EMDR Treatment in PTSD Following Cardiac Events
Phase: NA
Conditions: Posttraumatic Stress Disorder, Myocardial Infarction, Eye Movement Desensitization and Reprocessing
Sponsor: University of Zurich

s wi s s e t h i c s  
Schweizerische Ethikkommissionen für die Forschung am Menschen 
Commissions d’éthique suisses relative à la recherche sur l'être humain 
Commissioni etiche svizzere per la ricerca sull'essere umano 
Swiss Ethics Committees on research involving humans 
 
Clinical Protocol Template 
ClinO Chapter 4 Other Clinical Trials 
(without drugs / medical devices) 
 
 
 
V8, 17.05.2022 
EMDR Treatment in PTSD Following Cardiac Events 
 
Study Type: 
Other Clinical Trial according to ClinO, Chapter 4 
 
Risk Categorisation: 
 
Risk category A according to ClinO, Art. 61 
 
Study Registration: 
The study will be registered at the ClinicalTrials.gov Protocol Registration System 
 
The study will be registered at the SNCTP (Swill National Clinical Trial Portal) 
upon approval of the study protocol by the KEK.  
 
Sponsor: 
PD. Dr. med. Christoph Mueller-Pfeiffer 
 
Principal Investigator 
PD. Dr. med. Christoph Mueller-Pfeiffer   
Department of Consultation-Liaison Psychiatry and Psychosomatic   Medicine, 
University Hospital Zurich 
Culmannstrasse 8, 8091 Zurich 
+41 44 255 52 80 
christoph.mueller-pfeiffer@access.uzh.ch  
 
Investigated Intervention: 
Randomized controlled trial to investigate the efficacy of eye movement 
desensitization and reprocessing (EMDR) therapy in treating posttraumatic stress 
disorder (PTSD) following cardiac events  
 
Protocol ID 
NCT04672551 
 
Version and Date: 
 
Version 8 (dated 17.05.2022) 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the property of the sponsor-investigator. The information 
may not - in full or in part - be transmitted, reproduced, published, or disclosed to others than the applicable Competent 
Ethics Committee(s) and Regulatory Authority(ies) without prior written authorisation from the sponsor-investigator 
except to the extent necessary to obtain informed consent from those who will participate in the study. 
 
Protocol Signature Form    
 
Study Title 
EMDR Treatment in PTSD Following Cardiac Events 
Study ID 
2019-00817 
 
 
The Sponsor-Investigator has approved the protocol version 8 (dated 17.05.2022) and confirms hereby to conduct 
the study according to the protocol, current version of the World Medical Association Declaration of Helsinki, and the 
principles of Good Clinical Practice. 
 
 
Sponsor-Investigator: 
 
Name: PD Dr. med. Christoph Mueller-Pfeiffer 
 
 
Date: 
17.05.2022 
 
Signature: 
 
 

 
 
1 
 
TABLE OF CONTENTS 
1 STUDY SYNOPSIS 
4 
2 BACKGROUND AND RATIONALE 
7 
2.1 PTSD and Cardiovascular Disease 
7 
2.2 Consequences of Posttraumatic Stress Disorder after Cardiac Events 
7 
2.3 Eye Movement Desensitization and Reprocessing (EMDR) Therapy for PTSD 
7 
2.4 Eye Movement Desensitization and Reprocessing (EMDR) Therapy 
7 
2.5 EMDR for PTSD after  cardiac events 
8 
3 STUDY OBJECTIVES AND DESIGN 
8 
3.1 Hypotheses and objectives 
8 
Primary hypothesis: 
8 
Secondary hypotheses: 
8 
3.2 Primary and secondary endpoints 
8 
Primary endpoint 
8 
Secondary endpoints 
8 
3.4. Study intervention 
9 
3.4.1 Study Therapists 
9 
3.4.2. Intervention group 
9 
3.4.3. Waiting control group 
9 
4 STUDY POPULATIOIN AND STUDY PROCEDURES 
9 
4.1 Inclusion and exclusion criteria, justification of study population 
9 
4.2 Recruitment and informed consent procedure 
9 
4.2.1 Recruitment: Cardiology Intensive Care Unit 
9 
4.3 Study procedures 
10 
4.3.1 Screening: Screening for inclusion and exclusion criteria prior to study inclusion
 
10 
4.3.2 Baseline: Definitive inclusion, baseline measurements 
10 
4.3.3 Randomization and Intervention 
11 
4.3.4 
Post 
Treatment 
and 
6-months 
Follow-up 
(a/b): 
Post-intervention 
measurements 
11 
4.4 Measurement procedures and instruments 
11 
4.4.1 CAPS-5 
11 
4.4.2 Loud-tone procedure 
11 
4.4.3 Cardiovascular parameters, stress hormones 
11 
4.4.4 Psychometric data 
11 
Screening instruments 
11 
Additional parameters (covariates and for exploratory purposes) 
12 
Psychiatric symptoms and disorders 
12 
Personality 
12 
Cardiac-related variables 
12 
4.5 Withdrawal and discontinuation 
12 
5 STATISTICS AND METHODOLOGY 
12 
5.1. Statistical analysis plan 
12 
5.2. Handling of missing data and drop-outs 
12 
6 REGULATORY ASPECTS AND SAFETY 
12 

 
 
2 
 
6.1 Local regulations / Declaration of Helsinki 
12 
6.2 (Serious) Adverse Events 
12 
Reporting of SAEs (see ClinO, Art. 63,) 
13 
6.3 (Periodic) safety reporting 
13 
6.4 Amendments 
13 
6.5 (Premature) termination of study 
13 
6.6 Insurance 
13 
7 FURTHER ASPECTS 
14 
7.1 Overall ethical considerations 
14 
7.2 Risk-benefit assessment 
14 
8 QUALITY CONTROL AND DATA PROTECTION 
14 
8.1 Quality measures 
14 
8.2 Specification of Source Documents 
14 
8.3 Data recording 
15 
8.4 Confidentiality and coding 
15 
8.5 Retention of study data and biological material 
15 
9  MONITORING AND REGISTRATION 
15 
10 FUNDING / PUBLICATION / DECLARATION OF INTEREST 
16 
11 ADDITIONAL SIGNATURES 
16 
11 REFERENCES 
17 
 
 
 

 
 
3 
 
GLOSSARY OF ABBREVATIONS 
AE 
 
Adverse Event 
BASEC  
Business Administration System for Ethical Committees 
BLS 
 
Bilateral Stimulation 
CHD 
 
Coronary Heart Disease 
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: OClin, in Italian: 
OSRUm) 
CVD 
 
Cardiovascular Disease 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
EMDR  
Eye Movement Desensitization and Reprocessing 
FADP 
 
Federal Act on Data Protection (in German: DSG, in French: LPD, in Italian: LPD) 
eCRF 
 
electronic Case Report Form 
GCP 
 
Good Clinical Practice 
HR 
 
Heart Rate 
HRA 
 
Human Research Act (in German: HFG, in French: LRH, in Italian: LRUm) 
HRV 
 
Heart Rate Variability 
Hs-CRP High-sensitivity C-reactive protein 
ICAM-1  
Intercellular adhesion molecule-1 
ICD-11  
International Classification of Diseases, 11th edition 
ICH 
 
