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A De Paepe

Aeilko H Zwinderman

Barbara JM Mulder

BS Brooke

DM Milewicz

DP Judge

ER Neptune

F Ramirez

J De Backer

JP Habashi

L Faivre

LJ Meijboom

Maarten Groenink

Marieke JH Baars

P Lavoie

Piet de Witte

RD Cohn

Teodora Radonic

English

PubMed

BACKGROUND: Marfan syndrome (MFS) is one of the most common systemic disorders of connective tissue with the incidence of approximately 2-3 per 10 000 individuals. Aortic disease, leading to progressive aneurysmal dilatation and dissection is the main cause of morbidity and mortality of Marfan patients. Current treatment (e.g. beta blockers and elective surgery) does postpone but cannot prevent aortic complications in these patients. Recent studies have found transforming growth factor beta (TGF beta) to be involved in the aortic aneurysm formation. Losartan, an angiotensin II type 1 receptor blocker inhibits TGFbeta in a mouse model of Marfan syndrome leading to inhibition of aortic growth. The main objective of this trial is to assess whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome. METHODS/DESIGN: COMPARE study (COzaar in Marfan Patients Reduces aortic Enlargement) is an open-label, randomized, controlled trial with blinded end-points. Treatment with losartan will be compared with no additional treatment after 3 years of follow-up. We will enroll 330 patients with MFS who will be randomly assigned to receive losartan or not. Patients taking beta-blockers will continue taking their standard treatment. The primary end-point is the largest change in aortic diameter at any aortic level measured by means of MRI. Secondary end-points are change in mortality, incidence of dissection, elective aortic surgery, aortic volume, aortic stiffness and ventricular function. We will also investigate gene and protein expression change in the skin under losartan therapy and create prediction models for losartan-treatment response and aortic dilatation. DISCUSSION: The COMPARE study will provide important evidence of effects of losartan treatment in adult Marfan patient population. We expect losartan to significantly reduce the occurrence and progression of aortic dilatation. This trial investigates a wide spectrum of clinical, genetic and biochemical effects of losartan aiming to provide further insight in the pathogenesis and treatment of Marfan syndrome. TRIAL REGISTRATION: Netherlands Trial Register NTR142

Radonic, T.

Witte, P.

Baars, M.J.H.

Zwinderman, A.H.

Mulder, B.J.M.

Groenink, M.

International Migration, Integration and Social Cohesion online publications

Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial

Abstract Background Marfan syndrome (MFS) is one of the most common systemic disorders of connective tissue with the incidence of approximately 2-3 per 10 000 individuals. Aortic disease, leading to progressive aneurysmal dilatation and dissection is the main cause of morbidity and mortality of Marfan patients. Current treatment (e.g. beta blockers and elective surgery) does postpone but cannot prevent aortic complications in these patients. Recent studies have found Transforming Growth Factor β (TGF β) to be involved in the aortic aneurysm formation. Losartan, an Angiotensin II type 1 receptor blocker inhibits TGFβ in a mouse model of Marfan syndrome leading to inhibition of aortic growth. The main objective of this trial is to assess whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome. Methods/Design COMPARE study (COzaar in Marfan Patients Reduces aortic Enlargement) is an open-label, randomized, controlled trial with blinded end-points. Treatment with losartan will be compared with no additional treatment after 3 years of follow-up. We will enroll 330 patients with MFS who will be randomly assigned to receive losartan or not. Patients taking beta-blockers will continue taking their standard treatment. The primary end-point is the largest change in aortic diameter at any aortic level measured by means of MRI. Secondary end-points are change in mortality, incidence of dissection, elective aortic surgery, aortic volume, aortic stiffness and ventricular function. We will also investigate gene and protein expression change in the skin under losartan therapy and create prediction models for losartan-treatment response and aortic dilatation. Discussion The COMPARE study will provide important evidence of effects of losartan treatment in adult Marfan patient population. We expect losartan to significantly reduce the occurrence and progression of aortic dilatation. This trial investigates a wide spectrum of clinical, genetic and biochemical effects of losartan aiming to provide further insight in the pathogenesis and treatment of Marfan syndrome. Trial registration Netherlands Trial Register NTR1423.</p

Zwinderman Aeilko H

Baars Marieke JH

de Witte Piet

Radonic Teodora

Mulder Barbara JM

Groenink Maarten

Directory of Open Access Journals

Trials

Witte, P. de

Bouma, B.J.

