Assessing the Incidence of Postoperative Delirium Following Aortic Valve Surgery
Conditions: Postoperative Delirium, Aortic Valve Stenosis
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
 
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Protocol Full Title prospective cohort study: 
 
Assessing the incidence of postoperative delirium following aortic valve 
interventions 
Protocol Acronym/short title: 
 
POD following TAVI or SAVR 
 
Version and date of final protocol: 
DH062018 version 02, 13-08-2018 
 
 
Sponsor: 
 
Name: UZLeuven 
Address: Herestraat 49, 3000 Leuven 
 
Principal Investigator: 
 
Name: Danny Hoogma 
Address: Herestraat 49, 3000 Leuven 
Telephone: +32 16 34 42 70 
Email: danny.hoogma@uzleuven.be 
 
Sub-investigator: 
 
Name: Steffen Rex 
Address: Herestraat 49, 3000 Leuven 
       Telephone: +32 16 34 42 70 
Email:steffen.rex@uzleuven.be 
 
 
 

 
 
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Signatures 
 
 
 
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Principal Investigator 
 
 
 
 
 
Date 
 
 
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Signature 
 
 
 
 
 
 
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Co-Investigator 
 
 
 
 
 
Date 
 
 
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Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table of Contents 
1. 
Study Synopsis ............................................................................................................................ 5 
2. 
Background and rationale ........................................................................................................... 9 
Contents summary ............................................................................................................................. 9 
Background ........................................................................................................................................ 9 
3. 
Trial objectives and Design ........................................................................................................ 12 
3.1 Trial objectives .................................................................................................................... 12 
3.2 Primary endpoint ................................................................................................................ 12 
3.3 Secondary endpoints ........................................................................................................... 13 
3.4 Trial Design ......................................................................................................................... 14 
3.5 Trial Flowchart .................................................................................................................... 14 
Anaesthesia ..................................................................................................................................... 14 
SAVR / transapical TAVI .................................................................................................................... 14 
General anaesthesia ......................................................................................................................... 14 
Transfemoral TAVI ............................................................................................................................ 15 
Sedation ........................................................................................................................................... 15 
Monitoring and hemodynamic management ................................................................................... 16 
Postoperative treatment ................................................................................................................. 17 
Intensive care unit treatment ............................................................................................................ 17 
Post anaesthesia care unit treatment in patients receiving fast-track anaesthesia ............................ 17 
Standard hospital care ...................................................................................................................... 18 
4. 
Selection and withdrawal of subjects ........................................................................................ 18 
4.1 Inclusion criteria .................................................................................................................. 18 
4.2 Exclusion criteria ................................................................................................................. 18 
4.3 Expected duration of trial .................................................................................................... 19 
5. 
Trial Procedures ........................................................................................................................ 19 
5.1 By visit ................................................................................................................................ 19 

 
 
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Baseline measurement visit (Visit 0) ................................................................................................ 19 
Anaesthesia for aortic valve intervention (Visit 1) ........................................................................... 19 
Visit 2 (first morning ICU/PACU)) ..................................................................................................... 20 
Visit on the ward, daily until postoperative day 5 (Visit 3-6)............................................................ 20 
30-day chart review ......................................................................................................................... 20 
5.2 Laboratory tests .................................................................................................................. 21 
6. 
Assessment of Safety ................................................................................................................ 21 
7. 
Statistics ................................................................................................................................... 21 
7.1 Sample size ......................................................................................................................... 21 
7.2 Analysis ............................................................................................................................... 22 
8. 
Quality assurance...................................................................................................................... 23 
9. 
Direct access to source data and documents ............................................................................. 23 
10. 
Ethics and regulatory approvals ........................................................................................... 23 
11. 
Insurance/Indemnity ............................................................................................................ 24 
12. 
References ........................................................................................................................... 25 
 
 
 

 
 
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1. Study Synopsis  
Title of clinical trial 
 
 
Assessing the incidence of postoperative delirium 
following aortic valve interventions 
Protocol Short Title/Acronym 
 