International Conference on Harmonisation  
IL 
 
Interleukin 
KISIM 
 
Klinikinformationssystem 
LC-NE  
Locus Coeruleus-Norepinephrine 
PTSD 
 
Posttraumatic Stress Disorder 
RDI 
 
Resource Development and Installation 
SAE 
 
Serious Adverse Event 
STEMI  
ST-elevation myocardial infarction 
SC 
 
Skin Conductance 
TNF- α  
Tumor Necrosis Factor- α 
USZ 
 
University Hospital Zurich 
VWF 
 
von Willebrand factor 
BIPQ 
 
Brief Illness Perception Questionnaire 
CAPS-5 Clinical Administered PTSD Scale for DSM-5  
DS14 
 
Distress Scale 14 
EQ-5D  
EuroQol -5 Dimensions 
ESSI 
 
Enriched Social Support Instrument 
GAD-7  
General Anxiety Disorder – 7 
IIEF 
 
International Index of Erectile Function (IIEF) 
LEC-5 
 
Life Events Checklist – DSM-5   
M.I.N.I.  
Mini International Neuropsychiatric Interview  
MQ 
 
Maastricht Questionnaire 
PAS 
 
Posttraumatic Adjustment Scale 
PHQ-9  
Patient Health Questionnaire – 9 
PSQI 
 
Pittsburgh Sleep Quality Index 
PTSD 
 
Posttraumatic Stress Disorder 
PTSS 
 
Posttraumatic Stress Symptoms 
RS 
 
Resilience Scale 
TAS-20  
Toronto Alexithymia Scale-20 
 
 

 
 
4 
 
1 
STUDY SYNOPSIS 
Sponsor-
Investigator 
PD Dr. med. Christoph Mueller-Pfeiffer   
Study Title 
EMDR Treatment in PTSD Following Cardiac Events 
 
Short Title / 
Study ID 
EMDR in Cardiac PTSD  
Protocol 
Version and 
Date 
Version 8 (dated 17.05.2022) 
Study 
Registration 
 
 NCT04672551 
 
 
Study 
Category and 
Rationale 
Risk category A: The here planned eye movement desensitization and reprocessing (EMDR) 
psychotherapy intervention is effective and well established in patients with posttraumatic 
stress disorder (PTSD) and acknowledged by the WHO as treatment of choice in PTSD. There 
are no known complications and the emotional distress arising from the confrontation with 
traumatic memories, which is part of the EMDR treatment, has been shown to be tolerable and 
only transient. The collection of biological samples (saliva, blood) and health-related personal 
data (psychophysiological and psychometric data) involves no risks for the participants. 
Therefore, the project is assigned to category A. 
Background 
and Rationale  
Background: Coronary heart disease (CHD)  remains a leading cause of death in Western 
societies, including Switzerland, where every sixth person dies from CHD each year. About 
70% of patients experience psychological responses including moderate to intense fear of 
dying and distress during cardiac events. The psychological consequences of cardiac events 
are substantial and 4-16% of all cardiac patients develop full or subsyndromal PTSD after the 
cardiac event. In addition to poor quality of life and impaired mental health, cardiac-induced 
PTSD is associated with a negative disease prognosis (e.g., twofold increased risk of adverse 
clinical outcomes including major adverse cardiac events, CHD-related hospital readmissions, 
and all-cause mortality). However, research on how to treat PTSD after cardiac events is 
lacking. Therefore, the here proposed project aims at investigating the effectiveness of EMDR 
therapy, which is one of the psychotherapies of choice in traditional PTSD. EMDR is very 
promising in treating cardiac-induced PTSD, which shows a different symptom cluster than 
traditional PTSD. In cardiac-induced PTSD, there is a positive feedback loop between anxiety 
and cardiovascular activity (e.g., normal cardiovascular sensations are experienced as threat, 
which in turn leads to stronger sensations). EMDR includes reprocessing of body sensations 
associated with the target event and may therefore disrupt the positive feedback loop proposed 
by the somatic threat model and reduce PTSD symptoms.  
Risk / Benefit 
Assessment 
Earlier studies have shown that EMDR was well accepted by patients, emotional arousal was 
tolerable, and no cardiac complications occurred during EMDR confrontation. The reactivation 
of traumatic memories can cause a transient burden for patients with PTSD. The collection of 
psychometric, psychophysiological and biological samples (saliva, blood) according to 
international standardized procedures are associated with no more than minimal risks and 
burdens. Moreover, patients participating in this study may benefit from the EMDR therapy in 
terms of PTSD symptom relief and CHD prognosis. Hence, we see a favourable risk-to-benefit 
ratio for the here proposed study.  
Objective(s) 
The here proposed study aims at testing EMDR therapy in cardiac-induced PTSD in a 
randomized controlled trial. More specifically, the efficacy of the standardized trauma-focused 
procedure in terms of a reduced PTSD symptom level will be tested against a passive waitlist 
control group. 
 
Primary hypothesis: 
1) Posttraumatic stress levels as assessed by the Clinician-Administered PTSD Scale at 3- and 
6-months follow-up will be lower in the intervention group (standardized EMDR treatment) than 
in the control group (waitlist control).  
 
Secondary hypotheses: 

 
 
5 
 
2a) Compared to the control group, the intervention group will show reduced 
psychophysiological responses to sudden noise bursts at 3- and 6-months follow up. 
2b) Compared to the control group, the intervention group will show a lower risk of 
cardiovascular disease evidenced by a more favourable level of inflammation markers, 
metabolic factors, circulating biomarkers of haemostatic and endothelial function, and stress 
hormones at 3- and 6-months follow up. 
Endpoint(s) 
Primary endpoint:  
Interviewer-rated posttraumatic stress level at baseline, three- and nine-months follow-up (by 
means of the clinician-administered PTSD scale, CAPS-5).  
 
Secondary endpoints: 
• 
Psychophysiological responses (e.g., heart rate, skin conductance)  
• 
Cardiometabolic biomarkers (e.g. inflammation markers, metabolic factors) 
• 
Stress hormones 
Study Design 
Randomized controlled trial, two arms  
1) 
PTSD patients receiving EMDR on traumatic event 
2) 
PTSD patients in the wait-list 
Statistical 
Considerations 
Linear mixed models with three time points (assessments 1-3) as within-subject factors and the 
two groups (intervention vs. waitlist control) as between-subject factors will be applied to test for 
differences in primary and secondary outcomes between assessments and groups, probably 
taking sociodemographic, medical and psychometric covariates into account. The interaction 
effect between time and group is relevant to evaluate for different development depending on 
group membership. 
Inclusion- / 
Exclusion 
Criteria 
Inclusion criteria:   
• 
Age between 18-80 years 
• 
Men or women 
• 
Cardiac event (e.g. myocardial infarction, cardiac arrest, resuscitation)  
• 
Diagnosis of PTSD caused by the cardiac event 
Exclusion-criteria:  
• 
Current psychotic disorder, bipolar disorder, substance abuse as measured with the 
Mini International Neuropsychiatric Interview (M.I.N.I)  
• 
Acute suicidal ideation as assessed with the M.I.N.I. 
• 
Non-selective beta blockers (e.g., propranolol) and or benzodiazepine during the 
study period 
• 
Ongoing trauma-related treatment outside of the trial during the study period 
• 
Visionary problems, e.g. strabismus, which does not allow adequate eye movements 
• 
Insufficient knowledge of the German language  
• 
Expected inability or willingness to follow the study protocol 
Number of 
Participants 
with Rationale 
Based on previous studies, including our own work performed in Switzerland, about 10% will 
develop PTSD after an acute cardiac event. In our experience, about half of the patients will 
participate in the initial screenings, whereby only a few will not consent to participate once they 
are informed about probably having PTSD. Therefore, over a 4 -year period we assume that 
we will enroll the target sample size of 60 cardiac-induced  PTSD at our hospital. According to 
meta-analyses, compared to waitlist controls a large effect size of EMDR treatment on PTSD 
symptom level can be expected (Cohen’s d = 0.8). Power analysis (α = 0.05, 1-β = 0.8, two-
sided) revealed that a sample size of 25 patients per group is needed to provide a significant 
interaction effect between group and time. Expecting 15% of participants to drop out after 
informed consent, recruiting of 60 patients in total will be necessary (30 patients per group).  
Study 
Intervention 
EMDR focusing on the trauma: Eight individual EMDR sessions will be provided over eight 
weeks by licensed EMDR therapists. The first two sessions will be used for establishing a 
therapeutic alliance, explaining the EMDR process, obtaining a medical history, and initiating 
relaxation and safety procedures. The next sessions will be used for assessment of the cardiac 
event and desensitization and installation procedures according to the standard three-pronged 
EMDR therapy protocol. In the last session, closing and debriefing will take place. Treatment 
adherence will be controlled by independent reviewing of 10 percent of the sessions using 
recordings of the sessions and the therapist's protocols. 
Control 
Intervention 
1. 
Watchful waiting group: no treatment takes place.  
Study 
procedures 
  

