Comparison of irbesartan vs felodipine in the regression after 1 year of left ventricular hypertrophy in hypertensive patients (the SILVER trial). Study of Irbesartan in Left VEntricular hypertrophy Regression

Abstract

The SILVER (Study of Irbesartan in Left VEntricular hypertrophy Regression) trial is designed to test the hypothesis that the newly developed angiontensin-II receptor antagonist, irbesartan, will produce a greater reduction in left ventricular (LV) mass than felodipine ER, in a population of hypertensive patients defined by seated diastolic blood pressure (SeDBP) in the range 95-115 mmHg or seated systolic blood pressure (SeSBP) in the range 160-200 mm Hg. A population of 360 men and women of non-childbearing potential, >18 years of age, with hypertension, newly diagnosed or after a 3-week washout from previous anti-hypertensive or vasodilator therapies, will be randomised at approximately 80-90 European sites. Add-on therapy with hydrochlorothiazide and atenolol will be allowed for blood pressure control. Patients will be studied by two-dimensional and M-mode echocardiography at baseline (central validation of LV hypertrophy), on randomisation day, and after 6 and 12 months randomised therapy. Blinded analysis of echocardiograms will be performed at a central laboratory, which will provide measurements of the LV mass index (LVMI), determined by M-mode readings according to Devereux formula and using the Penn convention. The primary end-point of the study will be the change in LVMI from baseline to 12 months. The study power is 90% to detect differences between groups from baseline of approximately 8 g/m2.

Full text

Journal of Human Hypertension (1998) 12, 479–483
 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00
http://www.stockton-press.co.uk/jhh
ORIGINAL ARTICLE
Comparison of irbesartan
vs
felodipine in
the regression after 1 year of left
ventricular hypertrophy in hypertensive
patients (The SILVER trial)
A Cohen
1
, B Bregman
2
, E Agabiti Rosei
3
, B Williams
4
, O Dubourg
5
, P Clairefond
2
,
P Brudi
2
, P Gosse
6
and P Gue
´
ret
7
1
Ho
ˆ
pital St-Antoine, Paris, France;
2
Bristol-Myers Squibb, Paris La De
´
fense, France;
3
Ospedali Civili,
Brescia, Italy;
4
Leicester Royal Infirmary, Leicester, UK;
5
Ho
ˆ
pital Ambroise-Pare
´
, Boulogne-Billancourt,
France;
6
Ho
ˆ
pital St-Andre
´
, Bordeaux, France;
7
Ho
ˆ
pital Henri-Mondor, Cre
´
teil, France
The SILVER (Study of Irbesartan in Left VEntricular
hypertrophy Regression) trial is designed to test the
hypothesis that the newly developed angiontensin-II
receptor antagonist, irbesartan, will produce a greater
reduction in left ventricular (LV) mass than felodipine
ER, in a population of hypertensive patients defined by
seated diastolic blood pressure (SeDBP) in the range
95–115 mm Hg or seated systolic blood pressure
(SeSBP) in the range 160–200 mm Hg. A population of
360 men and women of non-childbearing potential, ⬎18
years of age, with hypertension, newly diagnosed or
after a 3-week washout from previous anti-hypertensive
or vasodilator therapies, will be randomised at approxi-
mately 80–90 European sites. Add-on therapy with
Keywords: hypertension; left ventricular hypertrophy; angiotensin II receptor antagonists; echocardiography
Introduction
Numerous data are available which indicate that left
ventricular hypertrophy (LVH), as a complication of
hypertension,
1
is a major risk factor of life-threaten-
ing cardiovascular events.
2–4
To address this issue,
several studies investigated the positive effect of
anti-hypertensive therapy on LVH regression and
provided evidence that lowering blood pressure (BP)
is likely to induce a regression of LVH, in a first step
with uncontrolled, open, non-randomised data
5,6
obtained on small population size, then more
recently through larger scale, controlled, random-
ised, blinded studies.
7–9
Furthermore, this decrease
in LVH was associated with a reduced risk of cardio-
vascular morbidity and mortality events.
10–12
Additional studies are being carried out to test the
hypothesis that the regression of LVH on anti-hyper-
tensive treatment will lower the rate of morbid and
fatal cardiovascular events.
