Cvct 2005, résumés
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 9
EUROPEAN SOCIETY OF CARDIOLOGY
WORKING GROUP ON CARDIOVASCULAR
PHARMACOLOGY AND DRUG THERAPY
Ettore AMBROSIONI, Bologna - ITA
Philippe LECHAT, Paris - FRA
BEST IN CLASS VS. CLASS EFFECT ISSUES
LE MEILLEUR DE LA CLASSE VS EFFET DE CLASSE
Ettore AMBROSIONI, Bologna - ITA
Graduated in Medicine at the University of Bologna in1962.
Academic positions:Research Assistant at the Mayo Graduate School ofMedicine, Rochester Minnesota, in 1967-1968.
Head Hypertensive Unit and Director of the Centerfor the Diagnosis and Treatment of Hypertension in
the University of Bologna since 1972.
Specialist in Cardiology and Rheumatology.
Assistant Professor of Cardiology from 1978 to 1980 in the Institute ofCardiology, Faculty of Medicine, University of Bologna.
Full Professor of Clinical Pharmacology and Therapeutics and DirectorService of Clinical Pharmacology and Therapeutics from 1980 to 1989,Faculty of Medicine, University of Bologna.
Full Professor of Internal Medicine and Director of the Division of InternalMedicine Clinica Medica III, Faculty of Medicine, University of Bolognasince 1990.
Member of the Scientific Council of the International Society ofHypertension from 1992 to 2000.
President of Ethical Committee of the University of Bologna-HospitalS.Orsola-Malpighi from 1999.
Member of the following Scientific Societies:Member of the Italian Society of Cardiology.
Member of the Italian Society of Internal Medicine.
Member of the European Society of Cardiology.
Chairman of the Working Group on Cardiovascular Pharmacology andDrug Therapy of the European Society of Cardiology (2004-2006).
Member and charter member of the American Society of Hypertension.
Member of the Scientific Council of the Italian Society of the Hypertensionand from the beginning of the year 2004 Past-President of the same. Principal Investigator of the SMILE Study.
Member of the Committee of Data and Safety Monitoring Board (DSMB)of the OPERA Trial. Editor in chief of "High Blood Pressure and Cardiovascular Prevention"from 1995 to 2001.
Editor in-chief of "La Cardiologia nella Pratica Clinica".
Member of the Editorial Board of the Journal of Hypertension 2000-2001Author of 720 publications.
10 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
ARE ALL BETA-BLOCKERS ALIKE FOR THE
TREATMENT OF HEART FAILURE?
Table 1: Effects of different beta-blockers in large scale clinical trials onheart failure
TOUS LES BÉTA-BLOQUANTS SONT-ILS
IDENTIQUES DANS LE TRAITEMENT DE
Composite end point
-38 % (p < 0.001)
-65 % (p < 0.001)
-21 % (p = 0.0004)
-34 % (p < 0.0001)
-25 % (p < 0.001)
-34 % (p < 0.0001)
COPERNICUS (2001) 2289
-24 % (p < 0.001)
-35 % (p = 0.0014)
Kurt STOSCHITZKY, Graz - AUT
-17 % (p = 0.0017)
Born 1958 in Graz, Austria. Medical school at
-14 % (p = 0.039)
Karl-Franzens University, Graz. 1985 Doctor ofMedicine, 1989 General Practitioner (Hartberg and
Table 2: Particular features of beta-blockers recommended in heart failure
Graz), 1989 Specialist in Emergency Medicine
(Hartberg), 10/1993 - 01/1994 scientific training in
Zürich, Switzerland (Prof W Kiowski), 1995 Specialist
Administration once daily
in Internal Medicine (Hartberg [Dr KM Stepan] and
Graz [Prof GJ Krejs]), 1997 Specialist in Cardiology
Administration once daily
(Graz, Prof W Klein), 1997 Venia legendi in Internal Medicine (Graz),
Inhibition of sympathetic alpha1-receptors
2002 National Diploma in Clinical Investigation (Austria), 2003 Specialist
in Internal Intensive Care Medicine (Graz). 1987 - present: Scientific
Increase of insulin sensitivity
cooperation with Prof W Lindner (Institute of Analytical Chemistry, Vienna,
No effect on nocturnal melatonin release
Austria) in the field of Stereoselectivty of beta-adrenergic antagonists.
No release from adrenergic cells
1997 - present: Specialist in Internal Medicine and Cardiology, and head
Administration twice daily
of the Working Group on Clinical Cardiovascular Research, Division of
Cardiology, Department of Medicine, Medical University of Graz, Austria.
2000 - present: Secretary of the Working Group on Cardiovascular
No effect on nocturnal melatonin release
Pharmacology and Drug Therapy of the European Society of Cardiology.
No release from adrenergic cellsAdministration once daily
In the present year, 2005, there is no doubt that "All patients with stable,mild, moderate and severe chronic heart failure from ischaemic or
1. Lopez-Sendon J, Swedberg K, McMurray J, Tamargo J, Maggioni AP,
non-ischaemic cardiomyopathies and reduced left ventricular ejection
Dargie H, Tendera M, Waagstein F, Kjekshus J, Lechat P, Torp-Pedersen
fraction, in NYHA class II-IV, should be treated with ß-blockers, unless
C. Expert consensus document on beta-adrenergic receptor blockers.
there is a contraindication" - thus being a Recommendation class I with
Eur Heart J 2004; 25: 1341-1362
Level of evidence A. Actually, four beta-blockers - metoprolol, bisoprolol,carvedilol and nebivolol - have been shown in large scale clinical trials to
2. Reiter MJ. Cardiovascular drug class specifity: Beta-blockers.
decrease mortality in patients with heart failure (Table 1).
Prog Cardiovasc Dis 2004; 47: 11-33
Nevertheless, it is not clear whether or not one of these four beta-blockers might be superior to the others, since they all have particular
3. Stoschitzky K. Additional features of beta-blockers.
features that might distinguish them from one another (Table 2).
Heart Drug 2005; 6-10
However, it has not been shown convincingly that clinical outcome inpatients with heart failure is better with one beta-blocker compared to
4. McMurray J. Making sense of SENIORS. Eur Heart J 2005; 26: 203-
another. The COMET trial (Lancet 2003; 362: 7-13) compared carvedilol
with metoprolol tartrate and found a significant decrease in mortality withcarvedilol whereas the composite endpoint of mortality and all-cause
5. Guidelines on the diagnosis and treatment of acute heart failure.
hospital admission failed to reach statistical significance (Table 1).
Eur Heart J 2005; 26: http://www.escardio.org/NR/rdonlyres/CBA6844E-
However, this study was critisised since carvedilol was compared with
metoprolol tartrate (the formulation used in the older MDC trial which
failed to reduce mortality) but not with metoprolol succinate (the
formulation used in the MERIT-HF trial which showed a clear reduction inmortality). In addition, the daily doses of metoprolol used in COMET were
markedly lower than those shown in MERIT-HF to be effective. Therefore,the results of COMET, although statistically significant, should not be
1. Which of the following beta-blockers did not show a decrease in
seen as "the final solution of all questions."
mortality in patients with heart failure?
In this context, the "Expert consensus document on beta-adrenergic
receptor blockers" of the Task Force on Beta-Blockers of the European
Society of Cardiology (Eur Heart J 2004; 25: 1341-1362) outlines that
"the COMET trial illustrates that selection of a beta-blocker and the dose
used may have a significant impact on the outcome of patients with heart
Right answer: a
failure. Accordingly only bisoprolol, metoprolol in the formulation anddose used in MERIT-HF and carvedilol are recommended for the
2. Which of the following effects is not exerted by carvedilol?
treatment of patients with heart failure." Since the SENIORS trial -
a) Blockade of beta1-receptors
published recently (Eur Heart J 2005; 26: 215-225) but after the
b) Blockade of beta2-receptors
publication of the Expert consensus document mentioned above - has
c) Blockade of alpha1-receptors
shown that nebivolol also may decrease mortality in patients with heart
d) NO-derived vasodilation
failure, this drug should be added to the beta-blockers recommended for
e) Increase of insulin sensitivity
the treatment of heart failure (at least in the elderly as shown in
Right answer: d
Since the last decade, recommendations in the treatment of arterial
3. What is not true for Nebivolol ?
hypertension have focused on the patient as a whole, including all
a) Nebivolol shows high beta1-selectivity
additional diseases and risk factors, rather than on blood pressure alone.
b) Nebivolol shows alpha1-receptor blockade
Maybe a similar therapeutic strategy with beta-blockers in heart failure
c) Nebivolol shows NO-derived vasodilation
would make sense, i.e., to focus the choice of a special beta-blocker in
d) Nebivolol does not decrease nocturnal melatonin release
the treatment of heart failure on additional diseases and risk factors of
e) Nebivolol is not released from adrenergic cells
each individuum according to the particular features of the drugs
Right answer: b
(Table 2). However, further studies are needed in order to find outwhether or not such policy may further improve clinical outcome.
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 11
ARE ALL ALDOSTERONE RECEPTOR BLOCKERS
Further differences include the side effect profiles reported for the two
ALIKE? SPIRONOLACTONE VS EPLERENONE.
compounds. The problem of hyperkalemia and impaired renal functionwith spironolactone has been clearly documented by various groups after
TOUS LES ANTAGONISTES DES RÉCEPTEURS DE
the publication of the RALES study. For this reason the cardiovascular
L'ALDOSTÉRONE SONT-ILS INTERCHANGEABLES ?
community looked eagerly upon this issue as data from the EPHESUS
SPIRONOLACTONE VS EPLERENONE.
trial were presented. Unfortunately, the current level of evidence does notclearly suggest an advantage of eplerenone over spironolactone withregard to hyperkalemia or renal dysfunction. However, a clear side effect
Dan ATAR, Oslo - NOR
advantage was documented in terms of gynecomastia and breast pain,favouring eplerenone.
Dan Atar, MD, (46) is Head of Cardiology at AkerUniversity Hospital, Oslo, Norway, and holds a full
One further difference between these two compounds can be stipulated
Professorship in Cardiology at the University of Oslo,
when looking at the parameter "time to benefit". Looking at the Kaplan
Norway, along with a Visiting Associate
Meyer mortality curves for the RALES trial, there is no visible advantage
Professorship at the Johns Hopkins Unversity,
of survival within the first three months, while eplerenone reduced
Baltimore, Maryland, USA.
mortality by 31% already at day 30 in the EPHESUS study. Hence, it may
Dan Atar trained in Denmark, Switzerland, and the
be speculated whether a more immediate onset of effect is conferred by
United States before receiving his board certification
the synthetic aldosterone antagonist eplerenone.
in Internal Medicine and Cardiology in 1995. His research focuses ontroponin, myocardial function, heart failure and cardiovascular pharma-
Finally, one of the differences in the real world is price and
cology. He has written numerous articles and book chapters and holds
reimbursement. In most countries, the difference in expenditure for
the fellowship-titles FESC, FACC, and inaugural FAHA. Dan Atar is the
spironolactone versus eplerenone treatment, respectively, is in the
Vice-Chairman of the Working Group 3 (WG-3: Cardiovascular
magnitude of 5 - 10, favoring spironolactone. In some countries,
Pharmacology and Drug Therapy) of the ESC, and Editor-in-Chief of the
governmentally controlled reimbursement schemes are in fact reluctant
international peer-reviewed cardiovascular journal "HeartDrug - Excellence
to grant free access to eplerenone reimbursement. The cardiovascular
in Cardiovascular Trials", which is officially affiliated with the WG-3.
community must face these politically imposed restraints in a climate ofincreased awareness of healthcare-related costs.
During the past twenty years, treatment of heart failure has decreased
overall mortality rates substantially.
While initial heart failure mortality in the late seventies was estimated at
1. Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK,
35%/year, the addition of ACE-inhibitors to standard treatment in the
Blomme EAG, McMahon EG, Delyani JA: Aldosterone induces a vascular
early eighties significantly decreased this number to approximately 25%.
inflammatory phenotype in the rat heart.
An additional survival benefit was achieved when betablockers were
Am J Physiol Circ Physiol. 2002;283:H1802-H1810.
added to standard congestive heart failure (CHF) treatment around 15years ago, resulting in a decreased mortality rate of approximately 15%
2. Garnier A, Bendall JK, Fuchs S, Escoubet B, Rochais F, Hoerter J,
per year. While the cardiovascular community embarked on
Nehme J, Ambrosine ML, De Angelis N, Morineau G, d'Estienne P,
implementing such comprehensive pharmacological treatment to heart
Fischmeister R, Heymes C, Pinet F, Delcayre C: Cardiac Spesific
failure populations, an additional therapeutic concept appeared:
Increase in Aldosterone Production Induces Coronary Dysfunction in
aldosterone inhibition. One of the rationales for such additional
Aldosterone Synthase-Transgenic Mice. Cirulation. 2004;110:1819-1825
neurohormonal blockade was the finding of the so-called "aldosteroneescape" phenomenon, i.e., the fact that aldosterone levels graduallyrelapse to an increased stage in patients treated with ACE inhibitors even
3. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky
though the initial blockade normalized aldosterone levels. At the same
J, Wittes J. For the Randomized Aldactone Evaluation Study
time, increasing evidence documented severe deleterious effects on the
Investigators. Randomized Aldactone Evaluation Study. N Engl J Med.
cardiovascular system induced by aldosterone. For example, locally
produced aldosterone alters coronary vascular function, and myocardialcollagen synthesis and subsequent fibrosis was shown to be stimulated
4. Pitt B, Remme W, Zanned F, Neaton J, Martinez F, Roniker B, Bittman
by increased aldosterone levels. Thus, the role of aldosterone in heart
R, Hurley S, Kleiman J, Gatlin M, for the Eplerenone Post-AMI Heart
failure became a focused issue, for which a proof of concept was needed
Failure Efficacy and Survival Study Investigators. Eplerenone, a Selective
on the level of a large scale clinical trial. This evidence was delivered by
Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after
Pitt, Zannad et al., who in the RALES (Randomized Aldactone Evaluation
Myocardial Infarction. N Engl J Med. 2003;348:1309-1321.
Study) trial showed that spironolactone on top of standard heart failuretherapy was superior to standard therapy alone in terms of survival of
5. Svensson M, Gustafsson F, Galatius S, Hildebrandt PR, Atar D:
patients with CHF in NYHA class III and IV. In addition to this milestone
Hyperkalaemia and impaired renal function in patients taking spironolac-
finding, another trial, EPHESUS (Eplerenone Post-AMI Heart Failure
tone for congestive heart failure: retrospective study. BMJ
Efficacy and SUrvival Study), has documented the beneficial role of
aldosterone blockade in a slightly different heart failure population, i.e.,patients with documented impaired left ventricular function shortly after a
6. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A,
survived acute myocardial infarction (AMI). In this study, the synthetic
Redelmeier DA. Rates of Hyperkalemia after Publication of the
aldosterone inhibitor eplerenone was utilized on top of standard post
Randomized Aldactone Evaluation Study. N Eng J Med. 2004 ;351:543-51
infarction and CHF treatment, and compared to placebo. Also this trial
indicated a highly significant relative risk reduction of total mortality in thispost-AMI CHF population.
When it comes down to a comparison between spironolactone and
1. Which of the following fits best?
eplerenone, there are a number of differences that can be put forward.
a) Aldosterone inhibition in patients with impaired left ventricular
One of the obvious differences is in the molecule itself, i.e., the synthetic
function is a concept that awaits final proof-of-concept from
aldosterone antagonist eplerenone has higher aldosterone receptor
specificity than spironolactone. Furthermore, metabolism and excretion is
b) One of the proposed mechanisms of the beneficial effect of
prolonged with spironolactone as compared to eplerenone.
aldosterone inhibition in heart failure patients is a so-called "aldosterone-escape" that has been reported to occur during
Further, one of the major differences relates to the populations
investigated in the above mentioned two trials. Obviously, patients in the
c) Aldosterone inhibitors seem less effective in preventing cardiac
RALES trial had a more severe stage of CHF, as expressed by higher
events in heart failure patients than ACE-inhibitors and
NYHA class. On the other hand, patients in the EPHESUS trial had a
much higher fraction (100%) of post infarction patients than RALES,
d) Non of the above are correct.
where an ischemic etiology of heart failure accounted for 55%, simply
e) All of the above are correct.
because AMI was an enrollment criterium for the EPHESUS study.
Right answer: b
12 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
2. Which of the following fits best?
a) In comparing spironolactone and eplerenone with regard to
hyperkalemia as a potential side-effect, none of these 2compounds stands out as clearly superior.
b) In comparing spironolactone and eplerenone with regard to renal
dysfunction as a potential side-effect, none of these 2 compoundsstands out as clearly superior.
c) In comparing spironolactone and eplerenone with regard to
gynecomastia as a potential side-effect, none of these 2compounds stands out as clearly superior.
d) All of the above are correct.
e) a and b are correct.
Right answer: e
3. Which of the following fits best?
a) While both the "RALES" and the "EPHESUS" trial have
scrutinized heart failure populations, there are major differencesin the characteristics of the enrolled patients.
b) One of the differences between "RALES" and "EPHESUS" was in
the baseline medication, with far more patients in "EPHESUS"being on betablockers.
c) One of the differences between "RALES" and "EPHESUS" was in
the severity of CHF, with far more patients in "RALES" being inNYHA class III or IV.
d) One of the differences between "RALES" and "EPHESUS" was in
the side effect profile, with far more male patients in "RALES"complaining of gynecomastia and breast pain.
e) All of the above
Right answer: e
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 13
ARE ALL ANGIOTENSIN RECEPTOR BLOCKERS
of elimination of ARBs may also be of clinical relevance: Irbesartan,
ALIKE? CLASS EFFECT VS DIFFERENTIAL
losartan, telmisartan and valsartan undergo predominant biliary excretionwhile eprosartan and candesartan are excreted by the kidney. Thus, the
route of elimination has to be taken into account when ARBs are
TOUS LES ANTAGONISTES DE L'ANGIOTENSINE
administered to patients with impaired renal or hepatic function.
SONT-ILS SEMBLABLES ? EFFET DE CLASSE VS
LA PHARMACOLOGIE DIFFÉRENTIELLE.
Conclusions:1. There are at present no well documented differences between ARBsregarding their long term effects on disease progression and mortality
Ferenc FOLLATH, Zurich - SUI
2. Pharmacokinetic and pharmcodynamic differences are relevant for thechoice of an optimum dosage regimen of the available ARBs.
F. Follath MD, FESC, University Hospital Zurich,Switzerland
Date of Birth: 1938
1. Reduced renal function prolongs the elimination and leads to drugaccumulation with an increased risk of adverse events with:
University: Medical School of Basel University,
a) ACE inhibitors (enalapril, lisinopril)
Switzerland (1957 - 1963)
b) Betablockers (metoprolol, carvedilol)c) Angiotensin receptor blockers (irbesartan, losartan, valsartan)
Internal Medicine [Dept. of Medicine, University Hospital in Basel andGeneva (1964 - 1969, 1972 - 1974)]
Question type K'. Right answers: a+, b-, c-, d+
Cardiology [Hammersmith Hospital, London (1969 - 1970) and Division ofCardiology & Cardiovascular Surgery, University Hospital Basel (1971 -1972)]
2. Apparent diuretic resistance in patients with CHF may be overcome by:
Clinical Pharmacology [Hammersmith Hospital, London (1974)]
a) Intravenous instead of oral administration of furosemideb) Combination of loop diuretics and thiazide diuretics
c) Combination of loop diuretics and spironolactone
MD and Professor of Medicine and Clinical Pharmacology, University of
d) Correction of hypokalemia
Basel (until 1990)
Right answers: a+, b+, c+, d-
Professor of Medicine, University of Zurich (since 1990)FESC (Fellow European Society of Cardiology)
Positions: - Director of Medicine A, Department of Internal Medicine, University Hospital, Zurich (from July 1990 - present)- Head of Clinical Pharmacology Division, University Hospital, Basel(1975 - 1990)- Deputy Head of Medical University Clinic B, Basel (1975 - 1990)
Scientific Interests: Cardiovascular Drug Therapy, Heart Failure, Arrhythmias, Endocarditis
(more than 300 original papers published)
Medical Societies:- Swiss Society of Internal Medicine (Past-President)- Swiss Society ofCardiology- European Society of Cardiology (Fellow)- Nucleus Working Group on Cardiovascular Pharmacology and DrugTherapy (Past Chairman)- Science Council ESC (Past-Member)- International Society of Cardiovascular Pharmacology (Board Member)- Swiss Society of Intensive Care Medicine (Member)
Several angiotensin receptor blockers (ARBs) have shown positivetherapeutic results in patients with hypertension, heart failure anddiabetic nephropathy in large scale comparative trials. Physicians nowhave the choice between several compounds with a similar mode ofaction on AT1-receptors. The question therefore arises: Are thereclinically relevant differences between ARBs?
