to one of the different phenotypes of PMI. Multivariable linear regression analyses will be 
performed to adjust for potential confounders including age, gender, comorbidities 
(cardiovascular risk factors), preoperative WHODAS 2.0 score, RCRI and surgical specialty.   
  
7.3 Secondary study parameter(s)  
- 
Disability free survival will be described as percentages with their accompanying 95% 
confidence interval (CI) among patients with or without PMI. Different combinations of 
elevation in biomarkers will be tested. Comparison between different PMI phenotypes will be 
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analyses will be done to take several covariates into account, which are similar to 
confounders described for the primary analyses. 
- 
Similar to disability free survival, MACE (including PMI and NITE), noncardiac MAPE and all-
cause mortality will be presented as proportions with their accompanying 95% CI. 
Multivariable logistic regression analyses will be performed using MACE, noncardiac MAPE or 
all-cause mortality as outcomes, both in-hospital events and at 6 months (except for 
noncardiac MAPE as these will not be measured at 6 months). Different combinations of 
elevations in biomarkers (preoperative, postoperative and change between pre- and 
postoperative) will be tested against these outcomes to uncover correlations between 
particular combinations of elevated biomarkers to assess what disease entities are related to 
the outcome.  
- 
A Kaplan-Meier method will be used to assess whether the cumulative incidence of 6-month 
mortality differs between patients with and without PMI. The probabilities of 6-month 
mortality between patients with and without elevation in (one or more) biomarker(s) will be 
compared using log-rank tests provided assumptions for this test are met.  Cox-proportional 
hazard analyses will be performed to examine whether (one or a combination of several) 
biomarker(s) are associated with 6-month mortality adjusted for potential confounders.  
- 
The added prognostic value of each of the biomarkers (or combinations of biomarkers) will 
be tested to predict MACE, both in-hospital and at 6-months. The biomarkers will be 
analyzed as continuous variables and using predefined clinical thresholds to define whether 
that particular biomarker is elevated. Multivariable logistic regression analyses will be 
performed using the predictors of the RCRI (i.e. high risk surgery, history of cerebrovascular 
disease, history of myocardial infarction, congestive heart failure, elevated creatinine and 
insulin dependent diabetes) as predictors together with the addition of elevation in 
biomarkers. Discrimination and calibration of the prediction models will be assessed using 
the c-statistic, Hosmer-Lemeshow test. The net reclassification index (NRI) and the Integrated 
Discrimination Index (IDI) will be calculated to quantify how well the updated RCRI 
reclassifies patients as compared to the traditional RCRI.  
 
 
 

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 ETHICAL CONSIDERATIONS 
8.
8.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (Adopted by the 
18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 64th WMA general 
Assembly, Fortaleza, Brazil, October 2013) and in accordance with the Medical Research Involving 
Human Subjects Act (WMO).  
 
8.2 Recruitment and consent 
Study eligibility will be checked by study personal working at the anesthesia preoperative 
consultation clinic. If study in- and exclusion criteria are met, patients will be informed about the 
proposed study by the anesthesiologist at the preanesthesia outpatient clinic. If interested, the 
patient will receive a written study information letter. One week before surgery, patients will be 
approached for the second time by telephone by the study investigator or a trained research nurse. 
In case patients are willing to participate, informed consent will be signed by the participant and the 
study investigator at the day of hospital admission before surgery. If patients decline study 
participation, they will receive perioperative care as usual.  
 
8.3 Benefits and risks assessment, group relatedness 
This is a non-therapeutic study without involvement of minors and/or incapacitated adults studying 
the independent prognostic effect of different PMI phenotypes and noncardiac MAPE on 
postoperative disability status. The burden to patients is low as in addition to routine care, only 
noninvasive imaging techniques (i.e. TTE and ECG) will be performed, extra venous blood will be 
drawn during standard blood sampling rounds, and a short questionnaire needs to be filled out 
twice. The study is associated with a negligible risk as appearance of any adverse events due to the 
study is very low. The patient might benefit from participation in this study as unexpected findings 
from the TTE and/or ECG might change the treatment strategy and individual prognosis of that 
patient. 
 
8.4 Compensation for injury 
The sponsor, University Medical Center Utrecht, wishes to obtain dispensation from the statutory 
obligation to provide insurance, because participating in the study is without risks. The Medical 
Ethical Committee of the UMCU agreed to provide dispensation for this study. 
 

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8.5 Incentives 
No travel or other expenses will be reimbursed as all hospital visits are being part of usual care. 
 
 

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 ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
9.
9.1 Handling and storage of data and documents 
Study data will be collected in encrypted electronic Case Report Forms (CRF’s) using unique 
identification numbers to ensure confidentiality.  A separate document will contain the key to 
link the subject identification numbers to the study participants. This key will be safeguarded by 
the data manager.  Data will be accessible to the research team, study monitors/auditors and the 
inspection. Results of the blood and imaging biomarkers will not be available for treating 
physicians meaning that this data will not be used in clinical practice, except if the treating 
physician requests determination of one (or more) biomarker(s). Patients will be followed up 
after 6 months by sending two questionnaires using name and address details. Data will be 
stored for 15 years.  
Blood samples will be stored at the Centrale Biobank of the UMC Utrecht for undetermined 
period of time. Usage of these blood samples by other investigators (from the UMC Utrecht) for 
future research purposes will be possible if they submit a specific research question to the 
‘Toetingscommissie Biobanken’. 
 
9.2 Monitoring and Quality Assurance  
Monitoring will be performed by a qualified monitor according to the monitoring plan (see K6. 
Monitoring plan for a more detailed description).  
 
9.3 Amendments  
Amendments are changes made to the research after a favorable opinion by the accredited METC 
has been given. All amendments will be notified to the METC that gave a favorable opinion.  
 
9.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
9.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a period 
of 8 weeks. The end of the study is defined as collection of the last patient’s 6-months WHODAS 

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2.0. The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action.  
 In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination.  
 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC.  
 
9.6 Public disclosure and publication policy 
The results of the proposed study are publically disclosed on the basis of the participation of 
patients in it, following the principles of the CCMO’s statement on disclosure of publication of 
results. The sponsor is entitled to examine the manuscript prior to publication and to make 
comments on it. 
 
 

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