13
LVH regression was
observed with several anti-hypertensive drug
Correspondence: Professor Ariel Cohen, Ho
ˆ
pital St-Antoine, 184
rue du Faubourg St-Antoine, 75571 Paris Cedex 12, France
Received 5 February 1998; accepted 6 March 1998
hydrochlorothiazide and atenolol will be allowed for
blood pressure control. Patients will be studied by two-
dimensional and M-mode echocardiography at baseline
(central validation of LV hypertrophy), on randomisation
day, and after 6 and 12 months randomised therapy.
Blinded analysis of echocardiograms will be performed
at a central laboratory, which will provide measure-
ments of the LV mass index (LVMI), determined by M-
mode readings according to Devereux formula and
using the Penn convention. The primary end-point of the
study will be the change in LVMI from baseline to 12
months. The study power is 90% to detect differences
between groups from baseline of approximately 8 g/m
2
.
classes, such as diuretics,
8,9,14–16
␤
-blockers,
9,14,17,18
angiotensin-converting enzyme (ACE) inhibi-
tors
6,9,17,19
or calcium channel blockers.
8,20–22
It should be highlighted from these data that the
greater reduction of LVH was obtained after a fol-
low-up of 1 year
9,21
or even longer,
22
therefore far
longer than the follow-up required to observe a low-
ering effect on BP.
Angiotensin-II receptor antagonists are a new
class of anti-hypertensive agents currently under
investigation
31
already evidenced as at least equal
to ACE inhibitors,
24
calcium channel blockers or
␤
-
blockers.
25
Data which indicate that angiotension-II
receptor antagonists induce LVH regression are still
scarce and controversial.
26
However, recent evi-
dence indicates that in spontaneously hypertensive
rats, although an angiotensin-II receptor antagonist
lowered BP to a comparable degree compared to an
ACE inhibitor or calcium-channel blocker, it caused
regression of LVH to a greater extent than the lat-
ter.
27
Irbesartan (SR 47436;BMS 186295) is a new
anti-hypertensive agent
28–30
belonging to this
class.
31–33
The aim of the present study is to ascer-
tain the effect of irbesartan on LVH, versus a calcium
channel blocker, felodipine.
34,35
Felodipine was

Irbesartan: The SILVER Trial
A Cohen
et al
480
selected because it has been shown as effective in
the regression of LVH.
22,23
In addition, it offered the
possibility of titration, in parallel with the double-
blind titration of irbesartan.
36
Finally, few studies
are available comparing two anti-hypertensive
agents with such different pharmacological proper-
ties.
Subjects and methods
Study design
The SILVER trial is designed to test the following
hypothesis: administration of an irbesartan regimen
once daily for 12 months will produce a greater
reduction in LVH than a felodipine regimen admin-
istered once daily for 12 months in a patient popu-
lation with hypertension, defined by seated diastolic
BP (SeDBP) 95–115 mm Hg or seated systolic BP
(SeSBP) 160–200 mm Hg, associated with LVH.
Objectives
The primary objective is a comparison of the change
in left ventricular mass index (LVMI), measured by
echocardiography, following 52 weeks of once daily
therapy with either irbesartan regimen or felodipine
regimen in patients with hypertension. The second-
ary objectives: (i) the changes in LVMI after 24
weeks of either therapy regimen, (ii) the changes in
both SeDBP and SeSBP from baseline at 24 and 52
weeks, respectively, (iii) the safety and tolerability
of either therapy regimen during 52 weeks of treat-
ment, and (iv) the incidence of patients reporting
oedema related to study drug.
Study outline
The study schematic plan is shown in Figure 1.
SILVER is a randomised, double-blind, double-
Figure 1 Diagram showing the study schematic plan, with the screening and lead-in phases, followed by randomisation to irbesartan
or felodipine, as an elective titration followed by adjunction of open-label anti-hypertensive agents HCTZ then atenolol. (Abbreviations:
A25 = atenolol 25 mg; F5 = felodipine 5 mg; F10 = felodipine 10 mg, H12.5 = hydrochlorothiazide 12.5 mg; H25 = hydrochlorothiazide
25 mg; I150 = irbesartan 150 mg; I300 = irbesartan 300 mg).
dummy, parallel-group study, which will consist of
a 3-week (optional 4-week) single-blind placebo
lead-in period A (wash-out/qualification), followed
by a 52-week randomised, double-blind period B.
