Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02884141 |
| Other study ID # |
P071241-Arcadia |
| Secondary ID |
2009-A00288-49 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
August 25, 2016 |
| Last updated |
September 1, 2016 |
| Start date |
November 2009 |
| Est. completion date |
December 2014 |
Study information
| Verified date |
May 2016 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
France: Ministry of HealthFrance: Institutional Ethical Committee |
| Study type |
Observational
|
Clinical Trial Summary
ARCADIA is a national registry designed to document phenotypic and genetic traits in
patients with renal and/or cervical artery fibromuscular dysplasia (FMD).
FMD is a group of arterial diseases that most commonly involve renal and carotid arteries.
Patients with FMD may present with renovascular hypertension and/or with cerebrovascular
symptoms. Angiographic classification includes the multifocal type and the focal type. FMD
may affect one or more vascular beds and progress to more severe stenosis and to renal or
cerebrovascular complications. FMD may be familial (OMIM #135580).
Our main objective is to create a FMD registry that will collect standardized information
from all consenting patients diagnosed with the condition in 16 participating centers. This
registry, along with a collection of leukocyte DNA, will constitute a resource for further
clinical research on FMD. The first application will be the assessment of the frequency of
multi-site FMD, i.e. the frequency of cervical artery FMD in patients presenting with renal
artery FMD and vice-versa. The second application will be a case-control study to identify
susceptibility genes for FMD.
Patients are eligible in the registry if: (a) they have renal or cervical artery FMD with
either multifocal or focal lesions at CT-angiography, MR-angiography, or intra-arterial
angiography; (b) they give informed consent to leukocyte DNA analysis and to the collection
of bioclinical and morphologic information. Phenotypic assessment will be performed in
accordance with current recommendations and best clinical practice.
Given the multicenter nature of the study and the recruitment capacity of each centre,
enrollment of 500 FMD cases is expected over 5 years. This number will 1) allow an accurate
estimation of the frequency of multi-site FMD: when the sample size is 500, a two-sided 95%
confidence interval will extend 0.035 from the observed proportion for an expected
proportion of 0.20 based on a previous report and from our unpublished data. 2) In addition
to a collection of 400 renal FMD already collected at HEGP, give sufficient power for a
genome-wide association study seeking for susceptibility genes
Description:
1. Background
1. Definition
FMD is a group of nonatherosclerotic, noninflammatory arterial diseases that most
commonly involve the renal, cervical (carotid, and vertebral) arteries.
Histological classification discriminates three main subtypes, intimal, medial and
perimedial, which may be associated in a single patient. Angiographic
classification includes the multifocal type, with multiple stenoses and the
'string-of-beads' appearance that is related to medial FMD, and tubular and focal
types, which are not clearly related to specific histological lesions
(unclassified FMD).
Aneurysms and dissections are considered to be complications of FMD but frequently
arise in individuals with no FMD. Therefore, their presence without direct
evidence of FMD does not suffice to diagnose the condition.
2. Presentations
The prevalence of symptomatic renal artery FMD is about 4/1000 and the prevalence
of cervical FMD is probably half that.
Renovascular hypertension is the most common manifestation of renal artery FMD.
Multifocal stenoses with the 'string-of-beads' appearance are observed at
angiography in more than 80% of cases, mostly in women aged between 30 and 50
years; they generally involve the middle and distal two-thirds of the main renal
artery and in some case also renal artery branches. Spontaneous renal artery
dissections are rare but frequently coexist with FMD.
Cervical FMD can be complicated by dissection with headache, Horner's syndrome or
ischemic stroke, or associated with intracranial aneurysms. As intracranial
aneurysms may rupture and lead to subarachnoid haemorrhage, the American Heart
Association recommends performing magnetic resonance angiography (MRA) of
intracranial arteries in patients with cervical artery FMD.
Mesenteric and iliac arteries were examined during renal artery angiography and
cervical arteries were systematically examined using ultrasonography. In the
European Georges-Pompidou Hospital (HEGP) cohort (unpublished results), cervical
arteries were not systematically examined. The prevalence of diagnosed multi-site
FMD was 28.0% in the Zurich University Hospital study and 16.4% in HEGP patients.
This is probably a bottom estimate because most cervical artery FMD lesions affect
the C1-C2 segment of the carotid arteries, a segment difficult to examine using
ultrasonography. In order to estimate study power and the number of patients
needed, the prevalence is considered of multi-site FMD at 20-25%.