 
 
6 
 
 
 
Study Duration 
and Schedule 
Study duration for each participant: 36 weeks 
First-Participant-In: 11/2020 
Last-Participant-Out: 11/2024 
Investigator 
PD Dr. med. Christoph Mueller-Pfeiffer, Senior Psychiatrist ("Leitender Arzt"), Department of 
Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich, 
Culmannstrasse 8, 8091 Zurich, +41 44 255 52 80, christoph.mueller-pfeiffer@access.uzh.ch 
Study 
Center(s) 
Study Center (s): Monocentric study which will take place exclusively at the University Hospital 
Zurich. 
Data privacy 
Project data will be handled with uttermost discretion and is only accessible to authorized 
personnel who require the data to fulfil their duties within the scope of the research project. On 
the CRFs and other project specific documents, participants are only identified by a unique 
participant number.    
Biological material in this project is not identified by participants’ name but by a unique 
participant number. Biological material is appropriately stored in a restricted area and only 
accessible to authorized personnel.   
Health-related personal data and biological material will be handled with uttermost discretion 
and is only accessible to authorized personnel who require the data to fulfil their duties within 
the scope of the research project. Data and biological material will be stored according to HRO, 
art. 5, at the Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine of 
the USZ.  To ensure confidentiality, personal data and biological material will be coded. 
Participants are only identified by a unique participant number. The assignment of the number 
to the participant is safely stored according to HRO, art. 5, at the Department of Consultation-
Liaison Psychiatry and Psychosomatic Medicine and protected against unauthorized access. 
Personal data and biological material will only be disclosed in case of an emergency, if 
disclosure is necessary for the protection of the physical and psychological integrity of the 
participant, or if there is a legal basis.   
Ethical 
consideration 
Social / scientific value:  If our randomized-controlled trial proves EMDR to be an effective 
treatment for the reduction of PTSD symptoms in patients with cardiac events, EMDR could be 
implemented as a first-line treatment. This knowledge might inform larger trials to test whether 
poor prognosis following major adverse cardiovascular events can be improved through EMDR 
in patients with types of cardiac-induced PTSD. 
 
Justification of the inclusion of vulnerable participants: Patients suffering from PTSD can be 
considered vulnerable and should be treated carefully. As EMDR is already well established and 
the therapy of choice for the treatment of PTSD, no harm is to be expected. Moreover, it has 
already been implemented in patients with PTSD resulting from other cardiac events, where 
EMDR was accepted by patients, emotional arousal was tolerable, and no cardiac complications 
occurred during EMDR confrontation.  
 

 
 
7 
 
Justification of the study design: In order to investigate the efficacy of EMDR, it is inevitable to 
include subjects with PTSD and assign them to a control group. Hence, participants in the control 
group may be at a disadvantage. However, this disadvantage is only temporary, as they are 
offered EMDR therapy upon completion of the study in week 36. 
GCP Statement 
This study will be conducted in compliance with the protocol, the current version of the 
Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as well as all 
national legal and regulatory requirements.  
 
 
2 
BACKGROUND AND RATIONALE  
2.1 PTSD and Cardiovascular Disease 
Several risk factors for the development of posttraumatic stress disorder symptoms after myocardial infarction have 
been identified. These factors can be categorized into demographics (e.g., young age, female sex), personality 
characteristics (e.g., alexithymia, type D-personality), mental and cardiac history (e.g., previous traumatization, 
recurring cardiac symptoms), negative affect, poor coping strategies, low social support, subjective experience of the 
myocardial infarction, and acute stress disorder  [1]. There is an intriguing recent line of research suggesting that it is 
much less objective markers of myocardial infarction severity such as cardiac enzyme levels and left ventricular ejection 
fraction that predict posttraumatic stress after myocardial infarction, but rather the subjective perception of severity [1].  
Available evidence suggests that cardiac-induced PTSD symptoms may differ from those observed in traditional PTSD. 
First, traditional PTSD includes foremost event-related intrusive thoughts (i.e., “flash-backs” of the traumatic event) [2, 
3]. Cardiac patients do exhibit intrusion symptoms not necessarily related to the traumatic event itself, as they also 
respond to unspecific myocardial infarction stimuli such as ambulance sirens during clinical interviews [4]. Second, as 
cardiac events are manifestations of an internal, chronic disease, patients are often exposed to enduring internal 
somatic threats such as palpitation or dyspnoea, which may sustain fears of recurring cardiac events in the future. 
These phenomena are termed “flash-forward” intrusions [4] and can be explained by the somatic threat model [2]. This 
model proposes a positive feedback loop between anxiety and sympathetic cardiovascular activity. Survivors of a 
cardiac event experience cardiovascular physical sensations, e.g., heart beating, as threat cues. The threat-related 
increase in sympathetic activity, in turn, further increases anxiety. Third, other than in PTSD resulting from external 
causes, avoidance can have severe health consequences, for example if patients with PTSD avoid doctors’ visits and 
intake of cardiac medications after cardiac events [5]. Fourth, hyperarousal symptoms such as a fast heart beat and 
palpitations can become somatic cues of cardiac threats that can be misinterpreted as life-threating cardiovascular 
symptoms [2].  
2.2 Consequences of Posttraumatic Stress Disorder after Acute Cardiac Events 
Available evidence suggests that PTSD is predictive for incident cardiovascular disease morbidity and mortality and 
may thus additionally worsen cardiovascular prognosis in patients with PTSD [2, 3, 5-10]. In addition to poor quality of 
life and impaired mental health [4], Cardiac-induced PTSD is associated with a twofold increased risk of adverse clinical 
outcomes assessed 1-3.5 years later, including major adverse cardiac events, cardiovascular-related hospital 
readmissions, and all-cause mortality [10]. While intrusion, avoidance, and hyperarousal symptoms have all been 
shown to affect cardiac prognosis [5], studies suggest that prominent intrusion symptoms are most deleterious [8]. 
PTSD associated unhealthy life styles, low adherence with cardiac therapy, and direct pathophysiological changes 
related to neuroendocrine and autonomic dysfunction, along with inflammatory and prothrombotic states, both 
facilitating atherosclerosis progression, are plausible mechanisms to explain poor cardiac prognosis in patients with 
PTSD [3].  
As cardiac events area very prevalent which may result in PTSD and as PTSD severely worsens cardiovascular 
disease prognosis, effective PTSD treatments are needed. These treatment approaches need to be specific for PTSD 
after cardiac events, because cardiac-induced PTSD symptoms differ from traditional PTSD. 
2.3 Eye Movement Desensitization and Reprocessing (EMDR) Therapy for PTSD 
Eye Movement Desensitization and Reprocessing (EMDR) is a psychotherapy treatment to reduce PTSD symptoms 
[11]. A meta-analysis comparing EMDR against waitlist controls, cognitive behaviour therapy involving exposure, and 
other treatment modalities found an “overall superiority of EMDR compared to the other active treatment conditions” 
[12]. The efficacy of EMDR as PTSD treatment has now been established in several meta-analyses [13-15] and 
approximately 20 randomized controlled trials in both civilian [13-15] and combat veteran populations [16]. These 
findings led to the acknowledgment of EMDR as one of the psychotherapies of choice in the treatment of PTSD in 
adults by the World Health Organization (2013) [17].  
2.4 Eye Movement Desensitization and Reprocessing (EMDR) Therapy 
Eye Movement Desensitization and Reprocessing (EMDR) is a psychotherapy treatment to reduce PTSD symptoms 
such as disturbing memories and hyperarousal by means of reprocessing a traumatic memory. The main component 
is the alternate bilateral stimulation (BLS, i.e., saccadic eye movements, tapping, or ear tones) inducing a dual focus 