The following criteria may be used for such comparisons:1. Documented superiority and/or better tolerance in clinical trials2. Pharmacokinetic characteristics3. Pharmacodynamic effects of various dosage regimens
At present there are no long term trials with direct comparisons of ARBswith regard to disease progression and mortality. Short term evaluationsof the blood pressure lowering efficacy of different doses of losartan,valsartan, irbesartan and candesartan showed differences inantihypertensive actions after once daily administration which could bemainly due to the pharmacokinetic properties of these drugs.
Candesartan, irbesartan, olmesartan and telmisartan have half lives of10-24 h explaining their longer duration of action. Losartan and its activemetabolite (EXP 3174), valsartan and eprosartan have shorter half-livesand somewhat shorter durations of actions. Differences in the the mode
14 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
ARE ALL ACE INHIBITORS ALIKE?
MEET AND EAT WITH THE EXPERTS
CLASS EFFECT VS DIFFERENTIAL PHARMACOLOGY.
RENCONTRE ET DÉJEUNER AVEC LES EXPERTS
TOUS LES IEC SONT-ILS ÉGAUX ? EFFET DE
CLASSE VS LA PHARMACOLOGIE DIFFÉRENTIELLE.
HEART RATE MANAGEMENT:
RELEVANCE TO HEART FAILURE
Wiek VAN GILST, Groningen - NED
LA FRÉQUENCE CARDIAQUE :
IMPORTANCE DANS L'INSUFFISANCE CARDIAQUE.
Wiek H. van Gilst, PhD is Professor of
Christian THUILLEZ, Rouen - FRA
Cardiovascular and Clinical Pharmacology at theUniversity of Groningen in Groningen, TheNetherlands. Dr. van Gilst received his PhD (cum
Date of birth April 5, 1950, France
laude) in Pharmacology at the Medical School of the
University of Groningen in 1985. Immediatelyfollowing postdoctoral training, he was appointed
- Education: University Paris VI, France
Research Fellow for the departments of Cardiology
and Clinical Pharmacology at the University of Groningen. His present
- Professor of Pharmacology, Faculty of Medicine,
position was instituted in 1995 by the Interuniversity Cardiology Institute
University of Rouen, France
Netherlands, a national institute of the Royal dutch Academy of Sciences
- Chief of the Department of Clinical Pharmacology,
in Amsterdam. Dr. van Gilst is currently director of the Cardiovascular
University Hospital of Rouen, France
Institute in Groningen, member of the committees on Heart Failure and
- Director INSERM U644 (Pharmacology of Endothelial adaptation
Pharmacotherapy of the Dutch Society of Cardiology, member of the
dysfunction and Myocardial adaptation)
board of the Dutch Atherosclerosis society, nucleus member of the ESCworking group on heart failure and coordinator of the Educational
Other professional positions:
Program on Critical Appraisal at the Medical School of the University of
- Dean of the Faculty of Medicine, University of Rouen
Groningen. His research interest includes the role of calcium antagonists
- Member of the administrative council of the University Hospital of Rouen
and modulations of the local renin-angiotensin systems in ischemic
- Member of the French Agency for the safety of Health Products
syndromes, heart failure and vascular function. He has published over
200 papers on these subjects.
- Secretary of the Clinical Section of the French Society of Pharmacology- Past President of the French Society of Hypertension- Member of the Editorial Board of Journal of CardiovascularPharmacology and Fundamental and Clinical Pharmacology
Main fields of interest:- Clinical evaluation of drugs on endothelial function and vascularmechanic properties in healthy subjects before registration of drugs andin patients in different pathological situation (Heart failure, RenalInsufficiency, Hypertension)- Cardiovascular Pharmacological Experimental Research concerningvascular and myocardial aspects of heart failure and hypertension inanimal models (hemodynamic and echographic studies), isolatedvessels, and cell cultures.
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 15
MEET AND EAT WITH THE EXPERTS
MEET AND EAT WITH THE EXPERTS
RENCONTRE ET DÉJEUNER AVEC LES EXPERTS
RENCONTRE ET DÉJEUNER AVEC LES EXPERTS
HEART RATE MANAGEMENT:
HEART RATE MANAGEMENT:
RELEVANCE TO HEART FAILURE
RELEVANCE TO HEART FAILURE
LA FRÉQUENCE CARDIAQUE :
LA FRÉQUENCE CARDIAQUE :
IMPORTANCE DANS L'INSUFFISANCE CARDIAQUE.
IMPORTANCE DANS L'INSUFFISANCE CARDIAQUE.
Alain BERDEAUX, Kremlin-Bicêtre - FRA
Filipe MARTINEZ, Cordoba - ARG
Alain Berdeaux is presently Head of the Laboratory of Pharmacology and
Professor of Internal Medicine - Cordoba National
INSERM (U 660) in the Faculty of Medicine in Creteil, France. It's main
research interest is the discovery and design of new drugs and cellular
Director - Rusculleda Foundation for Clinical
therapies for cardioprotection of the ischemic and post-infarcted
Past President - Argentine Federation of Cardiology
Ellected President - Scientific Committee WorldCongress of Cardiology - 2008
Author of 116 publications
Member of 14th Steering Committees
16 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
CARDIOVASCULAR OUTCOME PREVENTION WITH
ACE INHIBITORS. AN UNFOLDING STORY.
PRÉVENTION DES ÉVÉNEMENTS
CARDIOVASCULAIRES AVEC LES IEC.
Michel BERTRAND, Lille - FRA
Willem REMME, Rhoon - NED
Michel BERTRAND, Lille - FRA
Michel E. Bertrand graduated in Medicine in 1964 atthe University of Lille. He was appointed asAssociate Professor of Cardiology in 1970 andbecame Professor of Cardiology in 1978. He was theChairman of the Department of Cardiology at LilleUniversity Heart Institute from 1978 to 2000 and theDirector of the Federative Institute of Research onVascular Biology from 1996 to 2000.
From January 1991 to September 1994 he was the President of theEuropean Society of Cardiology. He was the President of the FrenchSociety of Cardiology in 1997. Dr Bertrand is member or honorary member of a number of medicalorganizations and societies, including the American Heart Association,the American College of Cardiology, the Royal College of Physicians(UK), the Italian, Portuguese, Spanish, Swedish, Hungarian, Turkish,Polish and Lebanese cardiac societies. The main topics of interest arecoronary artery disease and interventional cardiology.
Dr Bertrand was a member of several Steering and DSMB committees.
He was the principal or Co-principal Investigator of large multicenterrandomized trial (CLASSICS, PREDICT, VIP, TARGET, EUROPA etc…)Dr Bertrand was invited to deliver the Paul Dudley White InternationalLecture of the American Heart Association in 1999 and several othernamed international Lectures (Williams Stokes lecture in- Dublin,Jean-René Leveque lecture in Montreal, Jean Lequime lecture inBrussels, Karl Neuhaus lecture in Mannheim, Andreas Gruntzig lecturein Lausanne). Dr Bertrand serves as Member of the Editorial Board ofseveral International journals (Circulation, Journal of American College ofCardiology (2000-2004), European Heart Journal). He is the author or theco-author of more than 500 papers of which 245 were published inpeer-reviewed international journals.
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 17
PHARMACOLOGY AND VASCULAR PROTECTION
changes, resulting in a highly significant relative risk reduction in all-
WITH ACE INHIBITORS: ENDOTHELIAL DYSFUNCTION
cause and cardiovascular mortality. The multifactorial antiatheroscleroticprofile of perindopril suggests a beneficial effect not only in uncomplicated
AND VASCULAR REMODELING. / PHARMACOLOGIE
hypertensives, but also in patients with established coronary heart
ET PROTECTION VASCULAIRE AVEC LES IEC :
disease or previous stroke, as exemplified by the EUROPA and the
DYSFONCTION ENDOTHELIALE ET
Stéphane LAURENT, Paris - FRA
1. Laurent S, Boutouyrie P.Arterial stiffness and stroke in hypertension:
Pharmacologist, Cardiologist. Paris, France
therapeutic implications for stroke prevention. CNS Drugs. 2005;19:1-11.
Title and/or Degrees
2. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM.
Professor, MD, PhD
Impact of aortic stiffness attenuation on survival of patients in end-stagerenal failure. Circulation. 2001; 20;103:987-992
Current position Head, Department of Clinical Pharmacology, Hôpital
3. Schwartzkopff B, Brehm M, Mundhenke M, Strauer BE. Repair of
Européen Georges Pompidou, Paris.
coronary arterioles after treatment with perindopril in hypertensive heart
Head, INSERM EMI 0107 ("Biomechanics and pharmacology of the
disease. Hypertension. 2000;36:220-5.
Professor of Pharmacology, "René Descartes" Medical School, Paris 5.
4. Girerd X, Giannattasio C, Moulin C, Safar M, Mancia G, Laurent S.
Regression of radial artery wall hypertrophy and improvement of carotidartery compliance after long term antihypertensive treatment: the Pericles
Special area of interest and expertise
study. J Am Coll Cardiol 1998, 31:1064-1073.
Arterial hypertension and cardiovascular diseases. Pathogenesis and regression of structural and functional changes of
5. Antony I, Lerebours G, Nitenberg A. Angiotensin-converting enzyme
inhibition restores flow-dependent and cold pressor test-induced dilations
Clinical investigation and pharmacology of large arteries.
in coronary arteries of hypertensive patients. Circulation. 1996;94:3115-22.
Other activities Has lectured widely to international audiences on hypertension, cardio-vascular diseases, and non invasive clinical investigation of large
arteries. Past President of the French Society of Hypertension (2001-2002).
1. The vascular remodeling in response to long-term antihypertensive
Chairman of the Scientific Council of the 14th Meeting of the European
treatment with ACE inhibitors includes:
Society of Hypertension (ESH, Paris, June 2004).
a) A reduction of endothelial dysfunction
Member of several international scientific societies, including the
b) A decrease in arterial stiffness
European Society of Hypertension (ESH), the American Heart
c) A decrease in coronary reserve
Association Council for High Blood Pressure Research, the International
d) A decrease in large artery lumen diameter
Society of Hypertension (ISH), and the European Council for
e) A decrease in small artery lumen diameter
Cardiovascular Research (ECCR).
f) A decrease in intima-media thickness
Visiting Professor (1999) in Cardiology at Harvard Medical School and
Right answers: a, b, f
Brigham and Women's Hospital, Boston.
2. Long-term antihypertensive treatment with ACE inhibitors induce
Editorial boards and publications
vascular remodeling through the following mechanisms :
Member of the editorial board of Hypertension, Journal of Cardiovascular
a) Reduction of endothelial dysfunction
Pharmacology, Journal of Hypertension, and Clinical Science.
b) Fall in blood pressure
More than 180 original papers in refereed journals, 60 review publications
c) Increase in renin secretion
including editorials and book chapters, and 350 reports, including
d) Blockade of the trophic effects of Ag II
Right answers: a, b, d
Structural and functional changes in large and small arteries in hypertension,even at early stages, may affect one or several end organs like the brain,heart, and kidney, contributing to cardiovascular morbidity and mortality.
Therefore, modern treatment strategies should not only target bloodpressure (BP) reduction but also normalize vascular structure andfunction. The purpose of this communication is to review the large bodyof evidence from randomized double-blind clinical trials, that has beengathered with perindopril, a long acting once - daily lipophilic angiotensin-converting enzyme (ACE) inhibitor with a high tissue ACE affinity.
Perindopril has demonstrated its efficacy in reducing BP, reversingabnormalities of vascular structure and function in patients with essentialhypertension, and ultimately preventing CV events. At the site of smallresistance arteries, long-term treatment with perindopril, but not atenolol,reduced arterial wall hypertrophy for a given BP reduction. The improvementof small artery function in response to structural changes is exemplifiedat the site of the coronary circulation. Indeed, perindopril increasedcoronary blood flow and coronary reserve, in parallel with the regressionof periarteriolar and interstitial collagen of coronary arterioles. At the siteof large arteries, long-term treatment with perindopril reduced carotid andradial artery wall hypertrophy, and reduced carotid artery internaldiameter. In response to these structural changes, large artery functionimproved at the site of the carotid and brachial arteries, showing a higherarterial distensibility, and at the site of the coronary circulation, showinga normalized arterial dilation in response to a cold-pressor test or anincrease in blood flow. Moreover, in patients with end-stage renaldisease, perindopril decreased pulse wave velocity independently of BP
18 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
PREVENTION OF EVENTS IN CORONARY ARTERY
4. Nissen S, Tuzcu EM, Libby P, et al Effect of the antihypertensive
DISEASE PATIENTS WITH ACE INHIBITORS:
agfents on cardiovascular events in patients with coronary disease andnormal blood pressure. The CAMELOT study; a randomized controlled
AN UPDATE (HOPE, EUROPA, PEACE).
trial. JAMA 2004; 292; 2217-26
LA PRÉVENTION DES ÉVÉNEMENTS
CARDIOVASCULAIRES PAR LES IEC
5. The PEACE trial investigators. Angiotensin-converting-enzyme
CHEZ LE PATIENT CORONARIEN : MISE À JOUR.
inhibition in stable coronary artery disease. N Engl J Med 2004; 351:2058-68
Nicolas DANCHIN, Paris - FRA
Nicolas DANCHIN, M.D, F.E.S.C., F.A.C.C.:Nicholas DANCHIN is a Professor of Medicine,Consultant Cardiologist and Head of the Departmentof Cardiology and Coronary artery disease at HôpitalEuropéen Georges Pompidou in Paris, France. Hehas a special interest in coronary artery disease, itstreatment modalities including interventionalcardiology and its prevention, and has written
extensively on these and related topics. He is currently Vice-President ofthe French Society of Cardiology, consultant for the French Drug Agency,and a member of the Scientific Committee of the French National HealthInsurance Authority (CNAM). He also co-chairs Task Force 1 of theCardiovascular Round Table of the European Society of Cardiology. Heedits the Annales de Cardiologie et Angéiologie and Consensus Cardi,oand is on the Editorial board of Heart and ACCEL. To date, he haspublished approximately 300 papers in peer-reviewed journals.
Angiotensin converting enzyme (ACE) inhibitors are an undisputedtreatment in patients with congestive heart failure or those with coronaryartery disease (CAD) and concomitant left ventricular dysfunction. Incoronary artery disease patients without heart failure or important leftventricular dysfunction, however, discrepant results have been observedamong several recent randomized trials. In particular, the results of therecently published PEACE trial diverge from those of HOPE andEUROPA. In order to document whether ACE-inhibitors should be usedsystematically in patients with CAD and no left ventricular systolicdysfunction, the results of all trials assessing the long-term efficacy ofACE-inhibitors in such patients have to be compared and analysed. Fivetrials including more than 1,000 patients each (HOPE, QUIET, EUROPA,PEACE and CAMELOT) compared ACE-inhibitors with placebo in CADpatients without LV dysfunction or heart failure. Treatment with ACE-inhibitors decreased overall mortality (OR 0.87, 95% CI: 0.80-0.94),cardiovascular mortality (OR: 0.82; 95% CI: 0.74-0.92), myocardialinfarction (OR: 0.82; 95% CI: 0.75-0.89) and stroke (OR: 0.76; 95% CI:0.66-0.88). Other end-points such as resuscitated cardiac arrest,myocardial revascularization, and hospitalization for heart failure werealso reduced. The reasons of the discrepancies between trials arespeculative; there is no consistent pattern as regards the pharmacologicproperties of the different ACE-inhibitors tested, nor any definiterelationship between the degree of blood pressure reduction and theeffects observed. Of note, though, the 2 trials which were undoubtedlypositive were those in which the highest doses of ACE-inhibitors wereused. Conclusion: ACE-inhibitors reduce total mortality and all majorcardiovascular end-points in patients with CAD and no left ventricularsystolic dysfunction or heart failure. They should be used as anauthentic secondary prevention therapy.
1. The Heart Outcomes Prevention Evaluation Study investigators.
Effects of an angiotensin-converting -enzyme inhibitor, ramipril, oncardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-53
2. The European trial on reduction of cardiac event with perindopril instable coronary artery disease investigators. Efficacy of perindopril onreduction of cardiovascular events among patients with stable coronaryartery disease: randomised, double-blind, placebo-controlled multicentretrial (the EUROPA
study). Lancet 2003; 362: 782-8
3. Pitt B, O'Neill B, Feldman R, et al. The Quinapril Ischemic Event Trial(QUIET): evaluation of chronic ACE inhibitor therapy in patients withischemic heart disease and preserved left ventricular function. Am JCardiol 2001 ; 87 : 1058-63
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 19
WHY AND HOW DOES ACE INHIBITOR THERAPY
The possibility that direct vascular effects are involved come from further
WORK IN CORONARY ARTERY PATIENTS.
sub-studies of EUROPA. The PERGENE study found a significantimprovement in the bradykinin and cNOS levels of patients treated with
INSIGHT FROM SUBSTUDIES AND SUBANALYSES
perindopril, along with a reduction in angiotensin II, cytokines, apoptosis
OF MAJOR TRIALS? / POURQUOI ET COMMENT LES
rate and von Willebrand factor. The latter suggest improved endothelial
IEC SONT-ILS EFFICACES CHEZ LES PATIENTS
function, which was observed also in the PERFECT sub-study in > 300
CORONARIENS ? RESULTATS DES ETUDES ET
patients during a 36-month treatment with perindopril and placebo.
In particular the increase in bradykinin is of interest, and indicates that
ANALYSES ANCILLAIRES DES PRINCIPAUX
perindopril, having good tissue-affinity, inhibits local vascular ACE, a
ESSAIS CLINIQUES ?
property which is only shared by a few other ACE inhibitors. Thesefindings suggest a direct anti-atherosclerotic effect of this particular ACE
Willem J. REMME, Rhoon - NED
inhibitor and reinforce the notion that the secondary preventive effects ofperindopril should not be considered a class effect, but specific forperindopril and effective in a broad range of patients with stable coronary
Title and/or Degrees:
disease irrespective of cardiac function or cardiovascular risk profile.
MD, PhD, FESC, FACC, FAHA
Professor of Medicine
Current Position:- Director and Chairman, "Sticares" Cardiovascular
1. The European Reduction Of cardiac events with Perindopril in stable
Research Foundation, Rotterdam-Rhoon, The
coronary Artery disease Investigators. Efficacy of perindopril in reduction
of cardiovascular events among patients with stable coronary artery
- Professor of Medicine, Department of Internal Medicine, Division of
disease: randomized, double-blind, placebo-controlled multicentre trial
Cardiology, "Carol Davila" University, Bucharest, Romania
(EUROPA). Lancet 2003;362:782-8.