 
Postoperative delirium following TAVI or SAVR 
Sponsor name 
 
 
UZ Leuven 
Principal Investigator 
 
 
Danny Hoogma 
Medical condition or disease under 
investigation 
 
Postoperative delirium (POD) 
Purpose of clinical trial 
 
 
Identifying the incidence of POD following aortic 
valve interventions using either trans-femoral or 
trans-apical transcatheter aortic valve implantation 
(TAVI) and surgical aortic valve replacement (SAVR) in 
the elderly population age ≥70y. 
Primary endpoint 
 
 
Incidence of POD during the first five postoperative 
days assessed daily by using the 3-minute Diagnostic 
confusion assessment method (3D-CAM) or the 
derived version for intensive care unit (CAM-ICU) 
Secondary endpoints 
 
- 
Onset moment of POD (from surgery until 
postoperative day 5) 

 
 
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- 
Duration of POD 
- 
Severity of POD (assessed with the delirium 
severity measure-based CAM (CAM-S Long) 
- 
Incidence of subsyndromal delirium (SSD) 
- 
Intensive care unit (ICU) length of stay 
- 
Hospital length of stay 
- 
Early safety (at 30 days) defined by the Valve 
Academic Research Consortium (VARC)-2 
- 
Clinical efficacy (at 6 months) as defined by VARC-
2 
- 
Discharge destination 
 
 Recorded baseline data 
 
- 
EuroQol five dimensional questionnaire five levels 
(EQ-5D-5L) validated Dutch version and EuroQol 
Visual Analogue Scale (EQ-VAS) 
- 
Instrumental Activities of Daily Living 
- 
Anticholinergic Loading Scale 
- 
Informant Questionnaire on Cognitive Decline in 
the Elderly (IQCODE) 
- 
Mini Mental State Examination (MMSE) 
- 
Clock completion 
- 
European System for Cardiac Operative Risk 
Evaluation II (EuroSCORE II) 
- 
Tilburg Frailty Indicator 
- 
Essential Frailty Toolset 
Trial Design 
 
This prospective cohort study will be performed at 
the University Hospital of the KU Leuven. An 

 
 
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investigator will assess the primary outcome 
parameters. Perioperative data will be collected by 
the 
attending 
anaesthesiologist, 
written 
and 
electronically. 
Sample Size 
 
 
We expect, based on institutional data, that 250 
patients will meet the inclusion criteria, with 70 
patients having a TAVI and 180 a SAVR. 
Summary of eligibility criteria 
 
 
Inclusion criteria are as follows: 
- 
Patients scheduled to undergo elective 
o TAVI 
o SAVR (with or without coronary artery 
bypass grafting (CABG)) 
- 
Age ≥ 70 years 
- 
Patient able to read and understand the research 
materials 
Exclusion criteria are as follows: 
- 
Inability to give informed consent 
- 
Presence of delirium at baseline as screened with 
the 3-minute Diagnostic Confusion Assessment 
Method (3D-CAM) 
- 
Combined surgical procedures ( other valve 
surgery) 
Maximum duration of follow-up of a 
subject 
 
Incidence of POD during the first five postoperative 
days, if positive, patients will be followed-up until 
POD has resolved or until discharge. Follow-up by 

 
 
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phone for mortality and ADL at 30 days and 6 months 
postoperative. 
Version and date of final protocol 
 
 
DH062018 version 2, 13-08-2018 
 
 
 
 

 
 
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2. Background and rationale 
Contents summary 
Postoperative delirium (POD) is a common complication after cardiac surgery, causing a 
significant burden on the patient’s well-being and the community. Identifying patients at risk 
might significantly reduce the overall morbidity and mortality. Currently, data regarding the 
incidence of postoperative delirium in patients undergoing modern techniques of aortic valve 
interventions, is lacking. The objective of this study is to determine the incidence of POD in 
elderly patients undergoing aortic valve interventions including transcatheter aortic valve 
implantation (TAVI) and minimally invasive or median sternotomy surgical aortic valve 
replacements (SAVR).  
Background 
POD is characterized by acute and fluctuating cardinal features of inattention and disorganized 
thinking, affecting up to 82% of patients older than 60 years1,2.  
POD can be clinically categorized into three motor subtypes: hypoactive, hyperactive and 
mixed. As clinical symptoms are frequently uncharacteristic and hence overlooked, several 
standardized diagnostic tests have been developed and validated of which the Confusion 
Assessment Method (CAM), 3-minute Diagnostic Confusion Assessment Method (3D-CAM) 
and its derived version for patients on the intensive care unit (CAM-ICU) are the most 
commonly used methods3-5.  
Plenty of risk factors are associated with POD, with some predisposing the patient to the 
development of POD and others precipitating POD. Predisposing factors are patient-related, 
are present already preoperatively and can usually not be modified: advanced age, cognitive 
impairment, low level of education, anemia, dehydration, malnutrition and electrolyte 
abnormalities. Two validated risk models are available for the prediction of POD in cardiac and 
non-cardiac surgery6. In contrast, precipitating factors typically prevail in the immediate 
perioperative phase and are potential candidates for preventive strategies. Blood pressure 