 
 
8 
 
of attention (i.e., on the bilateral stimulation) during memory reactivation and thereby ameliorates traumatic reactions 
[14, 18, 19]. 
2.5 EMDR for PTSD after  cardiac events 
To our knowledge, EMDR has only in one study been tested against other evidence-based PTSD treatments in cardiac 
patients. In that study, 42 patients undergoing cardiac rehabilitation after cardiac surgery, many in the wake of a cardiac 
event and scoring high on PTSD symptoms, were randomly assigned to either EMDR (all eight phases) or prolonged 
imaginary exposure therapy for 4 weeks [19]. In agreement with meta-analytic data suggesting that EMDR treatment 
may be slightly more effective than cognitive behavioural therapy for the treatment of PTSD [20], EMDR was associated 
with a significantly higher reduction of PTSD, anxiety, and depressive symptoms in cardiac surgery patients than 
Imaginary Exposure [19].  In a study testing EMDR therapy in 16 patients with implantable cardioverter defibrillator 
shock-induced PTSD, a reduction of PTSD, anxiety, and depressive symptoms was found 1 year after treatment. EMDR 
was accepted by patients, emotional arousal was tolerable, and no cardiac complications occurred during EMDR 
confrontation [21].  
However, there is a lack of research on the efficacy of psychotherapy and especially EMDR in cardiac-induced PTSD 
[4, 7]. In the light of cardiac-induced PTSD having different symptoms than traditional PTSD, this lack of research is 
highly problematic. Specifically, the unique symptom profile in cardiac-induced PTSD related to the enduring somatic 
threat model [2] was not addressed in any of the studies targeting PTSD in cardiac patients. In this regard, EMDR might 
be most promising: The EMDR protocol includes the assessment of body sensations associated with the target event, 
which is followed by reprocessing. The bilateral eye movements during reprocessing seem to have de-arousing effects 
[22] and may thereby interrupt the positive feedback loop between cardiovascular sensations and anxiety-induced 
arousal [19] as explained by the enduring somatic threat model. Hence, EMDR might be more suitable in cardiac PTSD 
patients compared to treatment protocols that motivates patients to keep focusing on the traumatic event such as 
Prolonged Exposure, where higher emotional involvement seems to be related to a better outcome [23]. Therefore, the 
here proposed study aims at testing EMDR therapy in cardiac-induced PTSD in a randomized controlled trial. 
11 STUDY OBJECTIVES AND DESIGN  
3.1 Hypotheses and objectives 
The here proposed study aims at testing EMDR therapy in cardiac-induced PTSD in a randomized controlled trial. More 
specifically, the efficacy of the standardized trauma-focused procedure in terms of a reduced PTSD symptom level will 
be tested against a passive waitlist control group. 
Primary hypothesis: 
1) Posttraumatic stress levels as assessed by the Clinician-Administered PTSD Scale at 3- and 6-months follow-up will 
be lower in the intervention group (standardized EMDR treatment) than in the control group (waitlist control).  
Secondary hypotheses: 
2a) Compared to the control groups, the intervention group will show reduced psychophysiological responses to 
sudden noise bursts at 3- and 6-months follow up. 
2c) In terms of cardiovascular disease risk, the intervention group will show a more favourable level of inflammation 
markers, metabolic factors, circulating biomarkers of hemostatic and endothelial function, and stress hormones than 
the control groups at 3- and 6-months follow up.  
 
In order to examine changes from before to after treatment, variables will be measured before the treatment ) and after 
the treatment (week 12 and 36).  
3.2 Primary and secondary endpoints 
Primary endpoint 
The primary endpoint is the interviewer-rated posttraumatic stress level at three- and six-months follow-up (by means 
of the Clinician-Administered PTSD Scale, CAPS-5).  
Secondary endpoints 
- 
Noise-related psychophysiological responses 
o 
Heart rate (HR) and skin conductance (SC) responses 
o 
Heart rate variability (HRV): Total power, high frequency power, low frequency power, low-to-high 
frequency power ratio 
- 
Stress hormones: 
o 
Plasma norepinephrine and epinephrine, salivary cortisol 
- 
Cardiometabolic biomarkers 
o 
Metabolic Factors: total cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, 
triglycerides, glucose 
o 
Inflammation markers: high-sensitivity C-reactive protein(hs-CRP), interleukin (IL)-6, tumor necrosis 
factor (TNF)-α 
Circulating biomarkers of hemostatic and endothelial function: Fibrinogen, cardiac troponin T (cTNT). It is a national, 
monocentric, prospective, randomized-controlled two-arm trial to test the effectiveness of EMDR therapy in cardiac-
induced PTSD. Participants will be randomly assigned to the intervention group (receiving EMDR) or to the control 

 
 