- Director, Sticares-InterACT Research Institute, Rotterdam-Rhoon, TheNetherlands
2. The Heart Outcomes Prevention Evaluation Study Investigators.
1st Chairman of the Working Group on Heart Failure of the European
Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardio-
Society of Cardiology
vascular events in high-risk patients. N Engl J Med 2000;342:145-53
Chairman SHAPE - Study group on Heart failure Awareness andPerception in Europe
3. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J, for theHeart Outcomes Prevention Evaluation (HOPE) Study Investigators.
- Honorary Membership
Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet
French Society of Cardiology
Romanian Society of Cardiology
4. Simoons ML, Vos J, de Feyter PJ, et al. EUROPA substudies,
- Editorial Boards and Publications:
confirmation of pathophysiological concepts. Eur Heart J 1998;19(suppl
Editor-in-Chief of Cardiovascular Drugs and Therapy.
5. Zhuo JL, Mendelsohn FAO, Ohishi M. Perindopril alters vascular
angiotensin-converting enzyme, AT1 receptor and nitric oxide synthase
While the SAVE and SOLVD studies indicated that ACE inhibition leads
expression in patients with coronary artery disease. Hypertension
to a reduction in ischemic events in patients with asymptomatic left
ventricular dysfunction or heart failure, the HOPE trial subsequentlyshowed similar effects in patients at high risk of cardiovascular events,
but not necessarily known with coronary artery disease. The EUROPA study recently broadened the concept of secondary
1 What is the more important reason for the secondary preventive
prevention with ACE inhibition. In this study, the ACE inhibitor perindopril
effects of some ACE inhibitors in coronary disease:
significantly reduced major cardiovascular outcomes, includingcardiovascular death and myocardial infarctions in a broad population of
a) blood pressure reduction
patients with coronary disease without heart failure, not selected on the
b) direct vascular, anti-atherosclerotic effects
basis of a reduced ventricular function or cardiovascular risk factors.
Right answer: b
2. Is a high dose ACE inhibitor needed for secondary prevention
Subsequent analyses showed a comparable effect of the ACE inhibitor in
patients with low, medium and high risk. Moreover, the risk reduction was
slightly greater in patients without left ventricular dysfunction (the largemajority of the study population) as compared to the overall study group.
Right answer: a
3. Is secondary prevention of coronary disease by ACE inhibition a
Several mechanisms may explain the preventive effects of the ACE
inhibitor. Experimental studies in animals as well as in man indicate direct
vascular effects, including anti-atherosclerotic properties, restoration of
intima-media proliferation, improvement of endothelial dysfunction,enhanced fibrinolysis, a reduction of plague rupture and a decrease in
Right answer: b
4.If not, what makes perindopril and other agents like ramipril and
ischemia-induced vasoconstriction. Moreover, by reducing ventricular
quinapril different from other ACE inhibitors like captopril and enalapril?
hypertrophy ACE inhibitors may improve the myocardial oxygen supply-
a) Antiatherosclerotic effect
b) Tissue penetration
Also, blood pressure reduction could play a role. In the EUROPA trial
c) Longer half life
there was an average reduction of 5 and 2 mm Hg in systolic anddiastolic blood pressure, respectively, compared to placebo. A retrospective
Right answer: b
analysis, however, did not show any interaction of baseline blood pressuresand subsequent treatment effect. Moreover, whereas during a one monthrun-in period all patients received open-label perindopril up to a dose of8 mg daily, there was again no relation between blood pressure reductionduring that period and treatment effect. Indeed, the risk reduction wascomparable between patients with and without blood pressure reduction.
A co-variant analysis comparing treatment with perindopril and bloodpressure changes during the randomized study period, indicated a mere3% risk reduction through blood pressure reduction as compared to a23% perindopril effect. Blood pressure reduction therefore appearsunlikely to be of major importance in the effect of ACE inhibition, anobservation confirmed in the HOPE study.
20 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
CONCLUSIVE REMARKS FOR THE DAILY PRACTICE
REMARQUES POUR LA PRATIQUE QUOTIDIENNE.
Faiez ZANNAD, Nancy - FRA
Faiez Zannad has obtained his Medical Doctordegree in 1979 from the Faculté de Médecine de
Nancy. He also graduated there as a Cardiology
specialist in 1979. During year 1981, he served as a
Mean systolic/diastolic blood pressure (mm Hg)
Research Fellow at the Clinical Pharmacology
Mean body mass index
Medical Research Unit of Oxford University, UK. In
1986, he obtained his Ph.D. in cardiovascular clinical
pharmacology at the University of Lyon.
He is now Professor of Therapeutics at the Medical Faculty of the Henri
Poincaré University of Nancy. He is Head of the Division of Heart Failure,
Medication use at baseline (%)
Hypertension and Preventive Cardiology/ department of Cardiovascular
Disease of the academic hospital of Nancy, and Director of the Clinical
Investigation Center (CIC), mutually funded by the academic hospital and
the INSERM and of a research group (Equipe d'Accueil) "Cardiac and
Calcium channel blocker
arterial remodelling" at the Faculté de Médecine. He conducts his
Annual event rate (%)
research, in the area of physiopathology, genetics and pharmaco-therapeutics of hypertension and heart failure.
PEACE is the only study where LVEF was measured in all patients. Also,PEACE patients received the most contemporary optimised medical
Dr Zannad is Fellow of the European Society of Cardiology (FESC),
therapy. This may explain that they had lower risk as compared to
member of the Board of the French Society of Hypertension as well as of
patients in the other trials. The results of this trial should be interpreted
a large number of international societies in cardiology, hypertension,
with these main differences in mind.
pharmacology and therapeutics. He is had served as a member on the
So far, only ramipril 10 mg and perindopril 8 mg has proven to be
Editorial board of the Journal of Hypertension and the Journal of
effective. Altough trandolapril 4 mg was not effective on the primary
Cardiovascular Pharmacology. He has contributed more than 200
endpoint, the main results and not inconsistent with the results of HOPE
scientific publications and published several books on cardiovascular
and EUROPA. Meta-analysis of three trials gives further robustness of
pharmacotherapy. He is currently Co- Editor in chief of Fundamental and
the evidence for the benefit of ACE inhibitor therapy in patients with
Clinical Pharmacology, the official journal of the European Pharmacology
coronary artery disease. Class effect is most likely.The dose of 4 mg
Society. With Professor Bertram Pitt (Ann Arbor, USA), he is chairman
trandolapril may have been insufficient in PEACE. Therefore, only
and organizer of an annual international meeting (from 1997 to 2002 :
ramipril 10 mg and perindopril 8mg may be recommended because of
"Advanced Drug Research in Cardiology" and "Global CardioVascular
established and favourable estimate of benefit to risk ratio.
Clinical Trialists Forum" since 2004) and of the Cardiovascular ClinicalTrialists Workshop.
Dr Zannad has contributed to the design, conduct and steering ofseveral large clinical trials in cardiology
Member of the Critical Event Committee in the CAPRICORN, and theRESPECT
Data and Safety Monitoring Board in the HEAAL study
Steering Committee membership: APSI, FIRST, CIBIS I and II (Executivecommittee), RALES (Executive committee), CAPRICORN, FOSIDIAL(Chairman), VALIANT, RECOVER, MOXCON, EPHESUS (Executivecommittee), AURORA (Executive committee) TATAMI
Has participated in the protocol writing groups in the RALES,CAPRICORN, CIBIS II and EPHESUS studies.
HOPE, EUROPA and PEACE trials investigated the effects of an ACEinhibitor in patients with CAD, irrespectively of there BP status. Based onthe results of HOPE and EUROPA trials, it is now recommended that anACE inhibitor should be added to the drug regimen of high risk patientswith CAD. It is noteworthy that BP decreased significantly with the ACEinhibitor in both trials, raising the possibility that BP lowering in itself mayhave contributed significantly to the CV morbidity-mortality benefits of thedrug. If positive, the PEACE trial is most likely to extend the results of HOPEand EUROPA to patients with lower risk.
Main differences among the three trials are summarized in the followingtables.
Known CAD, MI, stroke
Known CAD MI, CV death,LVEF >40
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 21
2. Collins R and MacMahon S. Blood pressure, antihypertensive drug
WHAT MATTERS IS HOW MUCH BP IS LOWERED
treatment and the risks of stroke or coronary heart disease.; BR MEDBULL 1994;50:272-98
L'IMPORTANT EST DE COMBIEN ON ABAISSE
LA PRESSION ARTÉRIELLE
3. Effects of different blood-pressure - lowering regimens on major
cardiovascular events: results of prospectively-designed overviews of
Christian THUILLEZ, Rouen - FRA
randomised trials. Blood pressure lowering treatment trialists'
Stéphane LAURENT, Paris - FRA
collabaration. LANCET 2003; 362:1527-35.
ANTIHYPERTENSIVE TREATMENT BENEFIT IS
BY BLOOD PRESSURE LOWERING.
1. Which of the following outcomes is most sensitive to the protective
LES BENEFICES DU TRAITEMENT ANTI-
effects of blood pressure lowering?
HYPERTENSEUR SONT PRINCIPALEMENT LIES
a) Coronary heart disease
A L'ABAISSEMENT DE LA PRESSION ARTERIELLE.
b) Strokec) Heart failure
Right answer: b
Fiona TURNBULL, Newtown - AUS
2. For which class of agent is the strongest evidence of a drug-specific
Fiona Turnbull is a Senior Research Fellow with the
Heart and Vascular Division at the George Institute
for International Health in Sydney, Australia. Fiona is
a Public Health Physician with primary responsibility
c) Calcium antagonists
for the Blood Pressure Lowering Treatment Trialists
Right answer: c
Collaboration, an initiative established in 1995 toprovide reliable evidence about the effects of
3. "Normotensive" individuals do not derive any cardiovascular benefits
different blood pressure lowering regimens on major
from blood pressure reduction.
cardiovascular morbidity and mortality. The most recent findings from this
collaboration were reported in the Lancet and will provide important
evidence to guide decisions in healthcare policy and practice about the
Right answer: b
use of commonly-used treatment regimens. Her current work with thecollaboration centres on determining the effects of treatment in importantpatient subgroups, such as those with diabetes. Fiona also has a stronginterest in cardiovascular disease in low and middle income countries inthe Asia-Pacific region and is currently working with Chinese CardiacSociety to develop, implement and evaluate clinical pathways for themanagement of Acute Coronary Syndromes in China.
It clear from large-scale observational studies that lower blood pressurelevels are associated with lower risks of stroke and coronary heartdisease. Furthermore, there is no evidence of a lower threshold belowwhich these risks do not continue to decrease . In line with theseobservational data, large-scale randomised trials have shown thatlowering blood pressure reduces the risks of stroke and heart attackamong both hypertensive and non-hypertensive patients at risk ofvascular disease . While blood pressure control is widely recognisedas an important preventive therapy, there remains considerable clinicaluncertainty about whether particular drug classes provide greaterprotection against major cardiovascular events than others. Individualtrials have variously reported greater effects of regimens based on anumber of different agents but the findings have been inconsistent andalthough small-scale trials studying surrogate outcomes suggestdifferences between drug classes, there is little evidence that thesedifferences translate into importantly different effects on majorcardiovascular outcomes. Recently, systematic overviews incorporating the results of many trials and very large numbers ofindividuals have defined more clearly, the comparative effects of differentregimens on stroke, coronary heart disease and heart failure.
Increasingly, it appears as if the key to prevention of these major eventsis the magnitude of the blood pressure reduction rather than the agentwith which the reduction is achieved. This evidence is reflected in mostrecent guidelines relating for the use of blood pressure loweringtherapies. Although, these overviews do not preclude certain drug-specific effects (independent of blood pressure lowering), by comparisonwith the benefits derived from reducing blood pressure, any such effectsare likely to be very small. As a result, clinicians should direct their effortsat achieving lower blood pressure goals in their patients. In mostinstances, this will require treatment with multiple blood pressurelowering agents.
1. MacMahon S, Peto R, Cutler J et al. Blood pressure, stroke andcoronary heart disease. Part 1, Prolonged differences in blood pressureprospective observational studies corrected for regression dilution bias.
Lancet 1990; 335; 765-774.
22 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
BETA-BLOCKER THERAPY IN MODERN TIMES
3. Wilkinson IB, Qasem A, McEniery CM, et al. Nitric oxide regulates local
LE TRAITEMENT BÉTA-BLOQUANT :
arterial distensibility in vivo. Circulation. 2002;105:213-7.
UNE ÈRE NOUVELLE
4. Cockcroft JR, Chowienczyk PJ, Brett S, Chen C PL-H, Dupont AG, van
Neuten L, Wooding SJ, Ritter JM. Nebivolol vasodilates human foream
Ferenc FOLLATH, Zurich - SUI
vasculatiure: evidence for an L-arginine/NO-dependent mechanism.
Kurt STOSCHITZKY, Graz - AUT
J Pharmacol Exp Ther. 1995; 274(3):1067-71.
THIRD GENERATION BETA-BLOCKERS.
5. McEniery CM, Wilkinson IB, Qasem A, Schmitt M, Webb DJ, Avolio AP,
ANTIADRENERGIC EFFECTS AND BEYOND.
Cockcroft JR. Nebivolol reduces arterial stiffness in vivo. Hypertension2004; 44: 305-310.
LA TROISIÈME GÉNÉRATION DE BÉTA-BLOQUANTS.
AU-DELÀ DES EFFETS ANTI-ADRÉNERGIQUES.
John COCKCROFT, Cardiff - GBR
Professor Cockcroft is Professor of Cardiology at theWales Heart Research Institute in Cardiff. He is alsoSpecial Professor of Cardiovascular DiseasePrevention at the University of Nottingham andvisiting Professor in the Graduate School ofBiomedical Engineering, the University of New SouthWales, Sydney, Australia.
His major research interests focus on endothelial
function and arterial stiffness in health and disease. He has publishedover a 100 peer reviewed articles in this field and has co-authored bookson hypertension and coronary heart disease. He is a founding member ofthe Association for Research into Arterial Structure and Physiology(ARTERY) and is co-organiser of the Association's conferences.
Professor Cockcroft's clinical interests focus on hypertension andcardiovascular disease prevention and he was a member of thecommittee which produced the Welsh National Service Framework forcardiovascular disease.
Arterial stiffness is an emerging risk factor for cardiovascular disease.
Indeed, increased arterial stiffness is an independent predictor ofmortality in a number of different population groups including patientswith hypertension. Hypertension is also a major risk factor for morbidityand mortality, and the benefits of blood pressure reduction have beenclearly demonstrated in large clinical outcome trials which have alsosuggested that it is blood pressure reduction per se rather than the agentused that is of most importance. However, a recent meta analysis hassuggested that the first generation beta blocker, atenolol, may havedetrimental effects in terms of cardiovascular outcome. In addition, therecent LIFE study has shown the angiotensin II receptor antagonistlosartan to be more effective in reducing cardiovascular events thanatenolol, despite similar reductions in peripheral blood pressure.
However, central blood pressure may have been different between thetwo groups. Indeed, a recent rotation study has shown that beta-blockadehas differential effects on peripheral and central blood pressure.
Drugs that reduce arterial stiffness and blood pressure may confer a urvival advantage in patients with stiffened arteries (ref). However, dataon the effects of beta blockade on arterial stiffness are conflicting.
We have previously shown that large arterial stiffness is regulated in partby endothelium derived nitric oxide (NO) (ref). Nebivolol is a thirdgeneration beta blocker which produces vasodilatation via an NOmediated mechanism (ref). We have recently demonstrated that nebivolol,but not atenolol, decreases arterial stiffness; an effect independent of anyeffect on blood pressure lowering. Therefore third generation vasodilatorbeta blockers such as nebivolol may be effective in reducing largearterial stiffness, especially in conditions associated with increasedarterial stiffness such as isolated systolic hypertension, diabetes andhypercholesterolaemia. These properties of third generation betablockers will translate into improved cardiovascular outcome that willrequire further data from large clinical intervention studies.
1. Morgan T, Lauri J, Bertram D, Anderson A. effect of different anti-hypertensive drug classes on central aortic pressure. Am J Hypertens2004; 17: 118-123.
2. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London G.
Impact of aortic stiffness attenuation on survival of patients in end-stagerenal failure. Circulation 2001; 103:987-992
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 23
EXPANDING THE SCOPE OF BETA-BLOCKER
ejection fraction was 36% (with 35% having ejection fraction >35%) and
THERAPY IN HEART FAILURE TO THE ELDERLY AND
68% had a prior history of coronary heart disease. The mean maintenancedose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary
TO THE PRESERVED LEFT VENTRICULAR
outcome occurred in 332 patients (31.1%) on nebivolol compared to 375
(35.3%) on placebo (hazard ratio [HR] 0.86, 95% CI 0.74-0.99;
RESULTS OF THE SENIORS TRIAL
p = 0.039). There was no significant influence of age, gender or ejection
LES BÉTA-BLOQUANTS DANS L'INSUFFISANCE
fraction on the effect of nebivolol on the primary outcome. Death (allcause) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on
CARDIAQUE DES PERSONNES ÂGÉES ET
placebo (HR 0.88, 95% CI 0.71-1.08; p = 0.21).
À FONCTION SYSTOLIQUE VENTRICULAIRE
In conclusion, SENIORS has shown that nebivolol is an effective and well
GAUCHE PRÉSERVÉE. RÉSULTATS
tolerated treatment for heart failure in the elderly, whatever LVEF value.
DE L'ESSAI SENIORS.
Alain COHEN SOLAL, Paris - FRA
Alain COHEN SOLAL, MD, Ph D, 49, is bothProfessor of Cardiology at the Faculty of Medicine-Paris 7, and the Head of the Department ofCardiology at the Hospital Beaujon, in Clichy, Hautsde Seine, next to Paris.
Pr A COHEN SOLAL has a diploma of GeneralMedicine, of Cardiology, of Echocardiography and
made his Ph Dthesis on the Cardiovascular Response to Exercise inCHF.
Pr A COHEN SOLAL is a member of several professional organizations,including the French Society of Cardiology, the French Society ofHypertension, the European Society of Cardiology. He is member of theWorking Group on Heart Failure of the ESC and Vice President of theWorking Group on Cardiac Rehabilitation and Exercise Physiology of theESC.
He is currently the past president of the Groupe de Reflexion sur laRecherche Cardiovasculaire, a working group of the French Society ofCardiology, in charge of cardiological research.
He acted as the principal investigator in France on several trials in HF,including recently REACH 1, CHARM, SENIORS, SURVIVE as well asIMPROVEMENT and SHAPE, two initiatives of the Study Group onDiagnosis of the WG on Heart Failure of the ESC. He has participated invarious Steering Committees of Studies on Heart Failure.
Pr A COHEN SOLAL is now leading a department of cardiology of 32beds and 8 beds of intensive care. This department is mainly orientedtowards the care of patients with acute and chronic heart failure. A multi-disciplinary ambulatory program of care of patients with CHF is ongoingas well as a programme of cardiac rehabilitation for patients with HF orafter heart transplantation.
He has focused his research on several aspects of HF : mainly :- the abnormalities of the cardiac and peripheral responses to exercisein CHF- the evaluation of CHF by cardiopulmonary exercise testing- the diagnostic and prognostic role of neurohormones (BNP)- the païdo-pathologie of diastolic heart failure
Pr A COHEN SOLAL has written several articles published in peer-reviewed medical journals, including Circulation, the Journal of theAmerican College of Cardiology, the American Journal of Cardiology,Heart, the European Heart Journal, the Journal of Hypertension. He isalso on the éditorial board of the European Journal of Cardiac Preventionand Rehabilitation.
