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European Journal of Heart Failure 9 (2007) 1212 – 1222
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Rationale and design of a randomised, controlled, multicenter trial
investigating the effects of selective serotonin re-uptake inhibition
on morbidity, mortality and mood in depressed
heart failure patients (MOOD-HF) ☆
Christiane E. Angermann a,⁎,1 , Götz Gelbrich b,1 , Stefan Störk a , Andreas Fallgatter c ,
Jürgen Deckert c , Hermann Faller d , Georg Ertl a
on behalf of the MOOD-HF Investigators
a
University of Würzburg, Department of Internal Medicine I/Center of Cardiovascular Medicine, Würzburg, Germany
b
University of Leipzig, Coordination Centre for Clinical Trials, Leipzig, Germany
c
University of Würzburg, Department of Psychiatry and Psychotherapy, Würzburg, Germany
d
University of Würzburg, Institute of Psychotherapy und Medical Psychology, Würzburg, Germany
Received 22 March 2007; received in revised form 21 September 2007; accepted 17 October 2007
Abstract
Background: Depression and chronic heart failure (CHF) are common conditions, both of which are clinically and economically highly relevant.
Major depression affects 20–40% of CHF patients and predicts adverse outcomes in terms of quality of life, morbidity and mortality as well as
health care expenditure, independent of other factors of prognostic relevance.
Aims: The purpose of the MOOD-HF trial is to clarify whether antidepressant pharmacotherapy improves outcome in CHF patients, and if so by
which mechanism(s).
Methods: MOOD-HF is a prospective, randomised, double-blind, placebo-controlled, 2-armed, parallel-group multicenter trial investigating the
effects of the serotonin re-uptake inhibitor (SSRI) escitalopram on morbidity and mortality (primary endpoint), severity of depression, anxiety,
cognitive function, quality of life and health care expenditure in 700 patients with symptomatic systolic CHF and major depression diagnosed by
structured clinical interview. All patients will receive optimised pharmacotherapy for CHF. Duration of follow-up, including close safety
monitoring, is 12–24 months from randomisation.
Perspective: MOOD-HF is the first prospective randomised controlled trial to assess the effects of antidepressant pharmacotherapy on hard somatic
endpoints, the mechanism(s) of action of SSRI treatment, as well as safety in New York Heart Association functional class II-IV CHF patients. The
results are expected to promote the development of evidence-based recommendations for managing depression in the context of CHF.
Trial registration: ISRCTN.org. Identifier: ISRCTN33128015
© 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Depression; Chronic heart failure; Selective serotonin re-uptake inhibition; Prognosis; Quality of life; Cost effectiveness
☆
This study is funded by the German Ministry of Education and Research
(BMBF, project number GFVT01024505) and registered with number
ISRCTN33128015 as a controlled clinical trial.
⁎ Corresponding author. Klinikstrasse 6-8, D-97070 Würzburg, Germany.
Tel.: +49 931 20170450; fax: +49 931 20171240.
E-mail address: [email protected]
(C.E. Angermann).
1
Both authors contributed equally to this work.
1. Introduction
Major depression affects 20–40% of patients with chronic
heart failure (CHF) [1–4] and is 4–5 times more common in
CHF than in the general population [5]. Recently published
1388-9842/$ - see front matter © 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2007.10.005
C.E. Angermann et al. / European Journal of Heart Failure 9 (2007) 1212–1222
baseline data from the MIND-IT trial indicate that after
myocardial infarction, the prevalence and severity of depression are interrelated with the degree of cardiac dysfunction and
CHF development [6]. In patients with CHF, depression was
associated with higher short and long-term morbidity and
mortality rates [7–9] and also worse outcome in terms of
health-related quality of life and health care expenditure
[2,10].
1.1. Pathophysiological implications of depression in
cardiovascular disease
The adverse effects of depression in cardiovascular disease
(CVD) may be mediated by shared pathophysiological
mechanisms. We have previously demonstrated in an
experimental model that in CHF natriuretic peptides may be
specifically altered in brain areas regulating blood pressure
and fluid control [11]. Drugs commonly used in CHF may
reverse these changes [12]. Central natriuretic peptides
represent an antagonistic principle against pressure and fluid
retention neurotransmitters [13], but have also been shown to
be associated with mental and emotional changes in CHF
patients [14]. Depression may contribute to dysregulation of
the autonomic nervous control in CHF, resulting in reduced
parasympathetic and increased sympathetic tone, which is
known to increase resting heart rate, decrease heart rate
variability, and lower the threshold for myocardial ischaemia
and adverse cardiac events in patients with CVD [15–17].
Augmented sympathetic tone is also associated with increased
levels of plasma cortisol [15], serotonin, renin, aldosterone,
angiotensin and free radicals [5]. Elevated levels of circulating
catecholamines may induce a pro-coagulant state by enhancing platelet activation through direct agonist effects [18,19],
and may inhibit vascular synthesis of protective eicosanoids
by increasing haemodynamic stress on the vascular wall [20].
