Implementation of a Trimodal Prehabilitation Program as a Preoperative Optimization Strategy in Cardiac Surgery
Phase: NA
Conditions: Coronary Artery Disease, Valvular Heart Disease
Sponsor: Hospital Clinic of Barcelona

Study Protocol and Statistical Analysis plan, April 4, 2018 
Implementation of a Trimodal Prehabilitation Program as a Preoperative Optimization 
Strategy in Cardiac Surgery and Heart Transplant 
 
NCT03466606 
 
STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN. 
 
 
Document upload date: August 27, 2024. 
 
 

Study Protocol and Statistical Analysis plan, April 4, 2018 
STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN: 
 
Subproject: #1 
A single-center, ambispective cohort study is designed involving consecutive elective 
heart transplantation candidates from July 2017 to July 2021 once officially included in 
the waiting list. The trial has obtained local ethical committee approval 
(HCB/2017/0708). Written consent will be obtained for all patients participating in the 
prehabilitation group.  
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Participants  
From July 2017, all patients included in the waiting list for elective heart 
transplantation will be considered for inclusion in the prehabilitation program. 
Exclusion criteria are clinical instability precluding exercise training, refusal, or 
unavailability to participate. Exercise training sessions will be delivered at the 
outpatient clinic and patients’ agreement to attend twice weekly for at least eight 
weeks (intensive phase) is considered a mandatory requirement.  
The control group will be consisted of a historical cohort of consecutive elective heart 
transplantation recipients from 2014 to 2017 (prior to the implementation of the 
prehabilitation program on July 2017), and contemporaneous elective heart 
transplantation recipients who will not be involved in the prehabilitation program due 
to logistic issues (waiting-list period <2 weeks or not being able to attend twice a 
week). Data from those patients will be obtained from the transplant database and 
hospital medical records.  
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 Intervention  
A baseline assessment of prehabilitation patients will be performed during the first 
week after being included in the heart transplantation waiting list and all participants 
will be reassessed eight weeks thereafter, once the intensive training phase is 
completed.  
The assessment consists of (i) clinical history and physical examination; (ii) Clinical 
Frailty Scale (CFS); (iii) forced spirometry test (BodyBox Plethysmography; Medisoft; 
Sorinnes, Belgium); (iv) functional capacity evaluation by standard incremental cycle 
ergometer cardiopulmonary exercise testing (CPET) and endurance time (ET) 
measured by a cycling constant work-rate exercise testing at 80% of peak oxygen 
uptake (Ergocard Professional; Medisoft; Sorinnes, Belgium), 6-Minute Walking Test 
(6MWT), hand-grip strength, and 30” Sit-To-Stand (STS) test; (v) physical activity by the 
Yale Physical Activity Survey (YPAS); (vi) health-related quality of life by Minnesota 
Living with Heart Failure Questionnaire (MLHFQ); (vii) emotional status by Hospital 
Anxiety and Depression Scale (HADS); and (viii) nutritional status by Patient-Generated 
Subjective Global Assessment, a 3-day food record, and nutritional profile determined 
by blood sample analysis.  
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Prehabilitation Program  