Large randomised trials have shown that beta blockers reduce mortalityand hospital admissions in patients with heart failure. The effects of betablockers in elderly patients with a broad range of left ventricular ejectionfraction have been uncertain.
The SENIORS study was performed to assess effects of the betablocker, nebivolol, in patients >70 years regardless of ejection fraction.
2128 patients aged ≥ 70 years with a history of heart failure (hospitaladmission for heart failure within previous year, or known ejection fraction
≤ 35%), 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg oncedaily) and 1061 to placebo. The primary outcome was a composite of allcause mortality or cardiovascular hospital admission (time to first event).
Analysis was by intention to treat. Mean duration of follow-up was 21months. Mean age was 76 years (SD 4.7), 37% were female, mean
24 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
HOW TO IMPROVE AND OPTIMIZE BETA-BLOCKER
starting beta-blocker treatment first before ACE inhibition. Such initiation
THERAPY IN HEART FAILURE PATIENTS?
of treatment with beta-blocker could provide optimal prevention ofsudden death. On the other side, the best therapeutic strategy in case of
COMMENT AMÉLIORER ET OPTIMISER
heart failure worsening remains a matter of debate. The B-Convinced
LE TRAITEMENT BÉTA-BLOQUANT
study compares beta-blocker interruption versus continuation in HF
CHEZ L'INSUFFISANT CARDIAQUE ?
patients receiving a beta-blocker and presenting with a HF worseningepisode with acute pulmonary oedema.
Philippe LECHAT, Paris - FRA
Results of these studies will provide additional information which will helpto improve individual adaptation of beta-blocker treatment in patients with
Professor of Pharmacology, Cardiologist
Head of the Pharmacology Department and of theClinical Research Unit Pitié-Salpêtrière Hospital, Paris- France.
Past chairman of the French Society ofPharmacologyCorresponding member at the French drug
Coordinator of the CIBIS trials.
Beta-blocker treatment has become one landmark treatment of heartfailure (HF) in combination with diuretics and angiotensin convertingenzyme inhibitors in patients with low ejection fraction. However, somequestions remain on the conditions of administration of such a treatmentin order to optimize its efficacy and tolerance. Both parameters relatedwith pharmacological properties of beta-blocker compounds and frompatient characteristics may influence benefit / risk ratio of such treatmentin HF patients. Among the different compounds that have proven benefitin heart failure, the meta-analysis of randomized trials could not detectany major difference between bisoprolol, metoprolol and carvedilol. Thedirect comparison between carvedilol and metoprolol has providedarguments in favour of a better efficacy of carvedilol, as far as mortalityis concerned. Controversy has raised however on the comparability ofthe doses used in the COMET trial, but it remains possible that theachieved level of beta-blockade could be higher with carvedilol comparedto that obtained with metoprolol, even with the highest tested doses ofmetoprolol. Efficacy of beta-blocker treatment which depends on the levelof inhibition of beta-adrenergic receptor stimulation, is basically indeeddose dependent. The optimal dose to be administrated to a given patientwith a given compound remains however unknown and is currently basedon tolerance, the highest tolerated dose being considered as the optimaldose.
Patient condition also influences therapeutic strategy and doseadaptation. Indeed, severity of heart failure enhances sensitivity to beta-blockade, a similar level of beta-blockade being achieved with lowerdoses when severity of heart failure increases, as shown in CIBIS II andMERIT trial. This is related with the progressive down regulation of beta-adrenergic receptors. Etiology of heart failure, however does not seem toinfluence efficacy or tolerance to beta-blocker treatment in HF. Baselineheart rate and quality of cardiac rhythm (sinus rhythm or atrial fibrillation)do not appear to influence beta-blocker benefit but amplitude of heart ratereduction could play a role for long term benefit.
Interactions between treatments may influence long term prognosis inheart failure patients: Combination of beta-blockers with statin wasassociated with best prognosis in CIBIS II trial. Combination withangiotensin II receptor antagonists provided different results withvalsartan (Valheft) and with candesartan (Charm), probably related todifferent event rates. When event rate is greatly reduced by beta-blockertreatment, addition of angiotensin II receptor antagonist does not seem toprovide additional benefit. This was the case in the Valheft trial.
Genetic profile of patients has the potential to influence beta-blockaderesponse but different results have been obtained with geneticpolymorphisms and so far no prospective study has studied theprognosis value of polymorphisms such as those of beta-adrenergicreceptors.
The most recent study with nebivolol in aged patients, the SENIORSstudy has demonstrated an overall benefit, with morbi-mortality reductionof 14%, confirming the benefit of beta-blocker treatment in elderly with HFwhatever the value of LV ejection fraction.
Therapeutic strategy of beta-blockade in HF is currently investigated intwo directions which will provide useful information for individualadaptation: On one hand, the CIBIS III study evaluates the possibility of
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 25
Pleiotropic Effect of Statins: Several experimental observations have
demonstrated the capacity of statins of carrying out direct anti-inflammatory effects on atheromatous plaques. Evidence showing that
these effects have a clinical significance is still limited, and it is especiallydifficult to separate the effect of lowering LDL-C, which in itself already
ARE ALL STATINS ALIKE?
has anti-inflammatory consequences at the vascular level from pleiotropicactions. However, in support of pleiotropic effects of the statins, at least
TOUTES LES STATINES SONT-ELLES ÉGALES ?
on the basis of HPS and ASCOT study results, it is the significant
reduction (-28%) of the cerebrovascular events observed in patients
Bertram PITT, Ann Arbor - USA
treated that could involve actions which are independent of the LDL-C
Michel KREMPF, Nantes - FRA
Clinical Benefits of Statins: The major considerations to chose between
PHARMACOLOGICAL DIFFERENTIATION AMONG
statins for CVD patient therapy include clinical benefits and safety (i.e.
STATINS. CLINICALLY RELEVANT?
evidence-based medicine). Primary prevention trials with pravastatin,simvastatin, atorvastatin and lovastatin and secondary prevention trials
DIFFÉRENCIATION PHARMACOLOGIQUE PARMI LES
with pravastatin, fluvastatin and simvastatin have established the clinical
STATINES. CLINIQUEMENT PERTINENTES ?
benefits of statins.
Finally, it is interesting to note that all the statin clinical trials carried out
Alberto CORSINI, Milano - ITA
to date have consistently shown that LDL cholesterol reductions in therange 25-35% is associated with a 24-37% decrease in cardiovascular
Present: Full Professor of Pharmacology,
events. As yet there is no firm evidence from long-term statin clinical
Department of Pharmacological Sciences, University
trials that lowering LDL cholesterol below levels observed in the trials
provides increased outcome benefits, although trials such as SEARCHand TNT may soon provide an answer.
Degrees: Doctor in Pharmacy 1981, PhD in Experimental
In conclusion, even if the serum LDL cholesterol-lowering activity
Pharmacology 1983, PhD in Experimental Medicine
certainly represents an effect of the class of statins, at present these
drugs cannot all be considered the same. First of all, it must be recalledthat "evidence based medicine" has not reached the same level of
Membership of Societies: International Atheroslerosis Society, American
documentation for all the statins and that it is possible that the profiles of
Heart Association, The New York Academy of Sciences, European
efficacy and safety over long term are not completely the same. A careful
Tissue Culture Society, Italian Society of Atherosclerosis, Italian Society
evaluation of the characteristics of each specific statin must guide the
of Pharmacology, Italian Association of Tissue Culture
physician in the selection of the most appropriate drug in order to
Reviewer for: Arteriosclerosis, Thrombosis and Vascular Biology;
optimize the antiatherosclerotic effects and the prevention of clinical
Atherosclerosis; Circulation; Drugs; The Faseb Journal; European
events in the various typologies of patients at high cardiovascular risk.
Journal of Clinical Investigation; Journal of Cardiovascular Pharma-cology; Lipids; Science, Pharmacological Research.
1. Chong PH. Lack of therapeutic interchangeability of HMG-CoA
Postdoctoral Researcher, Laboratory of Cellular Pharmacology of
reductase inhibitors. Ann Pharmacother. 2002 Dec;36(12):1907-17.
Atherosclerosis, Institute of Pharmacological Sciences, University ofMilan, Italy (1981 - 1985)
2. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical
Postdoctoral Fellow, Gladstone Foundation Laboratories for
pharmacokinetics and drug interactions.
Cardiovascular Disease, Cardiovascular Research Institute, Department
Circulation. 2004 Jun 15;109(23 Suppl 1):III50-7.
of Pathology and Medicine, University of California, San Francisco, USA(1986 - 1987)
3. Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA,
Fellow of the Institute of Pharmacological Sciences, University of Milan,
Leitersdorf E, Marz W, Reckless JP, Stein EA. Risk for myopathy with
Italy (1988 - 1990)
statin therapy in high-risk patients. Arch Intern Med. 2003 Mar
Assistant Professor of Pharmacology, Institute of Pharmacological
Sciences, University of Milan, Italy (1990 - 1997)Visiting Scientist, Department of Biochemistry (Howard Hughes Medical
4. Corsini A. The safety of HMG-CoA reductase inhibitors in special
Institute), University of Washington, Seattle, USA (1993 - 1999)
populations at high cardiovascular risk.
Cardiovasc Drugs Ther. 2003 May;17(3):265-85.
Honors, scholarships, fellowships:
Selected winner of an International Atherosclerosis Society VisitingFellowship. (1998)
PhD Student in "Experimental Medicine: Atherosclerosis" University ofSiena directed by Prof G Weber (1985 89)
1. Is it present for all statins the evidence based-medicine?
Postdoctoral fellowship of the Nutrition Foundation of Italy. (1984 85)
a) all statins have shown evidence based-medicine
Fellow of the Institute of Pharmacological Sciences, University of Milan.
b) no, only simvastatin, atorvastatin and pravastatin have shown
Scientific interest in the area of Pharmacology of Lipid lowering agents
c) yes, only for LDL cholesterol lowering
and Atherosclerosis. Author of > 100 peer-reviewed publications. Editor
Right answer: b
2. Does pleiotropic activity play a clinical role?
a) no, it has only an experimental meaning
b) yes, but additional data are requiredc) no, the only mechanism of statins is to reduce LDL cholesterol
Pharmacological Properties of Statins: Statins share several common
Right answer: b
features including the mechanism of action, i.e. inhibition of HMG-CoAreductase, as well as LDL-cholesterol and triglyceride lowering propertiesbut they also show minor differences in chemical structure, that couldtranslate into a different pharmacological properties. For example, somestatins are particularly hydrophilic (see pravastatin and rosuvastatin)while others prove to be particularly lipophilic (see simvastatin andatorvastatin). Even pharmacokinetic properties evidence the diversityamong the various statins, a diversity which can have notable practicalconsequences, and we can recall that often variations in interindividualresponses and pharmacological interactions have a pharmacokineticbasis.
26 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
EVIDENCE FROM MECHANISTIC STUDIES.
3. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive
BIOMARKERS AND IMAGING SURROGATES.
compared with moderate lipid-lowering therapy on progression ofcoronary atherosclerosis: a randomized controlled trial. JAMA
DONNÉES DES ÉTUDES MÉCANISTIQUES.
BIOMARQUEURS ET IMAGERIE.
4. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, et al.Reversal of
Serge KOWNATOR, Thionville - FRA
Atherosclerosis with Aggressive Lipid Lowering (REVERSAL)Investigators.Statin therapy, LDL cholesterol, C-reactive protein, andcoronary artery disease. N Engl J Med. 2005 Jan 6;352(1):29-38.
Beside the lipid effect of statins there is today substantial quantity of datashowing that statins exert effects of various parameters from theendothelial function to the volume of atherosclerosis, through effect oninflammatory parameters such as CRP or effect on the arterial wall.
All the available statins have been tested showing different resultsaccording to there dose, the importance of cholesterol lowering but alsoto the molecule. This different results support the controversy on the socalled pleiotropic effects and on the class effect.
In experimental studies one can find several results according to themolecule, depending particularly on there lipophilic or hydrophilicproperties.
In a study by Sukhova, the inflammatory parameters are improved andthere is a trend toward the stabilization of the plaque independently of theimportance of cholesterol lowering. This effect depends highly on thedose and the molecule. In another study by Bustos, atorvastatin 5 mg/kgabolish atherosclerotic plaques infiltration by macrophages in femoralartery of rabbits.
In human, there is no strong evidence for a significant difference betweenstatins on the CRP lowering. Nevertheless, an intensive treatment byatorvastatin appears to be more effective on the CRP then usual dosesof pravastatin. Intensive cholesterol lowering seems to be also a key point regarding theeffect of statin on the carotid IMT. In the ASAP study, atorvastatin 80 mgprovides at two years a 50.5 % reduction of LDL cholesterol and a 20 %regression of carotid IMT. In the same study, simvastatine induces a40.2 % reduction of LDL cholesterol but no regression of carotid IMT. Inthe ARBITER study comparing atorvastatin 80 mg to pravastatin 40 mg,there is a regression of IMT with atorvastatin (48.5 % LDL lowering) andno effect with pravastatin (27.2 % LDL lowering).
Plaque regression is another major endpoint with statins. R Corti in a MRIstudy shows nicely a regression of the plaque with simvastatin.
He demonstrates that after 12 month a first effect appears on arterialremodelling. After 18 months he shows an augmentation of the vessel'slumen. The most important study regarding statin's effect onatherosclerotic plaque is probably the REVERSAL study with IVUS. Hereatorvastatin 80 mg shows after 18 months a stabilization of atheroscleroticlesions as compared to a progression with pravastatin 40 mg. in the sametime atorvastatin provides a 36.4% reduction of CRP vs 5.1% withpravastatin.
Conclusion:There is an amount of evidence that statins are effective on the arterialwall through several mechanisms and mainly through an anti-inflammatory way. Are these effects only the consequences of theimportance of cholesterol lowering, is there a difference according to themolecule? Further studies in this direction are still mandatory for anobjective answer to the question.
1. Bonetti PO, Lerman LO, Napoli C, Lerman A . Statin effects beyondlipid lowering-are they clinically relevant? European Heart Journal (2003)24, 225-248
2. Balk EM, Lau J, Goudas LC, Jordan HS et al.Effects of Statins onNonlipid Serum Markers Associated with Cardiovascular Disease ASystematic Review. Ann Intern Med. 2003;139:670-682.
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 27
THE LEVEL OF EVIDENCE FROM OUTCOME
could be reached and is beneficial in high risk patients with no major side
STUDIES. CHOLESTEROL LOWERING AND BEYOND
effects. Therefore, many data support the hypothesis "lower is better" forLDL-C and prevention of cardiovascular diseases. However the reduction
IN PRIMARY AND SECONDARY PREVENTION
of LDL-C could not explain all the clinical data reported in these trials. An
TRIALS WITH STATINS / DIMINUTION DU
other effect of statins, called "pleotropic effect" is also suggested from in
CHOLESTÉROL ET AUTRES MÉCANISMES
vitro data but also from few clinical trials. It was suggested that 40 % of
DES STATINES DANS LES ESSAIS CLINIQUES DE
the effect of statins on cardiovascular events is not related to thereduction of LDL-C. But it is not clear if this observation is specific of few
PRÉVENTION PRIMAIRE ET SECONDAIRE.
statins or shared by all of them. Only trials comparing drugs couldanswer to this question by using hard clinical end points and identical
Michel KREMPF, Nantes - FRA
efficacy on LDL-C. This is the next challenge of the statin story.
Michel Krempf is professor of Human Nutrition atNantes School of Medicine. He is leading a clinical
department of metabolic diseases and participates inmany clinical and therapeutic trials with statins and
1. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA,
other drugs. He is leading an INSERM Research
Crowe T, Howa G, Brodie B, Grines CL, DeMaria AN. Effect of intensive
Team and his main topic regards kinetics of
compared with moderate lipid-lowering therapy on progression of
lipoproteins by using stable isotopes and mass
coronary atherosclerosis : a randomized controlled trial. JAMA 2004, 291:
spectrometry. He is focusing on the mechanisms
involved in dyslipidemia occurring in metabolic syndrome and type 2diabetes.
2. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, BelderR, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Comparison of intensive andmoderate lipid lowering with statins after acute coronary syndromes.
N Engl J Med 2004, 350.
Date of birth : April 23, 1953. Meknès (Morroco)Nationality : French
3. Scandinavian Simvastatin Survival Study Group. Randomised trial of
Medical Register N° : 44 1 03972 4 1
cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344: 1383-
University of Lyon, M.D. 1979
University of Nantes, specialist in Nutrition and Endocrinology, 1984University of Paris, Research Degree in Human Biology (Clinical
4. Grundy SM, Cleeman JI, Merz NB, Brewer HB, Clark LT, Hunninghake
DB, Pasternak RC, Smith SC, Stone NJ. Implications of recent clinical
Massachusetts Institute of Technology, Boston - 1986-1987, postdoctoral
trials for the national cholesterol education program adult treatment panel
fellowship (Pr V.R. Young).
III guidelines. Circulation 2004, 110: 227-239.
5. Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of cholesterol-lowering with simvastatin in 5963 people
1) 1996-1997, Director of the research team " Fonctions Digestives et
with diabetes : a randomised placebo-controlled trial. Lancet 2003, 361:
Nutrition " EA 1160 (grant : 60 000 US $ /yr).
The main topic of this team is to study kinetic aspects of humanmetabolism and specially lipoproteins using stable isotopes and mass
6. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low
spectrometry. Animal models (rats, pigs and dogs) as well as culture cell
density lipoprotein cholesterol, ischaemic heart disease, and stroke:
models are also available.
systematic review and meta-analysis. BMJ 2003, 326 : 1423-1427.
2) 1990, Professor of Nutrition - School of Medicine, NantesDepartment of Human Nutrition, Metabolic Diseases and Endocrinology -University Hospital, Nantes
3) 1986-1987, Research Post Doc fellowship on the use of isotopes inhumans. Massachusetts Institute of Technology, U.S.A. (laboratory ofHuman Nutrition - Pr V. Young)
4) 1984/1990, Assistant Professor of the Department of Human Nutrition,Metabolic Diseases and Endocrinology, University Hospital, Nantes.
5) 1978/1984, Internal Medicine and Human Nutrition Resident at theUniversity Hospital of Nantes
Society member: - French Society on Atherosclerosis (ARCOL).
- French societies on Nutrition (SNDLF et CEN).
Clinical and therapeutic studies:Involved in many human studies using statines (pravastatine, fluvastatine,cerivastatine, atorvastatine in dyslipidemic and diabetic patients) as wellas fibrates (fenofibrate) or 3 (maxepa or omacor). Main nationalinvestigator of three studies. Involved also in studies and Europeanexpert board for Orlistat (obesity treatment) as well as sibutramine.
Many clinical trials with statins showed a tremendous effect on cardio-vascular disease prevention. This was demonstrated in secondaryprevention or in primary prevention, mainly in patients with highcardiovascular risk. Whatever the statins used and the patients enrolledin trials, a clear relationship was observed between the reduction ofcardiovascular events and the decrease of LDL-C. According to the trialsand the efficacy of the last marketed statins, a goal of 70 mg/dl of LDL-C
28 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
INTEGRATING NEW EVIDENCE INTO GUIDELINES
AND CLINICAL PRACTICE. TIME FOR ACTION.
INTÉGRATION DES NOUVELLES DONNÉES DANS
LES RECOMMANDATIONS DE PRATIQUE.