9 
 
group (watchful waiting). It will be examined whether the intervention group (n = 25) receiving EMDR differs from the 
control group (n = 25) in terms of primary and secondary outcomes. To that end, the subjects in both groups will 
undergo a baseline clinical interview to measure PTSD symptom severity and peripheral physiological reactivity to a 
stressor (i.e., white noise burst), and blood and saliva sampling to collect stress hormones and cardiovascular 
biomarkers (week 4). After EMDR treatment (week 12 and 36), participants will return, and the procedure will be 
repeated. 
3.4. Study intervention 
3.4.1 Study Therapists 
Recruitment, physiological assessments, and blood sampling will be performed by research assistants at the 
University Hospital of Zurich. CAPS-5 interviews will be administered by licensed psychiatrists or psychotherapists. 
Study therapists are certified EMDR therapists. They will perform the EMDR therapy under supervision of an 
experienced EMDR therapist (Dr. Michael Hase, Lüneburger Zentrum für Stressmedizin, Lüneburg, Germany). Dr. 
Michael Hase will offer a supervision once a month. He will be part of our study team and is listed as a co-author. The 
supervisions for the EMDR-therapy (30 patients) will be organized per “Click Meeting”.  
3.4.2. Intervention group 
The intervention group consists of 25 patients diagnosed with full PTSD induced by cardiac events. Eight individual 
EMDR sessions lasting for 1 hours will be provided over 8 weeks by licensed EMDR therapists from the German-
speaking part of Switzerland. Each EMDR session follows a standardized 8-phase protocol. As Shapiro [24] posits 
that it is necessary to adapt the standard procedures to the unique needs and characteristics of the patient and to 
apply different EMDR protocols for different pathologies [25], the therapy for cardiac event patients was adapted from 
the standard protocol [26]. After each session, the EMDR therapist records the date of the session, the number of the 
session (from 1-8), the duration of the session (in minutes), if the session was audiotaped and any comments (if 
necessary).  
3.4.3. Waiting control group 
Other than the assessments described in section 4.3 (Study Procedure), no intervention or any other procedure will be 
conducted during the study period of 36 weeks. Afterwards these subjects will be offered an EMDR therapy as provided 
in the intervention. 
12 STUDY POPULATIOIN AND STUDY PROCEDURES 
4.1 Inclusion and exclusion criteria, justification of study population 
Approximately 800 patients/year are referred to the cardiac care unit of the University Hospital Zurich. Based on 
previous studies, including our own work performed in Switzerland, about 10% will develop PTSD after the acute 
cardiac event. In our experience, about half of the patients will participate in the initial screenings, whereby only a few 
will not consent to participate once they are informed about probably having PTSD. Therefore, over a 4-year period 
we assume that we will enroll the target sample size of 60 cardiac-induced PTSD at our hospital. According to meta-
analyses, compared to waitlist controls a large the mean effect size of EMDR treatment on PTSD symptom level can 
be expected (Cohen’s d = 0.8) [14]. Power analysis (alpha = 0.05, power = 0.8, two-sided) revealed that a sample 
size of 25 patients per group is needed to provide a significant interaction effect between group and time. Expecting 
15% of participants to drop out after informed consent, recruiting of 60 patients in total will be necessary (30 patients 
per group). Inclusion criteria will be: 1) Age between 18-80 years, 2) Men or women; 3) cardiac event (e.g. cardiac 
arrest, myocardial infarction, resuscitation, shock delivery) 4) Diagnosis of PTSD caused by the cardiac event. 
Exclusion criteria will be: 1) Current psychotic disorder, bipolar disorder, substance abuse as measured with the Mini 
International Neuropsychiatric Interview; 2) Acute suicidal ideation as assessed with the M.I.N.I.; 3) Non-selective 
beta blockers (e.g., propranolol) during the study period; 4) Ongoing  trauma-related treatment outside of the trial 
during the study period; 5) Visionary problems, e.g. strabismus, which does not allow adequate eye movements; 7) 
Insufficient knowledge of the German language, 6) Expected inability or willingness to follow the study protocol; 8) 
Regular medication with benzodiazepine 
 
 
4.2 Recruitment and informed consent procedure 
4.2.1 Recruitment: Cardiology Intensive Care Unit  
Patients will be enrolled via flyer and advertisement within 4 years (November 2020 and November 2024). We will 
send the flyers to all hospitals, cardiac rehabilitations, cardiology practices, general practitioner practices and 
psychological and psychiatric practices in Switzerland. The advertisement will be made in newspapers, magazines 
and online platforms. All interested patients will be screened for potential PTSD via telephone screening (about 20 
minutes).  
4.2.2. Informed consent procedure 
We will conduct a pre-screening procedure by phone/e-mail where we get implicit informed consent. 
Subjects who will screen positive for study inclusion, will be invited for a first assessment, where we get 
written informed consent. To each participant, we will explain the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits and any discomfort it may 

 
 
10 
 
entail. Each participant will be informed that the participation in the study is voluntary and that he or she 
may withdraw from the study at any time and that withdrawal of consent will not affect his or her 
subsequent medical assistance and treatment. The participant will be informed that his or her medical 
records may be examined by authorised individuals other than their treating therapist. All participants will 
be provided a participant information sheet and a consent form describing the study and providing 
adequate information for participants to make an informed decision about their participation in the study. 
Potential participants can decide in their own time if they want to participate in the study. The formal 
consent of a participant, using the approved consent form, will be obtained before the participant is 
submitted to any study procedure. The consent form will be signed and dated by the study assessor at 
the same time as the participant signs. A copy of the signed informed consent will be given to the study 
participant. The consent form will be retained as part of the study records. The informed consent process 
will be documented in the patient file and any discrepancy to the process described in the protocol must 
be explained. Participants from the intervention group will be handed out an additional informed consent 
to record the therapeutic sessions on a tape recorder. This informed consent is given by the EMDR 
therapist.  
4.3 Study procedures 
 
 
 
 
 
4.3.1 Screening: Screening for inclusion and exclusion criteria prior to study inclusion 
The Screening will be conducted by phone and/or e-mail. Eligible participants will be screened for inclusion and 
exclusion criteria. Screening for a probable PTSD diagnosis will be conducted using Part III of the PCL-5 for DSM-5 
[27, 28]. Subjects who meet a total sum score of 28 or more, will be invited for Baseline a.  
4.3.2 Baseline: Definitive inclusion, baseline measurements 
Assessment 1 consists of two appointments (a, b) taking place at the University Hospital Zurich. During the first 
appointment (a), the CAPS-5 and the M.I.N.I will be administered in order to ascertain a PTSD and other psychiatric 
diagnoses. By means of the CAPS-5, it will be determined whether the participants have full PTSD (inclusion criterion 
and baseline assessment of primary outcome). The assessment of the traumatic event during the interview can 
cause distress (although only minimal and transient), which affects biomarkers [30, 31], the assessment of 
cardiovascular biomarkers and stress sensitization by means of the loud-tone procedure will be carried out at a 
separate appointment. The second appointment (b) will be scheduled as close as possible to the first appointment to 
assess the baseline of all secondary endpoints: 1) saliva and blood samples will be collected to obtain, stress 
hormones, and cardiovascular biomarkers, including blood pressure; 2) the loud-tone procedure will be administered; 
3) patient's medication will be documented. Moreover, the following information will be obtained from the potential 
participants or from hospital charts [32]: Demographic factors, established cardiovascular risk factors and life style 
behavior, heart diseases in the past objective indices of myocardial damage and severity, related blood parameters 
measured in hospital, variables related to patient referral to the cardiac care unit, complications/surgeries during the 
hospital stay, number of days at the hospital/intensive care unit/intermediate care unit recurrent cardiac symptoms, 

 
 
11 
 
recurrent hospitalizations, hospital (if patients were referred to another hospital), cardiac rehabilitation, doctor visits, 
pharmacological treatment, adherence to medication, medical comorbidities. 
4) psychometric data will be collected by means of questionnaires. These questionnaires will be completed during the 
second appointment or from home via eCRF (Red Cap). 
4.3.3 Randomization and Intervention 
Participants will be randomized into either the intervention group (EMDR treatment) or the wait-list control group. 
Assessors who ascertain the primary outcome variable, i.e. CAPS scores, will be blind to the subject's treatment 
condition. Randomization will be conducted by a person  of the study team. After randomization, the intervention 
(EMDR therapy) will be carried out according to section 3.4.  
4.3.4 Post Treatment and 6-months Follow-up (a/b): Post-intervention measurements 
After the intervention (week 12), procedures of assessment 2 related to primary and secondary endpoints (i.e., CAPS, 
psychophysiological reactivity, psychometry, blood and saliva sampling) will be repeated as well as life style behavior 
will be reassessed. In order to test whether the effects of EMDR-treatment are long-lasting, measurements will be 
repeated at 6-months follow-up. Assessors who ascertain the primary outcome variable, i.e. CAPS scores, will be blind 
to the subject's treatment condition. Participants from the control group will receive an information letter stating that 
they can undergo an EMDR- treatment after the follow-up and that they can register in advance for registration. 
 