Study Protocol and Statistical Analysis plan, April 4, 2018 
The intervention is designed to improve (i) functional capacity by exercise training and 
promotion of physical activity, (ii) nutritional status by nutritional counseling and whey 
protein supplementation, and (iii) psychological resilience using mindfulness therapy.  
The physical program includes three main actions: (i) a motivational interview, (ii) a 
moderate to high-intensity exercise training program, and (iii) promotion of daily 
physical activity. The exercise training will consist of one-hour sessions of 
individualized, supervised moderate to high-intensity interval training (HIIT) and 
resistance training at the hospital outpatient gym facility twice weekly for eight weeks. 
A sports cardiologist will perform the exercise training prescription, and the sessions 
will be conducted by a physical therapist.  
HIIT will be performed on a stationary bicycle (Bike Forma; Technogym; Cesena, Italy). 
The program is personalized to subjects according to their peak work rate (WR) per- 
formed on CPET at baseline assessment. Each session will include 5 min of warm-up 
and 5 min of cool-down pedaling at 30–40% of the peak WR. The interval training will 
consist of at least five rounds combining 2 min of high-intensity exercise (starting at 
70% of peak WR and progressing to 90–100% of peak WR through the program) 
interspersed with 3 min of low-intensity recovery periods (40–50% of the peak WR). 
WR progress during the sessions will be tailored on an individual basis, according to 
the subjects’ symptoms and response to the exercise in previous sessions, to maximize 
the training effect. All subjects will be monitored during the HIIT using a 3-lead 
electrocardiogram, pulseoximetry, non-invasive arterial pressure, and levels of self-
perceived exertion using the modified Borg scale. Strength training will be performed 
(if not contraindicated) and consists of upper-limb and core muscle exercise based on 
local muscular exhaustion within the range of 6 to 12 repetitions and avoiding Valsalva 
maneuvers. The intensity and/or the number of repetitions will increase every week 
when symptomatology allows it. In addition, all patients will be instructed on 
breathing exercises with an incentive inspirometer (Coach 2; Smith Medical; London, 
UK).  
After completing the first eight weeks and until heart transplantation, patients will 
follow a mixed maintenance program consisting of one session per week of supervised 
exercise training and were encouraged to maintain a physical activity plan using 
community-based facilities or home-based exercising.  
The nutritional intervention includes nutritional education and a tailored dietary plan 
according to clinical nutrition in surgery ESPEN guidelines based on the Mediterranean 
diet. Moreover, participants will be prescribed dietetic recommendations to enhance 
protein intake including whey protein supplementation (Fresubin® protein powder, 
Fresenius- Kabi, Madrid, Spain) within 1 h after exercise to maximize muscle protein 
synthesis, and before going to sleep to achieve an intake of 1.5–2 g/kg/day of protein. 
These recommendations will be prescribed to all patients if not contraindicated and 
individualized advice will be given if any other supplementation is needed.  
All patients will be invited to attend a weekly mindfulness group session. This anxiety- 
coping intervention is strongly recommended to those patients showing signs of 

Study Protocol and Statistical Analysis plan, April 4, 2018 
anxiety/depression (defined by a HADS score >8). A weekly 60-min group session of 
breathing and relaxation exercises will be conducted by a mindfulness-based stress 
reduction expert psychologist.  
Usual care for both groups consists of regular cardiological follow-up with medical and 
heart failure nurse visits, physical activity recommendations, intravenous iron 
administration if iron deficiency anemia, and nutritional intervention if needed.  
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Costs  
The analysis will include heart transplantation surgical procedures, direct 
hospitalization (until discharge), and prehabilitation costs. Data will be obtained 
through microcosting techniques according to resource use, combined with diagnostic-
related center-specific hospital fees. Prehabilitation costs include specialists’ fees 
(physical therapist, nutritionist, and psychologist), gym structural costs (hospital-
specific fee), and protein costs.  
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Outcomes  
Predefined main study outcome variables assessment will be blinded to the 
interventional groups and included: in-hospital complications according to Clavien-
Dindo Classification and Comprehensive Complication Index (CCI), postoperative 
mechanical ventilation time, intensive care unit (ICU) length-of-stay and total 
hospitalization stay, destination at hospital discharge (home vs. rehabilitation facility), 
and hospital readmissions during the first 30 days as well as mortality at 30 days, 3 
months, and 1 year. To minimize variability, it is important to note that decisions about 
ventilation time, ICU length of stay, and total length of stay as well as the discharge 
from ICU to a normal ward, and the destination at hospital discharge will follow 
standardized procedures according to the center protocol.  
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Statistical Analysis and Sample Size Estimation  
Study data will be exhaustively collected and managed using Research Electronic Data 
Capture (REDCap) tools.  
Considering CCI as the primary outcome and assuming a pooled standard deviation of 
20 units, the study would require at least a sample size of 28 for each group to achieve 
a power of 80% and a level of significance of 5% (two-sided), for detecting a true 
difference in means between the test and the reference group of −15 (from 50 to 35) 
units.  
Continuous variables will be described by mean (standard deviation) or median 
(interquartile range (Q1–Q3)) as appropriate, while categorical variables will be 
presented as frequencies (percentages). Costs will be described by median 
(interquartile range (IQR)), and the difference between control and intervention 
(prehabilitation) groups, so positive values should be interpreted as savings.  