Blinded study medication will be electively titrated
according to the return of BP to normal values
(SeDBP ⬍90 mm Hg or SeSBP ⬍140 mm Hg). Echo-
cardiograms will be recorded at baseline, on day of
randomisation, and at 24 and 52 weeks of random-
ised therapy regimen. The study protocol was sub-
mitted and approved by all relevant ethical boards
and committees from the various European coun-
tries participating to the trial.
Subjects
A total of 360 men and women of non-childbearing
potential, aged ⬎18 years will be randomised to
either irbesartan or felodipine treatment regimens.
Patients will be selected on the basis of increased
echocardiographic LVMI, 116 g/m
2
in men and
104 g/m
2
in women.
3,11,37
Subjects will be screened
according to a newly diagnosed hypertension or
after washout from previous anti-hypertensive or
vasodilator therapies. A screening echocardiogram
will be performed by the investigating site and sent
to the central echocardiography laboratory for qual-
ity control assessment and confirmation that the
LVMI value meets the eligibility requirements of the
study. The central echocardiography laboratory will
provide the response to the investigating site within
5 working days starting from the receipt of the echo-
cardiography video tape at the central laboratory.
Inclusion and exclusion criteria
To enter the screening phase, patients must have
hypertension defined as SeDBP in the range 95–110
mm Hg (95–115 mm Hg for randomisation) or SeSBP

Irbesartan: The SILVER Trial
A Cohen
et al
481
in the range 160–200 mm Hg and provide written
informed consent. BP measurement guidelines rec-
ommend to obtain both SeDBP and SeSBP from
three replicate measurements performed at least
after 1-min intervals. Except for the screening BP
reading, all BP measurements will be made at
trough, ie, 24 ± 3 h after the last dose of the study
drug. SeDBP will be recorded at the cessation of
phase V Korotkoff sounds. Among the main
exclusion criteria, patients with severe BP, ie,
SeDBP ⬎115 mm Hg or SeSBP ⬎200 mm Hg, will
not be eligible to enter the study, as well as patients
having a history of coronary heart disease within 6
months, or cerebrovascular disease within 12
months, or clinically significant arrhythmias, or
heart failure evidenced by a left ventricular ejection
fraction ⬍40%.
Unpermitted concomitant medications will
notably comprise of all other anti-hypertensive or
vasodilator therapies, immunosuppressive agents,
long-term treatment with psychotropic drug ther-
apies, anti-convulsant agents, cimetidine, oral con-
traceptives, or steroid or adrenocorticotropic hor-
mone therapy. Echocardiographic causes of error in
LVMI measurement will be exclusions, ie, all
marked regional wall motion abnormalities, asy-
metric LVH (ratio septum/posterior wall ⬎1.5), sep-
tal subaortic hypertrophy, or ventricular dilatation
defined as left ventricular end-diastolic dilatation
⬎3.1 cm/m
2
.
Treatment regimens
Patients will start receiving single-blinded placebo
capsules for at least 3 weeks (optional 4 weeks), and
will have to show an 80–120% compliance assessed
by capsule count (period A). Randomised, blinded
treatment (period B) will be administered once daily
in the morning between 6 am and 10 am for 12
months. Patients will be randomised (1:1) to either
irbesartan 150 mg capsules or felodipine ER 5 mg
tablets. At their week 6 visit, or at anytime there-
after, patients with SeDBP ⭓90 mm Hg or SeSBP
⭓140 mm Hg will be titrated to either irbesartan
300 mg or felodipine ER 10 mg. At their week 12 and
week 18 visits, respectively, or at anytime thereafter,
patients with Se DBP ⭓90 mm Hg or SeSBP ⭓140
mm Hg will receive adjunction of open-label hyd-
rochlorothiazide (HCTZ) 12.5 mg (week 12), then
25 mg (week 18). At their week 24 visit, or at any-
time thereafter, patients with SeDBP ⭓90 mm Hg or
SeSBP ⭓140 mm Hg will receive adjunction of
open-label atenolol 25 mg. In addition, patients on
full study drug therapy (including HCTZ 25 mg and
atenolol) at or after week 36 visit, with SeSBP ⬎160
mm Hg or SeDBP ⬎95 mm Hg and SeSBP decrease
from baseline ⬍15 mm Hg and SeDBP decrease from
baseline ⬍10 mm Hg, will be able to be discon-
tinued from the study and receive alternative ther-
apy. At any time during the study, the finding of
a SeSBP ⬎200 mm Hg or SeDBP ⬎115 mm Hg will
necessitate the withdrawal of the subject from the
study.