There is now little doubt that statins decrease the risk to suffer
LE TEMPS DE L'ACTION.
myocardial infarction and stroke. Recent trials including ASCOT andCARDS comparing atorvastatin to placebo and conducted in hypertensive
Eric BRUCKERT, Paris - FRA
and diabetic subjects, respectively, extended the patients who maybenefit from statin. Indeed these two trials were stopped prematurely due
Eric Bruckert (12 march 1957), Medical Doctor. Pitié-
to evidence of a decrease in the number of cardiovascular events. Statin
Salpêtrière Hospital, Paris, France
therapy is now mandatory in all patients at risk and recent guidelinesindicated the need to further decrease LDL-c in these patients. However,
Professor of Endocrinology (1995). He is responsible
we are far from reaching the adequate goals in clinical practice. In the
for the "Prevention of Cardiovascular Disease
EUROASPIRE study, only 51% of patients on lipid lowering therapy
Center" in the Endocrinology & Metabolism
achieved goal. Furthermore patients at higher risk such obese subjects
Department (University Hospital Pitié-Salpêtrière).
were even less likely to reach the adequate LDL-c target.
He is in charge of teaching endocrinology at the
A number of explanations can be found. These explanations include 1)
Medical University (Paris VI)
treatment characteristics, 2) patient demographics, 3) the disease itself(hypertension, diabetes and hyperlipidemia are more difficult to manage
Research: President of the strategic committee of INSERM (public
because they are often aymptomatic), 4) the physician and 5)
research organization in France) Member of the Research center
miscellaneous (environmental) reasons. In practice we need to identify
INSERM U551 (Director, MJ Chapman, Pitié-Salpêtrière Hospital).
patients at risk of side effects and to reassure patients on the tolerabilityof statin treatment. Indeed there is a discrepancy between perceived
muscular side effects and the rate of adverse events in large trials
President elect of the French Society of Atherosclerosis. Founding
conducted with these drugs. Patients characteristics include lack of time,
member of ARCOL (French Committee for the Co-ordination of research
cost, complex treatment regimen (polypharmacy), psychological aspects
in Atherosclerosis and Cholesterol). He is also a member of the French
and preponderance of emotional aspects over scientific evidence. These
Society of Endocrinology, the French Society of Cardiology, and the
aspects will be presented in details. Finally, therapeutic education is
Editorial Board of 10 scientific French journals.
emerging as a promising approach to help patient follow their drug
He is an expert of the French Regulatory Agency for drugs.
treatment and all advice aimed at increasing physical activity andimproving diet.
He wrote 5 books and more than 500 papers of which 70 are inpeer-reviewed Anglo-Saxon reviews.
Example of recent publications
Chadarevian R, Bruckert E, Leenhardt L, Giral P, Ankri A, Turpin G.
Components of the Fibrinolytic System Are Differently Altered in
1. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT,
Moderate and Severe Hypothyroidism. J Clin Endocrinol Metab. 2001;
Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; Coordinating
Committee of the National Cholesterol Education Program. Implicationsof recent clinical trials for the National Cholesterol Education Program
Bruckert E, Giral P, Ratziu V, Poynard T, Chapman MJ, Opolon P, Turpin
Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44(3):
G. A constellation of cardiovascular risk factors is associated with
hepatic enzyme elevation in hyperlipidemic patients. Metabolism.
2. Varma R, Aronow WS, Gandelman G, Zammit C. Prevalence ofadequate control of increased serum low-density lipoprotein cholesterol
Bruckert E, Giral P, Tellier P. Perspectives in cholesterol-lowering
in self-pay or Medicare patients versus Medicaid or private insurance
therapy: the role of ezetimibe, a new selective inhibitor of intestinal
patients followed in a University General Medicine Clinic. Am J Cardiol.
cholesterol absorption. Circulation. 2003, 107 (25): 3124-8
Sposito AC, Gonbert S, Bruckert E, Atassi M, Beucler I, Amsellem S,
3. Erhardt LR, Pearson TA, Bruckert E, Leiter LA, Conroy RM, Hobbs
Khallouf O, Benlian P, Turpin G. Magnitude of HDL Cholesterol Variation
FDR, Smaha LA, Ducimetière P, Assmann G, Fruchart JC, Komajda M,
After High-Dose Atorvastatin Is Genetically Determined at the LDL
Olsson, AG, Wood DA. Guidelines and their implementation: a discussion
Receptor Locus in Patients With Homozygous Familial
document focused on the best approaches to drive improvement.
Hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2003;23(11):
Vascular Disease Prevention 2004, 1 : 167-174
Liu YM, Moldes M, Bastard JP, Bruckert E, Viguerie N, Hainque B,
4. Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G. A
Basdevant A, Langin D, Pairault J, Clement K. Adiponutrin: A new gene
comprehensive description of muscle symptoms associated with
regulated by energy balance in human adipose tissue. J Clin Endocrinol
lipid-lowering drugs. Cardiovasc
Metab. 2004 Jun;89(6):2684-9.
Consoli SM, Bruckert E. Educational level has a major impact on therepresentations of cholesterol: a study in 1579 hypercholesterolemicpatients. Prev Med. 2004 Mar;38(3):323-9.
Jublanc C, Bruckert E, Giral P, Chapman MJ, Leenhardt L, Carreau V,Turpin G. Relationship of circulating C-reactive protein levels to thyroidstatus and cardiovascular risk in hyperlipidemic euthyroid subjects: lowfree thyroxine is associated with elevated hsCRP. Atherosclerosis. 2004Jan;172(1):7-11.
Erhardt LR, Pearson TA, Bruckert E, Leiter LA, Conroy RM, Hobbs FDR,Smaha LA, Ducimetière P, Assmann G, Fruchart JC, Komajda M, Olsson,AG, Wood DA. Guidelines and their implementation: a discussiondocument focused on the best approaches to drive improvement.
Vascular Disease Prevention 2004, 1 : 167-174
Hansel B, Giral P, Nobecourt E, Chantepie S, Bruckert E, Chapman MJ,Kontush A. Metabolic syndrome is associated with elevated oxidativestress and dysfunctional dense high-density lipoprotein particlesdisplaying impaired antioxidative activity. J Clin Endocrinol Metab. 2004;89(10):4963-71.
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 29
CARDIOVASCULAR PREVENTION AND
Albert MIMRAN, Montpellier - FRA
NEPHROPROTECTION. NEW AVENUES
WITH ANGIOTENSIN RECEPTOR BLOCKERS.
Professor Albert MIMRAN was born on February 28th1940 in Perregaux, Algeria. He is of French
PROTECTION CARDIOVASCULAIRE ET RÉNALE.
Nationality. His undergraduate tuition was at the
NOUVELLES VOIES POUR UN NOUVEL
University of Montpellier, France in the Faculty of
ANTAGONISTE DE L'ANGIOTENSINE.
Pharmacy and then the Faculty of Medicine.
Following graduation and junior doctor years he
Michel MARRE, Paris - FRA
completed his postgraduate MD degree after which
Albert MIMRAN, Montpellier - FRA
he moved to Boston as a research Fellow of Dr
Norman Hollenberg in the Division of Nephrology, Department of
Michel MARRE, Paris - FRA
Medicine in the Harvard Medical School from October 1971 to April 1973.
He returned to Montpellier in France where he was made Professor ofInternal Medicine in 1977 and served as Chief of Service in Internal
Professor Michel MARRE, born in 1951, was
Medicine and Hypertension in the Centre Hospitalier Universitaire in
educated in University Paris VI and he got his Ph.D.
Montpellier from 1984 to the present.
in 1979 and his MD in 1980.
Professor Mimran has served in a number of posts in medical societies.
He served as President of the French Society of Hypertension (1990-
He is currently Head of the Endocrinology
1992) and was a council member of the International Society of
Diabetology and Nutrition Department and Director of
Hypertension (1994-2004). He then was elected as President of the
the INSERM Research Unit U695 entitled "Genetic
International Society of Hypertension (2000-2002) and continued for two
determinants of type 2 diabetes and its vascular
further years on the Council as Past President. He was elected a Fellow
of the Council for High Blood Pressure (American Heart Association,USA) and served on the Council of the European Society of
His main topic deals with diabetic nephropathy and, by consequence,
Hypertension. He is a member of many learned societies including the
cardiovascular disease in diabetes.
American Society of Hypertension and the French Society of Nephrology.
Professor Mimran has served on a number of editorial boards ofpeer-review journals, and regularly acts as a reviewer for such journalsas Hypertension, American Journal of Kidney Disease, KidneyInternational, Journal of the American Society of Nephrology, AmericanJournal of Hypertension and the British Journal of Clinical Pharmacology.
Professor Mimran has carried out research over many years, the resultsof which have been published in journals of high impact. These studieshave addressed fundamental questions which have taxed the medicalprofession - such as the effects of dietary sodium on the heart and linksbetween vasoactive hormones and renal and cardiac function. Wherethese questions have been difficult to address in man, studies have beencarried out in experimental animals. Hence for example, the influence ofdietary sodium on the heart and kidneys has been studied in rats andlater taken to studies in man to document relationships between sodiumintake, pulse pressure and organ damage in patients with essentialhypertension. Another point of focus over the years has been micro-albuminuria as a marker of renal and cardiovascular risk. ProfessorMimran pointed out early that the various antihypertensive drug classeshave discrepant effects on urinary albumin excretion and likely thereforehad different capacities to protect against renal damage for example indiabetes and in hypertension. The renin-angiotensin system has beenanother focus of research attention over many years and the effects ofblocking this system with angiotensin converting enzyme (ACE) inhibitors,angiotensin receptor blockers and with combined NEP (neutralendopeptidases)/ACE inhibitors in experimental animals and man havebeen documented. Lipid-lowering drugs (the statins) and their effects oncardiac damage induced by the renin-angiotensin system were reportedrecently. Over many years, Professor Mimran has directed his attentionto the disorders which are known to have an adverse impact on thecardiovascular system and renal function, especially hypertension,diabetes mellitus and elevated lipid levels and to social habits which maycontribute to these disorders, especially smoking and a high dietarysodium intake.
Professor Mimran has been invited in several boards organized by thepharmaceutical industry.
30 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
MICROALBUMINURIA: HOW FREQUENT?
regimen in the primary prevention of microalbuminuria.
HOW IMPORTANT? INSIGHT FROM EPIDEMIOLOGY
In conclusion, microalbuminuria is an important risk factor in allpopulations for cardiovascular morbidity and overall mortality. The
presence of microalbuminuria in any patient population should therefore
LA MICROALBUMINURIE : QUELLE FREQUENCE ?
be taken seriously and treated aggressively.
QUELLE IMPORTANCE ?
Giancarlo VIBERTI, London - GBR
1. Tobe SW, McFarlane PA, Maimark DM. Microalbuminuria in diabetesmellitus. CMAJ 2002;167:499-503.
Professor Giancarlo VIBERTI MD FRCP, Professor ofDiabetes and Metabolic Medicine GKT School of
2. Romundstad S, Holmen J, Kvenild K et al. Microalbuminuria and all-
Medicine (Guy's Campus), King's College London
cause mortality in 2,089 apparently healthy individuals: a 4.4-year follow-study. The Nord-Trondelag Health Study (HUNT), Norway. Am J Kidney
Dr Viberti obtained his MD in1968 at the University of
Milan and specialised in Endocrinology at theUniversity of Turin in 1971. In 1975 he joined the Unit
3. Viberti G, Wheeldon NM. MicroAlbuminuria Reduction with VALsartan
for Metabolic Medicine in the Division of Medicine at
(MARVAL) Study Investigators. Microalbuminuria reduction with valsartan
Guy's Hospital Medical School, London University and in 1978 was
in patients with type 2 diabetes mellitus. A blood pressure independent
awarded a Wellcome Senior Research Fellowship in Clinical Science.
effect. Circulation 2002;106:672-8.
In 1984 he was appointed Senior Lecturer and Honorary Consultant in
4. Ruggenenti P, Fassi A, Parvanova Ilieva A et al for the Bergamo
Medicine and in 1985 was awarded the Membership of the Royal College
Nephrology Diabetes Complications Trial (BENEDICT) Investigators.
of Physicians because of academic distinction.
Preventing Microalbuminuria in Type 2 Diabetes. N Engl J Med
He became a Fellow of the Royal College of Physicians in 1990.
Giancarlo Viberti has been Professor of Diabetes and Metabolic Medicinesince 1987 and Director of the Unit for Metabolic Medicine in the GKT
School of Medicine at King's College London, London since 1990. He hasbeen, inter alia, the Robert Campbell medal winner of the Ulster Medical
1. Does prevention of microalbuminuria in type 2 diabetes protect against
Society, Camillo Golgi Lecturer and Pedroli Prize winner of the EASD,
Banting Lecturer of the British Diabetic Association (now Diabetes UK),
Areteus Lecturer, Pan Hellenic Diabetes Society, Ruth Østerby Lecturer
of the European Diabetic Nephropathy Study Group (EASD) and Visiting
Professor to Universities around the world. He speaks frequently at
national and international meetings and is an active researcher, clinician
and teacher with major research interests in the study of diabetic
Right answer: e
nephropathy and diabetic vascular complications in man. He has
2. In the prevention of progression of albuminuria in diabetes, are calcium
published more than 200 original papers and 140 reviews, editorials and
book chapters on these topics.
a) As effective as ACE inhibitors?b) More effective than ACE inhibitors?
c) Less effective than ACE inhibitors?d) Efficacy depends on their biochemical structure (dihydropyridine
Microalbuminuria, defined as persistent urinary albumin excretion (UAE)
vs non- dihydropyridine compounds)? None of the above?
of 20-200 g/min, is the best documented predictor of diabetic
Right answer: c
nephropathy (UAE>200µg/min) in both type 1 and type 2 diabeticpatients. Over 10 years, the risk of progression from microalbuminuria todiabetic nephropathy is 25%, a rate which is similar for both type 1 andtype 2 diabetes. Microalbuminuria is also a strong predictor for all-causemortality, particularly from cardiovascular disease in diabetes.
There are several possible explanations for the association betweenmicroalbuminuria and cardiovascular mortality. Microalbuminuria isassociated with enhanced thrombotic activity, it may reflect endothelialdysfunction, leading to increased vascular permeability and may be amarker of a low-grade inflammation which in itself can be associated withincreased cardiovascular risk.
It is postulated that the microalbuminuria exhibited in diabetic patientsreflects not only endothelial disturbance in the glomerulus, but also of theentire cardiovascular system, where transudation of protein in the vesselwall can promote the atherogenic process. Microalbuminuria is also a risk factor in non-diabetic patients withhypertension and in otherwise healthy adults. In patients with essentialhypertension, the presence of microalbuminuria is associated withincreased neointimal thickness of the carotid arteries. Over a follow-upperiod of 7 years, 21% of the patients who had microalbuminuria atbaseline had suffered a cardiovascular event, compared with only 2% ofpatients without microalbuminuria (p<0.0002). In patients with both type2 diabetes and hypertension, the risk associated with microalbuminuria iseven higher than in patients with either condition alone. In a systematicreview of seven studies that estimated the cardiovascular risk associatedmicroalbuminuria in patients with hypertension and type 2 diabetes, therisk of mortality was 2-8 times higher in patients with, compared withthose without, microalbuminuria. Blockade of the renin angiotensinsystem is a very effective treatment for preventing the progress of micro-albuminuria to proteinuria. The efficacy of angiotensin II receptor blockers(ARBs) in diminishing the progression from microalbuminuria to overtnephropathy in diabetic patients has also been shown. Recentevidence seems to indicate that ACE inhibition independently of actualarterial blood pressure is more effective than other anti-hypertensive
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 31
RENAL AND CARDIOVASCULAR PREVENTION IN
diabetic patients. Recently, the possibility to attain such an aim by using
DIABETIC PATIENTS WITH ARBS (ROADMAP).
an ACE inhibitor alone or in combination with a calcium channel blockerhas been shown by the BENEDICT study. A total of 1200 type 2 diabetic
PROTECTION RÉNALE ET CARDIOVASCULAIRE
patients were included in one of four arms and the risk of developing
CHEZ LE PATIENT DIABÉTIQUE AVEC
microalbuminuria was positively diminished by the ACEi. A bigger study,
LES ANTAGONISTES DE L'ANGIOTENSINE.
the ROADMAP, including 4400 type 2 diabetics is actually beingperformed. Olmesartan is being compared to placebo (+ other antihyper-tensive agents). This study will extend and clarify the issue of primary
Luis M. RUILOPE, Madrid - ESP
prevention of microalbuminuria beyond the BENEDICT because:1- BP control will be totally different; in BENEDICT mean BP remained
Graduated as MD at the University of Madrid.
above 140 mmHg systolic and here it will be below 130/80 mmHg;2- The possibility of uptitrating till maximal doses the ARB is contemplated
Residence and fellowship in Nephrology at the
in ROADMAP; this is relevant because of the exhaustion of response ti
Jiménez Díaz Foundation. Madrid.
inhibition of the RAA system with time; 3- The fact that around 50% 0fpatients in BEBEDICT were on drugs blocking the sympathetic that can
Doctoral Thesis : "Factores que regulan la secreción
lower albumin excretion enhance the need for the ROADMAP data.
de aldosterona en sujetos normales binefrectomiza-
In summary, primary prevention will become a very relevant target in the
dos y pacientes hipertensos esenciales". Madrid,
near future when treting type 2 diabetic patients.
Associate Professor Department of Physiology. Medical School,
Complutense University. Madrid 1977 - 1984
1. Ruggenenti et al, N Eng J Med, 2004; 351: 1941-1951
Actual position Head Hypertension Unit 12 de Octubre Hospital, Madridand Associate Professor of Internal Medicine at the Complutense
2. Barnett et al, N Eng J Med 2004; 351: 1952-1961
3. Segura et al. J Hypertens 2004; 22: 1679-1681
Member of the Scientific Council of the International Society ofHypertension and International Fellow of the Council for High Blood
Secretary of the Spanish Hypertension League 1991 - 1994
1) Microalbuminuria represents:
Mainfield of interest Hypertension and the Kidney.
a) a major cardiovascular risk factorb) a major renal risk factor
Officer at large, Scientific Council of the European Society of
c) a disorder of endothelial permeability
Hypertension 1993 - 1997
d) all are correct (*)
Member of the Editorial Board of: Journal of Hypertension, Blood
Right answer: d
Pressure, High Blood Pressure & Cardiovascular Prevention andMedicina Clinica.
2) An estimated creatinine clearance below 60 ml/ min
a) Is frequent in patients with established CV disease
Member of the Board of the Spanish Society of Hypertension,
b) Is a potent predictor of a poor outcome in heart failure patients
Nephrology, Dialysis & Transplantation and Journal Human
c) Predicts CV death in post-MI patients
d) Its predictive capacity is additive to that of a concomitant
Member Council on the Kidney in Cardiovascular Disease (American
Heart Association) since 1984
Right answer: e
Chairman of the EndPoint Committee, VALUE Study the morbi-mortalidad in Hypertension 1998
Member of: the Scientific Committee of the European Society of Cardiology for 1998,of the ISH 2000 International Scientific Program Committee, of theSteering Committee in the following Studies HOT, INSIGHT, SCOPE,CONVINCE, of the Awards Committee of the Council for High BloodPressure (January 2000 - November 2001), of DATA SAFETYMONITORING COMMETTEE of study OCTAVE, of the Council on HighBlood Pressure Research. December 2001 - November 2003
Associate Editor of Current Hypertension Report.
Title the Specialist on Hypertension by the European Society ofHypertension, January 2001
Associate Editor American Journal of Kidney Diseases. January 2002
President Committee Organizing 7o Congress Sociedad Española deHipertensión/Liga Española para la Lucha contra la Hipertensión Arterial.