Study Protocol and Statistical Analysis plan, April 4, 2018 
The normality of distribution will be assessed with the Shapiro-Wilk Test. Between-
group comparison of continuous variables and costs will be performed using either 
Student’s t- test or the Mann–Whitney U test according to their distribution while 
Pearson’s χ2 test or Fischer’s test will be used for categorical variables. Quantile 
regression will be used for medians. To control for the usually skewed distribution of 
costs, a bootstrapping analysis will be performed to increase the robustness of the 
analysis.  
All comparisons will be two-sided, with a significance level of 0.05. All statistical 
analyses will be made with R version 4.0.2, (R-Foundation, Vienna, Austria) software or 
STATA v.17 software.  
 
 
Subproject: #2 
This is a prospective, randomised, open-label, controlled trial with allocation ratio 1:1 
comparing standard of care versus 4–6 weeks of a multimodal prehabilitation 
programme. The recruitment period is scheduled from March 2018 to January 2021. 
Both primary endpoint and baseline data will be blindly assessed. Intention-to-treat 
criteria will be used in order to define the analysis population; all randomised patients 
will be included in the analysis according to assigned group. The study protocol and 
informed consent have been evaluated and accepted by the Medical Research Ethics 
Committee at Hospital Clinic de Barcelona (2017/0708). The trial will be conducted 
according to the rules of Good Clinical Practice.  
METHODS AND ANALYSIS 
- Setting 
This trial will be conducted in a single academic tertiary hospital in Barcelona, Spain 
(Hospital Clinic de Barcelona). Assessments and study interventions will be performed 
at the outpatient ambulatory infrastructure of Hospital Clinic de Barcelona. Surgery 
and postoperative hospitalization will take place in the aforementioned hospital.  
-Eligibility criteria  
Inclusion criteria: Patients older than 18 years old scheduled for CABG and/ or valve 
surgery, with an expected waiting time before surgery of 6 weeks or more and that 
accept to participate in this clinical trial.  
Exclusion criteria: Functional or anatomical physical impairment that makes it 
impossible to complete the assessments and the prehabilitation programme, 
determined by an experienced physiotherapist in cardiopulmonary rehabilitation; 
cognitive impairment that would impede understanding of study procedures, informed 
consent or study questionnaires; cardiac instability; dynamic left ventricle outflow 
tract obstruction, proven exercise induced arrhythmias; other comorbidities that imply 
clinical instability; patient refusal to participate in the study or impossibility to attend 

Study Protocol and Statistical Analysis plan, April 4, 2018 
supervised training sessions. Specifically, we will not exclude patients with severe 
pulmonary hypertension or severe valvular stenosis.  
-Study outline  
Participant screening, recruitment, randomization and informed consent (T-1) 
Participant selection will begin after surgery is proposed by the cardiac surgeon and a 
referral for preoperative evaluation is done. Within 1 week of the referral patient will 
be seen by an anaesthesiologist who will screen for eligibility criteria and will explore 
the willing of participating in a study related with cardiopulmonary reserve and 
postoperative outcome. If eligibility criteria are met, patient will be approached by a 
research medical staff involved in the trial. The research medical staff in charge of 
obtaining informed consent will randomize prior to meeting with the patient and 
proposing study participation.  
Participants will be randomised with 1:1 ratio by a computer-generated sequence 
using Macro-SCReN soft- ware V.4.8.1.8302 (2018 Elsevier).  
Baseline assessment (T0)  
After signing the informed consent all participants will undergo a full blinded baseline 
medical, functional, nutritional and psychological assessment. Allocation to study 
group will be revealed to the part of the research team that will carry out the 
intervention once baseline assessment is completed. The functional capacity 
assessment will be conducted by a physiotherapist on different days to avoid fatigue 
related to it, and will consist in a standard incremental cardiopulmonary exercise 
testing on cycloergometer (CPET), where physiological variables in response to 
exercise and workload in watts (W) will be measured at the anaerobic threshold and at 
VO2 peak, Endurance time (ET) in seconds will be measured by a cycling constant 
work-rate exercise test performed at a load equivalent of 80% of the peak workload 
(PWR) the patient could tolerate on the incremental CPET (Ergo- line 900, Ergoline, 
Bitz, Germany and Ergocard Professional, Medisoft, Sorinnes, Belgium). It will detect 
the responsiveness of interventions in terms of improved exercise capacity. 
Participants will also undergo hand grip strength test (Jamar Hydraulic Hand 
Dynamometer; Sammons Preston, Bolingbrook, Illinois, USA), 6min walk test (6MWT) 
and sit-to-stand (STS) test. The 6MWT will assess functional capacity in relation to 
activities of daily living. Constant work rate exercise test and 6MWT are 
complementary in the comprehensive evaluation of these patients. Nutritional status 
will be assessed by a registered dietitian using the Patient Generated Subjective Global 
Assessment, weight, body mass index, prealbumin and glycosylated hemoglobin 
(HbA1c). American Society of Anesthesiologists status, Charlson Comorbidity Index and 
Euroscore II data will be recorded. Physical activity will be measured by the Yale 
Physical Activity Survey (YPAS), functional capacity by Dukes Activity Status Index 
questionnaire and Anxiety and depression measured using the Hospital and Anxiety 
Scale (HADS). All patients will be reassessed using the same tests before undergoing 
cardiac surgery (T7) and at 3 months postoperatively (T9).  

