final program and abstracts · 9/12/2010 · 2 th th7 global cardiovascular clinical trialists...

7th Global Cardiovascular Clinical Trialists Forum • Paris 2010 1

Final Program and AbstractsUnder the auspices ofEndorsed by

2 7th Global Cardiovascular Clinical Trialists Forum • Paris 2010 7th Global Cardiovascular Clinical Trialists Forum • Paris 2010 3

FACULTY

GENERAL PRESENTATION

Organized in collaboration with the European Society of Cardiology Working Group on CardiovascularPharmacology and Drug Therapy, endorsed by the US NHLBI, CME accredited by EBAC and ACCME accredited by University of Michigan, the CardioVascular Clinical Trialists Forum (CVCT) is a meeting specifically and totally dedicated to the discussion of clinical trials in cardiovascular disease.

CVCT Forum is attended by experts principally engaged in cardiovascular clinical trials. Participants are internatio-nal opinion leaders and represent various functions linked with primary care, regulation, pharmaceutical, biomar-ker and device industries, as well as publishing houses from around the world.

Outstanding faculty members are committed to sharing concise data from controlled clinical trials that contribute to better clinical care. We come together to discuss and identify issues such as how to conduct better clinical trials, how to satisfy regulatory authorities, and most importantly, how to improve cardiovascular health care.

The CVCT Forum is a ‘grass roots’ meeting, attended by individuals who are eager to communicate with one another and to share experiences with primary care physicians and the people who create and analyze major trials.

CVCT meetings are primarily oriented toward open dialogue as opposed to lecturing to a broad audience. Thought process counts, communication (during the meeting, but importantly also informal discussions outside of the meeting and during networking lunches/dinners) is the important agenda, rather than dictating doctrine or pro-motional marketing of a new therapy. Beyond plenary sessions the meeting is structured with a variety of small interactive brainstorming workshops, expert discussions and how-to sessions.

CVCT Forum objectives: ■ Familiarize practitioners and young investigators with the science of clinical trials from trial protocol design to trial result interpretation

■ Examine the background of knowledge which led to the design of major trials

■ Discuss the regulatory environment for drug, device and biomarker trials

■ Identify and understand best evidence from clinical trials

■ Examine the consequences of trial results on the updating of guidelines

■ Consider the consequences and relative weight of Evidence-based vs. Mechanism-based and Marketing-based medicine

■ Identify emerging important issues in cardiovascular medicine

■ Examine opportunities and needs for new trials

We are delighted that you will share with us the excitement of this unique learning experience. We hope you enjoy your stay in Paris.