Echocardiographic methods
Echocardiograms will be centrally reviewed by the
echocardiography laboratory from Henri-Mondor
Hospital, Cre
´
teil, France. Echo video tapes will be
blindly reanalysed by three independent reviewers,
each of them being allocated video tapes at random.
Echocardiography guidelines were provided to each
study site, in writing as a manual of operations, and
as a video tape prepared at the central echocardio-
graphy laboratory, describing the technical pro-
cedures for appropriate echocardiography measure-
ments. The echocardiographer shall be the same for
the same patient at each site. The echocardiography
performance protocol requires the subject being in
the left lateral decubitus position at end expiration.
An M-mode recording under two-dimensional guid-
ance will be performed in the parasternal projection
perpendicular to the walls at the level of the tip of
the anterior mitral leaflet. Other projections (eg, sub-
costal projections) may be considered when the
other views are unsatisfactory.
38
All procedures will
be followed according to the recommendations of
the American Society of Echocardiography.
39,40
Only subjects for whom technically satisfactory rec-
ordings are obtained will be eligible. A test echocar-
diography recording will be obtained at each site
before the first screening echocardiogram is
recorded on any study patient in order to assess the
overall quality of the recordings. In order to avoid
early dropouts, that may be as frequent as 47%,
9
the
screening echocardiogram will be recorded prior to
the administration of the first dose period. A study
medication (placebo lead-in). The next echocardio-
gram will be obtained after randomisation but prior
to the first dose of double-blind study medication.
The two next echocardiograms will be recorded at
24 and 52 weeks, respectively. Therefore a total of
four echocardiograms per patient completing the 52-
week double-blind follow-up will be centrally
reviewed.
All measurements and calculations will be based
on the average of three consecutive cardiac cycles;
in case of irregular rhythm, an average of five cycles
will be used. All measurements will be made by
standard procedures according to the Penn conven-
tion.
41
The calculation of LVM will be done using
the Devereux formula:
42
LVM = 1.04 [(IVS
d
+ LVID
d
+ PWT
d
)
3
− LVID
d
3
] −
13.6 g,
where LVID
d
= left ventricular inner diameter
diastole
,
IVS
d
= intraventricular septal thickness
diastole
, and
PWT
d
= posterior left ventricular wall thickness
diastole
LVMI will be determined by the ratio LVM/body
surface area.
Sample size justification
The primary purpose of this study is to compare the
changes of LVMI from baseline to 52 weeks random-
ised therapy. With 132 subjects in each group at the
week 52 analysis time point, there will be 90%
power to detect differences between groups in
change from baseline of approximately 8 g/m
2
.

Irbesartan: The SILVER Trial
A Cohen
et al
482
Calculations assume that the standard deviation of
change from baseline in LVMI is approximately
20 g/m
2
and that all statistical testing will be two-
sided with significance level = 0.05. The sample size
has been increased to 180 subjects per group to
allow for the possibility of 25% non-completion
rate.
Statistical methods
Demographic data (eg, gender, race, age, weight and
height), duration of hypertension, and baseline effi-
cacy measures will be summarised by treatment
regimen. All efficacy analyses including the primary
analysis of the change in LVMI at week 52 will be
performed with the available data from all random-
ised subjects. The primary efficacy variable is the
change of LVMI from baseline to week 52 of double-
blind therapy. The mean changes from baseline
between the treatment groups will be analysed using
anlaysis of covariance with treatment as main factor
and baseline measure as covariate.