Further, diminished inhibition of macrophage activation via
cholinergic anti-inflammatory pathways may contribute to an
elevation of pro-inflammatory markers such as C-reactive
protein (CRP) and cytokines such as IL-1β, IL-6, and TNF-α
in depression. Administration of tumour necrosis factor
(TNF)-α to healthy volunteers not only resulted in elevated
extracellular serotonin levels [21], but also in depressed mood,
sleep disorders and general malaise. From experimental
research, there is strong evidence for an important modulating
role of the immune system in the interrelationship between
depression and CVD, acting via the hypothalamic–pituitary–
adrenal axis and the autonomic nervous system (reviewed
in [22]).
However, firm clinical evidence corroborating these
suggestive experimental findings is lacking. Most clinical
studies were case-controlled or cross-sectional and did not
control for behavioural mediators such as poor treatment
adherence. Although multiple interrelations between emotions
and cardiovascular pathophysiology have been demonstrated,
to date, a causal relationship has not been established in
humans.
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1.2. Treatment trials in depressed patients with
cardiovascular disease
Three major randomised outcome trials of antidepressant
therapy in patients with CVD have been published. The
SADHART trial proved safety and efficacy of the selective
serotonin re-uptake inhibitor (SSRI) sertraline in depressed
patients after myocardial infarction, but was underpowered to
detect a survival benefit [23]. In a similar patient population,
the ENRICHD trial showed that cognitive behavioural therapy
plus optional SSRI treatment improved depression but not
survival [24]. A recent post-hoc analysis of ENRICHD revealed, however, that the risk of reaching a hard cardiovascular endpoint was significantly lower in patients receiving
SSRI compared with those on placebo [25]. Both SSRI and
structured psychotherapy were effective in relieving major
depression symptoms in patients without comorbid CVD [26].
The MIND-IT trial evaluated the presence of depression in
patients with a recent myocardial infarction, and also compared antidepressant pharmacotherapy with care as usual. The
first-choice treatment was double-blind placebo-controlled
administration of the selective noradrenalin re-uptake inhibitor
mirtazapine. In case of refusal or insufficient treatment
response after eight weeks, open treatment with the SSRI citalopram was offered. Over an 18 month observation period,
antidepressants did not alter long-term depression and also did
not improve cardiac prognosis [27]. A post-hoc analysis of the
MIND-IT trial comparing responders to antidepressant
medication with either non-responders or untreated control
subjects provided preliminary evidence that non-response to
treatment and thus persistence of post-myocardial infarction
depression may be associated with an even increased cardiac
event rate [28]. The recent CREATE trial documented safety
and antidepressant efficacy of citalopram, which, in contrast
to interpersonal psychotherapy, had a significantly better
response rate than placebo in patients with chronic CVD [29].
The duration of this trial was too short, however, to elucidate
effects on cardiovascular event rates. The only published
evidence in depressed patients with CHF originates from a
recent small randomised study with a 12 week observation
period comparing the SSRI paroxetine (controlled-release)
with placebo in 28 patients with NYHA II or III CHF. In this
study, a higher recovery rate from depression CHF was observed in the intervention arm [30]. To the best of our
knowledge, no larger randomised outcome trials to evaluate
either treatment efficacy with regard to depression or longterm effects on somatic endpoints of antidepressant medications have been carried out or are under way in patients with
symptomatic CHF comprising also advanced CHF stages. The
ongoing SADHART Congestive Heart Failure study, which
compares treatment with either sertraline or placebo, is including only CHF patients in NYHA functional class II.
Accordingly, we have designed a large randomised
placebo-controlled trial to investigate MOrbidity, mOrtality
and mood in Depressed Heart Failure patients (MOOD-HF),
testing the hypothesis that the SSRI escitalopram would
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C.E. Angermann et al. / European Journal of Heart Failure 9 (2007) 1212–1222
improve outcome in depressed patients with NYHA II to IV
CHF and impaired LV systolic function.
2. Design of the MOOD-HF trial
MOOD-HF is an investigator-initiated prospective, randomised, double-blind, placebo-controlled, 2-armed, parallelgroup, multicenter, phase IV clinical trial, using an approved
drug, escitalopram, for an indication covered by the approval.
Although approval of escitalopram is backed by consistent
data showing efficacy, safety and tolerability in otherwise
healthy subjects with depression, data in patients with physical
comorbidities such as CHF are less clear. The aim of the
MOOD-HF study is to test the safety and efficacy of escitalopram with respect to mortality, morbidity, severity of
depression, anxiety, cognitive function, quality of life, and
health care expenditure, as well as to surrogates known or
presumed to possess clinical and/or prognostic relevance in
CHF. The anticipated duration of the entire trial is 36 months
with a projected minimum/maximum intervention period per
patient of 12/24 months, respectively, followed by a one
month down-titration phase.
2.1. Patient selection criteria
Table 1 lists the study inclusion and exclusion criteria.
Patients with symptoms of CHF (≥NYHA II) of any
aetiology, a left ventricular ejection fraction (LVEF) b 45%
and a Diagnostic & Statistical Manual-IV diagnosis of a
current episode of major depression based on the structured
clinical interview for depression (SCID) [31], will be included.
The study aims to recruit a representative sample of the ‘real
world’ adult CHF population characterised by a high prevalence of suspected major depression according to the Patient
Health Questionnaire (PHQ-9 [32]), multiple comorbidities
and high mortality and morbidity. Therefore, exclusion criteria
have been kept to a minimum.