Mulder, B.J.

Baars, M.J.

Timmermans, J.

Hamel, B.C.J.

Berg, M.P van den

Tintelen, P.J. van

Scholte, A.J.

Hilhorst-Hofstee, Y.

NARCIS 

Background: Marfan syndrome (MFS) is one of the most common systemic disorders of connective tissue with the incidence of approximately 2-3 per 10 000 individuals. Aortic disease, leading to progressive aneurysmal dilatation and dissection is the main cause of morbidity and mortality of Marfan patients. Current treatment (e.g. beta blockers and elective surgery) does postpone but cannot prevent aortic complications in these patients. Recent studies have found Transforming Growth Factor β (TGF β) to be involved in the aortic aneurysm formation. Losartan, an Angiotensin II type 1 receptor blocker inhibits TGFβ in a mouse model of Marfan syndrome leading to inhibition of aortic growth. The main objective of this trial is to assess whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome.Methods/Design: COMPARE study (COzaar in Marfan Patients Reduces aortic Enlargement) is an open-label, randomized, controlled trial with blinded end-points. Treatment with losartan will be compared with no additional treatment after 3 years of follow-up. We will enroll 330 patients with MFS who will be randomly assigned to receive losartan or not. Patients taking beta-blockers will continue taking their standard treatment. The primary end-point is the largest change in aortic diameter at any aortic level measured by means of MRI. Secondary end-points are change in mortality, incidence of dissection, elective aortic surgery, aortic volume, aortic stiffness and ventricular function. We will also investigate gene and protein expression change in the skin under losartan therapy and create prediction models for losartan-treatment response and aortic dilatation.Discussion: The COMPARE study will provide important evidence of effects of losartan treatment in adult Marfan patient population. We expect losartan to significantly reduce the occurrence and progression of aortic dilatation. This trial investigates a wide spectrum of clinical, genetic and biochemical effects of losartan aiming to provide further insight in the pathogenesis and treatment of Marfan syndrome.Trial registration: Netherlands Trial Register NTR1423

Radonic, Teodora

de Witte, Piet

Baars, Marieke J.H.

Zwinderman, Aeilko H.

Mulder, Barbara J.M.

Groenink, Maarten

Losartan therapy in adults with Marfan syndrome: Study protocol of the multi-center randomized controlled COMPARE trial

Baars, Marieke J. H.

Mulder, Barbara J. M.