 
 
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fluctuations7 but also several medications including anticholinergics, antidepressants, 
benzodiazepines and ketamine3 or high dose of sufentanil or fentanyl8 have been associated 
with an increased risk of POD. Furthermore, prolonged ventilation or the stay in the intensive 
care unit (ICU) increases the risk for POD9,10. As such, an enhanced recovery program with 
early extubation and avoidance of the ICU-setting is a promising strategy to reduce the 
incidence of POD11-13. 
POD has been consistently associated with short-term complications. While older studies 
neglected the effects on long-term outcome, POD appears to have a more profound and long-
lasting effect than initially thought14. Prospective studies have shown that patients with POD 
have an increased length of stay (LOS) in the intensive care unit, higher complication-rate, an 
increased hospital LOS and perioperative mortality15,16. POD is also associated with functional 
decline, increased use of hospital resources and health care costs 17. 
The pathophysiology of postoperative cognitive disorders is still far from being understood. 
The pathogenesis of POD is multifactorial and several pathophysiological mechanisms have 
been suggested to be in close interplay with each other18. A first mechanism would be 
neuroinflammation. Perioperative surgical stress and the cardiopulmonary bypass (CPB) cause 
a systemic inflammatory response syndrome (SIRS) with the release of cytokines, chemokines, 
and other inflammatory mediators, probably resulting in the disruption of the blood-brain 
barrier. The peripheral inflammatory stimulus is then amplified within the brain by the 
microglia, causing neuroinflammation and ultimately neuronal dysfunction or even neuronal 
death19. Risk factors for a weakening of the blood-brain barrier also include older age and 
exposure to anesthetics. Moreover, it has been suggested that sedation causes acute hypoxia 
in endothelial cells, resulting in swelling of capillaries. This endothelial dysfunction affects the 
integrity of the blood-brain barrier. Subsequent reperfusion leads to production and release 
of active metabolites causing a chemotactic activation of activated neutrophils, eventually 
leading to nervous system injury 
20,21. Secondly, after clinical observations the 
neurotransmitter hypothesis was proposed. The use of substances that alter neurotransmitter 

 
 
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function resulting in either increased cerebral dopamine levels or reduced levels of 
acetylcholine appeared to cause delirium18,22,23. The cholinergic system is one of the essential 
modulatory neurotransmitter systems in the brain, controlling awareness, attention, sleep 
and memory. Thus, drugs with an anticholinergic potential may precipitate the development 
of delirium. Even if not exposed to these drugs, patients still could have low cholinergic 
activity. There is evidence for endogenous anticholinergic substances produced during acute 
illness, hypoxia, hypoglycemia or immobilization18.  
Surgical aortic valve replacement is a well-known technique performed via limited or full 
sternotomy using CPB and myocardial arrest. In our institution CPB is performed with mild to 
moderate hypothermia on a conventional CBP circuit with cardiac arrest induced by antegrade 
or retrograde infusion of cold crystalloid cardioplegic solution. Prior to CPB, heparin is 
administered to achieve an activated clotting time of > 400 s. Extracorporeal circulation is 
performed with 2.2-2.5 L min-1 m-2. After weaning from CBP, heparin is antagonized with 
protamine24. 
TAVI is a less invasive technique compared to SAVR25, being at least non-inferior to SAVR with 
regard to mortality and morbidity in patients at high or intermediate surgical risk26. During 
this procedure, a bioprosthetic valve is suspended within an expandable metal stent and 
deployed on the end of a delivery catheter. Before deployment of this valve, a balloon aortic 
valvuloplasty is performed. Both procedures are facilitated with brief periods of rapid 
ventricular pacing to interrupt cardiac output27. 
TAVI stimulated the interest in surgical techniques using rapid deployment of stent-mounted 
valve prostheses28, dramatically reducing aortic crossclamp and CPB times when compared to 
the implantation of conventional aortic valve protheses. In our institution, the Perceval S 
(Sorin Biomedica Cardio Srl, Sallugia, Italy) bioprothesis is routinely used in elderly patients29. 
Given the reduction in surgical invasiveness from conventional SAVR over mini sternotomy 
SAVR using rapid-deployment prostheses to TAVI, the systematic use of fast-track protocols 