Madrid, March 2002
Microalbuminuria is nowadays considered as a major cardiovascular riskfactor according to recently published Guidelines. Prevalence of microal-buminuria is high in either hypertensive and diabetic patients andrepresents a risk for the development of cardiovascular events and deathas well as for the development of chronic renal failure. Primaryprevention of microalbuminuria is then considered as an objectiverelevant to prevent cardiovascular and renal disease in hypertensive and
32 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
WHAT ARE THE MAJOR DETERMINANTS OF
2. Devereux RB et al : Prognostic significance of LVM change during
TARGET ORGAN PROTECTION? BAROMETRIC VS.
treatment of hypertension. JAMA 2004, 292: 2350-6
NON-BAROMETRIC EFFECTS OF
3. Gosse P et al : Efficacy of very low dose perindopril 2mg/indapamide
0.625 mg combination on left ventricular hypertrophy in hypertensive
QUELLES SONT LES DÉTERMINANTS PRINCIPAUX
patients: The PICXEL study rationale and design. J.Hum.Hypertens
DE LA PROTECTION D'ORGANE CIBLE ?
2002, 16: 653-659.
EFFETS BAROMETRIQUES VS EFFETS
NON-BAROMETRIQUES DES AGENTS
Philippe GOSSE, Bordeaux - FRA
CardiologistHead of the Hypertension unit in the Universityhospital of Bordeaux, France.
Member of the French Society of Hypertension,European Society of Hypertension and InternationalSociety of Hypertension.
Member of the Editorial Board of the Journal ofHypertension.
Over 150 publications in international journals, mainly on Left ventricularHypertrophy and ambulatory BP monitoring.
The question of the relative importance of how much or how the BP islowered is a matter of intense debate. The answers may be different forthe different events that threaten the hypertensive patients (stroke,ischaemic heart disease or renal failure) and should be considered at thelevel of early end organ damage. Left Ventricular Hypertrophy has nowbeen proved to be a good substitution criteria and deserves specialattention.
LVH is correlated to increases BP and in experimental models cannotdevelop without increased myocardial mechanical stress. Howeverincreased left ventricular mass as measured with echocardiography orMRI depends not only on the hypertrophy of cardiomyocytes but also onincreased collagen content and fibrosis which may be influenced by nonmechanical factors. The correlation between LVM and BP is usuallysignificant but weak even when using 24h ABPM. In the Bordeaux cohortof hypertensive patients, at baseline before any antihypertensivetreatment, the correlation between LVM and average 24h SBP is 0.40(n=800, p<0.001). Only 22% of LVM variance can be explained when 24hmean BP and arterial stiffness (QKD interval) are entered in the model inthis population. This leaves much room to the influence of nonmechanical factors.
LVH is able to regress with antihypertensive treatment but the correlationbetween LVM reduction and BP lowering is usually weak even when BPis monitored during 24h. Some antihypertensive treatment such ashydralazine an minoxidil, have shown poor efficacy on LVH regressionboth in animal and human studies. In the few available clinicalcomparative trials with sufficient power, some differences in LVMreduction has been shown with different antihypertensive treatmentdespite similar BP reduction. This is the case with the LIVE trial showinga greater LVM decrease with indapamide than with enalapril or in theLIFE trial showing the superiority of the combination losartan+HTZversus atenolol+HTZ. In the PICXEL trial there is a clear difference in BPlowering when comparing the perindopril-indapamide combination to theenalapril alone, however the difference in LVM reduction seems to gobeyond what can be explained by the effects on BP. Moreover LVHregression provides additional benefit on the reduction of cardiovascularevents, beyond that obtained from BP control in the LIFE study.
In conclusion there is strong evidence that a barometric effect of anti-hypertensive is necessary to observe LVH regression but there is alsosome evidences that it may not be enough and that different anthyper-tensive strategies may cause different LVM reduction independently oftheir barometric effect.
1. Gosse P et al,. : Regression of left ventricular hypertrophy in hyper-tensive patients treated with indapamide SR 1.5 mg versus enalapril 20mg: the LIVE study. J.Hypertension 2000, 18: 1465-1475.
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 33
who were already treated, and PROGRESS investigated
OF THE MULTIPLE RISK PATIENT
survivors of stroke - the stroke preventing effect was present in those whowere hypertensive and normotensive.
LA PRISE EN CHARGE DU PATIENT
À HAUT RISQUE CARDIOVASCULAIRE
Recently, LIFE showed 25% lower stroke rate on losartan than on
atenolol in patients with LVH; also in LIFE was stroke the most frequent
Nicolas DANCHIN, Paris - FRA
of the cardiovascular endpoints. The results of SCOPE indicated some
Leif ERHARDT, Malmö - SWE
stroke reductions with the AII-antagonist candesartan compared tocontrol; these results tended to support the AII-antagonist benefit in LIFEthough they were not adjusted for a difference in blood pressure in
MANAGEMENT OF THE HIGH RISK HYPERTENSIVE
SCOPE. In the VALUE trial there was no overall difference in primary
PATIENT. WHAT HAVE WE LEARNT FROM TRIALS?
cardiac endpoint between valsartan and amlodipine based treatments of
PRISE EN CHARGE DU PATIENT HYPERTENDU
high-risk hypertensives, however, amlodipine lowered blood pressurebetter early in the study while the AII-antagonist prevented heart failure
À HAUT RISQUE CARDIOVASCULAIRE.
towards the end of the study, particularly when adjusted for the
QU'AVONS-NOUS APPRIS DES ESSAIS CLINIQUES ?
difference in blood pressure.
In conclusion, stroke is the most frequent cardiovascular endpoint
Sverre E. KJELDSEN, Oslo - NOR
reported in hypertension outcome trials published through the lastdecade - trials that have enrolled the typical high-risk hypertensive
Sverre E. Kjeldsen received his clinical and research
patients seen in practise. Treatment of hypertension per see, i.e.
training from the Department of Internal Medicine,
reasonable well control of the high blood pressure lowers stroke rate with
Ullevaal University Hospital in Oslo, Norway as well
40% or more. Some recent trials in hypertensives (NORDIL, LIFE,
as from the Division of Hypertension, University of
SCOPE) and other high risk patients (HOPE, PROGRESS) seems
Michigan, Ann Arbor, Michigan, USA, and is currently
promising for further stroke reductions beyond what has been expected
holding a position as chief physician in the
for the blood pressure reduction alone. The VALUE trial results suggest
Department of Cardiology, Ullevaal University
that early blood pressure control may be important for prevention of both
Hospital in Oslo, and adjunct professor in the
stroke and myocardial infarction in high risk hypertensives.
Department of Cardiovascular Medicine, University of Michigan Hospital,Ann Arbor, Michigan. Sverre E. Kjeldsen graduated from the University of
Oslo Medical School 1979 and received his PhD degree in medicine alsofrom University of Oslo Medical School 1984. He has since then
1. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U,
continued his research interest in the pathophysiology, epidemiology and
Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm
treatment of human hypertension and has currently published almost 200
LH, Nieminen MS, Omvik P, Oparil S, Wedel H for the LIFE Study Group.
full peer reviewed articles within this area. Much of his research activities
Cardiovascular morbidity and mortality in the Losartan Intervention For
lately have been related to recent and ongoing large clinical trials in
Endpoint reduction in hypertension study (LIFE): a randomised trial
hypertension such as HOT, NORDIL, INSIGHT, LIFE, VALUE and
againt atenolol. Lancet 2002; 359: 995-1003.
ASCOT. He has coordinated the LIFE Study and he is co-chairing theValue Trial. His interest extends into the pathogenesis of hypertension,
2. Kjeldsen SE, Dahlöf B, Deverux RB, Julius S, Beevers G, Faire U,
especially sympathetic nervous system, platelet function, lipids and
Fyhrquist F, Ibsen H, Kristianson K, Pedersen OL, Lindholm LH,
insulin resistance. He has published extensively on issues related to
Nieminen MS, Omvik P, Oparil S, Wedel H for the LIFE Study Group.
mental stress as well as on blood pressure measurement.
Effects of losartan on cardiovascular morbidity and mortality in patientswith isolated systolic hypertension and left ventricular hypertrophy. A
Sverre E. Kjeldsen is responsible for series of investigations related to
losartan intervention for endpoint reduction (LIFE) substudy. JAMA 2002;
pathogenetic studies in 19-year-old borderline hypertensive men in Oslo
and also other large cohorts of healthy male subjects in the Oslo region.
Sverre E. Kjeldsen has been the mentor of several young researchers at
3. Julius S, Kjeldsen SE, Weber M, Brunner H, Ekman S, Hansson L,
the University of Oslo, Norway. He holds membership and offices in a
Hua A, Laragh J, McInnes GT, Mitchell L, Schork A, Smith B, Zanchetti A.
number of professional national and international societies, including
Cardiac events, stroke and mortality in high-risk hypertensives treated
being a fellow of the Council for High Blood Pressure Research of the
with valsartan or amlodipine: Main outcomes of The VALUE Trial.
American Heart Association and officer at large of the Scientific Council
http://image.thelancet.com/extras/04art4187web.pdf. Lancet 2004; 363:
of the European Society of Hypertension. He has received several
honors and awards such as the International Society of Hypertension -Schering Plough Fellowship Award, Ullevaal University Hospital
4. Weber M, Julius S, Kjeldsen SE, Brunner H, Ekman S, Hansson L,
Research Award, Blood Pressure Young Author Award as well as the
Hua A, Laragh J, McInnes GT, Mitchell L, Schork A, Smith B, Zanchetti A.
Norwegian Society of Cardiology Ole Storstein Scientific Award.
Blood pressure dependent and independent effects of antihypertensivetreatment on clinical events in the VALUE Trial.
http://image.thelancet.com/extras/04let5020web.pdf. Lancet 2004; 363:
Epidemiological studies like the one in Framingham show that myocardial
5. Kjeldsen SE, Julius S. Hypertension mega-trial with cardiovascular
infarction is more frequent than cerebral stroke. In the meta-analysis of
end points: Effect of angiotensin converting enzyme inhibitors and angio-
the first 14 prospective, randomised and controlled hypertension trials
tensin receptor blockers. Am Heart J 2004; 148: 747-54.
(Lancet 1990) comprising about 37.000 patients with hypertension from
very mild to the more severe stages, myocardial infarction was 1.6 timesmore frequent than stroke. However, later all published hypertension
studies have reported more strokes (ALLHAT and MRC-2 did not reportthe exact numbers of myocardial infarction). Stroke is the number one
1. The LIFE Study comprised high-risk hypertensive patients with:
endpoint to prevent in typical patients participating in hypertension
a) LVH on echocardiography
b) LVH on ECG accepting Sokolov-Lyon Criteriac) LVH on ECG accepting Cornell Voltage Criteria
The hypertension trials comparing active treatment, mostly diuretic/
beta-blocker and later calcium-antagonist based, with placebo or no
treatment showed a stroke reduction of about 40% (meta-analysis of first
Right answer: d
14 trials in Lancet 1990; STOP-1, SHEP, MRC-2, SYST-EUR,
2. The LIFE Study had the following pre-specified subgroups:
SYST-CHINA). Comparative trials have mainly shown the same effect on
a) Patients renal failure
stroke (STOP-2, ALLHAT, INSIGHT) or a difference can be explained by
b) Patients with known coronary heart disease
a blood pressure difference (CAPPP); the NORDIL study however
c) Patients with diabetes
showed a 20% lower stroke incidence on diltiazem compared to diure-tic/beta-blocker treatment despite 2-3 mmHg higher systolic blood pres-
d) Patients with isolated systolic hypertension
sure on diltiazem. HOPE and PROGRESS showed stroke reductions vs.
Right answer: e
placebo of ACE-inhibitors; HOPE comprised coronary or diabetic patients
34 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
3. The VALUE Trial compared outcome on following drugs:
CARDIOVASCULAR PROTECTION PRE- AND
a) Valsartan and atenolol
POST-PCI. CURRENT MANAGEMENT
b) Valsartan and amlodipine
AND NEW EVIDENCE.
c) Losartan and atenolold) Valsartan and losartan
PROTECTION CARDIOVASCULAIRE PRÉ ET
e) Valsartan and ramipril
POST ANGIOPLASTIE. PRATIQUES ACTUELLES
Right answer: b
ET NOUVELLES DIRECTIONS.
4. The VALUE Trial showed:
a) Similarity for cardiac morbidity and mortality
Nicolas DANCHIN, Paris - FRA
b) Similarity for first CV endpoint stroke includedc) Significant difference in heart failure
d) Difference in cardiac morbiditye) Difference in cardiac mortality
Right answer: a
The time when percutaneous coronary interventions (PCI) are performedis crucial in the implementation of measures of secondary prevention.
Numerous clinical trials have shown that patients undergoing PCIbenefit from the usual medications of secondary prevention currentlyused in coronary patients. More specifically, the LIPS trial has shown thatlipid lowering therapy with fluvastatin after PCI improved long-termcardiovascular outcomes. Observational studies have shown thatpatients undergoing PCI for acute coronary syndromes receive moreappropriate secondary prevention than patients who do not undergoangioplasty. A notable proportion of them, however, still do not receive allrecommended medications, justifying the continued efforts to improvethis situation. More recently, attention has been drawn on the cardioprotective effect ofthe pre-administration of statins in patients undergoing PCI. Both inobservational and randomised studies, patients receiving statins beforethe intervention had more limited myocardial damage following theprocedure. Beside the role of statin therapy, emphasis has also been puton the importance of appropriate antiplatelet therapy at the time of PCIand in the months thereafter. In patients with acute coronary syndromes,GP IIb/IIIa receptor blockers are recommended in high risk patients whoundergo coronary angiography. The early administration of clopidogrel,with a 300 mg loading dose also improves long-term cardiovascularoutcomes. In patients with elective procedures, the CREDO trial hasshown overall benefit in patients pre-treated with clopidogrel and in whoma combination of clopidogrel and aspirin was maintained for an averageof 9 months. Very recently, further evidence of myocardial injuryprevention using a high (600 mg) loading dose of clopidogrel before PCIwas brought (ARMYDA-2). On the whole, powerful antiplatelet regimensappear beneficial at the time of the procedure. The debate remains openon the optimal duration of combined antiplatelet therapy following PCI.
Patients receiving drug eluting stents need prolonged combinationtherapy, the duration of which, however, remains controversial. Likewise,the duration of combined antiplatelet therapy beyond one month inpatients receiving bare stents remains a matter of discussion.
1. Serruys PWJC, de Feyter P, Macaya C, et al. Fluvastatin forprevention of cardiac events following successful first percutaneouscoronary intervention. A randomized controlled trial. JAMA 2002; 287:3215-22
2. Randomized trial of atorvastatin for reduction of myocardial damageduring coronary intervention. Results from the ARMYDA (Atrovastatin forReduction of Myocardial Damage during Angioplasty) study. Circulation2004; 110: 674-8
3. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G.
Randomized trial of high loading dose of clopidogrel for reduction ofperiprocedural myocardial infarction in patients undergoing coronaryintervention. Results from the ARMYDA-2 (Antiplatelet therapy forReduction of Myocardial Damage during Angioplasty) study. Circulation2005; 111: e-publication
4. The Clopidogrel in Unstable Angina to Prevent Recurrent Events trialinvestigators. Effects of clopidogrel in addition to aspirin in patients withacute coronary syndromes without ST-segment elevation. N Engl J Med2001 ; 345: 494-502
5. Steinbuhl SR, Berger PB, Mann JT III et al. For the CREDOinvestigators. Early and sustained dual oral antiplatelet therapy followingpercutaneous coronary intervention. A randomized controlled trial. JAMA2002 ; 288: 2411-20
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 35
MULTIPLE DRUG INTERVENTION FOR
IN THE DYSMETABOLIC SYNDROME.
NTERVENTION MÉDICAMENTEUSE MULTIPLE POUR
LA PROTECTION CARDIOVASCULAIRE
DANS LE SYNDROME DYSMÉTABOLIQUE.
Denis RACCAH, Marseille - FRA
Professor Denis RACCAH, MD, PhD
Member of the French Society of Diabetology, European Association for the Study of Diabetes and the American Diabetes Association. Director of the Research Unit of Diabetology andNutrition, University of Marseille, FRANCE. Head of the Department of Nutrition, Endocrinology
and Metabolic Diseases University Hospital Sainte Marguerite, Marseille, FRANCE.
36 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
HOW TO INTEGRATE GLOBAL RISK MANAGEMENT
goal for blood pressure and that many patients have cholesterol values
INTO CLINICAL PRACTICE: GUIDELINES AND
that are not below target. (EUROASPIRE I and II. Lancet 2001;357:995-1001)
COMMENT INTÉGRER LA PRISE EN CHARGE DU
Similar observations have been made in the US. Even more alarming is
RISQUE GLOBAL DANS LA PRATIQUE CLINIQUE :
the fact that very few patients are actually treated to both goals for BP
RECOMMANDATIONS ET MISE EN PRATIQUE.
and cholesterol, in one survey less than 5%.
In summary, our targets of treatment have changed from being focused
Leif ERHARDT, Malmö - SWE
on high cholesterol levels or high BP values, to managing the global riskof the individual. All individuals should be subjected to risk assessment
Leif R. W. Erhardt, MD, PhD, FESC, is Professor of
and those with identified risk properly treated. Unfortunately, we are still
Cardiology at Lund University in Lund, Sweden and
not using methods for risk assessment in our daily clinical practices. Too
Chief Physician, Department of Cardiology at Malmö
many patients are not treated to goal, neither for blood pressure nor
University Hospital in Malmö, Sweden. Professor
cholesterol. A change in management is necessary to improve the
Erhardt received his MD and PhD in 1974 at the
overall prognosis of patients at risk for CVD events. (Erhardt L et al.
Karolinska Institute in Stockholm. He was Assistant
Vascular Disease Prevention. 2004;I:167-175).
Professor of Internal Medicine (1975), Specialist inInternal Medicine (1975), and Specialist in
Cardiology (1977) at the Karolinska Institute. He has served as Presidentof the Swedish Society of Cardiology (1994-1997), President of the 20th
1. Emberson JR et al. Eur Heart J 2003; 24:1719-1726
European Society of Cardiology (ESC) Congress of Cardiology in 1997,Chairman of the ESC Education Committee 2000-2002, and Principal
2. EUROASPIRE I and II. Lancet 2001;357:995-1001
Investigator for PRISM and PRISM 2. Professor Erhardt's clinical trialinvolvement includes: EVC chairman of the EXPEDITION trial; EVC
3. De Backer G et al. Eur Heart J. 2003;24:1601-1610
member of the AIRE and COMET trials; Data Safety Monitoring Boardmember of the ASCOT trial; Steering committee member of the
4. Hobbs FDR, Erhardt L. Family Practice. 2002;19:596-604.
EUROPA trial and Steering committee chairman of the LoWASA trial. His
Erhardt L et al. Vascular Disease Prevention. 2004;I:167-175
professional activities include Chairman of the ESC Task Force "The
Management of Chest Pain"; Member of the Advisory Board, World HeartFederation, Geneva; Chairman of the Swedish Society of Cardiology
Task Force "Quality Assurance of Secondary Prevention of CAD;" andMember of the Expert Group of the Swedish Board of Health and Welfare
1. What is the definition of a high risk patient according to the most recent
for the creation of the National Guidelines for the Management of Heart
Joint European Guidelines of CVD Prevention?
Disease. He is on the Editorial Board of several scientific journals.
a) More than 20% risk of having a CVD event over 10 years
Professor Erhardt's research interests include heart failure and he is the
b) A 5% risk of having a fatal CVD event over 10 years
current treasuer of the Heart Failure Association of the ESC.He is also
c) A 10% risk of a CHD event,fatal or non-fatal over 10 years
involved in several projects within the field of secondary prevention of
d) A 20% risk of having a CHD event over 10 years
coronary artery disease. Professor Erhardt has published over 180
Right answer: b
papers in various medical journals such as Circulation, Lancet, AmericanHeart Journal, and the American Journal of Cardiology. He haspresented numerous papers at meetings in Sweden and abroad.