2.2. Study flow: screening, randomisation, treatment and
follow-up
Fig. 1 shows details of the study flow. Eligible patients enter
step 1 of the screening process for depression, by answering the
PHQ-9 [32]. Patients with a PHQ-9 sum score of N 11 are
suspected to suffer from a current episode of major depression.
These patients qualify for step 2 of the screening process and
will undergo a Structured Clinical Interview (SCID [31]). The
SCID will be performed by a certified expert at least 14 days
after the PHQ-9 testing, to confirm major depression according
to the Diagnostic & Statistical Manual of Mental Disorders [31].
If current major depression is verified, all other inclusion and
exclusion criteria will be reviewed and the patient will be
familiarised with the concept of the MOOD-HF trial. Informed
consent will be obtained the next day. No patient will undergo
any study-related procedures before his/her written informed
consent has been given. Randomisation will take place at visit 1.
Table 1
Key inclusion and exclusion criteria for patients in the MOOD-HF trial
Inclusion criteria
Age N 18 years.
Systolic CHF of any aetiology (≥NYHA II and LVEF b45%).
Diagnostic and Statistical Manual-IV diagnosis of current episode of
major depression based on the SCID.
Provision of written informed consent.
Exclusion criteria
Recent history of acute myocardial infarction (b3 months) or acute
cardiac decompensation.
Recent (b3 months) or planned major cardiac surgery
(within next 12 months).
Advanced renal failure (GFR-MDRD b30 ml/min/1.73 m2), advanced
hepatic dysfunction or other medical contraindication against treatment
with SSRI.
Significantly reduced life expectancy due to other co-morbidity
(e.g. malignancy).
Use of any antidepressants including SSRI, lithium, or anticonvulsants for
mood disorder.
Currently undergoing any form of psychotherapy.
Absence of response to a previous adequate trial
of escitalopram treatment.
History of early termination (b8 weeks) of escitalopram treatment
because of adverse event or adverse reaction.
SCID documented bipolar disorder, major depression with psychotic
features; evidence of substance abuse or dependency during the previous
12 months.
Serious suicide risk based on clinical judgement.
Participation in other trials involving intake of study medication.
Pregnancy or nursing.
Investigators judgment that patient is unable/unwilling to comply with the
study protocol (e.g. co-morbidity, inability to speak German,
lack of access to telephone).
NYHA, New York Heart Association; LVEF, left ventricular ejection
fraction; GFR-MDRD, estimated glomerular filtration rate according to the
MDRD study; SSRI, selective serotonin re-uptake inhibitor; SCID,
Structured Clinical Interview for Depression.
The study intervention consists of optimal cardiological
care, according to current treatment guidelines [33] for all
patients, plus either escitalopram 10–20 mg or placebo 10–
20 mg p.o. once daily. Study medication will be up-titrated and
CHF therapy optimised over 3 months. During this time
patients will be seen at 0.75, 1.5 and 3 months (±2 days, visits
2–4; Fig. 1). Telephone monitoring of depression and cardiac
state will be performed weekly during up-titration and
bimonthly thereafter. Maintenance therapy will first be
evaluated after 6 months (visit 5). Thereafter, visits will take
place at 6-month intervals (visits 6–8). Patients will attend for
at least 6 visits, resulting in a minimum follow-up time of
12 months. Subjects recruited early in the trial will be
followed-up for longer (up to 24 months). Prior to downtitration, patients will be re-evaluated once more by MADRS
[34]. The decision to recommend open post-study antidepressant therapy will be based on these MADRS results. The
timing of patient assessments during the study is shown in the
trial flow diagram (Fig. 1). Scheduled safety and secondary
efficacy measures are described in more detail in Table 2.
C.E. Angermann et al. / European Journal of Heart Failure 9 (2007) 1212–1222
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Fig. 1. Study flow of the MOOD-HF trial. PHQ, Patient Health Questionnaire; MADRS, Montgomery Asberg Depression Scale; PHQ-GAD, Patient Health
Questionnaire on General Anxiety Disorder; MMSE, mini mental state examination; QoL, Quality of Life; SCID, Structured Clinical Interview for Depression.
2.3. Patient safety
The MOOD-HF study has reliable safeguards built-in to
assure patients' safety in both trial arms. The study drug will be
given on top of evidence-based, guideline-adjusted CHF therapy. The study protocol specifies careful up-titration of CHF
medication and regular monitoring of drug compliance with
cardiovascular medications besides supervision of the study
drug. Repeat determination of safety markers including natriuretic peptides during patients' visits to the study centres will
facilitate reliable CHF surveillance. Weekly telephone calls
during up-titration and bimonthly thereafter will (together with
repeat cardiac and depression assessment during the trial) ensure
timely recognition of worsening of the patients' mental and
physical state, and will facilitate close supervision of patients
particularly during the early treatment phase, thus accounting
for a possibly increased risk of suicide in the first weeks of
treatment with an SSRI [30]. Suspected suicidal tendencies or
significant worsening of depression will immediately initiate
pre-specified supportive strategies, such as psychiatric assessment and open pharmacological treatment according to the
patients' individual needs. The need for premature study termination will be a joint cardiological and psychiatric decision.
2.4. Sub-studies
There are four predefined sub-studies of MOOD-HF, which
are described briefly below.