 
 
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in minimal invasive SAVR and in TAVI, and the avoidance of CPB in TAVI, we suggest that the 
incidence of POD is reduced in parallel. One prospective study compared the incidence of POD 
after TAVI to SAVR. A high incidence of POD 44% and 66% respectively was identified in these 
patients. Although procedure time is recorded, there is no description of the procedure, nor 
is there any POD severity or long-term outcome reported30.  A retrospective cohort study 
identified an incidence of 27% for POD following TAVI, with only 12% POD following 
transfemoral-TAVI31. Some retrospective studies showed almost no difference in the POD 
incidence between TAVI (19-29%) or SAVR (20-33%)32,33, however, after propensity matching 
SAVR-treated patients developed POD more frequently32. Considering the controversial 
results, there is currently no valid data regarding the comparative incidence of POD after 
modern aortic valve interventions.  
We hypothesize that in older patients, the incidence of POD is lower in patients undergoing 
TAVI than in patients undergoing minimally-invasive SAVR with mini sternotomy than in 
patients undergoing conventional SAVR with full median sternotomy. 
3. Trial objectives and Design 
3.1 Trial objectives 
The primary aim of this study is to identify the incidence of POD following aortic valve 
interventions using either trans-femoral or trans-apical TAVI, compared to SAVR using mini 
sternotomy or median sternotomy in the elderly population age ≥70y. 
3.2 Primary endpoint 
Incidence of POD during the first five postoperative days.  
POD screening will be carried out using the 3D-CAM or CAM-ICU (only for intubated patients). 
Several features will be assessed: 1/ Acute onset, 2/ Inattention, 3/ Disorganized thinking, 4/ 
Altered level of consciousness. The diagnosis of full syndromal delirium by CAM requires the 
presence of both features 1 and 2 combined with the presence of either 3 or 4. 

 
 
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Throughout the ICU/CCU/PACU-stay, patients will be assessed for POD once daily by a trained 
research nurse using the CAM-ICU or 3D-CAM, if positive, severity of POD will be assessed 
with the delirium severity measure based on CAM long version (CAM-S Long)34. In addition, a 
daily chart review will be performed for the results of the Intensive Care Delirium Screening 
Checklist (ICDSC)35 and to check whether anti-psychotic therapy was administered. If a 
Richmond Agitation-Sedation Scale (RASS)36 of < -3 is found in the chart, this patient will be 
considered unconscious and unevaluable for POD. 
After transfer to the ward, patients will be assessed once daily by a trained research nurse for 
the presence of POD using the 3D-CAM and if needed a CAM-S Long. Patients’ charts will be 
checked daily over the previous 24-hours to identify key words suggestive for POD, to check 
whether anti-psychotic therapy was administered37 and for the results of the Delirium 
Observation Scale (DOS)38. 
3.3 Secondary endpoints 
Secondary endpoints, within the group of patients who develop POD, include onset moment 
of POD (from surgery until postoperative day 5), duration of POD, and severity of POD as 
assessed with CAM-S long. Moreover, we will assess the incidence of subsyndromal delirium 
[full syndromal delirium (FSD) versus subsyndromal delirium (SSD): FSD will be defined as 
demonstrating abnormalities in features 1 + 2 + (3 or 4) of the CAM-test. SSD will be defined 
as having one or more CAM symptoms, but not fulfilling criteria for FSD]. 
Other secondary endpoints include the determination of the predictive value of frailty scales 
on several outcome parameters. After discharge early safety (at 30 days) and clinical efficacy 
(at 6 months) will be recorded as defined by the Valve Academic Research Consortium (VARC)-
239. Also effects on the Cognitive Failure Questionnaire (6 months) 40 and EQ-5D-5L (6 months) 
will be evaluated. 
 