Pr. Faiez ZANNAD Pr. Bertram PITT

ACADEMYABRAHAM William T. (Columbus, USA)ADAMS Kirkwood (Chapel Hill, USA)AGEWALL Stefan (Oslo, NOR)AGOSTINI Denis (Caen, Fra)ARNOLD Malcolm (London, CAN)ATAR Daniel (Olso, NOR)BÖHM Michael (Homburg, GER)BORER Jeffrey S. (New York, USA)BRUNNER La ROCCA Hans-Peter (Maastricht, NED)BURRI Haran (Geneva, SUI)CAMICI Paolo G. (London, GBR)CLELAND John G.F. (Hull, GBR)CLEMMENSEN Peter (Copenhague, Den)COHEN SOLAL Alain (Paris, FRA)COHN Jay (Minneapolis, USA)COTTER Gad (Durham, USA)COWIE Martin R. (London, GBR)CUSHMAN William C. (Memphis, USA)DANCHIN Nicolas (Paris, FRA)DARGIE Henry (Glasgow, GBR)DICKSTEIN Kenneth (Stavanger, NOR)DOBRE Daniela (Nancy, FRA)FILIPPATOS Gerasimos (Athens, Gre)FIUZAT Mona (Durham, USA)GHEORGHIADE Mihai (Chicago, USA)GOLDSTEIN Sidney (Detroit, USA)HOLZMEISTER Johannes (Zurich, SUI)HUSTED Steen (Arhus, Den)JANKOWSKA Ewa (Wroclaw, POL)JANUZZI James (Boston, USA)JOURDAIN Patrick (Paris, FRA)KJELDSEN Keld (Copenhague, DEN)KOENIG Wolfgang (Ulm, Ger)KRUM Henry (Melbourne, AUS)LE HEUZEY Jean-Yves (Paris, FRA)LEWIS Basil (Haïfa, ISR)LIP Gregory (Birmingham, GBR)LOGEART Damien (Paris, FRA)LONN Eva (Hamilton, CAN) LORENZ Matthias W. (Frankfurt, Ger)MANCIA Giuseppe (Monza, ITA)MARTINEZ Felipe (Cordoba, ARG)MASIP Josep (Barcelona, ESP)Mc MURRAY John (Glasgow, GBR)MEBAZAA Alexandre (Paris, FRA)MEHRAN Roxana (New York, USA)METRA Marco (Brescia, ITA)MORAIS Carlos (Amadora, POR)MUELLER Christian (Basel, SUI)NACCARELLA Franco (Bologna, ITA)NOUIRA Semir (Monastir, TUN)O’CONNOR Christopher Michael (Durham, USA)PAIS Prem S. (Bangalore, IND)PATHAK Atul (Toulouse, FRA)PFEFFER Marc (Boston, USA)PIÑA Ileana L. (Cleveland, USA)PITT Bertram (Ann Arbor, USA)POCOCK Stuart (London, GBR)POPOV Vladimir (Moscow, RUS)REMME Willem J. (Rhoon, NED)RITZ Eberhardt (Heidelberg, Ger)

ROSANO Giuseppe (Roma, ITA)ROSSIGNOL Patrick (Nancy, FRA)ROULEAU Jean (Montreal, CAN)RUILOPE Luis Miguel (Madrid, ESP)RUSCHITZKA Frank (Zurich, SUI)SABBAH Hani N. (Detroit, USA)SCHMIDT Harald (Maastricht, NED)SCHUNKERT Heribert (Lübeck, GER)SEREBRUANY Victor (Towson, USA)SIMOONS Marteen (Rotterdam, NED)SLEIGHT Peter (Oxford, GBR)SOBHY Mohamed (Aexandria, EGY)STOSCHITZKY Kurt (Graz, AUT)SWYNGHEDAUW Bernard (Paris, FRA)TAVAZZI Luigi (Cotignola, ITA)THOM Simon (London, GBR)TORP-PEDERSEN Christian (Copenhague, DEN)VERHEUGT Freek W.A. (Amsterdam, NED)VON HAEHLING Stephan (Berlin, Ger)WALLENTIN Lars (Stockholm, SWE)WEDEL Hans (Gothenburg, SWE)WHELLAN David J. (Philadelphia, USA)ZANNAD Faiez (Nancy, FRA)

FDA / NHLBI (NIH)FINE Lawrence Jay (NHLBI, Bethesda, USA)GELLER Nancy (NHLBI, Bethesda, USA)GORDON David (NHLBI, Bethesda, USA)MASCETTE Alice (NHLBI, Bethesda, USA)ROSENBERG Yves (NHLBI, Bethesda, USA)STOCKBRIDGE Norman (FDA, Rockville, USA)

EMEA / AFSSAPSABADIE Eric (AFSSAPS, Paris, FRA)ALONSO Angeles (EMEA, Madrid, ESP)LASLOP Andrea (EMEA, Innsbruck, AUT)MAGGIONI Aldo Pietro (EMEA, Firenze, ITA)