SCREEN-MOOD: The objectives are to determine the
prevalence and positive predictive value of a PHQ-9 sum score
N 11 in a large cohort of patients with symptomatic systolic
CHF and to describe the correlation of the PHQ-9 sum score
and its positive predictive value with patients' sex, age and
NYHA class. All subjects entering screening step 1 will
participate in this sub-study.
THROMBO-MOOD: The objective is to investigate the
effect of escitalopram on platelet activation in depressed
patients with CHF. Consecutive subjects (n = 60) recruited
at the coordinating centre in Würzburg will be included.
Markers of platelet activation comprising platelet surface
expression of P-selectin and soluble CD40 ligand, binding
of fibrinogen to activated glycoprotein IIb/IIIa on the
platelet surface, and measurement of circulating platelet/
leucocyte and platelet/monocyte aggregates will be analyzed at baseline and after 6 months. In addition, soluble Pselectin, soluble CD40 ligand and thromboglobulin will be
determined in plasma.
VASO-MOOD: The objective is to assess vasoreactivity of
the dominant brachial artery and to relate baseline measurements and changes in vasoreactivity to the primary endpoint
and inflammation markers. Consecutive subjects (n = 100)
recruited at the coordinating centre in Würzburg will be included. The effects of escitalopram on endothelium-dependent
(flow-mediated) and -independent (nitroglycerin-induced)
vasoreactivity and concurrent changes in inflammation
markers and CHF severity will be determined at baseline
and after 6 months.
GENE-MOOD: Using polymerase chain reaction (PCR)
and matrix-assisted laser desorption/ionisation–time of flight
mass spectrometry (MALDI-TOF) techniques this sub-study
aims to investigate candidate gene polymorphisms that
predispose to depression in CHF, as well as polymorphisms
that determine the therapeutic response to escitalopram.
Objectives are a) to determine whether selected polymorphisms
in candidate genes are associated with an increased risk for
depression in CHF. Emphasis will be placed on candidate genes
which have already been linked to depression and CHF (e.g.,
ACE or NOS3); b) to investigate whether polymorphisms in
candidate genes affect plasma levels of escitalopram (pharmacogenomics, -kinetics); c) to test whether polymorphisms in
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C.E. Angermann et al. / European Journal of Heart Failure 9 (2007) 1212–1222
Table 2
Secondary efficacy measures of the MOOD-HF trial: domains, instruments, characteristics and targets
Domain
Instrument
Characteristics
Target
Symptoms
SF-36
KCCQ
PHQ-9
PHQ-GAD-7
MMSE
MADRS
SCID
Telephone questions
EuroQoL with SF-36
Clinical examination
SQ⁎, 36 items
SQ⁎; 23 items
SQ⁎; 9 items
SQ⁎, 7items
Therapist administered; 5 items
Therapist administered, 10 items
Standardised interview
Study nurse administered, 4 items
SQ⁎; 5 items & SQ⁎, 36 items
Blood pressure, BMI, waist–hip ratio,
NYHA class
Walking distance
Left ventricular dimensions & function
Basal heart rate, heart rate variability, arrhythmia
Total-, LDL-, HDL-cholesterol,
triglycerides
Natriuretic peptides, Troponins
Liver and renal profile,
glucose, electrolytes
Albumin/creatinine ratio
Norepinephrine excretion
Cortisol
Cortisol & aldosterone
–
–
CRP, uric acid, fibrinogen, TNF-α,
IL-6, IL-10, CD 40 L, sICAM
–
Escitalopram plasma levels
Compliance assessment
Health related quality of life
Disease-related quality of life
Vital exhaustion, depressive symptoms
Generalised anxiety symptoms
Cognitive function
Severity of depression
DSM-IV diagnosis of depression
Monitoring of general and emotional health
Health care utilisation
Classical risk factors
Heart failure severity
Physical capacity
Heart failure aetiology & severity
Autonomic dysfunction
Classical risk factors
Platelet surface: expression of P-selectin and
CD40 ligand, binding of fibrinogen to activated
GP IIb/IIIa; circulating platelet/leucocyte &
platelet/monocyte aggregates
Brachial artery vasoreactivity
Platelet function
Health economy
Somatic variables
6-minute walk test
Echocardiography
ECG & 24 h ECG
Blood sample
Clinical events
Study drug safety
Inflammatory/
endothelial markers
Study drug
compliance
Heart failure
medication
THROMBO-MOOD
sub-study (n = 60)
VASO-MOOD
sub-study (n = 100)
GENE-MOOD
sub-study
(all participants)
Urine sample
24 h urine sample
Saliva sample
Blood sample
CRF based questions
SUSAR reporting
Blood sample
Pill count
Blood sample
CRF based questions
Blood sample
High-resolution
ultrasound
Blood sample with
subsequent DNA
extraction
PCR and MALDI-TOF
Heart failure severity
Study drug safety parameters
Classical risk factors
Neuroendocrinological function
Neuroendocrinological function
Neuroendocrinological function
Clinical events, rehospitalisation
Study drug safety
Psycho-immunological reactivity
Compliance with study drug
Compliance with study drug
Optimisation of heart failure pharmacotherapy
Arterial endothelial function
Determination of candidate gene
polymorphisms for disease
and drug response
SF-36, Short Form Health Survey -36; PHQ, Patient Health Questionnaire; MADRS, Montgomery Asberg Depression Scale; PHQ-GAD, Patient Health
Questionnaire on General Anxiety Disorder; KCCQ, Kansas City Cardiomyopathy Questionnaire; SCID, Structured Clinical Interview for Depression; SQ,
standardised questionnaire; MMSE, mini mental state examination; DSM, Diagnostic & Statistical Manual of Mental Disorders; QoL, Quality of Life; ECG,
electrocardiogram; NYHA, New York Heart Association; LDL, low density lipoprotein; HDL, high density lipoprotein; CRF, case report form; SUSAR, suspected
unexpected severe adverse reaction; TNF, tumour necrosis factor; IL, interleukin; sICAM, soluble intercellular adhesion molecule; sCD40L, soluble CD40 ligand;
DNA, deoxyribonucleic acid; PCR, polymerase chain reaction; MALDI-TOF, matrix-assisted laser desorption/ionisation–time of flight mass spectrometry.