In terms of safety analysis, all subjects who
received at least one dose of study drug will be
included in the analyses of safety. Evaluations of
safety events such as adverse events and marked
abnormalities will be summarised by treatment
group, in the form of frequency distribution and
tabulations of descriptive statistics. The number of
subjects discontinuing thestudy prematurely will be
summarised by treatment regimen and by reason(s)
for premature discontinuation. Both treatment regi-
mens will be compared for the incidence of oedema
related to the study drug using Fisher’s exact test.
References
1 Mensah GA et al. Comparison of classification of
hypertension severity by blood pressure level and
World Health Organization criteria for prediction of
concurrent cardiac abnormalities and subsequent com-
plications in essential hypertension. J Hypertens 1993;
11: 1433–1444.
2 Koren MJ et al. Relation of left ventricular mass and
geometry to morbidity and mortality in uncomplicated
essential hypertension. Ann Intern Med 1991; 114:
345–352.
3 Levy D et al. Prognostic implications of echocardio-
graphically determined left ventricular mass in the
Framingham Heart Study. N Engl J Med 1990; 322:
1561–1566.
4 Bikkina M et al. Left ventricular mass and the risk of
stroke in an elderly cohort: the Framingham Heart
Study. JAMA 1994; 272: 33–36.
5 Liebson PR. Clinical studies of drug reversal of hyper-
tensive left ventricular hypertrophy. Am J Hypertens
1990; 3: 512–517.
6Da
¨
lhof B, Pennert K, Hannson L. Reversal of left ven-
tricular hypertrophy in hypertensive patients. A
metaanalysis of 109 treatment studies. Am J Hypertens
1992; 5: 95–110.
7 Liebson PR et al. Comparison of five antihypertensive
monotherapies and placebo for change of left ventricu-
lar mass in patients receiving nutritional-hygienic
therapy in the Treatment of Mild Hypertension Study
(TOMS). Circulation 1995; 91: 698–706.
8 Schmieder RE, Martus P, Klingbeil A. Reversal of left
ventricular hypertrophy in essential hypertension:
meta-analysis of randomized double-blind studies.
JAMA 1996; 275: 1507–1513.
9 Gottdiener JS et al. Effect of single-drug therapy on
reduction of left ventricular mass in mild to moderate
hypertension: comparison of six antihypertensive
agents: The Department of Veterans Affairs Cooperat-
ive Study Group on Anti-Hypertensive Agents. Circu-
lation 1997; 95: 2007–2014.
10 Muiesan ML et al. Association of change in left ven-
tricular mass with prognosis during long term antihy-
pertensive treatment. J Hypertens 1995; 13: 1091–
1105.
11 Muiesan ML et al. Persistence of left ventricular
hypertrophy is a stronger indicator of cardiovascular
events than baseline left ventricular mass or systolic
performance: 10 years of follow-up. J Hypertens 1996;
14 (Suppl): S43–S49.
12 Devereux RB et al. Regression of left ventricular
hypertrophy as a surrogate end-point for morbid
events in hypertension treatment trials. J Hypertens
1996; 14 (Suppl 2): S95–S102.
13 Devereux RB, Da
¨
lhof B, Levy D, Pfeffer MA. Compari-
son of enalapril vs nifedipine to decrease left ventricu-
lar hypertrophy in systemic hypertension (the PRE-
SERVE trial). Am J Cardiol 1996; 78: 61–65.
14 Fagard RH. Reversibility of left ventricular hypertro-
phy by antihypertensive drugs. Neth J Med 1995; 47:
173–179.
15 Curry CL et al. Regression of left ventricular hypertro-
phy in patients with essential hypertension. Results of
6 month treatment with indapamide. Am J Hypertens
1996; 9: 828–832.
16 Messerli FH, Oren S, Grossman E. Left ventricular
hypertrophy and antihypertensive therapy. Drugs
1988; 35 (Suppl 5): 27–33.
17 Gosse P, Roudaut R, Herrero G, Dallochio M.
␤
-Block-
ers vs angiotensin-converting enzyme inhibitors in
hypertension: effects on left ventricular hypertrophy. J
Cardiovasc Pharmacol 1990; 16 (Suppl 5): S145–S150.
18 Cruickshank J, Lewis J, Moore V, Dodd C. Reversibility
of left ventricular hypertrophy by differing types of
antihypertensive therapy. J Hum Hypertens 1992; 6:
85–90.