 
 
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3.4 Trial Design 
This prospective cohort study will be performed at the University Hospital of the KU Leuven. 
An investigator will assess the primary outcome parameters. Perioperative data will be 
collected by the attending anaesthesiologist, written and electronically.   
3.5 Trial Flowchart 
Eligibility for enrolment will be based on screening of the patients’ chart. Preoperatively, the 
investigator will obtain written informed consent and record baseline data (demographic 
data, routine clinical examination, surgical and medical history, EuroSCORE II, results of 
standard laboratory parameters and other tests). During a preoperative visit window, (1 day 
to a maximum of 6 weeks before cardiac surgery), the 3D-CAM, the Mini Mental State 
Examination (MMSE)41, clock completion42, self-administered Instrumental ADL (IADL) 43, 
Tilburg Frailty Indicator44, Essential Frailty Toolset (EFT)45,  self-administered EuroQol five 
dimensional questionnaire five levels (EQ-5D-5L) validated Dutch version and EuroQol Visual 
Analogue Scale (EQ-VAS) 46 and an interview with a family member using the short form of 
the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)47 will be 
performed.  
The day of or before surgery the 3D-CAM will be assessed.  
Anaesthesia 
In general, management will be performed according to the following institutional standards. 
It is however possible that the attending anaesthesiologist changes this management to 
optimise the patients’ care. 
SAVR / transapical TAVI 
General anaesthesia 
Prior to anaesthesia, patients must be in a fasting state for 6 hours. Premedication is only 
given if explicitly requested by the patient and consists of alprazolam 0.5 or 1 mg.  

 
 
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After 5 minutes of pre-oxygenation (FiO2 = 1.0), general anaesthesia will be induced with a 
combination of remifentanil 0.5 µg kg-1 min-1 followed by a bolus of propofol 0.5-1 mg kg-1. 
Tracheal intubation will be facilitated by a bolus administration of rocuronium 1.0 mg kg-1. 
Further curarization will be left upon the discretion of the attending anaesthesiologist. 
General anaesthesia will be maintained with sevoflurane 1.5-2.0 % (FiO2 = 0.4-0.5), titrated to 
achieve a bispectral index (BIS) of 40-60. A continuous infusion of dexmedetomidine 0.5 µg 
kg-1 h-1 is started. Analgesia is achieved with a continuous infusion of remifentanil (0.15-0.30 
µg kg-1 min-1), starting after induction and adjusted depending on patients’ reactions, 
spontaneous movements, sweating and/or sudden increase in heart rate or arterial pressure. 
After completion of surgery the treatment differs depending on surgery and ICU or PACU 
admittance.  
- 
For TAVI, postoperative analgesia will be provided by local infiltration of the wound with 
10-20 ml levobupivacaine 0.5%. Patients are to be extubated on table and transferred to 
the ICU afterwards. 
- 
For SAVR, postoperative analgesia will be provided by a bolus of intravenous (IV) morphine 
0.1-0.2 mg kg-1 at end of surgery. Patients are transferred intubated to the ICU or PACU 
under mono-sedation with propofol (using a target-controlled infusion (TCI) with 
1.0µg/mL) and remifentanil (0.1 µg kg-1 min-1) 
Transfemoral TAVI 
Sedation 
Prior to anaesthesia, patients must be in a fasting state for 6 hours. Premedication is only 
given if explicitly requested by the patient and consists of alprazolam 0.5mg.  
Oxygen will be administered with a face mask (5 L min-1 O2) and sedation is provided with a 
continuous infusion of remifentanil (0.05-0.10 µg kg-1 min-1) and a TCI of propofol with 
calculated plasma concentrations of 0.2-1 µg ml-1 titrated, targeting a BIS of 60-80. Local 

 
 