null null

Springer - Publisher Connector

STUDY PROTOCOL Open Access
Losartan therapy in adults with Marfan syndrome:
study protocol of the multi-center randomized
controlled COMPARE trial
Teodora Radonic1*, Piet de Witte2, Marieke JH Baars3, Aeilko H Zwinderman1, Barbara JM Mulder2,
Maarten Groenink2,4, COMPARE study group
Abstract
Background: Marfan syndrome (MFS) is one of the most common systemic disorders of connective tissue with the
incidence of approximately 2-3 per 10 000 individuals. Aortic disease, leading to progressive aneurysmal dilatation
and dissection is the main cause of morbidity and mortality of Marfan patients. Current treatment (e.g. beta
blockers and elective surgery) does postpone but cannot prevent aortic complications in these patients. Recent
studies have found Transforming Growth Factor b (TGF b) to be involved in the aortic aneurysm formation.
Losartan, an Angiotensin II type 1 receptor blocker inhibits TGFb in a mouse model of Marfan syndrome leading to
inhibition of aortic growth. The main objective of this trial is to assess whether losartan treatment leads to a
clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome.
Methods/Design: COMPARE study (COzaar in Marfan Patients Reduces aortic Enlargement) is an open-label,
randomized, controlled trial with blinded end-points. Treatment with losartan will be compared with no additional
treatment after 3 years of follow-up. We will enroll 330 patients with MFS who will be randomly assigned to
receive losartan or not. Patients taking beta-blockers will continue taking their standard treatment. The primary
end-point is the largest change in aortic diameter at any aortic level measured by means of MRI. Secondary end-
points are change in mortality, incidence of dissection, elective aortic surgery, aortic volume, aortic stiffness and
ventricular function. We will also investigate gene and protein expression change in the skin under losartan
therapy and create prediction models for losartan-treatment response and aortic dilatation.
Discussion: The COMPARE study will provide important evidence of effects of losartan treatment in adult Marfan
patient population. We expect losartan to significantly reduce the occurrence and progression of aortic dilatation.
This trial investigates a wide spectrum of clinical, genetic and biochemical effects of losartan aiming to provide
further insight in the pathogenesis and treatment of Marfan syndrome.
Trial registration: Netherlands Trial Register NTR1423.
Background
Marfan syndrome (MFS) is one of the most common
systemic disorders of connective tissue with the inci-
dence of approximately 2-3 per 10 000 individuals [1].
MFS is an autosomal dominant disorder with cardinal
clinical features involving the cardiovascular, ocular and
skeletal systems. MFS is a clinical diagnosis which is
made when an index patient fulfils major criteria in two
systems and has an involvement in a third system
according to Ghent criteria[2]. Clinical features involve
ocular lens luxation, long bone overgrowth, lung emphy-
sema and cardiovascular complications including aortic
aneurysm and mitral valve prolaps.
Aortic disease, leading to progressive aneurysmal dila-
tation and dissection is the main cause of morbidity and
mortality of Marfan patients. Routine monitoring of aor-
tic growth is necessary to detect and quantify the pro-
gression of aortic dilatation, in combination with b
adrenergic receptor antagonist therapy to slow down
* Correspondence: t.radonic@amc.nl
1Department of Clinical Epidemiology, Biostatistics and Bioinformatics,
Academic Medical Center Amsterdam, the Netherlands
Radonic et al. Trials 2010, 11:3
http://www.trialsjournal.com/content/11/1/3
TRIALS
© 2010 Radonic et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
aortic growth[3]. Prophylactic aortic repair is indicated
when dilatation reaches sufficient size to threaten aortic
dissection[4]. Current therapy has improved life expec-
tancy of this group of patients. However, it is important
to note that even treated patients continue to have
abnormal aortic growth. Moreover, dissection may
occur in not-operated parts of the aorta. Therefore, cur-
rent treatment does postpone but cannot prevent aortic
complications in these patients.
MFS is caused by mutations in FBN1, the gene encoding
fibrillin-1, which is the main component of the extracellu-
lar matrix[5]. Fibrillin-1 was initially thought to play pri-
marily a structural role in connective tissue. Some of the
features of Marfan syndrome like lens luxation can be
explained by weakness of connective tissue due to a defect
fibrilline-1. However, this hypothesis was insufficient to
clarify the pathogenesis of other features, like bone over-
growth and facial appearance in these patients. The addi-
tional role of fibrilline-1 as a regulator of a cytokine
named Transforming Growth Factor b (TGF-b) emerged
[6-8]. TGF-b is a growth factor which is involved in many
biological processes including cellular proliferation,
deposition of the extracellular matrix, differentiation,
apoptosis etc [6-9]. In a mouse model of MFS, increased
TGF-b signaling appeared to play a causal role in many
phenotypic features of MFS like progressive aortic root
dilatation, defect lung development resulting in bullae for-
mation and failed muscle regeneration [6,7,9,10].
These new insights in the pathophysiology of MFS are
a major step forward in the understanding of connective