19 Agabiti-Rosei E et al. ACE inhibitor ramipril is more
effective than the beta-blocker atenolol in reducing left
ventricular hypertrophy in hypertension (Ramipril
Cardioprotective Evaluation) study. J Hypertens 1995;
13: 1325–1334.
20 Da
¨
lhof B, Hansson L. Regression of left ventricular
hypertrophy in previously untreated essential hyper-
tension: different effect of enalapril and hydrochloro-
thiazide. J Hypertens 1992; 10: 1513–1524.
21 Kirpizidis HG, Papazachariou GS. Comparative effects
of fosinopril and nifedipine on regression of left ven-
tricular hypertrophy in hypertensive patients: a dou-
ble-blind study. Cardiovasc Drugs Ther 1995; 9: 141–
143.
22 Cerasola G et al. Reversal of cardiac hypertrophy and
left ventricular function with the calcium antagonist
felodipine in hypertensive patients. J Hum Hypertens
1990; 4: 703–708.
23 Nalbantgil I et al. The efficacy of felodipine ER on
regression of left ventricular hypertrophy in patients
with primary hypertension. Blood Press 1996; 5:
285–291.
24 Devereux RB. Do antihypertensive drugs differ in their
ability to regress left ventricular hypertrophy. Circu-
lation 1997; 95: 1983–1985.
25 Franz IW, Ketelhut R, Behr U, To
¨
nnesmann U. Time
course of reduction in left ventricular mass during

Irbesartan: The SILVER Trial
A Cohen
et al
483
long-term anti-hypertensive therapy. J Hum Hypertens
1994; 8: 191–198.
26 Himmelmann A, Svensson A, Gergbrant A, Hansson L.
Long term effects of losartan on blood pressure and left
ventricular structure in essential hypertension. J Hum
Hypertens 1996; 10: 729–734.
27 Kim S et al. Effects of an AT1 receptor antagonist, an
ACE inhibitor and a calcium channel antagonist on
cardiac gene expression in hypertensive rats. Br J Phar-
macol 1996; 118: 549–556.
28 Cazaubon C et al. Pharmacological characterization of
SR47436, a new nonpeptide AT1 subtype angiotensin
II receptor antagonist. J Pharmacol Exp Ther 1993;
265: 826–834.
29 Necciari J et al. Pharmacokinetics of SR47436 (BMS-
186295), a new angiotensin II antagonist in man
(abstract). J Hypertens 1994; 12 (Suppl 3): 88.
30 Van den Meiracker AH et al. Hemodynamic and bio-
chemical effects of the AT1 receptor antagonist irbes-
artan in hypertension. Hypertension 1995; 25: 22–29.
31 Goofriend TL, Elliott ME, Catt KJ. Angiotensin recep-
tors and their antagonists. N Engl J Med 1996; 334:
1649–1654.
32 Ellis ME, Patterson JH. A new class of antihyperten-
sive therapy: angiotensin II receptor antagonists. Phar-
macotherapy 1996; 16: 849–860.
33 Data on file, Sanofi/Bristol-Myers Squibb.
34 Porcellati C et al. Ambulatory blood pressure monitor-
ing during sustained treatment with conventional and
extended-release felodipine in mild-to-moderate
hypertension. Eur J Clin Pharmacol 1989; 37: 555–557.
35 Hwang YS, Yen HW, Wong ECK. Efficacy of once-daily
felodipine monotherapy in systemic hypertension. Am
J Cardiol 1992; 69: 271–274.
36 Felodipine Summary of Product Characteristics, Dic-
tionnaire Vidal, 1997.
37 Ghali JK et al. The pronostic role of left ventricular
hypertrophy in patients with or without coronary
artery disease. Ann Intern Med 1992; 117: 831–836.
38 Abergel E, Tase M, Bohlender J, Chatellier G. Which
definition for echocardiographic left ventricular
hypertrophy? Am J Cardiol 1992; 19: 1550–1558.
39 Sahn DJ, DeMaria A, Kisslo J, Weyman A. The Com-
mittee on M-mode standardization of the American
Society of Echocardiography. Recommendations
regarding quantitation in M-Mode echocardiography:
results of a survey of echocardiographic measure-
ments. Circulation 1978; 58: 1072–1083.