Reimbursement 
After the fasting blood collection, a light /standardized breakfast containing of two rolls and an apple and water/non-
caffeinated tea or coffee will be served. Compensation of CHF 150 will be provided for complete study participation. 
Drop-outs will not be compensated. 
 
Covid-19 plan 
As long as there is a risk of a COVID-19 infection, all assessments with physical contact, including EMDR therapy, are 
carried out according to the detailed COVID-19 action plan (for further information see appendix cover letter). 
 
4.4 Measurement procedures and instruments 
4.4.1 CAPS-5 
The German version of the CAPS-5 [33, 34] will be administered to assess the presence of full PTSD.  The CAPS will 
be administered by licensed and trained psychiatrists or psychotherapists from our department.  
4.4.2 Loud-tone procedure 
The loud-tone procedure is a standardized procedure to assess stress sensitization of the central and autonomic 
nervous system. Auditory stimuli will consist of 500 msec, 95 db sound pressure level, white noise bursts presented 15 
times with inter-trial intervals pseudorandomly varying between 16 and 36 sec. Subjects will be instructed to keep their 
eyes open. Stimuli will be presented through over ear headphones. For the loud-tone procedure to work, subjects will 
be required to detect 25 db tones in both ears. Therefore, monaural audiometric testing will be conducted before the 
loud-tone procedure using 125, 250, 500, 1000, 2000, 4000, and 8000 Hz tones. Psychophysiological data acquisition 
will be the same as in our previous studies [35]. 
 
4.4.3 Cardiovascular parameters, stress hormones  
To assess cardiovascular parameters, 2x 5ml of venous blood will be collected in appropriate tubes. Measures of a 
prothrombotic state (D-dimer, PAI-1, fibrinogen) and of endothelial dysfunction (soluble tissue factor, VWF antigen, 
soluble ICAM-1)) will be determined in citrate plasma using the Clauss method (for fibrinogen) or commercial ELISA 
kits (D-dimer, PAI-1, VWF antigen, soluble tissue factor, soluble ICAM-1). Inflammatory markers will be measured in 
EDTA plasma with Luminex technology with magnetic bead-based immunoassays (IL-6, TNF-α) and with a high 
sensitivity reagent set for CRP (Beckman Coulter). Metabolic factors (total cholesterol, LDL cholesterol, HDL 
cholesterol, triglycerides, glucose, glycosylated hemoglobin A1c) will be measured in serum using Cobas standard test 
kits (Roche Diagnostics). Our lab has long-standing and extensive expertise in collecting, measuring and interpreting 
these biochemical measures. The inflammatory markers will be incorporated in the task and resting state imaging 
models as predictors of treatment response.  
Venous blood and saliva will be collected in appropriate tubes to assess stress hormone levels. Epinephrine and 
norepinephrine concentrations will be quantified in EDTA plasma using high-pressure liquid chromatography and 
electrochemical detection. To assess cortisol levels, saliva will be collected and stored at -20°C until analyzed using 
high performance liquid chromatography. Moreover, the systolic and diastolic blood pressure will be measured. 
4.4.4 Psychometric data 
Screening instruments 
- 
PTSD Checklist for DSM-V (PCL-5): The third part of the PCL-5 will be used to screen for patients for a 
probable PTSD diagnosis. It comprises 20 items rated on a 5-point Likert-scale [27, 28]. 
- 
Mini International Neuropsychiatric Interview (M.I.N.I.): We will apply the German version of the M.I.N.I to 
assess the 17 most common mental health disorders. The M.I.N.I. is a 30 minutes structured psychiatric 
diagnostic interview. We will apply the German adaptation of the M.I.N.I based on DSM-IV (or DSM-V if it is 
available until the beginning of the study) [36]. 

 
 
12 
 
Additional parameters (covariates and for exploratory purposes) 
T2 = Baseline (week 4), T3 = Post Treatment (week,12), T4 = 6-months Follow-up (week 36) 
 
T2 
T3 
T4 
Psychiatric symptoms and disorders 
 
 
 
Patient Health Questionnaire (PHQ-9) [37], Generalized Anxiety Disorder module (GAD-7) from 
the Patient Health Questionnaire [38, 39] Maastricht Vital Exhaustion Questionnaire (MQ) [40], , 
Atypical depression (IDR-SR), Adjustment Disorder (ADNM-20) 
x 
x 
x  
Personality 
 
 
 
Type D scale (DS14) [41, 42], Wagnild & Young Resilience Scale (RS) [43, 44]), Toronto 
Alexithymia Scale (TAS-20) [45] 
x 
 
 
 
 
 
 
 
 
 
 
Cardiac-related variables 
 
 
 
Perceived threat during cardiac event [14], Enhancing Recovery in Coronary Heart Disease 
Patients (ENRICHD) Social Support Inventory (ESSI), which has been designed to rate 
emotional, structural and instrumental support [46]; Life Events Checklist – DSM 5 (LEC-5) [47] ( 
x 
 
 
Brief self-rated revised illness perception questionnaire (BIPQ-R) [48], Heart Drawings [49], 
EuroQol group 5-dimension questionnaire (EQ-5D-5L) [50], Anxiety Sensitivity Index 
x 
x 
x 
*Purpose in Life Questionnaire, Short Form Health Survey (SF-12), Positive and Negative Affect 
Schedule (PANAS), Life-Orientation-Test – Revised (LOT-R) 
x 
 
 
 
*We will validate the questionnaire “Purpose in Life Questionnaire”. For construct validity, we will assess the Short Form Health 
Survey (SF-12), Positive and Negative Affect Schedule (PANAS), Life-Orientation-Test-Revised (LOT-R).  
4.5 Withdrawal and discontinuation 
A participant will be withdrawn from the project in the following cases: 1) Aggravation of the psychiatric or physical 
condition in the course of participation (as determined by the participant or by the investigator); 2) decision of the 
participant to withdraw informed consent; 3) non-compliance with the study protocol. If necessary, supportive 
measures will be taken (e.g., emergency service of the USZ). Data collected to this time point will be included in the 
analysis. Participants have been informed in the informed consent form that, after withdrawal, their data will neither 
be destroyed nor anonymized. 
13 STATISTICS AND METHODOLOGY 
5.1. Statistical analysis plan  
Data will be analyzed using SPSS Statistics 25 or higher (SPSS Inc. Chicago, IL) or R [51] with significance level set 
at p<0.05 (two-tailed). Before analysis, all continuous variables will be tested for normality by the Kolmogorov-
Smirnov test and, if necessary, transformed to obtain a normal distribution. Linear mixed models with three time 
points (assessments 1-3) as within-subject factors and the two groups (intervention vs. waitlist control) as between-
subject factors will be applied to test for differences in primary and secondary outcomes between assessments and 
groups, probably taking sociodemographic, medical and psychometric covariates into account. The interaction effect 
between time and group is relevant to evaluate for different development depending on group membership. These 
models will be calculated for patients completing the intervention program per protocol (PP) as well as for those with 
intention to be treated at baseline (ITT). Probably the models will be controlled for differences in outcome measures 
at baseline. P-values will be adjusted for multiple tests according to Holmes-Bonferroni. An interim analysis will be 
conducted with 10 participants each group for using as pilot data to apply for a Swiss National Foundation grant.  
5.2. Handling of missing data and drop-outs 
We assume 15% of patients will drop-out after informed consent. Thus, we will recruit 30 patients per group instead 
of 25 minimally needed according to power analysis. Probably ITT-analyses will include missing replacement by last-
observation-carried-forward (locf).  
6 
REGULATORY ASPECTS AND SAFETY 
6.1 Local regulations / Declaration of Helsinki 
This research project will be conducted in accordance with the protocol, the Declaration of Helsinki [52], the principles 
of Good Clinical Practice, the Human Research Act (HRA) and the Human Research Ordinance (HRO) [53] which 
supports particularly Clinical Trials Ordinance (ClinO) as well as other locally relevant regulations. The Project Leader 
acknowledges his responsibilities as both the Project Leader and the Sponsor. 
6.2 (Serious) Adverse Events 