candidate genes impact on the therapeutic response towards
escitalopram (pharmacogenomics, -dynamics). The panel of
candidate genes will focus on functional polymorphisms in the
serotonergic system (e.g., the serotonin transporter 5HTT,
5HT2a, and p11) (overview in [35]).
2.5. Outcome and efficacy measures
The primary efficacy endpoint of MOOD-HF is time to
the first event of either all-cause death or unplanned
hospitalisation. Domains, instruments, characteristics and
targets of secondary efficacy variables are listed in Table 2.
Outcome variables will be assessed at inclusion, and at all
or some of the following time points as appropriate: 0.75,
1.5, 3, 6, 12, 18 and 24 months. These time points represent
up-titration of cardiac medication and of escitalopram with
evaluation of safety and antidepressant efficacy (visits 1–3)
and follow-up visits (visits 4–8) with assessment of cardiac
and psychological well-being. Physical and mental wellbeing will also be ascertained by telephone-monitoring
at weekly or bimonthly intervals depending on the study
phase using the PHQ-2 [36] and selected questions
regarding CHF signs and symptoms. All endpoints will
also be analysed according to sex and age.
C.E. Angermann et al. / European Journal of Heart Failure 9 (2007) 1212–1222
2.6. Sample size considerations and power analysis
According to the literature and our own data, a 45% annual
event rate for the composite endpoint of morbidity and
mortality is assumed during the natural course in our target
population. We anticipate a 20% relative reduction of the event
rate by study participation per se (due to superior CHF therapy
and monitoring). Thus, the expected event rate in the placebo
group is 36%. Since a more than 2-fold event rate has been
observed in depressed compared with non-depressed CHF
patients [3], 18% of the events may be attributable to
depression. We assume that in the intervention group the
annual excess event rate due to depression is reduced to one
half or 27% by escitalopram. Observation of the first and last
patient will last 24 and 12 months, respectively. A 15% annual
drop-out rate is anticipated. Setting the type I error level at 5%
and the power to detect a difference in event rates (36 vs. 27%)
at 80%, 700 patients need to be randomised.
2.7. Primary efficacy analysis
For the primary efficacy analysis the log-rank test for
Kaplan–Meier estimates for event-free survival will be used.
This analysis includes all randomised patients according to the
intention-to-treat principle. Ambiguous cases will be decided
on by the Cardiovascular Endpoint Committee, which will
also advise regarding sensitivity analyses when an informative
drop-out (i.e., related to a foreseeable event) is suspected and
is blinded to group assignment. Secondary analyses of the
primary endpoint include Cox regression to identify and adjust
for covariates of the primary endpoint (e.g. sex, age, severity
of depression and CHF).
2.8. Safety analysis
Analyses will include: group comparison by Fisher's exact
test for frequency of particular adverse events; analysis of
variance for severity of adverse events and left ventricular
ejection fraction; Fisher's exact test for frequencies of, and
(if there are enough events) logistic regression to predict dropout, reduced compliance with CHF medication, and the need
for additional psychiatric intervention. A logistic regression
using interaction terms will be employed to test for sex related
differences in adverse reactions.
2.9. Secondary endpoints
Kaplan–Meier analysis for time to cardiovascular death or
hospitalisation, extended multiple-state Kaplan–Meier analysis
[37] for combined death and multiple hospitalisations, and time
alive out of hospital will be applied. Analysis of covariance will
be used to assess changes in depression and quality of life, and
for biological variables and pill count, as well as correlation
coefficients for the description of the relation between drug
plasma levels and biological variables. Multi-level graph-based
regression models will be employed to describe multivariate
1217
dependencies. Economic evaluation will examine whether the
costs of antidepressant therapy are outweighed by savings
resulting from a treatment-related reduction of clinical events
as well as by improved quality of life.
3. Discussion
Depression is a frequent co-morbidity and has an adverse
prognosis in CHF [3,7], but it remains unrecognised and
untreated in most cases. Cardiologists are aware of the pathogenetic impact of various lifestyle behaviours and often
attempt to manage problems such as overeating, physical
inactivity and smoking, but they rarely assess and treat
psychosocial risk factors. This may be partly a result of limited
awareness, but is probably also due to the lack of convincing
evidence for the efficacy of antidepressant treatment strategies
in CHF patients regarding hard clinical end points. If
depression is diagnosed, the choice of therapy will largely
depend on clinicians' preference and experience with pharmacological or non-pharmacological treatment options. Neither current German nor European [33] guidelines for CHF
management provide specific handling directives for patients
with CHF and depression.