40 Henry WL et al. Report of the American Society of
Echocardiography Committee on nomenclature and
standards in two-dimensional echocardiography. Cir-
culation 1980; 62: 212–217.
41 Devereux RB, Reichek N. Echocardiographic determi-
nation of left ventricular mass in man; anatomic vali-
dation of the method. Circulation 1997; 55: 613–618.
42 Devereux RB et al. Echographic assessment of left ven-
tricular hypertrophy: comparison to necropsy. Am J
Cardiol 1986; 57: 450–458.
Appendix
Steering Committee
Ariel Cohen, MD, PhD, Paris, France (Chairman);
Pascal Gueret, MD, Creteil, France; Bryan Williams,
MD, Leicester, UK; Enrico Agabiti-Rosei, MD, Bres-
cia, Italy.
Central echocardiography review
Pascal Gueret, MD, Creteil, France; Olivier Dubourg,
MD, Boulogne-Billancourt, France; Philippe Gosse,
MD, Bordeaux, France.
Clinical sites and investigators
Belgium: DL Clement, Brussels; J-P Degaute, Brus-
sels; P Dupont, La Louvie
`
re; R Lins, Antwerp; J-L
Vandenbossche, Brussels.
France: A Cohen, B BenHalima, Paris; J-C Aldigier,
N Darodes, Limoges; J-Y Artigou, K Zherouni,
Bobigny; J-P Balducchi, Nimes; P Barnier, Etampes;
R Barraine, J Allal, L Christiaens, D Coisne, Poitiers;
P Bickert, Beauvais; D Conte, Toulouse; P Desoutter,
J-L Spiteri, S Banoun, Le Raincy; J-P Elbeze, St-Laur-
ent-du-Var; B Estampes, F Lacombe, Bry-sur-Marne;
B Grivet, Lyon; J-L Pasquie, J Rondes, Montpellier;
J-L Guermonprez, E Abergel, F Ledru, Paris; C
Guerot, C Dupuy, O Grenier, N Mirochnik, Paris; G
Habib, P Ambrosi, M Garcia, Marseille; K Khalife, J-
P Rinaldi, Metz; F Labaki, P Dambrine, A Gabriel,
Freyming-Merlebach; J-A Leonetti, A Proton, Anti-
bes; M Mansour, Belfort; X Marcaggi, K Aswad,
AMAT Vichy; A Marek, B Hanssens, E Laine, Ami-
ens; G Mialet, M Benghanem, L Beausoleil, D Mou-
houb, La Roche-sur-Yon; R Mossaz, Frejus; F Pernin,
F Nassar, Villeneuve-St-Georges; A Raveleau, Thou-
ars; B Riescher, J Amelot, Vitre; L Denis, St-
Chamond; P Sultan, Ales-en-Cevennes; T Tibi,
Cannes; M Tissot, F Barthes, A Lacoste, Pontarlier;
A Verdun, M Heitz, P Valentin, Colmar; S Witchitz,
D Pellerin D Czitrom, Le Kremlin-Bicetre.
Point Medica: C Meridzen, Mallemont; JM Letz-
elter, Strasbourg; L Blanchard, Montignar; C Fau-
gare, C Pauret, Bordeaux; J Pietrera, Montpellier; L
Grynstegn, Lille; J Luciani, Coligny.
MG Recherches: J Blaignan, Toulouse; M Bourgoin,
Marseilles; L Lacoin, Albens.
Italy: Agabiti-Rosei, Brescia; G Carboni, Rome; L
Corradi, Broni; E d’Annunzio, Pescara; C Fiorentini,
Milan; A Ganau, Sassari; M Lombardo, Milan; M
Orlandi, Lodi; A Pirelli, Bari.
Spain: V Barrios, Madrid; F Lombera, Madrid; L
Rodriguez-Padial, Toledo; JF Sotillo, Valencia.
UK: B Williams, Leicester; AB Atkinson, Belfast; D
Goldsmith, Brighton; L Hughes, Norwich; A
Mehrzad, Bishop Auckland; AL Shamma, Glasgow;
WA Littler, Birmingham; D Scobi, Gillingham; D
Darowski, Slough.