2. How may patients are treated to both goals (blood pressure andcholesterol) according to available surveys.
b) Between 10 and 25%
The most important risk factors for the development of cardiovascular
disease (CVD) are cholesterol and blood pressure (BP). Both convey an
d) Between 25 and 50%
increased risk from very low to higher levels, and there is no magic
Right answer: a
threshold at which they become dangerous. (Emberson JR et al. EurHeart J 2003; 24:1719-1726). It is therefore of great importance tocorrectly identify and manage both BP and cholesterol.
European and American guidelines for the prevention of CVD recognizethe importance of identifying individuals with a high risk of developingclinical events. To reduce future risk, it becomes pivotal to identify globalrisk, rather than looking for individual cholesterol and blood pressurevalues.
The recent European joint guidelines define high risk as CVD death > 5%over 10 years or if it will exceed 5% if projected to 60 years of age. (DeBacker G et al. Eur Heart J. 2003;24:1601-1610) Charts have beenconstructed to reflect both high- and low-risk CVD regions. The Americanguidelines define a high risk as a combination of death and coronaryheart disease (CHD) events. A high risk is defined as > 20% over 10years and is based on the presence of various risk factors according to a"point-scoring" system. (Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adult.JAMA 2001;285:2486-2497)
The physcian must master the correct understanding of how the differentrisk-calculating principles function and how the risk is modified bylowering BP. Doctors in general underestimate the risk of their patients.
(Backlund L et al. Prim Health Care Res Dev 2004; 5(2):153-161) There is no substitute for using a risk chart of some sort, be itthe European or US algorithm
When we look at how physicians have integrated the global risk conceptinto their practices, a clear picture emerges. (Hobbs FDR, Erhardt L.
Family Practice. 2002;19:596-604). From the Euroaspire surveys weknow that only about half of patients with recognised CHD are treated to
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 37
PILL AND DEVICE STRATEGIES FOR CHF
TREATMENT: BACK TO THE HEART.
PILULES ET DISPOSITIFS MÉDICAUX
POUR LE TRAITEMENT
DE L'INSUFFISANCE CARDIAQUE CHRONIQUE :
RETOUR AU CŒUR
John CAMM, London - GBR
Faiez ZANNAD, Nancy - FRA
HOW RELEVANT TO HEART FAILURE.
ASYNCHRONIE, DYS-SYNCHRONIE :
QUELLE FRÉQUENCE ? QUEL INTÉRÊT POUR LE
TRAITEMENT DE L'INSUFFISANCE CARDIAQUE.
John CLELAND, Hull - GBR
Foundation Chair in Cardiology
The University of Hull
Hull and East Yorkshire
Hospitals NHS Trust
Castle Hill Hospital
Hull Royal Infirmary
Birthplace and Date:Lanark. Scotland. UK. 11th June 1955
Medical Education: University of Glasgow 1972-1977
Qualifications:Bachelor of Medicine & Surgery (with commendation) 1977Doctor of Medicine 1991Fellow of the Royal College of PhysiciansFellow of the European Society of CardiologyFellow of the American College of Cardiology
Previous Senior Appointments:1989-1994Senior Lecturer in Cardiology, Royal Postgraduate Medical School, Hammersmith Hospital.
1994-1998Senior British Heart Foundation Research Fellow, Medical Research Council Clinical Research Initiative in Heart Failure. University of Glasgow.
Research Focus: Clinical aspects of advanced heart disease rangingfrom epidemiology, through pathophysiology to clinical trials designed toimprove patients' symptoms and well-being and to prolong their survival.
Since 1999 an international reference centre for the management ofheart failure has been established in Kingston upon Hull placing it in thetop 10-20 clinical research centres for advanced heart disease in theworld. It is the largest clinical programme for heart failure in Britain. Theprogramme allows the development of new techniques for earlier andmore accurate diagnosis, better risk assessment and for delivering thehighest quality modern therapy. The programme also examines the costsof delivering quality care to determine how limited resources can deliverthe most benefit for patients now and in the future.
Special Appointments:Consultant: World Health Organisation
National Institute of Clinical Excellence (UK)Editor in Chief: European Journal of Heart FailureEditorial Board: Journal of American College of Cardiology
Committee: Data Standards Committee, American College of Cardiology
Chairman: Study Group On Diagnosis Of Heart Failure, European Society of CardiologyChairman Elect: British Society for Heart FailurePast-Secretary: British Cardiac SocietyPast-Chairman: Working Group on Heart Failure, European Society of Cardiology
38 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
CARDIAC RESYNCHRONIZATION THERAPY AND
2. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T,
DEFIBRILLATION IN HEART FAILURE: RESULTS OF
Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM;Comparison of Medical Therapy, Pacing, and Defibrillation in Heart
MORBIDITY AND MORTALITY TRIALS (COMPANION,
Failure (COMPANION) Investigators. Cardiac-resynchronization therapy
SCD-HEFT, CARE-HF) / RESYNCHRONISATION ET
with or without an implantable defibrillator in advanced chronic heart
DEFIBRILLATEURS CARDIAQUES : RESULTATS DES
failure. N Engl J Med. 2004 May 20;350(21):2140-50.
ESSAIS DE MORBI-MORTALITE.
3. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP,Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter
Mihai GHEORGHIADE, Chicago - USA
A, Levine JH; Defibrillators in Non-Ischemic Cardiomyopathy TreatmentEvaluation (DEFINITE) Investigators. Prophylactic defibrillator
Dr. Gheorghiade is currently Professor of Medicine,
implantation in patients with nonischemic dilated cardiomyopathy. N Engl
Associate Chief of the Division of Cardiology, Chief of
J Med. 2004 May 20;350(21):2151-8.
the Cardiology Clinical Service, and Director of theTelemetry Unit at Northwestern University Feinberg
4. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B,
School of Medicine. He obtained his MD, Magna
Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K; Multicenter
Cum Laude, from the University of Rome in 1972 and
InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial
did his training in internal medicine and cardiology at
Investigators. Combined cardiac resynchronization and implantable
Brown University. Subsequently, he moved to
cardioversion defibrillation in advanced chronic heart failure: the
Virginia, where he became Chief of Cardiology at the Salem VA and
MIRACLE ICD Trial. JAMA. 2003 May 28;289(20):2685-94.
Associate Professor of Medicine at the University of Virginia. Then, hebecame Chief of the Cardiac Intensive Care Unit at the Henry Ford
5. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert
Hospital in Detroit, Michigan and Associate Professor of Clinical Medicine
JP, Higgins SL, Brown MW, Andrews ML; Multicenter Automatic
at the University of Michigan. From there, he moved to his current
Defibrillator Implantation Trial II Investigators. Prophylactic implantation
position in Chicago. Dr. Gheorghiade was a visiting professor at the
of a defibrillator in patients with myocardial infarction and reduced
major universities in the United States and abroad and received
ejection fraction. N Engl J Med. 2002 Mar 21;346(12):877-83.
numerous awards for teaching from both medical students and residents.
He is a member of many national and international committees andserves on the editorial board of many journals including the AmericanHeart Journal, The American Journal of Cardiology, and the Journal ofthe American College of Cardiology. Dr. Gheorghiade served as a guesteditor on numerous occasions for the American Journal of Cardiology,American Heart Journal, and American Journal of Medicine. He wasChairman of the Steering Committee for many heart failure trialsincluding OPTIME, ACTIV, IMPACT, PRESERVD, and STEP-CHF. He isco chairing the ongoing, international EVEREST trial and was a memberof the Steering Committee of RADIANCE, FIRST, CARS, RITZ 4, EPHE-SUS and OPTIMIZE-HF. Dr. Gheorghiade is the author of more than 300publications. He was the Chairman/Co-chairman of numerousinternational and national meetings. At present, his research interests arerelated to the pathophysiology, prognosis, and management ofhospitalized patients with heart failure and the roles of vasopressinantagonist in heart failure.
New developments in device therapy for heart failure patients are helpingto decrease morbidity and mortality in this challenging patient population.
Cardiac resynchronization therapy improves left ventricular ejectionfraction, quality of life, 6-min walk distances, and New York HeartAssociation scores in select patients. Implantable defibrillators canprevent sudden cardiac death in those who have left ventricular systolicdysfunction and are at risk for ventricular arrhythmias. Cardiac devicesare now becoming a standard of care for those with heart failure whomeet certain criteria. Despite advances in medical therapy for treating leftventricular systolic dysfunction, newly diagnosed patients face a 50%mortality rate in 5 years. The natural history of heart failure leads tocontinual deterioration of function unless adverse cardiac remodeling isreversed. Until recently, the only means for improving symptoms andcardiac function has been through the optimization of standard medicinesthat are indicated for left ventricular systolic dysfunction, such asangiotensin-converting enzyme inhibitors and beta-blockers. However,not all patients benefit from medical management alone. Cardiac devicesmay now be considered when significant symptoms persist after standardmedicines are optimized. When practitioners use a multiple-modalityapproach, careful patient selection based on the inclusion criteria used inthe trials outlined in this article will likely lead to improved managementof those with left ventricular systolic dysfunction.
1. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R,Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, IpJH; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)Investigators. Amiodarone or an implantable cardioverter-defibrillator forcongestive heart failure. N Engl J Med. 2005 Jan 20;352(3):225-37.
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 39
Patrick LACOLLEY, Nancy - FRA
Position- Directeur de Recherche (DR2)', l'INSERM since 01/01/1999- In charge of the research team ('Mechanical properties of large arteries
STEROIDS AND STEROID ANTAGONISTS:
and cell/matrix interactions) at the INSERM unit EMI 0107 (Director: Pr S.
A 45 YEAR STORY
Laurent)- Therapeutic activity in the hypertension Department of the Georges
STEROIDES ET ANTAGONISTES DES STEROIDES :
Pompidou Hospital, Paris
45 ANS D'HISTOIRES
Athanase BENETOS, Nancy - FRA
- Resident Internal Medicine, University Hospitals of Paris (1982-1989)
Patrick LACOLLEY, Nancy - FRA
- Medical Doctor, University of Paris 7 (1986) - DEA (Diplôme d'Etudes Approfondies) in Cardiovascular physiology,
Athanase BENETOS, Nancy - FRA
University of Paris 5 (1987) - Specialist in cardiology (1991)- Ph.D. in Pharmacology, University of Paris 6 (1992)
Born in Athens, Greece, on July 5, 1956Married, 4 children
Professional experience- Research Fellow, INSERM, Unit 228, Director H. Schmitt, Paris (1987-
Professor of Internal Medicine and Geriatrics (since
- Assistant, University Paris 7, Lariboisière Hospital (1989-1991)
- Research Fellow, University of Iowa, Dir: Michael Brody, Iowa, USA(1989-1990) - Researcher at INSERM (CR1), Unit 337 Dir. M. Safar and, EMI 0107,
Education, Training, and Former Positions
Dir. S. Laurent (1992-1998)
MD, Medical School of Athens, Greece (1974-1980)Research Fellow, Boston University, Boston (1984-1987)
Responsibilities and memberships
PhD, University of Paris VI (1994)
- Member of the INSERM committee n° 4 for heart, vessels, lungs,
Senior Consultant in Hypertension, Broussais Hospital Paris (1988-2002)
hematology, homeostasis and angiogenesis (Vice-President) (2003-
Research Director at INSERM (National Institute of Medical Research)
- Member of the INSERM committee CT2 for functional genomic andmedical genetic (2003-2007)
Publications and Scientific Work
- Member of the committee of cardiology of the Fondation de France
More than 160 publications in international scientific journals with peer
- Member Council of the Groupe de Réflexion sur la Recherche
Epidemiology, genetics and treatment of the age-related changes of large
arteries. Role of hypertension and other risk factors on cardiovascular
- Member of The American Physiological Society
morbidity and mortality. Role of the renin-angiotensin-aldosterone systemin cardiovascular disease
Award- Prix du Comité de Lutte contre l'Hypertension Artérielle from the French
National and International Commitments
Society of Hypertension (1995)
Member, French Society of Cardiology and HypertensionMember, French Society of Geriatrics
Referee for journals
Member, Greek Society of Hypertension and Greek Society of Cardiology
- Circulation, America Journal of Physiology (Heart), Cardiovascular
Member, European Society of Hypertension
Research, Journal of Cardiovascular Pharmacology, Clinical Science,
Member, International Society of Hypertension
Journal of Hypertension.
Fellow of the American Heart AssociationMember of the Editorial Board of "Hypertension" and "Current
Themes of research
- Experimental research in cardiovascular physiology and pharmacology,mechanical properties of large artery on in vivo and in vitro models(animal models, methods of echotracking systems, isolated vessels)- Clinical and therapeutic research in the field of arterial stiffness andcardiovascular complications in hypertension and in ageing.
40 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
ARTERIAL STIFFNESS AND CARDIAC FIBROSIS:
Taken together, all these hemodynamic changes indicate that:
PHARMACOLOGICAL TARGETS FOR
(i) systolic hypertension is not a necessary clinical expression of hyperal-dosteronism, since the increased arterial stiffness may be compensated by
reduced stroke volume, thus maintaining an unchanged systolic blood
RIGIDITÉ ARTÉRIELLE ET FIBROSE CARDIAQUE :
pressure level, and (ii) hyperaldosteronism may be clinically expressed
CIBLES PHARMACOLOGIQUES POUR
by numerous features involving congestive heart failure, cardiomyopathy,
rythmic disorders or hypertension, each of them being influenced by thelocation and magnitude of fibrosis, which is responsible in turn forincreased arterial stiffness, a major marker of cardiovascular risk.
Michel SAFAR, Paris - FRA
- Physician, 1966- Associate Professor, Broussais Hospital, Paris, 1971
1. BENETOS A, LACOLLEY P, SAFAR ME. Prevention of Aortic Fibrosis
- Chief of the Diagnosis Center, Broussais Hospital, Paris, 1981
by Spironolactone in Spontaneously Hypertensive Rats. Arterioscler
- Chief of the Department of Internal Medicine, Broussais, Hospital, Paris,
Thromb Vasc Biol. 17: 1152-1156, 1997.
1989- Consultant in the Diagnosis Center, Hôtel-Dieu Hospital, Paris 2003
2. LACOLLEY P, SAFAR ME, LUCET B, et al. Prevention of aortic andcardiac fibrosis by spironolactone in old normotensive rats. J Am Coll
Cardiol. 2001 ; 37(2): 662-667.
- Professor of Internal Medicine, Faculty "Broussais-Hôtel Dieu" (ParisVI), France, 1981
3. LACOLLEY P, LABAT C, PUJOL A, et al. Increased carotid wall
- Professor of Therapeutics, Faculty "Broussais-Hôtel Dieu" (Paris VI),
elastic modulus and fibronectin in aldosterone-salt-treated rats.
Circulation. 2002 ; 106: 2848-2853.
- Director for the post-graduate French teaching of Cardio-Vascular(clinical and experimental) pharmacology (in collaboration with Pr Jean
4. POJOGA L, GAUTIER S, BLANC H, et al. Genetic determination of
Sassard, Claude Bernard University, Lyon France) 1991
plasma aldosterone levels in essential hypertension. Am J Hypertens.
1998 ; 11: 856-860.
Research:- Chief of the Hemodynamic Laboratory of the Hypertension Research
5. BLACHER J, AMAH G, GIRERD X, et al. Association between
Center, Broussais Hospital, 1967-1990
increased plasma levels of aldosterone and decreased systemic arterial
- Director of Research (U 337), National Institute of Health, 1990-1998,
compliance in subjects with essential hypertension. American Journal of
Hypertension.1997 ; 10: 1326-1334.
The Topic of the Research Unit is : Mechanical aspects and molecularbiology of large arteries in hypertension, aging and atherosclerosis
Other:- Past-Member of the Board of the International Society of Hypertension,l990- Past- Treasurer of the International Society of Hypertension, 1990- Fellow of the Council for High Blood Pressure, 1981- Charter Member of the American Society of Hypertension, 1986- Member of the New York Academy of Science, 1977- Expert of the WHO, 1988- Member or past-member of the Board of the following Journals :Hypertension, Journal of Hypertension, Clinical Science, Journal ofCardiovascular Pharmacology.
- Invited editor of "Hypertension" for the Workshop on arterial structureand function, 1995, 1998- 1999: Zanchetti Award of the European Society of Hypertension
Hyperaldosteronism is a predictor of high blood pressure and mostly ofits cardiovascular complications, independently of Conn's syndromeand/or hypokaliemia. The clinical expressions of hyperaldosteronism arehowever poorly investigated.
Experimental findings: Long term infusion of aldosterone (4 weeks) inuniphrectomized rats under high sodium diet is responsible for anincrease in blood pressure, acting predominantly on pulse pressure, inassociation with a reduced elasticity of the myocardium and of thethoracic aorta. The resulting structural changes differ markedly betweenthe myocardium (fibrosis with slight cardiac hypertrophy) and the aorta(excess of EIIIA fibronectine without fibrosis but with vascular hypertro-phy) as well as for their magnitude and their composition. However, allthese tissular actions may be independently prevented by the selectiveadministration of the aldosterone antagonists spironolactone or eplererone,suggesting that hyperaldosteronism may have multiple clinicalexpressions in the cardiovascular system.
Clinical findings: Investigations have been performed in populations ofsubjects with either systolic-diastolic or isolated systolic hypertension,where positive relationships have been observed between arterialstiffness and plasma aldosterone. Studies of the CYP11B2 T/C genepolymorphism have shown that the TT genotype, which is frequentlyassociated with increased plasma aldosterone, may exhibit, inhypertensive men, several particular features: no increased incidence ofhypokaliemia, Conn's adenoma or systolic hypertension ; increased heartrate with marked increase in its variability; reduced stroke volume; andaccelerated increase of arterial stiffness with age.
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 41
STEROÏDS AND AGING. NEW THERAPIES AND
STÉROÏDES ET VIEILLISSEMENT. NOUVELLES
THÉRAPIE ET APPLICATION CLINIQUES.
Etienne BAULIEU, Kremlin-Bicêtre - FRA
French, born in Strasbourgon December 12, 1926
Successively Professor of Biochemistry in schools ofMedicine of Paris and Professor of HumanReproduction at the Collège de France since 1993.
INSERM (National Institute of Health & MedicalResearch) Research Director, Unit on Steroid
Hormones and Hormonal Communications. Chairman of INSERMScientific Council (1975-1979).
Co-founder of the WHO (World Health Organization) Program on HumanReproduction. Société de Secours des Amis des Sciences, Président.
French Académie des Sciences, Member (1982), Président (2003-2004)Collège de France, Member (1993) : Chair of Human ReproductionNational Academy of Sciences of the USA, Foreign Associate (1989)Honorary Member, The American Physiological Society (1993).
Academia Europea (1995)Société Française d'Endocrinologie (Past Président)
Roussel Prize (with E. Jensen, 1976)Gregory Pincus Memorial Award (with E. Jensen, 1978). Lasker Award (1989)Grand Prix de la Fondation pour la Recherche Médicale (FRM), 1995Ken Myer Medal, Australia 2000
Honorary degrees: Tufts University, Gand University, WorcesterFoundation, Karolinska Institute.
Main books: Hormones (with P. Kelly) : Hermann (Paris) and Chapman &Hall (New York) publishers, 1990. Generation Pilule, Ed. Odile Jacob,1990. The Abortion Pill, Simon & Schuster publisher (New York), 1991.
Contraception : contrainte ou liberté ? (with F. Héritier et H. Léridon), Ed.
Odile Jacob, 1999.