3. Diagnosis
The presence of renal artery FMD can be documented by the following non-invasive
tests, in increasing order of accuracy: Doppler ultrasound, gadolinium-enhanced
MRA, and computed tomographic angiography (CTA). Vasbinder et al. (2004)
prospective multicenter comparative study found that CTA and MRA had reasonably
good specificities for detecting renal artery stenosis due to FMD (92 and 84%,
respectively). There is no published comparative study of non-invasive tests for
detecting cervical artery FMD, although Doppler ultrasound may disclose irregular
patterns of stenosis that are suggestive. CTA and MRA are probably more effective
than ultrasonography for detecting lesions of the middle and distal portions of
the carotid and vertebral arteries and may also document or rule out associated
intracranial aneurysms.
The commonly accepted gold standard for diagnosing renal artery FMD is
intra-arterial angiogram with digital subtraction. However, this invasive test
should be reserved for patients in whom it is clinically justified to proceed with
revascularization in the same procedure. Stenosis quantification is, however,
frequently difficult in medial FMD with the "string-of-beads" appearance because
multiple web-like defects are often present in patients with FMD, contributing to
clinically significant stenoses that may not be apparent on angiography.
4. Management
The value of treatment has not been established for renal artery FMD without
hypertension. The management of hypertension associated with renal artery FMD
involves revascularization and/or antihypertensive medication. Current
recommendations reflect the knowledge acquired concerning atherosclerotic
renovascular hypertension, although indications for balloon angioplasty are wider
in FMD than in atherosclerotic renovascular disease because the BP outcome of
angioplasty is more favourable in FMD than in atherosclerosis. Revascularization
is recommended for patients with hemodynamically significant renal artery stenosis
- i.e. with bilateral stenoses or a unilateral stenosis causing more than 60%
reduction in luminal diameter - and accelerated hypertension, resistant
hypertension, malignant hypertension, hypertension with an unexplained unilateral
small kidney, and hypertension with intolerance to medication. It is also useful
in young patients with recent-onset hypertension and hemodynamically significant
renal artery stenosis due to FMD: in these cases the goal is to cure hypertension.
The standard revascularization procedure is balloon angioplasty with bailout stent
placement if necessary. Surgical reconstruction is indicated for patients with
complex FMD that extends to segmental arteries and those with macroaneurysms.
Antihypertensive drug treatment is indicated for patients with long-standing
hypertension or in those with persistent hypertension following revascularization.
Data on management of patients with symptomatic carotid or vertebral artery FMD
are scarce. Carotid or vertebral artery dissections are usually treated with
anticoagulation. In very rare patients with expanding or symptomatic
pseudo-aneurysm, percutaneous angioplasty or surgical repair can be considered.
5. Progression in FMD
Renal artery FMD may progress to more severe stenosis and to renal atrophy, and/or
to stenoses affecting more arteries within or outside the renal vasculature. The
risk of progression as assessed from available studies was probably overestimated
because documentation of progression was obtained from angiography, a procedure
which is not routinely undertaken in patients with favourable clinical and
biological outcomes. The disease is progressive, however, and a Slovut and Olin
overview (2004) stated that patients with FMD should undergo yearly duplex
ultrasonography to detect progression of disease, restenosis, or loss of kidney
volume.
There are very few data on prognosis of patients with symptomatic carotid or
vertebral artery FMD. The risk of arterial disease progression over time is
unknown. The risk of ischemic stroke ranged from 0 to about 3% per year in the few
studies which assessed that issue.
6. Best Clinical Practice
Published recommendations include:
- Screening for any cause of secondary hypertension - including renal artery
FMD - in case of juvenile, grade 3, malignant or resistant hypertension
- Irrespective of the severity of hypertension, screening for renal artery
stenosis in cases with a clinical clue for the condition, such as the
presence of paraombilical bruit or of asymmetrical kidneys
- Screening for cervical and intracranial FMD in case of renal artery FMD
- Renal revascularization in case of hemodynamic stenosis associated with
hypertension in a patient aged 30 or less, or associated with accelerated,
malignant or resistant hypertension, or associated with a small kidney or
treatment intolerance
- In case of documented renal artery FMD, providing follow-up of blood pressure
(BP), renal function and kidney height using ultrasonography on a yearly
basis or in case of hypertension persistence or recurrence following
revascularization, or in case with a poor control of BP.
In case of renal artery FMD progression, further renal imaging tests and renal
revascularization may be considered in accordance with the above indications for
revascularization. The investigators also consider that documented progression of
renal artery FMD is an indication to screen for new lesions or progression of
pre-existing lesions in cervical arteries.