 
 
13 
 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation subject which does 
not necessarily have a causal relationship with the trial procedure. An AE can therefore be any unfavorable or 
unintended finding, symptom, or disease temporally associated with a trial procedure, whether or not related to it. 
A Serious Adverse Event (SAE) (ClinO, Art. 63) is any untoward medical occurrence that 1) results in death or is life-
threatening, 2) requires in-patient hospitalization or prolongation of existing hospitalization, 3) results in persistent or 
significant disability or incapacity, or 4) causes a congenital anomaly or birth defect. The Sponsor-Investigator makes 
a causality assessment of any SAEs to the trial intervention (see table below based on the terms given in ICH E2A 
guidelines). Any event assessed as possibly, probably or definitely related is classified as related to the trial 
intervention. 
 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
The Sponsor-Investigator makes a severity assessment of the SAE as mild, moderate or severe. Mild means the 
complication is tolerable, moderate means it interferes with daily activities and severe means it renders daily activities 
impossible.  
Reporting of SAEs (see ClinO, Art. 63,) 
All SAEs are documented and reported immediately (within a maximum of 24 hours) to the Sponsor-Investigator of the 
study. If it cannot be excluded that the SAE occurring in Switzerland is attributable to the intervention under 
investigation, the Sponsor-Investigator reports it to the Ethics Committee via BASEC within 15 days. 
6.3 (Periodic) safety reporting 
An annual safety report is submitted once a year to the local Ethics Committee by the Sponsor-Investigator (ClinO, Art. 
43 Abs). 
6.4 Amendments 
Substantial changes to the project set-up, the protocol and relevant project documents will be submitted to the Ethics 
Committee for approval according to HRO Art. 18 before implementation. Exceptions are measures that have to be 
taken immediately in order to protect the participants. 
6.5 (Premature) termination of study 
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances, e.g. ethical 
concerns,, insufficient participant recruitment, when the safety of the participants is doubtful or at risk (e.g. when the 
benefit-risk assessment is no longer positive), alterations in accepted clinical practice that make the continuation of the 
study unwise, or early evidence of harm or benefit of the experimental intervention. Upon regular study termination, the 
Ethics Committee is notified via BASEC within 90 days (ClinO, Art. 38). Upon premature study termination or study 
interruption, the Ethics Committee is notified via BASEC within 15 days (ClinO, Art. 38). For the notification of 
completion, discontinuation or interruption of the clinical trial, the respective templates on www.swissethics.ch will be 
used. Upon project termination, data will be stored according to the guidelines for archiving research data of the 
Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine (USZ) for the duration of at least 10 years 
at the Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine. 
6.6 Insurance 
In the event of project-related damage or injuries, the liability of the Zürich Versicherungs-Gesellschaft AG (Police-
Nummer: 14.970.888, “Versicherung für klinische Versuche und nichtklinische Versuche“) provides compensation, 
except for claims that arise from misconduct or gross egligence. The insurance certificate is being submitted online to 
the ethical committee along with this proposal. 

 
 
14 
 
7 
FURTHER ASPECTS 
7.1 Overall ethical considerations 
Social / scientific value: Cardiac events are highly prevalent and a leading cause of death in Western societies. The 
experience of cardiac events may have substantial psychological consequences such as intense fear of dying and 
distress resulting in PTSD. In addition to poor quality of life and impaired mental health, cardiac-induced PTSD is 
associated with a twofold increased risk of adverse clinical outcomes including major adverse cardiac events, 
cardiovascular-related hospital readmissions and all-cause mortality. Currently, patients with cardiac-induced PTSD 
are not routinely offered trauma-focused therapies, with a lack of scientific evidence likely being one major reason for 
this omission. To generate evidence on how to best treat cardiac-induced PTSD, the here proposed project wants to 
investigate the effectiveness of EMDR therapy, which is, according to the WHO, the therapy of choice in traditional 
PTSD. For cardiac-induced PTSD, EMDR may be most promising: The EMDR protocol includes the assessment of 
body sensations associated with the target event, which is followed by reprocessing. The bilateral eye movements 
during reprocessing seem to have de-arousing effects [22] and may thereby interrupt the positive feedback loop 
between cardiovascular sensations and anxiety-induced arousal [19] as explained by the enduring somatic threat 
model. If our randomized-controlled trial proves EMDR to be an effective treatment for the reduction of PTSD symptoms 
in patients with cardiac events, EMDR could be implemented as a first-line treatment. This knowledge might inform 
larger trials to test whether poor prognosis following major adverse cardiovascular events can be improved through 
EMDR in patients with cardiac events and other types of cardiac-induced PTSD.  
Justification of the inclusion of vulnerable participants: Patients suffering from PTSD can be considered vulnerable and 
should be treated carefully. As EMDR is already well established and the therapy of choice for the treatment of PTSD, 
no harm is to be expected. Moreover, it has already been implemented in patients with PTSD resulting from other 
cardiac events, where EMDR was accepted by patients, emotional arousal was tolerable, and no cardiac complications 
occurred during EMDR confrontation [21].  
Justification of the study design: In order to investigate the efficacy of EMDR, it is inevitable to include subjects with 
PTSD and assign them to a control group (wait-list group). Hence, participants in the control group may be at a 
disadvantage. However, this disadvantage is only temporary, as they are offered EMDR therapy on traumatic events 
upon completion of the study in week 36. 
7.2 Risk-benefit assessment  
The EMDR therapy follows an established standardized protocol, is widely used, and is a well-tolerated procedure. No 
serious adverse events with EMDR therapy were observed. Earlier studies with cardiac patients have shown that EMDR 
was accepted by patients, emotional arousal was tolerable, and no cardiac complications occurred during EMDR 
confrontation. Moreover, patients participating in this study may immediately benefit from EMDR treatment. The 
reactivation of traumatic memories can cause a minimal and transient burden for patients with PTSD. The collection of 
biological samples (saliva, blood) and health-related personal data (psychophysiological data: HR, BP, HRV, 
psychometric data from questionnaires) is not associated with any risks and burdens. Moreover, patients participating 
in this study may benefit from the EMDR therapy in different ways. EMDR may reduce posttraumatic stress symptoms 
like hyperarousal and re-experiences and enhance an adaptive dealing with ongoing threats. In addition, EMDR may 
improve quality of life, reduce distress, and minimize avoidance behaviors. This facilitates regular intake of medications 
and enhances cardiac treatment adherence (regular physical activities). Moreover, if treatment is successful, it may 
have a positive impact on the cardiac prognosis, which in turn can reduce medical costs. Hence, we see a favourable 
risk-to-benefit ratio for the here proposed study.  
8 
QUALITY CONTROL AND DATA PROTECTION 
8.1 Quality measures  
All study procedures will be carried out under the close supervision of the principal investigator. Staff members 
complete the Good Clinical Practice (GCP) basic courses. Furthermore, only licensed and trained 
psychotherapists/psychiatrist will perform the CAPS-5 interview.  
All EMDR psychotherapists are certified in EMDR therapy and will be supervised by Dr. Michael Hase, an 
experienced EMDR therapist.  
On a regular basis, quality control will be carried out (e.g., investigation and assurance of the quality of data 
collection, entry, and processing). Study procedures will be documented (i.e., research activities such as trainings 
and supervision, quality controls, important project-related decisions, or decisions of participants to withdraw from the 
study) to ensure the transparency and replicability of the study for third parties. For quality assurance the Ethics 
Committee may visit the research sites. Direct access to the source data and all project related files and documents 
must be granted on such occasions. 
8.2 Specification of Source Documents 
The following documents are considered source data, including but not limited to: 1) SE and other worksheets, 2) 
electronic master file data; 3) clinical information system (“KISIM”) data 
Source data will be available at the site to document the existence of the study subjects and substantiate the integrity 
of study data collected. Source data will include the original documents relating to the study. 