Study Protocol and Statistical Analysis plan, April 4, 2018 
-Procedures  
Standard of care (T1–T6): Participants in the control group will follow the standard 
preoperative protocol at Hospital Clinic de Barcelona that includes physical activity 
recommendation, nutri- tional and smoking cessation advice. Moreover, patients 
suffering from iron-deficiency anaemia will receive intra- venous iron infusion. 
Multimodal Prehabilitation programme (PreHab) (T1–T6): Participants in the 
intervention group will undergo, in addition to the standard of care aforementioned, a 
4–6week personalized multimodal prehabilitation programme. The interventions 
included will be patient-centred aiming to optimize patients’ preoperative health 
status while enhancing their empowerment and engagement. The main components 
of the programme will consist in:  
1. Supervised exercise training programme: 1-hour session, two sessions per week at 
the hospital outpatient gym facility conducted by a physiotherapist. Heart rate, blood 
pressure, oxygen saturation and perceived exertion rate using the modified Borg scale 
will be monitored throughout the training session.  
i. Endurance training will be performed on stationary bicycle (Bike Forma; Technogym; 
Cesena, Italy) and will be tailored to the participants ac- cording to their PWR (baseline 
CPET). Each session includes 5min of warm-up and 5min of cool-down pedalling at 
30%–40% of their PWR. An interval training consists in at least 5 bouts combining 2 
min of moderate to high-intensity exercise (starting at 70% of PWR and progressing to 
90%–100% of PWR throughout the programme) interspersed with 3min recovery 
periods at lower intensity (40%–50% of the PWR). Progression during the sessions will 
be tailored on individual basis to maximize the training effect.  
ii. Strength training will consist in 2–3 upper (pectorals and latissimus dorsi) and lower 
(quadriceps) limb exercises based on 2–3 sets of 8–12 repetitions avoiding valsalva’s 
manoeuvres. The training is performed in a modular training station using external 
load (Plurima Multistation Wall, Technogym; Cesena, Italy). At the first session, the 
physiotherapist obtains for each muscle group, the tolerated weight for the eight-
repetition maximum test, to establish the initial weight for the strength training. The 
weight and/or the number of repetitions will increase every week to ensure strength 
progression and maximize the training effect. The strength training is performed 2 
days per week (in combination with the endurance training).  
2. Promotion of physical activity and healthy lifestyle: a physiotherapist 
adequately trained in behavioural strategies will use motivational interviewing 
techniques to promote physical activity and healthy lifestyle. The motivational 
interview will focus on empathy, reflective listening and affirmation, and will 
address the patients’ barriers and limitations related to physical activity, to get 
a change in behaviour.  
3. Respiratory physiotherapy: patients will be instructed on daily breathing 
exercises (chest expansions, diaphragmatic respirations and deep inspirations) 
with a volumetric incentive spirometer (Coach 2; Smith Medical; London, UK), 
at least twice per day, 1–2 sets of 10–15 breathings for each exercise.  