tissue disorders, offering new opportunities for treat-
ment of these patients.
Angiotensin II type 1 receptor (AT1) blocker losartan
was found to be potentially useful in MFS because it
leads to antagonism of TGF-b in animal models of
chronic renal insufficiency and cardiomyopathy[11].
Numerous studies describe the ability of losartan to
achieve a clinically relevant inhibition of TGFb. This led
to an assumption that losartan can treat or even prevent
some features of MSF. Promising preliminary results on
aortic dilatation inhibition have been achieved in a small
observational study with children with severe MFS[10].
MFS is a very pleiotropic disorder. Up-till now no
parameters of genotype-phenotype correlation have been
found [12]. Neither the location of the mutation nor the
type of aminoacid altered nor even the family presenta-
tion are sufficient to predict the phenotype both among
as within the affected families[13]. These findings sug-
gest that other genes may be involved in the pathogen-
esis modifying the phenotype.
Methods/Design
The COMPARE trial is an open-label, randomized, con-
trolled trial with blinded end-points. Treatment with
losartan will be compared with no additional treatment
after 3 years of follow-up. We will enroll 330 patients
with MFS who will be randomly assigned to receive
losartan or not. Patients taking beta-blockers will con-
tinue taking their standard treatment. This multi-center
study will be conducted in four academic centers in the
Netherlands: Academic Medical Center in Amsterdam,
University Medical Center St. Radboud in Nijmegen,
University Medical Center Groningen and Leiden Uni-
versity Medical Center. A flow chart of the study design
is shown in the Figure 1.
Objectives
Primary objective
The main objective of this study is to assess whether
losartan reduces aortic dilatation at any aortic level,
from the aortic root to the bifurcation. The primary
end-point is the largest aortic diameter at any level mea-
sured by means of Magnetic Resonance Angiogram
(MRA). If MRA is contraindicated, a Computed Tomo-
graphy (CT) will be performed.
We will therefore test the null hypothesis that there is
no significant difference in aortic diameters after 3 years
of follow-up in the treated and the control groups.
MRA’s will be assessed by a person who is blinded for
patient’s treatment.
Secondary objectives
The secondary objectives are to asses whether losartan
influences:
• Mortality, incidence of newly diagnosed dissection
in any main vessel and incidence of elective aortic
surgery combined into one event endpoint
• Aortic volume measured by means of MRA
• Aortic pulse wave velocity (PWV) and distensiblity
measured by means of Magnetic Resonance Imaging
(MRI)
• Ventricular function measured by means of MRI
Objectives of genetic expression studies
This study aims also to provide further understanding of
the pathofysiology of MFS. Skin samples will be used as
a model of the aortic tissue. We will assess gene expres-
sion in the skin samples of the treated patients at three
points: at baseline, after four weeks of treatment and
after one year of losartan treatment. Genome wide
expression will be measured to identify genes the
expression of which changes under losartan therapy.
The expression analysis is mainly exploratory and will
be performed also for pathways involved in the patho-
genesis of Marfan syndrome, i.e. TGF-b pathway.
Expression panels will be correlated with the rate of aor-
tic dilatation. Results will be used to build prediction
models of the losartan-therapy response and to identify
genes which may influence the phenotype. Results will
be validated in aortic tissue collected from Marfan
Radonic et al. Trials 2010, 11:3
http://www.trialsjournal.com/content/11/1/3
Page 2 of 5
patients operated in one of the four participating
centers.
Inclusion criteria are
- Diagnosis of MFS according to Ghent criteria
- Age ≥ 18 years
Exclusion criteria
- More than one vascular prosthesis
- Aortic root diameter > 50 mm
- Aortic dissection
- Renal dysfunction (creatinine > 130 μg/ml and/
or K > 5 mmol/ml)
- Treatment with Angiotensin-Converting
Enzyme (ACE) inhibitors or Angiotensin Recep-
tor Blockers (ARB’s)
- History of angioedema or other intolerance to
ACE-inhibitors and ARB’s.
- Intolerance of intravenous contrast for MRI/
CT.
- Aortic surgery within 6 months of inclusion
Eligible patients will be randomly assigned in a 1:1
ratio to receive losartan 2 × 50 mg or not. We will start
with 50 mg and double the dosage to 100 mg after 14
days. The maximal tolerable dosage will be continued.
Randomization is stratified according to site, with blocks
of 10.
Follow-up
After inclusion the following will be obtained during the
baseline investigations (V1):
Figure 1 Flow of participants, COMPARE study.
Radonic et al. Trials 2010, 11:3
http://www.trialsjournal.com/content/11/1/3
Page 3 of 5
• Patients medical history
• Echocardiography
• MRI or a CT of the heart and entire aorta
• Blood samples
• Punch skin biopsy
Patients will be evaluated after one, two and three
years of treatment by means of echocardiography. After
4 weeks and one year of the treatment an additional
skin biopsy will be obtained. At every visit, patient’s
medical history will be obtained. Date of dissection,
operation or death will be carefully noted.
The final assessment will be after 3 years of treatment
by means of MRI.