INDUSTRY BERNAUD Corine (AstraZeneca, BEL)CODY Robert (Merck, USA)FRIEDMAN Jeffrey (Boehringer Ingelheim, Ger)GAY Alain (Bayer, FRA)JACOBSON Arnold J. (GE Healthcare, USA)KHDER Yasser (Boehringer Ingelheim, FRA)KUPFER Stuart (Takeda, USA)MASSET Sandrine (Boston Scientific, BEL)PEREZ Alfonso (Takeda, USA)REVKIN James (Boehringer Ingelheim, USA)ROESSIG Lothar (Bayer, GER)SAZOVA Ogun (AstraZeneca, BEL)SHI Harry (Pfizer, USA)SCHUBERT Bernd D. (Boston Scientific, BEL)SLEEP Daryl (Takeda, USA)VINCENT Alphons (Medtronic, GER)VINCENT John (Pfizer, USA)WIENHUES-THELEN Ursula-Henrike (Roche, GER)WOERLE Hans-Jürgen (Boehringer Ingelheim, GER)ZALEWSKI Andrew (Novartis, USA)ZAUGG Christian (Roche Diagnostics, SUI)


SCIENTIFIC PRoGRAM

Thursday 2 December .................................................................................................................6

Friday 3 December ....................................................................................................................9

Saturday 4 December ...............................................................................................................13

ACKNoWLEDGEMENTS .............................................................................. 19

ABSTRACTS ............................................................................................. 21

PoSTERS .................................................................................................. 53

TARGET AUDIENCEPractitionersGain a better understanding of the results of recent major trials and their impact on clinical practice.AcademicsExchange ideas with practitioners about the relevance of ongoing research and future trials.Pharmaceutical and device companiesPresent and discuss current research and future trials with scientific and regulatory professionals.RegulatorsHear from international colleagues and other industry stakeholders on the latest research results and trends in trial methodology.

European Board for Accreditation in Cardiology

The CVCT Forum is accredited by the European Board for Accreditation in Cardiology (EBAC) for 18 hours of External CME credits. Each participant should claim only those hours of credit that have actually been spent in the educational activity. EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME), which is an institution of the European Union of Medical Specialists (UEMS).

This programme is sponsored by the University of Michigan Medical SchoolThe University of Michigan Medical School is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

University of Michigan Medical School designates this educational activity for a maximum of 19 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.The University of Michigan Office of Continuing Medical Education (UM OCME) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by UM OCME for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Each presenter will disclose conflict of interest on a slide, presented to the audience at the beginning of their presentation.SYN

OPS

ISPROGRAM AT A GLANCE

ExPErT WOrkSHOPBiomarkers

to guide therapy in heart failure patients- Is the concept proven ?

ExPErT WOrkSHOP

myocardial innervation imaging- from prognostication to guiding therapy

Salon Orsay Nord

Foyer Orsay Nord

PLENArY SESSION

Optimizing the risk to benefit ratio

with new reversible antiplatelet therapies

in acute coronary syndromes

PLENArY SESSION

risk guided cardiovascular

preventive drug therapy- from individual risk

factors to risk scoring

Salon Orsay Sud

Thu

rsda

y D

ecem

ber 2

nd , 20

10

Investigator meetingAldostrerone receptor

blockers across the heart failure

spectrum

Investigator meeting

with steeringcommittee

PLENArY SESSION

Trials of new anti-diabetic drugs.A shift in paradigm

Frid

ay D

ecem

ber 3

rd , 20

10

ExPErT WOrkSHOPDevice Therapy

for mild to moderate heart failure

ExPErT WOrkSHOP

Methodological, practical and regula-tory framework for conducting

an anti-thrombotic therapy outcome trial

in atrial fibrillation

PLENArY SESSIONHeart rate reduction with Ivabradine: from clinical trials to clinical

practice

Salon Orsay Nord

Foyer Orsay Nord

Salon Orsay Sud

MEET&EAT with theExperts Safety Issues

related to serum potassium in Cardiovascular trials. Falling from charybde

to scylla ?