Study Protocol and Statistical Analysis plan, April 4, 2018 
4. Nutrition counselling and supplementation: participants will meet with a 
registered dietitian that will assess their nutritional status and their diet based 
on a self-reported 3-day food diary. Nutritional teaching and a Mediterranean, 
well-balanced cardioprotective diet will be instructed. An adequate protein 
intake of 1.2–1.5 g/kg/day will be aimed to meet the European Society for 
Clinical Nutrition and Metabolism recommendations. If patient does not reach 
the recommended daily protein intake with diet, protein supplementation with 
whey protein (Fresubin Protein powder, Fresenius Kabi España) will be 
provided to reach the aforementioned daily protein intake.  
5. Weekly mindfulness sessions: Patients will be invited to attend 1 weekly hourly 
session of Mindfulness-Based Stress Reduction conducted by a registered 
psychologist. It will be strongly recommended to those who reported high rates 
of anxiety and depression on the baseline HADS.  
Compliance to the prehabilitation programme will be calculated counting the number 
of supervised sessions attended out of the total intended sessions. The occurrence of 
any exercise-related adverse events during the prehabilitation period will be recorded 
and will be reported immediately to the principal investigator.  
Preoperative (T7) and 3-month postoperative functional assessment (T9): All 
participants’ functional capacity will be reassessed before surgery and 3 months 
postoperative using ET, hand grip strength test, 6MWT and STS test. Anxiety and 
depression and physical activity questionnaires will be also recorded at these time 
points.  
Surgery and hospital admission (T8): Surgery will take place in the habitual waiting 
timeframe and will be performed by the regular cardiac surgery teams present in 
Hospital Clinic de Barcelona. Perioperative clinical protocols will be followed in a usual 
fashion independently of the group allocation or study participation. Hospital staff, 
anesthesiologists, surgeons, nurses and other people involved in patient care will be 
blinded to the study arm. Intraoperative complications or events as well as the need 
blood product transfusion or any deviation from normal course will be recorded in the 
intraoperative case report form (CRF).  
The primary outcome of this study is the incidence of postoperative complications 
before patient discharge from the hospital. The type of complications included will be 
classified following the standards of the European Society of Anesthesiology and the 
European Society of Intensive Care medicine: Acute kidney injury, acute respiratory 
distress syndrome, arrhythmia, cardiac arrest, cardiogenic pulmonary oedema, deep 
vein thrombosis, delirium, gastrointestinal bleed, infection, source uncertain, 
laboratory confirmed bloodstream infection, myocardial infarction, pneumonia, 
paralytic ileus, post- operative haemorrhage, pulmonary embolism, stroke, surgical site 
infection and urinary tract infection.  
The severity of complications will be also recorded, as a secondary outcome measure, 
following the Clavien- Dindo classification. To ensure accuracy of the primary endpoint, 
the data will be collected by a physician member of the team, every day according to 
standard clinical care, and then reviewed by another researcher. Both of them will be 

Study Protocol and Statistical Analysis plan, April 4, 2018 
blinded to the study group to avoid bias. Patient- chargeable costs (ie, pharmacy and 
blood bank); tariff- chargeable costs (ie, medical care, diagnostic techniques, 
laboratories, interconsultations); other healthcare resources use (ie, ICU stay, total 
hospitalisation length of stay, readmissions, emergency room visits) and survival will 
be also assessed at 3 months and 1 year postcardiac surgery by chart review.  
Data collection management and monitoring: All participant’s de-identified data 
collected at different time points will be entered by research staff members into 
Research Electronic Data Capture (REDCap) CRF via a secure webpage interface. Online 
data will be stored in a safe server located the Hospital  
Data monitoring: Previous experiences in prehabilitation studies show a clear absence 
of safety problems related to the experimental procedure. In addition, it is an 
unmasked trial, which is easier and faster to detect a problem and take appropriate 
measures.  
The investigators of the present study are responsible for ensuring that the study 
meets the proposed milestones and deadlines. They will also be responsible for all 
aspects of the study design, management, ethical conduct, analysis and dissemination 
of results.  
Safety data, including new hospitalisation, worsening angina or heart failure and 
arrhythmias, will be captured and all adverse events will be reported. They are 
responsible to periodically evaluate the study data for participant safety and study 
conduct, in addition to making modifications and/or termination of the trial after 
communication to the Ethics Committee of Clinical investigation of Hospital Clinic de 
Barcelona.  
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Outcomes  
Clinical outcomes  
The primary outcome variable of the study is the incidence of postoperative 
complications classified following the standards of the European Society of 
Anaesthesiology and European Society of intensive Care Medicine. 
Secondary outcome variables will be: (1) severity of postoperative complications using 
Dindo-Clavien classification; (2) hospital and ICU days of stay and (3) 3-month and 1-
year mortality. Other outcome variables include: (1) ET measured by a cycling constant 
work-rate exercise testing at 80% of peak oxygen uptake; (2) distance covered in the 
6MWT; (3) STS test and hand-grip strength; (4) physical activity by the YPAS and (5) 
hospitalisation direct costs and use of healthcare resources into the follow-up 1-year 
period after surgery.  
Outcomes for feasibility of prehabilitation include incidence of adverse events during 
training, compliance to the supervised training sessions and adherence to the 
programme.  