 
 
15 
 
The following information (at least but not limited to) will be included in the source documents: 1) demographic data 
(age, sex, education, occupation, marital status); inclusion and exclusion criteria details; 3) participation in study and 
signed and dated Informed Consent Forms, 4) visit dates, 5) SEs (related) and concomitant medication, 6) reason for 
premature discontinuation  
8.3 Data recording 
Medical records will be collected using hospital charts (i.e., the Klinikinformationssystem; KISIM) and will from there 
be transferred into REDCap, the electronic Case Report Form (eCRF). Data obtained during the screenings at 
assessment 1-3 (CAPS-5, M.I.N.I., screening questions) will be documented on work sheets and consecutively be 
transferred into the eCRF. Data from blood and saliva (e.g., stress hormones, cardiovascular biomarkers) will be 
analyzed and relevant parameters for the final statistical data analyses will be recorded in the eCRF. Data from 
psychometric questionnaires will directly be entered into the eCRF by the participants. To that end, participants 
complete all questionnaires in REDCap (they will only have access to the questionnaire forms). REDCap was 
developed by an informatics core at Vanderbilt University in 2004, with ongoing support from US National Center for 
Research Resources (NCRR) and US National Institute of Health (NIH), grants NIH/NCATS UL1 TR000445. 
REDCap was specifically developed around HIPAA security guidelines and is GCP-compliant and fulfills the Swiss 
regulatory requirements regarding the collection of patient data in clinical trials or non-interventional studies and 
patient registries and the Swiss/EU data protections laws. 
In contrast to other source data, psychophysiological data will be recorded by coded identification (e.g. subject 
identification number), which allows storing on special storage locations, such as network attached storage or 
external hard drives. The large amount of these types of data cannot be stored on regular servers of the University 
Hospital Zurich where the other source data are stored. 
8.4 Confidentiality and coding 
Health-related personal data and biological material will be handled with uttermost discretion and is only accessible to 
authorized personnel who require the data to fulfil their duties within the scope of the research project. Data and 
biological material will be stored according to HRO, art. 5, at the Department of Consultation-Liaison Psychiatry and 
Psychosomatic Medicine of the USZ.  
To ensure confidentiality, personal data and biological material will be coded. Participants are only identified by a 
unique participant number. The assignment of the number to the participant is safely stored according to HRO, art. 5, 
at the Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine and protected against unauthorized 
access.  
Personal data and biological material will only be disclosed in case of an emergency, if disclosure is necessary for the 
protection of the physical and psychological integrity of the participant, or if there is a legal basis. Appropriate coded 
identification (e.g. pseudorandomization) is used in order to enter subject data into the database. All data entered into 
eCRFs is transferred to a mySQL database using encryption post filtering and sanitization to various relational database 
tables. The server hosting the EDC system and the database is kept in an off-site locked server-room. Only system 
administrators have direct access to the server and back-up tapes. 
 
8.5 Retention of study data and biological material 
Health-related personal data are stored for a minimum of 10 years after publication of the research project either 
electronically or in physical folders at the Department of Consultation-Liaison Psychiatry and Psychosomatic 
Medicine of the USZ. Only members of the project have access to these datafiles (with the exception of data from 
KISIM, to which attending medical staff of the USZ has access). Health-related personal data involves the following 
source data: 1) medical records (stored in KISIM), 2) paper-pencil data from screenings and assessments (CAPS-5, 
M.I.N.I., etc., stored in a physical or electronic folder); 3) physiological data (heart rate, skin conductance, etc., stored 
electronically); 4) psychometric questionnaires filled out by study participants (directly via eCRF).  
The psychometric questionnaires will be securely stored by CTU Zürich for at least 15 years (after the regular end or 
a premature termination of the respective study). The sponsor further maintains essential documents and source data 
and archives interim and final reports in electronic format for at least 10 years. 
For eligible participants who have been evaluated at the pre-screening procedure but are not included in the study (due 
to them not meeting the eligibility criteria), all data will be stored in the same way as for study participants. Biological 
materials (e.g., frozen plasma and saliva samples) will be coded and stored at a -80° freezer at the Department of 
Consultation-Liaison Psychiatry and Psychosomatic Medicine of the USZ. Materials are stored for a minimum of 10 
years after publication of the research project. Destruction of materials will be done in accordance with biohazard 
requirements and documented in written form.  
9  MONITORING AND REGISTRATION 
Monitoring will be carried out under responsibility of the primary investigator according to the monitoring plan 
(attachment). The source data/documents and the eCRF are accessible to monitors and questions are answered 
during monitoring. The study will be registered at clinicaltrials.gov and SNCTP (Swiss National Clinical Trial Portal) 
upon approval of the study protocol by the KEK. 

 
 
16 
 
10 FUNDING / PUBLICATION / DECLARATION OF INTEREST 
The study is financed by intramural research funds of the Department of Consultation-Liaison Psychiatry and 
Psychosomatic Medicine of the USZ and private research foundations. Data will be published in major peer-reviewed 
cardiovascular, psychiatry/psychosomatic and general medical journals. On reasonable request and after presenting 
a proper research question and analytic plan, data access will be granted to interested researchers outside the study 
team (in close collaborations (e.g., authorship policy) and with the agreement of the local ethics committee only). 
11 ADDITIONAL SIGNATURES 
 
The external supervisor confirms hereby to participate in the study team and acts as a supervisor for the EMDR 
treatment in online videoconference meetings with the study therapist(s). 
 
 
External supervisor: 
 
Name: Dr. Michael Hase, OFA d.R., Psychiater - Psychotherapie - Akupunktur, Associate Editor European Journal of 
Trauma and Dissociation, EMDR Senior Trainer, Lüneburger Zentrum für Stressmedizin, Dorette-von-Stern-Strasse 
14, 21337 Lüneburg 
 
 
Date: 
17.05.2022 
 
Signature: 
 
 
 
 

 
 
17 
 
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2. 
Edmondson, D., An Enduring Somatic Threat Model of Posttraumatic Stress Disorder 
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3. 
Fait, K., et al., Cardiac-disease-induced PTSD and Fear of illness progression: Capturing 
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4. 
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von Känel, R., et al., Non-fatal cardiovascular outcome in patients with posttraumatic 
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Edmondson, D., et al., Posttraumatic stress due to an acute coronary syndrome 
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Edmondson, D., et al., Posttraumatic stress disorder prevalence and risk of recurrence 
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Shapiro, F., Eye movement desensitization: a new treatment for post-traumatic stress 
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Taylor, S., et al., Comparative efficacy, speed, and adverse effects of three PTSD 
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