WOrkSHOPExpert statisticans

and trialists discuss

the major trials of the year

Cof

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Con

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08:00 08:30 09:00 09:30 10:00 10:30 11:00 11:30 12:00 12:30 13:00 13:45 14:00 14:30 15:00 15:30 16:00 16:30 17:00 17:30 18:00 18:30 19:00 19:30 20:00

ExPErT WOrkSHOPAcute Heart

Failure Trials. How to overcome

enrollment challenges

ExPErT WOrkSHOPAcute Heart

Failure Trials. How to overcome

enrollment challenges

Salon Orsay Nord

ExPErT WOrkSHOP«How to» WorkshopHow to stop a trial

prematurely for excessof benefit

Plenary Guest Lecture

Satu

rday

Dec

embe

r 4th

, 20

10Foyer Orsay Nord

ExPErT WOrkSHOPMaximizing

the benefits from angiotensin

receptor antagonists.

Enhanced potency and combination

therapy

ExPErT WOrkSHOPMaximizing

the benefits from angiotensin

receptor antagonists.

Enhanced potency and combination

therapy

Salon Orsay Sud

WOrkSHOPStudy design

issues in thrombosis trials

ExPErT WOrkSHOPCardiac

resynchronization therapy beyond LBBB

and wide QrS

ExPErT WOrkSHOP

Cardiac resynchronization therapy beyond

LBBB and wide QrS

WOrkSHOPStudy design

issues in thrombosis trials

Cof

fee

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Cof

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08:00 08:30 09:00 09:30 10:00 10:30 11:00 11:30 12:00 12:30 13:00 13:45 14:00 14:30 15:00 1530 16:00 16:30 17:00 17:30 18:00 18:30 19:00 19:30 20:00

Cof

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08:00 08:30 09:00 09:30 10:00 10:30 11:00 11:30 12:00 12:30 13:00 13:30 14:00 14:30 15:00 15:30 16:00 16:30 17:00 17:30 18:00 18:30 19:00 19:30 20:00

ESC Working Group

on Pharmacology and Drug

Therapy Nucleus Business Meeting

ESC Working Group on

Pharmacology and

Drug Therapy Nucleus Business Meeting

PLENArY SESSION

Trials of new anti-diabetic drugs.A shift in paradigm

MEET&EAT with theExperts

CV prevention: one drug, multi-

drugs or polypilll?

Cof

fee

Brea

k an

d po

ster

s vi

ewin

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ExPErT WOrkSHOPManagement of heart failure patients guided

by remote hemodynamic

monitoring. Is the concept

proven ?

Cof

fee

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Meeting of the French Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy

French speaking session

ExPErT WOrkSHOP«How to» WorkshopHow to stop a trial

prematurely for excessof benefit


ThURSdAY dECEmbER 2Nd, 2010

09:00-13:30 SALoN oRSAY SUD RooM 1ST INTERNATIoNAL MEETING oF THE FRENCH SoCIETY oF CARDIoLoGY WoRKING GRoUP oN CARDIovASCULAR PHARMACoLoGY AND DRUG THERAPY - French speaking session Présidents: Pierre GIBELIN, Nice - Atul PATHAK, Toulouse, FRA 09:00-10:00 Diabetes medication: what the cardiologist should know Anti-diabétiques oraux et pathologie cardiovasculaire: ce que le cardiologue doit savoir Chairman: Laurent MONASSIER, Strasbourg, FRA

Oldies but goldies: benefit/risk of standard diabetes medication Les «anciens» anti-diabétiques oraux: Bénéfices / risques cardiovasculaires

Paul VALENSI, Paris, FRA

GLP1, DPP Iv and others… new target and indication of newcomers Les «nouveaux» hypoglycemiants oraux (GLP1, DPPIv, autres): nouvelles cibles, effets cardiovasculaires François DIéVART, Lille, FRA

10:00-11:00 Keep your heart in mind / Médicaments neurologiques / psychiatriques et maladies cardiovasculaires Chairman: Pierre AMBROSI, Marseille, FRA

Cardiovascular effects of anticholinesterase drugs Effets cardiovasculaires des inhibiteurs des anticholinesterases