Study Protocol and Statistical Analysis plan, April 4, 2018 
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Statistical analyses  
Sample size for this trial has been calculated based on the primary outcome of the 
study that is the reduction of incidence of postoperative complications in the 
prehabilitation group. Our own data in a similar population of patients indicated that 
the incidence of postoperative complications was 30%. Accepting a two-sided alpha-
risk of 0.05 and beta-risk of 0.20, anticipating 10% of drop- outs, indicated the need of 
including 80 participants per group to detect a reduction of the percentage of patients 
with complications in the intervention group compared with the control group 20%. 
No adjustment for multiplicity was proposed due to this is a clinical trial with one 
primary outcome and without needed of interim analyses.  
This trial will use intention-to-treat criteria for main analysis; nevertheless, analysis per 
protocol will also be performed as supportive analysis. Categorical variables, as well 
primary outcome, will be analysed with Fisher’s exact test. Continuous variables will be 
compared with Student's t-test for independent groups and Mann-Whitney U test 
according to each variable distribution. Ordinal variables will be analysed by Mann-
Whitney U test.  
Secondary outcomes looking at the difference between groups for the change in 
functional capacity over the different time points (repeated measures) will be analysed 
using generalized estimating equations models and will be shown as estimated effect 
and their 95%CI. For these analyses, we will apply unstructured matrix in order to 
assess intra-subject correlation, for cases with no adjustments we will apply an 
autoregressive model (AR) (1) type matrix.  
A cost-effectiveness study will be carried out from the perspective of the hospital, 
taking into account the costs of the intervention and the expenses related to the 
disease during the follow-up (30 days). For costs, the mean or median and their 95%CI 
of difference in per-patient costs between the two groups will be computed (control-
group costs minus prehabilitation-group costs), so that positive values will be 
interpreted as savings of the prehabilitation programme. Considering previous 
experience with prehabilitation cost analysis, a highly skewed distribution will probably 
be present. Right-sided asymmetric distribution appears when some patients incur in 
high costs, mainly because of major medical complications. To deal with this, a non-
parametric approach (bootstrapping) will be used. Bootstrap analysis yields more 
robust when dealing with skewed cost data compared with non-parametric tests.  
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Perioperative neurocognitive disorders subproject 
Inclusion criteria: Patients included in the main study with age ≥50 years. 
Exclusion criteria: Those applied for the main study. Additionally, reading difficulties, 
and non-Spanish or Catalan native speakers will also be excluded.  
Baseline cognitive assessment (T0): We selected a battery of tests with input from a 
neurologist and a neuropsychologist – both experts on cognitive disorders.  Two 
blinded-trained professionals (JP, ML) will perform the cognitive assessment in a quiet 