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anaesthesia of the groin will be achieved with 10-20 ml levobupivacaine 0.5% to provide 
surgical anaesthesia. After completion of surgery, propofol and remifentanil will be stopped. 
Patients will be transferred awake and cooperative to the ICU. 
Monitoring and hemodynamic management 
Hemodynamic and respiratory monitoring will be provided according to our institutional 
routine. Patients will be instrumented with peripheral intravenous, arterial and central venous 
catheters. Depending on the intervention and the co-morbidities, a thermodilution or pacing 
pulmonary artery catheter will be placed.  
Whenever available, the following parameters will be recorded digitally every minute from 
the pre-anaesthetic period to the end of surgery: peripheral oxygen saturation (SpO2), heart 
rate (HR), invasive arterial blood pressure (IBP), central venous pressure (CVP), cardiac output 
(CO), mixed venous oxygen saturation (SvO2), mean pulmonary artery pressure (MPAP), 
fraction of inspired oxygen (FiO2), end-tidal carbon dioxide (etCO2), body temperature, BIS, 
cerebral tissue oxygenation (rSO2), urine output and blood loss. Transoesophageal 
echocardiography (TEE) will be performed during anaesthesia according to our institutional 
standards.  
For SAVR, blood gas analysis will be performed at the following time points: T0 = prior to 
induction, T1 = after induction, T2 = after sternotomy, T3 = after weaning from CPB, T4 = after 
sternal closure and T5 = end of surgery. In TAVI, blood gas analysis will be performed at the 
following fixed time points: Ta = prior to sedation/induction, Tb = after placement of central 
venous catheter, Tc = after deployment of aortic valve, Td = end of surgery. Further blood gas 
analyses will be left upon the discretion of the attending anaesthesiologist 
Intraoperative hemodynamic management will be standardized according to our clinical 
routine. Basic fluid substitution will be performed with 1 ml kg-1 h-1 balanced crystalloid 
solution. Hemodynamic stability will be defined as mean arterial blood pressure of >70 mmHg 
(50-60 mmHg during CPB) and SvO2 > 70 %. In case of hypovolemia (detected by TEE or visual 

 
 
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inspection of the heart chambers), a colloid solution will be infused. In case of anaemia, 
defined as a haemoglobin content less than 8.0 g dL-1, packed red blood cells (RBCs) will be 
transfused. In case of unstable haemodynamics despite adequate volume loading, a 
norepinephrine infusion will be started. Administration of other vasopressors, inotropes, PC, 
fresh frozen plasma (FFPs) and platelets will be left at the discretion of the attending 
anaesthesiologist.  
Postoperative treatment 
Intensive care unit treatment 
After SAVR, sedation on the ICU will be maintained with a propofol infusion of 2-3 mg kg-1 h-1. 
Analgesia will be achieved with a continuous infusion of fentanyl, supplemented by systemic 
acetaminophen (15 mg kg-1, administered IV every 6 hours) during the first postoperative day. 
Standard tracheal extubation and patients discharge criteria will be applied.  
Following TAVI, the patient will be transferred to the ICU awake and extubated. Analgesia for 
these patients will be achieved with intermittent intravenous administration of 
tramadolhydrocholoride (1 mg kg-1, every 6 hours if needed), supplemented by systemic 
acetaminophen (15 mg kg-1, administered IV every 6 hours).  
Post anaesthesia care unit treatment in patients receiving fast-track anaesthesia 
Following SAVR, patient that are transferred to the PACU will be sedated with propofol or 
dexmedetomidine. Analgesia will be achieved with infusion of remifentanil and subcutaneous 
morphine, supplemented by systemic acetaminophen (15 mg kg-1, administered IV every 6 
hours) during the first postoperative day. Standard tracheal extubation and patients’ 
discharge criteria will be applied. PONV prophylaxis is continued with administration of 
dexamethasone 5 mg IV every 12 hours and ondansetron 4 mg IV every 6 hours. Transfer to 
the ward will be done once standard discharge criteria are fulfilled.  
 
 

 
 
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Standard hospital care 
A bundle of non-pharmacological interventions is applied to prevent delirium, including: early 
mobilization; detection and treatment of pain; early removal of catheters, drains and probes; 
timely recognition of medical problems and treated accordingly; avoidance of precipitating 
pharmacological triggers of POD. Whenever POD is detected, known precipitating factors will 
be corrected and non-pharmacological measures based on our institutional and hospital-wide 
standard operating procedures will be initiated. Only if this proves to be insufficient, 
pharmacological treatment will be initiated.   
4. Selection and withdrawal of subjects 
Patients will be recruited by the principal investigator or co-investigator. Detailed information 
about the study design, background and protocol will be given. Questions brought forward by 
the patient will be answered. The eligible patient who is willing to participate will sign a written 
informed consent before any study procedure. 
4.1 Inclusion criteria 
- 
Patients scheduled to undergo elective 
o TAVI 
o SAVR with or without CABG 
- 
Age ≥ 70 years 
- 
Patient able to read and understand the research materials 
4.2 Exclusion criteria 
- 
Inability to give informed consent 
- 
Presence of delirium at baseline as screened with the 3-minute Diagnostic Confusion 
Assessment Method (3D-CAM) 
- 
Other combined surgical procedures (e.gother valvesurgery ) 