MOOD-HF will investigate a vulnerable cohort requiring a
dedicated interdisciplinary approach. The trial was initiated by
cardiologists with a study design tailored to the specific
medical needs of patients with CHF irrespective of commercial interests. Close cooperation with psychiatrists and/or
psychosomatic specialists will ensure expert guidance on and
evaluation of SSRI treatment and facilitate successful testing
of the study hypotheses. MOOD-HF will, for the first time,
address hard somatic endpoints in patients with CHF NYHA
II-IV rather than only psychometric variables measuring improvement of depression, anxiety or cognitive function.
3.1. Rationale of the MOOD-HF trial
In patients with CHF, no efficacy data regarding hard clinical
endpoints are available for any treatment modality of
depression. Considering i) the very large population at risk
qualifying for treatment in case of a positive study outcome,
ii) the physical incapacity of most elderly individuals with
advanced CHF precluding repeat visits to specialists, and iii) the
frequency of cognitive impairment in CHF [38,39], we propose
to evaluate antidepressant pharmacotherapy rather than psychotherapy vs. placebo on top of optimal CHF care according to
current guidelines [33] for all patients. Careful frequent
monitoring of the effects of CHF therapy, study medication
and of treatment safety will be complemented by optional
expert psychiatric support. Published evidence suggests that
SSRI are safe in patients with coronary artery disease
[4,23,29,40] and may favourably influence the mortality risk
by improving health behaviour and/or via direct modulation of
biological pathways. While some markers reflecting these
biological systems seem to vary with the severity of depression,
others may independently impact on prognosis. For example, a
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platelet sub-study of the SADHART trial demonstrated that
sertraline treatment in patients with coronary artery disease
was associated with diminished platelet/endothelial activation
despite co-administration of antiplatelet regimens including
aspirin and clopidogrel [41]. In addition, a large retrospective
study in patients with an acute coronary syndrome treated with
an SSRI showed a significant reduction in recurrent
myocardial ischaemia, heart failure or asymptomatic enzyme
elevation at the expense of a significantly higher bleeding rate
[42]. Correspondingly, the THROMBO-MOOD sub-study
will prospectively address the effects of escitalopram on
platelet function and determinants of plasmatic coagulation in
patients with CHF and thus at increased thromboembolic risk.
3.1.1. Rationale for the use of escitalopram
Escitalopram oxalate is the S-enantiomer of the racemic
bicyclic phthaline derivative citalopram and is approved in
Germany for treatment of major depression and anxiety. The
mechanism of its antidepressant action is presumed to be
linked to enhanced serotoninergic activity in the central nervous system, resulting from inhibition of neuronal re-uptake of
serotonin. Escitalopram has very little effect on other
receptors, rendering it the most selective SSRI so far. Escitalopram is N100 times more potent than the R-enantiomer; its
plasma concentration is approximately 1/3 of the total citalopram concentration indicating that the other 2/3 are biologically inactive [43]. Escitalopram was chosen in MOODHF for its superior efficacy, as demonstrated in a meta-analysis
of N 2000 patients treated with different antidepressants [40],
in conjunction with a more rapid onset of action, more
favourable side-effect profile compared with other compounds
(e.g. tricyclic antidepressants), and a relative lack of toxicity in
overdose. Also, its low potential for drug–drug interactions
renders escitalopram attractive in patients with CHF who are
usually taking multiple concomitant medications. Although
escitalopram is safe if contraindications are respected, safety
issues are reflected in the design of MOOD-HF by i) stepwise
up-titration of study medication, and ii) telephone-monitoring
of patient psychological and somatic well-being at short
intervals during the up-titration period.
3.1.2. Rationale for the use of placebo
We consider it ethically justified to withhold escitalopram
from a control population of depressed CHF patients. Currently, there is no established reference treatment for patients
with CVD in general and CHF in particular who suffer from
depression as co-morbidity. It remains to be demonstrated
whether the efficacy and tolerability of escitalopram are
superior to treatment with a pill-placebo in these patients, who
are usually elderly and multimorbid, show some degree of renal
failure, may suffer from diabetes, and take numerous other
medications. In contrast, optimised CHF care as offered to all
study participants is associated with a proven survival benefit
[33]. This constitutes an additional ethical justification for the
trial. In order to ensure the maximum safety for study
participants, the study schedule includes pre-specified support-
ive and therapeutic strategies including individualised psychiatric management. The need for premature study termination
will be a joint cardiological and psychiatric decision.
3.2. Hypotheses of the MOOD-HF trial
The major hypothesis of the MOOD-HF trial is that longterm therapy with escitalopram in patients with symptomatic
systolic CHF is safe and improves outcome defined as a
prolongation of the time to a first clinical event (death or
unplanned hospitalisation). We further hypothesise that
treatment with escitalopram improves depression as assessed
by serial PHQ-9- and MADRS- testing, anxiety as assessed by
the PHQ-GAD-7, cognitive function as assessed by the minimental state examination (MMSE) [38], generic quality of life
as assessed by the SF-36, and disease-related quality of life as
assessed by the KCCQ, the German version of which has been
validated by our group [44]. Further, we will test the
hypothesis that escitalopram increases the number of patient
days spent alive outside the hospital and reduces cardiovascular mortality and morbidity. By prospectively measuring a
variety of clinical and biological factors related to adverse
prognosis in patients with CVD and depression, we should be
able to generate and support new hypotheses for the biological
mechanism(s) by which escitalopram may improve outcome
in depressed CHF patients.