Study Protocol and Statistical Analysis plan, April 4, 2018 
setting. All tests will be performed in the same order: First, the cognitive assessment 
with the Memory Alteration Test (M@T), which is a validated tool for screening mild 
amnestic cognitive impairment and early Alzheimer’s disease; 21 Second, the digit span 
forwards and backwards subtests from the Wechsler Adult Intelligence Scale (WAIS-III) 
to explore attention span (digits forwards) and working memory (digits backward); 22 
Third,  the Trail Making Test (forms A and B) to measure visual-motor skills, alongside 
attention, sequencing, and cognitive flexibility; 23 Fourth, the Symbol Digit Modalities 
Test (SDMT), to assess cognitive processing speed; 24 Fifth, the Semantic Fluency Test, 
where participants will verbalise as many animals as possible within one minute, and 
the Phonetic Fluency Test, where participants will verbalise as many words as possible 
beginning with P, M, and R, to evaluate language and executive functions domains; 25 
Finally, we will use the Mini-Mental State Examination (MMSE) as a global cognitive 
screening tool.    Additionally, after the test completion, patients will be queried 
regarding subjective cognitive complaint by asking “Have you perceived any cognitive 
problems recently?” and “Have you experienced any memory problems recently?”.  
Postoperative cognitive assessment (T1):  
We will perform a cognitive assessment using the same setting and battery of cognitive 
tests than the basal assessment at the 3-month postoperative follow-up.  
Outcome: The main outcomes of this sub-study will be the incidence of cognitive 
impairment before surgery and postoperative cognitive disfunction. For the definition 
of cognitive impairment, we will exclude MMSE. Raw scores from each test will be 
adjusted to age and years of education using validated Spanish normative data from 
cognitively unimpaired subjects. 26  Abnormal tests will be those tests with adjusted 
scores bellow  1 or more standard deviation from cognitively unimpaired subjects.  
Cognitive impairment will be defined as two or more abnormal cognitive tests.  
Patients without preoperative cognitive impairment, showing a new cognitive 
impairment during the 3-month postoperative follow-up will be defined as having 
postoperative cognitive dysfunction.  
Statistical analysis: Randomized groups will be compared for balance on all potentially 
confounding baseline variables using descriptive statistics and the standardized 
difference (ASD), which is the difference in means or proportions divided by the 
pooled standard deviation. Criterion for imbalance will be an absolute standardized 
difference > 0.10. Any imbalanced baseline variables will be adjusted for in all analyses 
below. Data transformations will be made, or non-parametric analyses used to meet 
model assumptions, as appropriate. Analyses will be intent to treat, with a significance 
level of 0.05. We will assess the efficacy of the prehabilitation program to standard 
care on the incidence of POCD using either Pearson chi-square test or logistic 
regression if there is a need to adjust for baseline imbalance in potentially confounding 
variables. In either case, the relative risk of developing POCD at 3-months after surgery 
and its 95% confidence interval will be estimated. 
 
 

Study Protocol and Statistical Analysis plan, April 4, 2018 
Patient and public involvement  
Patient and public involvement was taken into consideration for the development of 
this protocol. A satisfaction questionnaire was given to a sample of patients who had 
undergone a prehabilitation programme as part of their clinical pathway before an 
abdominal surgery. They gave feedback about both the assessments and interventions 
included in this trial. As a result of their feedback we proceeded to reduce the number 
of questionnaires given during the assessments, as well as an assessment and 
intervention redesign, resulting in a more flexible schedule for the participants.  
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ETHICS AND DISSEMINATION  
Ethics approval for this trial has been obtained by the Ethics Committee of Clinical 
investigation of Hospital Clinic de Barcelona (HCB/2017/0708). This trial will be 
conducted according to the principles emanating from the Helsinki Declaration, with 
compliance to the Good Clinical Practice and the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines. Confidentiality for participants and their data will be guaranteed according 
to the Spanish data protection law ‘Ley Orgánica de Protección de Datos de Carácter 
Personal’ (15/1999, 13 diciembre) and the General Data Protection Regulation from 
the European Union (EU 2016/679).  
All the explorations and tests in this trial are considered minimally invasive and are 
performed in presence of a physician under strict monitoring. The non-
pharmacological characteristics of the intervention exclude the need for additional 
trial insurances.  
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Informed consent  
To avoid contamination among groups, there will be two informed consents: all 
participants allocated in the control group will be proposed to participate in a study to 
investigate the relationship between cardiopulmonary reserve and postoperative 
outcomes and will sign the informed consent for the control group. All participants 
allocated in the intervention group will be proposed to participate in a study that 
investigates the effects of a multimodal prehabilitation programme on postoperative 
outcomes. Patients in the intervention group will sign the intervention group informed 
consent, where the intervention is defined. All potential participants will be given time 
to read the informed consent form, consider participation and ask doubts or questions 
regarding the study participation. If patient agrees to participate, he or she will be 
asked to provide written consent in the informed consent document. Participants will 
be free to withdraw their consent and opt out from the trial at any time without 
needing to explain the reason why. Withdrawal from the trial will not carry any 
prejudice in the participant care.