 
 
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4.3 Expected duration of trial 
The enrolment period is planned over 24 months, starting September 2018 and ending August 
2020. A subsequent period of 6 months is planned for the primary data evaluation and 
statistical analysis. An additional 3 months is planned for the assessment of 6-month follow-
up, including additional data evaluation, statistical analysis and publication of the results. 
5. Trial Procedures 
5.1 By visit 
Baseline measurement visit (Visit 0) 
- 
MMSE 
- 
Clock completion 
- 
3D-CAM 
- 
Self-administered IADL 
- 
Self-administered EQ-5D-5L and EQ-VAS 
- 
EuroSCORE II  
- 
IQCODE 
- 
Tilburg Frailty Indicator 
- 
Essential Frailty Toolset 
- 
Anticholinergic Loading Scale48 
- 
Geriatric Depression Scale 
Anaesthesia for aortic valve intervention (Visit 1)  
- 
Perioperative hemodynamic and respiratory monitoring parameters 
- 
Duration of surgery, CPB and aortic cross clamp time 
- 
Minimum core temperature 
- 
Doses of vasopressors/inotropes 
 
 

 
 
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Visit 2 (first morning ICU/PACU))  
- 
CAM-ICU (intubated and/or analgosedated patients) / 3D-CAM (awake and extubated 
patients), in case of a positive result CAM-S Long. 
- 
Daily chart review keywords indicative for POD and administration of antipsychotic drugs 
- 
Extubation time 
- 
Time of chest drain removal 
- 
Anticholinergic Loading Scale 
Visit on the ward, daily until postoperative day 5 (Visit 3-6) 
- 
3D-CAM, in case of a positive result: CAM-S Long 
- 
Daily chart review for keywords indicative for POD, administration of antipsychotic drugs 
and DOS. 
- 
Anticholinergic Loading Scale 
30-day chart review 
- 
Hospital length of stay 
- 
Intensive care unit length of stay (ICU-LOS) 
- 
Early safety (at 30 days) as defined by VARC-2 
- 
Discharge destination 
6-months interview (by phone and mail) 
- 
Self-administered IADL 
- 
Self-administered EQ-5D-5L and EQ-VAS 
- 
Cognitive Failure Questionnaire 
- 
Clinical efficacy (at 6 months) as defined by VARC-2 
Patients in which POD develops during the first five postoperative days will be followed using 
CAM-ICU/3D-CAM until POD has resolved or until discharge. 

 
 
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5.2 Laboratory tests 
Data will be used from standard pre- and postoperative laboratory tests. At the beginning and 
at the end of surgery, 2 blood samples will be collected to examine the presence of neural 
injury markers.  
6. Assessment of Safety 
All patients will receive routine anaesthetic/surgical/interventional care according to our 
institutional standards. All procedures will be carried out in a cardiac surgical operation 
theatre fully equipped with all the necessary infrastructure for advanced cardiopulmonary 
monitoring and resuscitation. Patients will not receive any investigational treatment.  
This study has primarily an observational character consisting of completing several 
questionnaires with the exception of obtaining a blood sample at the end of surgery. As such, 
the potential for serious events appears too remote to require their definition, assessment or 
documentation. However, a variety of important safety parameters will be assessed as 
secondary endpoints, including early safety (at 30 days) and clinical efficacy (at 6 months) 
using the global VARC-2 criteria. 
7. Statistics 
7.1 Sample size 
Based on an expected accrual of 250 patients in total, assuming 70 and 180 patients in the 
TAVI and SAVR group, respectively, there will be 89% power to detect a difference of 15 
percentage points in POD (5%POD in TAVI group and 20% POD in SAVR group). 
The calculated power is an approximation, since the primary analysis will not be based on a 
classical Chi² test, but on the calculation of a relative risk, taking into account differences in 
number of evaluable days and differences in patient mix (using IPTW, cfr. Statistical analysis). 
 