3.2.1. Endpoint selection
Time to the first event of either death or unplanned
hospitalisation was chosen as the primary efficacy endpoint of
the MOOD-HF trial because it likely reflects the improvement
of patient well-being with the greatest sensitivity in a
population prone to hospitalisation or even CHF-related
death. All-cause (not cardiovascular) events were chosen in
order to avoid components of subjective assessment in the
primary endpoint in this multimorbid patient population.
Hospitalisation is an important component of the primary
endpoint, because depression is associated with 26–29%
excess costs for CHF hospitalisation in this patient population
[10] thus representing a key issue also for health economy. We
are aware that effects might be seen in only one component of
the combined endpoint, leading to a non-significant result in
the primary analysis. However, because little is known in this
research area we regard MOOD-HF as explorative rather than
confirmatory in this respect. ‘Days alive out of hospital’ is
perhaps the most relevant endpoint from the patients'
perspective, but was still specified as a secondary efficacy
measure because it may reflect not merely clinical but also
administrative aspects of hospitalisation due to the diseaserelated groups policy in Germany. ‘Cardiovascular mortality’
and ‘cardiovascular morbidity’ were also categorised as
secondary endpoints. These endpoints will be ascertained by
the Cardiovascular Endpoint Committee.
Changes in the MADRS, PHQ-9, PHQ-GAD-7 and MMSE
scores were selected as major secondary efficacy endpoints.
The MADRS is a 10-item therapist-administered psychometric
C.E. Angermann et al. / European Journal of Heart Failure 9 (2007) 1212–1222
tool measuring the direct effects of the intervention on
depression. Its use is particularly advantageous in patients
with somatic comorbidities, because it contains few somatic
items and is, therefore, not very sensitive to drug side-effects or
disease-related physical symptoms [45]. The self-administered
PHQ-9 questionnaire represents a widely used validated
instrument for depression diagnosis and serial monitoring
with proven responsiveness to antidepressant medication with
an SSRI [46]. The PHQ-GAD-7 has recently also been
recommended for the self-assessment of CHF patients when
anxiety was also recognised as important with regard to
prognosis [47]. During telephone-monitoring, the PHQ-2
serves as a brief multipurpose measure adequate for detection,
grading and monitoring of depression [29]. The MMSE is a
neuropsychological test with proven capability to quantify
cognitive impairment in patients with CHF and also assess
reversibility [38]. Changes in depression, anxiety and cognitive
function have been categorised as secondary, because the
principal efficacy of SSRI in improving these endpoints has
been established in other cohorts including patients with CVD
[6,29]. The variable ‘change in depression’ is assumed to act as
a mediator between the intervention and the primary endpoint.
Amongst the other secondary endpoints ‘quality of life’ is
particularly relevant for the patients. The SF-36 is widely
employed for quantitative assessment of generic quality of life
facilitating the comparison with other cohorts, whereas the
KCCQ facilitates assessment of disease-related quality of life.
We expect that improvement of depression due to pharmacotherapy with escitalopram will also result in improved quality
of life. Health economy assessment will allow assessment of
the cost effectiveness of escitalopram treatment [2,10]. This
information will be derived from demographic data, clinical
and treatment information, SF-36 and EuroQol [48]. Adherence to study medication will be ascertained by pill counting.
Adherence to CHF medication will be assessed from a detailed
history of the type and dosage of cardiovascular drugs taken.
This will allow us to clarify whether improvement in
depression increases compliance with CHF pharmacotherapy,
and/or conversely whether adverse reactions to escitalopram
treatment would possibly reduce compliance. Determination
of escitalopram plasma levels will not only ascertain
compliance with the study medication but also facilitate
correlation of escitalopram plasma concentrations with
antidepressant efficacy, and investigation of the interrelationship between escitalopram plasma levels and changes in
surrogate markers of the pathogenesis of CVD and CHF.
4. Perspective
Apart from a favourable individual risk–benefit ratio for
patients participating in the MOOD-HF trial, a yield regarding
future management strategies for the CHF population as a
whole may be expected. MOOD-HF has the potential to
impact significantly on CHF management practice guidelines
by (i) proving the safety and antidepressant efficacy of the
SSRI escitalopram in the entire symptomatic CHF population
1219
and (ii) by elucidating the pathophysiological links between
depression and CVD thus potentially also promoting
evidence-based management strategies for patients suffering
from both conditions.
5. Role of the funding sources
The investigator-initiated MOOD-HF study receives public
funding from the German Ministry for Education and
Research (BMBF, Project number GFVT01024505). Lundbeck A/S, Denmark, provides study medication and additionally contributes to case payment. Neither sponsor interfered in
any respect with the study design, or will influence data
collection, analysis and publication or interfere with the
investigators intellectual property rights.