7. Genetic factors
FMD appears to be a familial disease in 10% of cases (OMIM #135580). The
occurrence of renal FMD in sib pairs or identical twins first suggested its
possible inheritability. Our retrospective analysis of 104 patients with renal FMD
showed a prevalence of 11% for familial cases, i.e. 11% of cases had at least one
sibling with angiographic evidence of renal artery FMD. Using high-resolution
echo-tracking, elevated echo-tracking scores of the carotid artery in first-degree
relatives of index cases are also found. FMD is diagnosed earlier, renal artery
lesions are more frequently bilateral, and FMD lesions are more frequently found
in extra-renal arteries in familial than in apparently sporadic cases. The
presence of an underlying genetic disease could therefore be associated with
disease progression in FMD.
The investigators have already collected lymphocyte DNA and assessed baseline
characteristics, including renal artery morphology, in about 400 patients with
renal artery FMD who gave informed written consent to a familial study of renal
artery FMD (Sponsor INSERM, RBM#00-028, CPP Paris-Cochin). Data from patients
included in this previous study will be used for an extended case-control study.
8. Justification for an extended genome-wide study
As indicated above, several arguments exist for the presence of susceptibility genes
for FMD. Despite this evidence, only limited and negative candidate gene studies have
been conducted up to now, probably because of the low frequency of the disease, its
phenotypic heterogeneity and the absence of large national or international collection
of affected subjects. In the meantime, the knowledge acquired on the structure and
variations of the human genes by the Human Genome Project and the possibility of
rapidly genotyping hundreds or thousands of single nucleotide polymorphisms (SNPs)
through high-throughput technologies facilitate large case-control studies. Case
control studies are indeed powerful methods to investigate the implication of genetic
SNPs in complex traits. It can be applied either to candidate genes or through the
microarray technology. With this technique, it can test three to five hundreds of
thousands SNPs (300 to 500K) along the human genome (genome-wide association (GWA)
studies). Compared to candidate genes, GW-SNPs typing offers the advantage that new
pathways can be uncovered. Whereas this strategy usually requires large number of cases
and controls in complex traits, it has also been used with success for some categorical
traits in experimental settings investigating a small number of well characterized
subjects. To our knowledge, GWA studies have never been performed for FMD. The
collection of 400 FMD at HEGP together with the national prospective study now makes
this objective realistic.
2. Objectives of the ARCADIA registry
1. To collect standardized clinical, radiological, and biological data in patients
with FMD through a national registry.
The prospective collection of clinical, radiological and biological standardized
records should lead in a short period of time to a unique source of
well-phenotyped FMD cases that could help to standardize diagnostic and
therapeutic procedures at the national level. This unique database and
collaboration between centres will greatly stimulate basic, clinical and
therapeutic research and will help in the identification of new pathophysiological
mechanisms.
This collection of symptomatic patients will be established from centres dedicated
to hypertension care (renovascular lesions) or to cerebrovascular diseases care
(cervical lesions). It is expected to recruit 400 patients presenting with
renovascular lesions and 100 patients presenting with cervical FMD over three
years.
2. To estimate the prevalence of multiple sites disease, i.e. the prevalence of
cervical artery FMD in patients with renal artery FMD and vice versa.
As indicated above, screening for cervicocranial FMD is currently recommended in
patients with renal FMD. Although there is no similar recommendation to screen for
renal artery FMD in patients with cervical FMD, such screening is required at
least in patients with high blood pressure, i.e. with a clue for renovascular
disease. It is also useful in cases without definite hypertension as the presence
of renal artery FMD lesions would also help to confirm the FMD nature of cervical
lesions. The investigators therefore consider that a non-invasive investigation of
renal arteries in patients with probable or suspected cervical FMD reasonably
falls within best clinical practices.
3. To identify susceptibility genes for renal artery FMD and polymorphisms that could
play a role in disease progression and to assess potential phenotype-genotype
correlations.
4. To organize a clinical, radiological and biological database and a biobank that
will constitute a unique resource to initiate further clinical research.
Our goal is to share a common anonymous standardized database, the items of which have been
accepted by the participating centres, that will serve as a unique national FMD database
available for all Hypertension Reference Centres (ESH Hypertension Reference Centres) and
vascular neurologists involved in the study. The creation and the development of this
database will be a unique tool for future national studies and will stimulate similar
initiatives at the European level.