 

 
 
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7.2 Analysis 
For the evaluation of POD within 5 days (primary outcome), the relative risk (and 95% 
confidence intervals) will be reported. The estimate will be obtained from a Poisson regression 
model49 with the (log) number of evaluable days as offset (for some patients the number of 
evaluable days will be lower than 5 if the patient is considered unconscious (RASS score <-3) 
or died within the first 5 days).   
Secondary outcomes which are dichotomous will also be evaluated using relative risks. 
The potential difference in patient-mix between patients in the SAVR and in the TAVI group, 
caused by the observational character the study, can induce bias when comparing primary 
and secondary outcomes between the groups. To reduce the risk of bias, each subject will be 
weighted by its inverse probability of being in its specific group, conditional on the following 
variables suspected a priori to be related to POD (and potentially to other outcomes: 
EuroSCORE II, TFI, EFT). The objective is to create a weighted sample in which the distribution 
of these variables is the same in both groups.  The probabilities of group membership are also 
known as propensity scores50 and will be obtained with an approach proposed by  McCaffrey 
et al 51(this approach will be followed instead of a classical multivariable logistic regression 
model to avoid weights to be too extreme). Each individual is weighted by the inverse of its 
probability to belong to its group. Thus, the more typical a subject is for the group it belongs 
to, the lower its weight will be. The weights will be normalized to the sample size in each 
group, meaning the sum of weights in each group equals the sample size of that group. This 
approach is known as inverse probability of treatment weighting52. It uses the propensity 
score to construct weights, contrary to the more classical approaches where the score is used 
as a covariate in the analysis or is used to create a matched sample. All statistical analyses 
earlier mentioned will include the IPTW.  
All analyses will be performed using SAS software, version 9.4 of the SAS System for 
Windows. Copyright © 2002 SAS Institute Inc. SAS and all other SAS Institute Inc. product or 
service names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 

 
 
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An investigator or a study nurse will review completed CRFs for completeness and 
correctness before digitalization and statistical analysis. At this time point, missing data will 
be identified, if possible drawn from source data and filled into the CRFs. Missing data not 
being found back in source data will not be expected. Any deviations from the original 
statistical plan will be described and justified in the protocol and in the final report. 
8. Quality assurance 
The primary investigator and the principle study nurse of the investigational team have 
followed various certified courses in “Good Clinical Practice”. Further study personal will 
work under close supervision of these GCP-trained investigators. 
9. Direct access to source data and documents 
The investigator(s) and the institution will permit trial-related monitoring, audits, EC review, 
and regulatory inspections (where appropriate) by providing direct access to source data and 
other documents (ie patients’ case sheets, blood test reports, X-ray reports, histology reports 
etc).  
10. Ethics and regulatory approvals 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (current 
version), the principles of GCP and in accordance with all applicable regulatory requirements. This 
protocol and related documents will be submitted for review to Ethics Committee of the 
University Hopitals Leuven. 
The Study can and will be conducted only on the basis of prior informed consent by the Subjects, 
or their legal representatives, to participate in the Study. The Study Site shall obtain a signed 
informed consent form (ICF) for all patients prior to their enrollment and participation in the Study 
in compliance with all applicable laws, regulations and the approval of the Ethics Committee, if 

 
 
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required. The Study Site shall retain such ICFs in accordance with the requirements of all 
applicable regulatory agencies and laws. 
The Investigator shall treat all information and data relating to the Study as confidential and shall 
not disclose such information to any third parties or use such information for any purpose other 
than the performance of the Study. The collection, processing and disclosure of personal data, 
such as patient health and medical information is subject to compliance with applicable personal 
data protection and the processing of personal data (Directive 95/46/EC and Belgian law of 
December 8, 1992 on the Protection of the Privacy in relation to the Processing of Personal Data). 
11. Insurance/Indemnity 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, 
Sponsor shall assume, even without fault, the responsibility of any damages incurred by a Study Patient 
and linked directly or indirectly to the participation to the Study, and shall provide compensation 
therefore through its insurance.” 
 
 

 
 
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