Ethical aspects and trial organization
The protocol has been approved by the Medical Ethical
Committee of the Academic Medical Center in Amster-
dam. The feasibility approvals have been obtained of all
the participating centers. This trial is registered in the
Netherlands Trial Register under number NTR1423.
Enrollment began in March 2008 and in October 2009
230 patients have been enrolled.
Statistical considerations
Mean change in aortic diameter in patients with MFS is
0.9-1.5 mm/year[4]. Sample size calculation is based on
the primary endpoint (rate of change of aortic diameter).
The expected difference between two groups is 0.5 mm/
year with a standard deviation of 1.5 mm (2-sided a =
0.05; b = 0.2). Based on these assumptions we calculated
that 286 patients are required. To compensate for an
estimated 20% drop-out, the inclusion of at least 330
patients is advised.
Primary analyses will be performed on an intention to
treat basis. To evaluate the primary end-point a covari-
ate analysis of the diameter change will be used in two
groups (no treatment vs losartan) at baseline and after 3
years. Covariate analyses will be also used for the follow-
ing secondary points: aortic volume, distensibility, pulse-
wave velocity, left and right ventricle volumes. “Safety
parameters” (i.e. mortality, dissections, surgery) will be
evaluated by means of a X2 test.
Discussion
COMPARE study will provide important evidence of
effects of losartan treatment in adult Marfan patients and
lead to evidence-based recommendations. It is of immense
importance for this trial to be conducted before Losartan
(Cozaar®), an existent anti-hypertensive drug, is subscribed
to Marfan patients based on promising preliminary results.
This study aims to provide further insight in the pathogen-
esis and genetics of Marfan syndrome unraveling the phe-
notype-genotype correlation and may provide more
evidence based support for the counseling of this group of
patients. Insights in the causes and treatment of the aortic
dilatation in MFS and therefore the integrity of vascular
wall can undoubtedly be extended to other common types
of aneurysm.
List of abbreviations
MFS: Marfan syndrome; TGF-b: Transforming Growth
Factor b; AT1: Angiotensin II type 1 receptor; MRA:
Magnetic Resonance Angiogram; CT: Computed Tomo-
graphy; PWV: Pulse wave velocity; MRI: Magnetic Reso-
nance Imaging; ACE: Angiotensin-Converting Enzyme;
ARB: Angiotensin Receptor Blockers.
Acknowledgements
This study is supported by the Interuniversity Cardiology Institute of the
Netherlands (ICIN) and Dutch Marfan Association.
The study is funded by the Dutch Heart Association, grant 2008B115.
COMPARE study group:
Teodora Radonic, Aeilko H. Zwinderman, Department of Clinical
Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center
Amsterdam, the Netherlands.
Piet de Witte, Berto J. Bouma, Barbara J. M. Mulder, Maarten Groenink,
Department of Cardiology, Academic Medical Center Amsterdam, the
Netherlands.
Marieke J. H Baars, Department of Clinical Genetics, Academic Medical
Center Amsterdam, the Netherlands.
Janneke Timmermans, Department of Cardiology, University Medical Center
St. Radboud, Nijmegen, the Netherlands.
Ben CJ Hamel, Department of Clinical Genetics, University Medical Center St.
Radboud, Nijmegen, the Netherlands.
Maarten P. van den Berg, Department of Cardiology, University Medical
Center Groningen, the Netherlands.
Peter J. van Tintelen, Department of Clinical Genetics, University Medical
Center Groningen, the Netherlands.
Arthur J. H. Scholte, Department of Cardiology, Leiden University Medical
Center, the Netherlands.
Yvonne Hilhorst-Hofstee, Department of Clinical Genetics, Leiden University
Medical Center, the Netherlands
Author details
1Department of Clinical Epidemiology, Biostatistics and Bioinformatics,
Academic Medical Center Amsterdam, the Netherlands. 2Department of
Cardiology, Academic Medical Center Amsterdam, the Netherlands.
3Department of Clinical Genetics, Academic Medical Center Amsterdam, the
Netherlands. 4Department of Radiology, Academic Medical Center
Amsterdam, the Netherlands.
Authors’ contributions
TR participated in design and execution of the trial and drafted this
manuscript. PW participated in execution of the trial. MB contributed to the
design of the trial. AZ participated in the design and methodological
considerations of the trial. BM participated in the design and coordination of
the trial. MG participated in conceiving and coordination of the trial.
Competing interests
The authors declare that they have no competing interests.
Received: 9 October 2009
Accepted: 12 January 2010 Published: 12 January 2010
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Cite this article as: Radonic et al.: Losartan therapy in adults with
Marfan syndrome: study protocol of the multi-center randomized
controlled COMPARE trial. Trials 2010 11:3.
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Radboud Repository

BJ: Aortic root growth in men and women with the Marfan’s syndrome.

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Dietz HC: Fibrillin-rich microfibrils: Structural determinants of morphogenetic and homeostatic events.

Dietz HC: Marfan’s syndrome. Lancet

HC: Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med

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Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial

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