Appendix A. The MOOD-HF Trial Study Group
A.1. Organigram of the structural components
of MOOD-HF
Fig. 2 illustrates the organisational and management
components of the MOOD-HF trial. We have established an
Independent Data Monitoring and Safety Committee
(DMSC) and an Independent Advisory Board. An Independent Endpoint Committee serves to supervise in particular the
endpoint ‘hospitalisation’ to guarantee careful and unbiased
interpretation. Major decisions within the trial will be reached
in close cooperation between the Coordinating Investigator,
the Steering Committee, and the Advisory Board. Names and
affiliations of all participants are given below.
Appendix B. Committees and offices
B.1. Study chair and co-chair
Christiane E. Angermann MD (Chair), Götz Gelbrich PhD
(Co-chair).
B.2. Clinical and Biometrical Coordinating Centers
Medical Clinic I, Cardiovascular Center, Würzburg
University, Stefan Störk MD, PhD (Clinical Coordinator);
Coordinating Center for Clinical Trials Leipzig University,
Oana Brosteanu PhD, Götz Gelbrich PhD (Biometry, PI of
SCREEN-MOOD-Substudy), Markus Löffler MD, PhD,
Christiane Prettin PhD (Coordinator of Data and Quality
Management).
B.3. Psychometric Core Laboratory and Training Center
Dept. of Psychiatry and Psychotherapy, Jürgen Deckert
MD, Andreas J. Fallgatter MD. Andreas Reif MD (Coordinator of GENE-MOOD-Substudy); Institute for Psychotherapy and Medical Psychology Hermann Faller MD, PhD,
Marion Schowalter PhD.
1220
C.E. Angermann et al. / European Journal of Heart Failure 9 (2007) 1212–1222
Fig. 2. Organisational and management components of MOOD-HF Study DMSC, Data Monitoring & Safety Committee.
B.4. Core Laboratory Heart Rate Variability/Arrhythmia
Appendix C. Clinical Trial Centers
Dept. of Cardiology, Humbold University Berlin, Charité
Mathias Rauchhaus MD, PhD.
C.1. University of Würzburg
B.5. Central Laboratory/Endocrinology/Escitalopram
Plasma Levels
Medical Clinic I, Cardiovascular Center, Würzburg University,
Bruno Allolio MD, Martin Eigenthaler MD, Ulrich Walter MD.
B.6. Steering Committee Members
Christiane E. Angermann MD, Georg Ertl MD, Jürgen
Deckert MD, Hermann Faller MD, PhD, Götz Gelbrich PhD,
Markus Löffler MD, PhD, Heribert Schunkert MD, Bernhard
Maisch MD, B. Pieske MD.
Medical Clinic I, Cardiovascular Center: Bruno
Allolio MD (Core Laboratory Endocrinology), Christiane
E. Angermann (Chair of MOOD-HF and local PI), Johann
Bauersachs MD (PI of THROMBO-MOOD Sub-study),
Georg Ertl MD, Stefan Störk MD, PhD (PI of VASOMOOD Sub-study, Ulrich Walter MD (Central Core
Laboratory).
Psychiatrist/Psychologist: Andreas J. Fallgatter MD,
Hermann Faller MD, PhD, Marion Schowalter PhD, Andreas
Reif MD (PI of GENE-MOOD sub Study)
C.2. University of Lübeck
B.7. Data and Safety Monitoring Committee Members
Medical Clinic II: Heribert Schunkert MD, Joachim Weil
MD (local PI).
Psychiatrist/Psychologist: Günter Jantschek.
Günter Breithardt MD, Martin Gottwik MD, Hans-Werner
Hense MD, PhD, Kurt Laederach MD, Bernd Löwe MD,
PhD.
C.3. University of Essen
B.8. Independent Advisory Board Members
Division of Cardiolog, Essen Cardiac Center: Raimund
Erbel MD, Till Neumann MD (local PI).
Psychiatrist/Psychologist: Irini Savidou MD.
Otto Hess MD, Uwe Siebert MD, PhD, Ulrich Hegerl MD.
C.4. Humbold University Berlin, Charité
B.9. Independent Endpoint Committee Members
Uta Hoppe MD, Siegfried Kropf PhD, Stefan Anker MD,
PhD.
Department of Cardiology: Rainer Dietz MD, Mathias
Rauchhaus MD, PhD (local PI).
Psychiatrist/Psychologist: Martina Rauchfuβ MD.
C.E. Angermann et al. / European Journal of Heart Failure 9 (2007) 1212–1222
C.5. Heart & Diabetes Center NRW, Bad Oeynhausen
Division of Cardiology: Dieter Horstkotte, MD, Barbara
Lamp MD (local PI).
Psychiatrist/Psychologist: Susanne Krappel.
C.6. University of Marburg
Division of Cardiology: Bernhard Maisch MD, Sabine
Pankuweit MD (local PI).
Psychiatrist/Psychologist: Beate Kolb-Niemann MD,
Thomas Meyer MD.
C.7. University of Göttingen
Division of Cardiology & Pneumonology: Gerd Hasenfuss
MD, Burkert Pieske MD (local PI).
Psychiatrist/Psychologist: Ullrich Buss MD, Christoph
Herrmann-Lingen MD.
C.8. University of Heidelberg
Theresienkrankenhaus Mannheim, Medical Clinic: Markus
Haass MD (local PI).
Psychiatrist/Psychologist: Florian Lederbogen MD.
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