Grand Officier de la Légion d'Honneur
New clinical applications of steroids
Recent research has indicated novel uses of natural and syntheticsteroids in several health difficulties associated to aging: it will bereferred to 1. remyelination, 2. memory deficit, 3. depressive states, 4.
neuropathology prevention, and 5. pulmonary artery hypertension. Thesemedical applications are based on novel mechanisms of actioncomplementing the already known nuclear and membrane receptors'systems.
1. Science 1995, 268:1500-032. PNAS 2001, 98:14033-373. PNAS 1998, 95:4089-914. J Molecular Neuroscience 2004, 24:063-665. PNAS 2003, 100:9488-93.
42 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
OBESITY AND THE CARDIOLOGIST:
Several other drugs, thought to act on central targets have had problems
TIME FOR ACTION
in clinical development: the atypical anticonvulsant topiramate producedexcellent weight loss but clinical development has been discontinued
L'OBÉSITÉ ET LE CARDIOLOGUE :
because of adverse side effects. Drugs targeted at 5HTc-2 receptors
LE TEMPS DE L'ACTION
have proved difficult to develop in terms of pharmacokinetics and/or
specificity. Leptin, in 'normal' hyperleptinaemic obese individuals has had
Luc VAN GAAL, Edegem-Antwerp - BEL
disappointing efficacy as is also true for Axokine, a ciliary neurotrophic
Faiez ZANNAD, Nancy - FRA
factor thought to act through leptin-like pathways. Drugs targeted atGI-mediated pathways such as PYY-36 and CCK analogues are in
NEW PHARMACOLOGICAL TOOLS FOR OBESITY
development, as are drugs targeting the melanocortin system.
Peripherally-acting compounds that might modify body composition (GH
or GH fragments), or adipocyte function (TNF/IL-6 inhibitors; PPARs)may prove important targets for modifying the effects of obesity, but will
Nicholas FINER, Luton - GBR
be hard to evaluate along classical obesity drug paradigms since theyproduce little or no weight loss.
Dr N Finer B.Sc.(Hons), MBBS, FRCP, R.Nutr.
Clinical Director, Wellcome Trust Clinical ResearchFacility
1. Arbeeny, Cynthia M. "Addressing the Unmet Medical Need for Safe
Senior Research Associate, Cambridge University
and Effective Weight Loss Therapies." Obesity Research 12.8 (2004):
Hon. Consultant in Obesity Medicine, Addenbrooke's
HospitalHon Consultant Endocrinologist, Luton and
2. Donnelly, Richard. Researching new treatments for obesity: from
Dunstable Hospital NHS Trust
neuroscience to inflammation. Diabetes , Metabolism and Obesity 5,
Visiting Professor, Luton University.
Dr Finer qualified B Sc. (Hons) Biochemistry in 1970 and MBBS at
3. Finer, N. "Pharmacotherapy of obesity."
University College London in 1973, and trained in London at St George's
Best.Pract.Res.Clin.Endocrinol.Metab 16.4 (2002): 717-42.
and Guy's Hospitals. In 1986 he was Medical Research SocietyTravelling Fellow at the Laboratory of Neural Regulation (Dr RJ
4. Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Lau J.
Wurtman), Massachusetts Institute of Technology. He is currently a
Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus.
Clinical Senior Research Associate at Cambridge University, Clinical
The Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.:
Director of the Wellcome Trust Clinical Research Facility and Hon.
Consultant in Obesity Medicine at Addenbrooke's Hospital, Cambridge.
He is Visiting Professor at the Institute for Health Services Research at
5. Ramos EJ, Meguid MM, Campos AC, Coelho JC.Neuropeptide Y,
Luton University, a Fellow of the Royal College of Physicians and an
alpha-melanocyte-stimulating hormone, and monoamines in food intake
Accredited Nutritionist. He was Chairman of the UK Association for the
regulation. Nutrition. 2005 Feb;21(2):269-79.
Study of Obesity from 1993-1996. He is a member of the Clinical
Committee of the Society for Endocrinology and an editorial boardmember of the International Journal of Obesity. He is an examiner for the
Royal College of Physicians and sits on its Standing Committee onNutrition. Dr Finer has published widely on clinical and therapeutic
1. The following drugs used for treating obesity are thought to function
aspects of obesity and endocrinology and is engaged in research into
predominantly through effects on central monoamine neurotransmitters:
clinical and therapeutic aspects of human obesity.
The current status of anti-obesity medication is that two drugs (orlistat,
sibutramine) are licensed on the basis of moderate efficacy in terms of
weight loss and weight loss maintenance. Unlike other areas of drugtreatment, assessing the response to an anti-obesity drug is 'slow' in thatone can only evaluate efficacy on weight loss after several months'treatment and weight loss maintenance over much longer periods of time.
2. The effect on weight loss of an anti-obesity drug is enhanced by the
The development of predictors (be they clinical or pharmacogenetic)
could be an important tool in raising the cost-efficacy of these and future
anti-obesity drugs, perhaps leading to a greater willingness of health-care
Modest dietary restriction
purchasers to reimburse patients for their treatment. An increasing body
of evidence also now suggests that anti-obesity drugs can have
The presence of type 2 diabetes mellitus
desirable metabolic effects over and above that induced by weight loss
Higher doses than recommended by the spc
itself. Thus sibutramine appears to have direct effects on raising HDL-
Participation in clinical trials
Cholesterol, while orlistat has direct effects on LDL-Cholesterol andinsulin sensitivity. The recognition that the benefit of an anti-obesity drugshould not just be evaluated by weight loss itself is an important
3. The statements below are true
consideration in the clinical development of new pharmacological
Sibutramine cannot be usedin hypertensive patients
The opening up of knowledge concerning CNS pathways involved inlong-term body weight regulation, peripheral gastro-intestinal signaling
A high fat diet is needed for orlistat to work well
that influences more acute eating behaviour, and the importance of the
Early response always predicts
adipocyte as an endocrine organ has opened up many new drug targets
a good long-tern outcome
for treating obesity and its metabolic consequences and complications.
The endocannabinoid system has been shown to have an important role
Drug-responsive patients should stop treatment
centrally in terms of eating behaviour and body weight regulation, and
when their weight plateaus
peripherally on adipocyte function. The CB1 receptor antagonist
Regulatory guidance for licensing
rimonobant has completed its Phase III clinical development, and looks
anti-obesity drugs is consistent
promising both in terms of its effects on weight loss as well as metaboliceffects independent of weight loss. Other CB1 antagonists are in PhaseI and II development,
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 43
CARDIOVASCULAR BENEFIT/RISK ASSESSMENT OF
underway and should significantly enhance our knowledge about the
long-term benefits of weight loss in individuals at high risk forcardiovascular disease.
DES MEDICAMENTS ANTI-OBESITE.
Arya SHARMA, Hamilton - CAN
1. Douketis JD, Sharma AM. The management of hypertension in the
Professor of Medicine
overweight and obese patient: is weight reduction sufficient? Drugs.
Canada Research Chair for Cardiovascular Obesity
Research and ManagementDepartment of Medicine - McMaster University
2. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the
Hamilton, Ontario - Canada
prevention of diabetes in obese subjects (XENDOS) study: a randomizedstudy of orlistat as an adjunct to lifestyle changes for the prevention of
Arya Mitra Sharma is Professor of Medicine at the
type 2 diabetes in obese patients. Diabetes Care. 2004;27:155-61.
Michael deGroote School of Medicine, McMaster
University, Hamilton, Ontario, Canada, where he holds a Canada
3. Sharma AM, Golay A. Effect of orlistat-induced weight loss on blood
Research Chair for Cardiovascular Obesity Research and Management.
pressure and heart rate in obese patients with hypertension. J Hypertens.
Past appointments include positions as Associate Professor of Medicine
at the Free University of Berlin (1994-200) and the Franz-Volhard Klinik -Charité, Humboldt University Berlin (2000-2002). His research focuses
4. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris
on the prevention and management of cardiovascular complications
WH, Van Gaal LF. Effect of sibutramine on weight maintenance after
associated with obesity and the metabolic syndrome. He is a member of
weight loss: a randomised trial. STORM Study Group. Sibutramine Trial
several scientific associations, including the German, American, and
of Obesity Reduction and Maintenance. Lancet. 2000;356:2119-25
International Societies of Hypertension and Nephrology. He is a fellow ofthe Council for High Blood Pressure Research of the American Heart
5. Jordan J, Scholze J, Matiba B, Wirth A, Hauner H, Sharma AM.
Association and on the editorial board of Hypertension and the Journal of
Influence of Sibutramine on blood pressure: evidence from placebo-
Hypertension. He has authored and co-authored more than 180
controlled trials.Int J Obes Relat Metab Disord. 2005; [Epub ahead of
scientific articles and has lectured widely on the etiology and
management of hypertension, obesity, and related cardiovasculardisorders.
6. Birkenfeld AL, Schroeder C, Boschmann M, Tank J, Franke G, LuftFC,Biaggioni I, Sharma AM, Jordan J. Paradoxical effect of sibutramineon autonomic cardiovascular regulation. Circulation. 2002;106:2459-65.
Abdominal obesity is now well recognized as a defining characteristic ofthe metabolic syndrome and has been associated with increased risk for
1. The following drugs are approved for the long-term treatment of
type 2 diabetes, cardiovascular disease, loss of renal function, and
obesity (check all that apply)
stroke. Obesity is also associated with an increased risk for congestive
b) Sibutraminec) Phentermine
Numerous short-tem weight-loss studies have shown marked
improvements in surrogate measures of cardiovascular risk, however,
weight loss has rarely been maintained long enough to demonstrate apositive impact on hard outcomes. This is due to the inherent difficulty in
2. The following benefits are seen with obesity treatment (check all that
sustaining weight loss by lifestyle management alone. The high rate of
relapse must be seen in the context of powerful biological and
a) Decrease in HbA1c
environmental influences that make long-term maintenance of weight-
b) Decrease in HDL cholesterol
loss virtually impossible for the vast majority of obese indiviuals. This has
c) Decrease in blood pressure
led to the call for effective anti-obesity medications that are well tolerated,
d) Decrease in waist circumference
safe and effective in promoting long-term weight maintenance.
e) All of the above
Currently two drugs are available for long-term obesity treatment in most
3. Pharmacological treatment of obesity is generally superior to lifestyle
countries. Orlistat, a gastrointestinal lipase inhibitor, acts by reducing fat
management alone because (check all that apply)
absorbtion by 30%. It has been shown to effectively promote weight loss
a) Better weight loss
and weight maintenance in combination with a lifestyle program.
b) Better tolerabilty
Although generally well tolerated, individuals who cannot reduce their fat
c) Better weight maintenance
intake may experience unpleasant gastrointestinal side effects including
d) Better compliance
bloating, diarrhoea, and oily discharge. Nevetheless, randomized studies
e) Better reduction in "hard" endpoints
have shown that orlistat can significantly reduce blood pressure,dysglycemia and dyslipidemia and can reduce the onset of type 2diabetes in high-risk individuals.
The other anti-obesity drug currently licensed for long-term use issibutramine, a centrally and peripherally active serotonin andnorepinephrine re-uptake inhibitor. Sibutramine has been shown topromote weight loss and sustain weight maintenance with markedimprovements in lipid and glycemic profile. Although weight loss onsibutramine is associated with a decrease in blood pressure in themajority of individuals, blood pressure is reduced less than for a similarweight loss achieved by lifestyle changes alone. Nevertheless, thus farthere have been no reports of increase risk for cardiovascularcomplications in patients treated with sibutramine. The long-term cardio-vascular benefits of sibutramine are currently being studied in theSCOUT trial, a randomized controlled outcome trial with sibutramine in9000 individuals at high risk for cardiovascular disease.
Several meta-analyses confirm that pharmacological weight manage-ment is superior to lifestyle management alone, both in terms of themagnitude of weight loss as well as long-term weight maintenance.
Further studies into the long-term benefits of anti-obesity medications are
44 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
DRUG TRIALS FOR WEIGHT MANAGEMENT AND
neuro-physiologically sparse and seemingly adapted in obesity; their
CARDIOVASCULAR RISK REDUCTION
strength fades with age as shown by the lack of spontaneous weightreduction after overfeeding older rather than younger adults (3). Thus,
just as hyperglycaemia and hypertension need selective pharmacotherapy
NOUVEAUX ESSAIS POUR LE CONTRÔLE
operating on normal homeostatic mechanisms controlling glucose
DU POIDS ET LA RÉDUCTION
turnover and arterial pressures, so newer drugs aim to alter weight
DU RISQUE CARDIOVASCULAIRE.
homeostasis. Orlistat, the first new drug, however, persisted in focussingon an obesity inducing factor by reducing fat absorption - thesteatorrhoea amplifies behavioural fat restriction. The energy deficit diets
Philip JAMES, London - GBR
with orlistat aim to minimise the neuro-regulatory attempts to maintain theobesity when weight loss starts and many trials show modest butrelatively well sustained lower weights. Insulin resistance, LDL
Professor James graduated in physiology and
cholesterol and blood pressure fall beyond that expected from weight
medicine from University College, London, then
loss per se. These responses are in keeping with the known effects of
worked in the UK's MRC unit in Jamaica, the MGH in
dietary fats per se. Orlistat therefore, as expected, amplifies diabetes
Boston, USA, and the London School of Hygiene
prevention in the glucose intolerant (4).
before becoming Assistant Director, MRC DunnNutrition Unit, Cambridge, UK. He then became
Sibutramine operates neuro-chemically to amplify satiety and reduce the
Director for 17 years of the 450 strong Rowett
adaptive fall in basal metabolism thereby increasing both weight loss and
Research Institute in Aberdeen Scotland.
weight maintenance. The 2 year STORM trial(5) evaluated weight
He established that obese patients had high not low basal metabolic rates
maintenance rather than weight loss and confirmed the value of a
associated with a high lean body mass and that women preferentially
dietary design with specified intakes geared to allowing sibutramine's
store fat rather than lean tissue. He demonstrated that the hypertrophic
satiety mechanism to operate. Early weight losses and subsequent
classification of obesity was flawed, found differential energetic
weight maintenance were greater than in the diabetes or hypertension
responses to carbohydrate in familial obesity and demonstrated why beta
prevention trials and unexpectedly hypertensive patients did as well with
blockers led to weight gain. He compiled the first UK report on obesity
no indication of sympathetically induced hypertension despite the use in
research (in 1976), wrote the Royal College of Physicians' report on
a sub-group of 20mgms sibutramine which was later shown not to
obesity(1983), chaired and wrote the UK's obesity prevention report
enhance benefit/risk analyses. The favourable blood pressure response
(1995) and the SIGN guidelines on obesity management (1996).
may now be explained by the clonidine like neurophysiological effect of
He established and chairs the International Obesity Taskforce which
sibutramine. Triglyceride and VLDL falls were substantial and the
drafted the first WHO report on obesity (1997), chaired and wrote the first
progressive and marked increases over 2 years in HDL exceeded
WHO global and European policies on dietary prevention of chronic
greatly those seen with gemfibrozil where a 25% reduction in cardio-
diseases, the UN Millennium Commission on global nutrition and the
vascular mortality had been achieved. The stimulation of HDL seems to
proposals for the UK and EU Food Standards Agencies for Tony Blair
be weight independent.
(1997) and the EU Commissioners (1999). He developed the UN'scurrent basis for defining childhood and adult malnutrition and its
Neither orlistat nor sibutramine has yet been shown directly to reduce the
approach to estimating individual energy requirements. He developed the
cardiovascular and total mortality rate so the current SCOUT trial is
lithium technique for assessing different sources of dietary salt for
designed to test the value of weight management with sibutramine in
preventing hypertension, chairs the UK Coronary Prevention Group,
higher risk patients with pre-existing diabetes and/or cardiovascular
established the European Heart Network (1989) and designed the sign
disease. These latter patients are currently excluded from the regulatory
post food labelling system under current EU review. He developed the
guidelines on the use of the drug. These guidelines were based in part on
energy deficit diet system for the first orlistat and STORM trials which is
physiological data in normal adults given much higher doses than those
now in universal use. He chairs the Executive of the SCOUT trial on
currently used and before the cardiovascular and lipid responses to
weight management in high risk cardiovascular patients.
sibutramine were known. An update on the trial will be set out.
By W Philip T James, London School of Hygiene
and Tropical Medicine and IOTF
1. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ;Comparative Risk Assessment Collaborating Group. Selected major risk
The original drugs used in weight management e.g. thyroxine and
factors and global and regional burden of disease. Lancet. 2002 Nov
amphetamine essentially destroyed the respectability of weight
management in obese patients. The whole approach to the managementof hypertension, ischaemic heart disease(IHD) and diabetes developed
2. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen
independently of whether weight management should be considered
M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study
either feasible or particularly useful. Excess weight gain was then seen
Investigators. Effect of potentially modifiable risk factors associated with
as self imposed and only an indirect risk factor by both epidemiologists
myocardial infarction in 52 countries (the INTERHEART study):
and clinicians. The rejection of weight management with targeted
case-control study. Lancet. 2004 Sep 11;364(9438):937-52.
pharmacotherapy seemed to be confirmed by the withdrawal ofdexfenfluramine. Another problem was the scientific rejection of dietary
3. Roberts, SB, Fuss, P, Heyman, MB, Evans, WJ, Tsay ,R, Rasmussen,
issues when these were seen by physicians in the 1950-60s as simply
H, Fiatarone M, Cortiella, J, Dallal, GE, Young VR. (1995) Control of food
relating to deficiency diseases and had no relevance to modern clinical
intake in older men. JAMA. 1994 Nov 23-30;272(20):1601-6. Erratum in:
care. Yet WHO classified obesity as a disease in 1948 and Vague had
JAMA 273(9), 702.
highlighted the pathophysiological significance of abdominal fat evenearlier. Now the current "normal" but unsuitable diets and the current
4. Torgerson J S, Hauptman J, Boldrin MN Sjostrom L. XENical in the
physical activity patterns explain the majority of premature deaths and
Prevention of Diabetes inObese Subjects (XENDOS) Study.A
disability in Europe as well as the rest of the world, notwithstanding the
randomized study of orlistat as an adjunct to lifestyle changes for the pre-
importance of smoking (1,2)! Despite these facts our history and
vention of type 2 diabetes in obese patients. Diabetes Care.
prejudices ensure the neglect of weight management.
The use of drugs for improving weight maintenance rather than the initialweight loss is recent and reflects both new concepts of how to minimise
5. James WPT, Astrup A, Finer N, Hilsted J, Kopelman P, Rössner S,
specific major complications e.g. diabetes and IHD and the recognition
Saris WHN, Van Gaal LF. A two year sibutramine trial of obesity reduction
that there seems to be a resetting of the hormonal/hypothalamic control
and maintenance (STORM). The Lancet, 2000; 356:2119-2125.
of energy homeostasis in obesity. Thus once long term weight gain hasoccurred physiological and behavioural responses to weight reductionsignal semistarvation responses despite patients having 150k-1millionextra kcalories stored! Regulatory mechanisms for reducing weight are
2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005 - 45
1.Which of the following is correct?
a) Weight gain is not itself an important contributor to ill health b) Weight gain does not induce type 2 diabetes, hypertension
c) Once obese patients are persuaded to follow an appropriate diet
and exercise programme their problem resolves.
d) The benefits of weight loss disappear as weight regain occurs e) Modest weight loss brings surprising metabolic
and cardiovascular risk benefits
Right answer: e
2: Which of the following is correct?
a) The effects of current weight management drugs reflect the
impact of weight loss only.
b) Orlistat alters the total cholesterol/HDL ratio by affecting both
c) Longer-term weight management is practical in clinical settings.
d) Sibutramine is an anorectic drug.
e) Sibutramine stimulates the sympathetic nervous system.
Right answer: c
46 - 2nd Global CardioVascular Clinical Trialists Forum z Cannes 2005
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