Laurent MONASSIER, Strasbourg, FRA Michèle ESCANDE ORTHLIEB, Allauch, FRA

- Introduction et rappels pharmacologiques Laurent MONASSIER, Strasbourg, FRA - Effets délétères Michèle ESCANDE ORTHLIEB, Allauch, FRA - Effets bénéfiques et conclusions Laurent MONASSIER, Strasbourg, FRA

Cardiac effects of antipsychotic medications / Effets cardiovasculaires des traitements anti-psycotiques Milou DRICI, Nice, FRA

11:30-12:30 When cancer drugs affect the heart /Traitements oncologiques et coeur Chairman: Gérard ROUL, Strasbourg

Cardiotoxicity of chemotherapy medications / Chimiothérapie et cardiotoxicité Pierre GIBELIN, Nice, FRA

Antiangiogenic therapy and hypertension / Médicaments anti-angiogéniques et HTA Atul PATHAK, Toulouse, FRA

TNF alpha: the cardiologist’s point of view / Le cardiologue et les immunosuppresseurs Pierre AMBROSI, Marseille, FRA

12:30-13:30 vasodilating / Traitements urologiques / sexuel et coeur Chairman: François DIEVART, Lille, FRA

Alpha Blocker and the Heart / Alpha-bloquants chez le cardiaque Pascal PONCELET, Henin Beaumont, FRA

Clinical use of Phosphodiesterase-5 inhibitors in chronic heart failure Inhibition de la phosphodiéstérase 5 chez l’insuffisant cardiaque chronique

Gérard ROUL, Strasbourg, FRA


12:30-14:00 FoYER oRSAY NoRD RooM ESC WoRKING GRoUP oN PHARMACoLoGY AND DRUG THERAPY NUCLEUS BUSINESS MEETING

14:00-16:00 SALoN oRSAY SUD RooM PLENARY SESSIoN oPTIMIZING THE RISK To BENEFIT RATIo WITH NEW REvERSIBLE ANTIPLATELET THERAPIES IN ACUTE CoRoNARY SYNDRoMES Chairmen: Dan ATAR, Oslo, NOR - Lars WALLENTIN, Uppsala, SWE

Current guidelines and unmet needs in the management of thrombotic events in acute coronary syndromes Nicolas DANCHIN, Paris, FRA

New reversible antiplatelet drugs. Pharmacology and potential advantages Steen HUSTED, Arhus, DEN

The mechanisms of the mortality benefit of ticagrelor therapy. Adenosine mediated mechanisms beyond antiplatelet effects. Victor SEREBRUANY, Towson, USA

PLATelet inhibition and patient outcomes with ticagrelor or Clopidogrel (PLATo). Practical consideration Lars WALLENTIN, Uppsala, SWE

14:00-16:00 SALoN oRSAY NoRD RooM ExPERT WoRKSHoP BIoMARKERS To GUIDE THERAPY IN HEART FAILURE PATIENTS - IS THE CoNCEPT PRovEN? Chairmen: Lawrence FINE, Bethesda, USA - Alain COHEN SOLAL, Paris, FRA

Why do we need biomarkers in the heart failure patient? Stephan VON HAEHLING, Berlin, GER

What to monitor? Defining the right biomarker to prompt action James JANUZZI, Boston, USA

What is the evidence that biomarker guided therapy is useful? Hans Peter BRUNNER LA ROCCA, Maastricht, NED

Debate: The challenge of designing biomarker guided therapy trials. Optimization algorithms, endpoint and blinding issues, safety concerns.

Panellists: Kirkwood ADAMS, Chapel Hill, USA - Hans Peter BRUNNER LA ROCCA, Maastricht, NED - Jay COHN, Minneapolis, USA - John CLELAND, Hull, GBR - Robert CODY, Merck, USA - Alain COHEN SOLAL, Paris, FRA Kenneth DICKSTEIN, Stavanger, NOR - Daniela DOBRE, Nancy, FRA - Lawrence FINE, Bethesda, USA Mona FIUZAT, Durham, USA - James JANUZZI, Boston, USA - Mihai GHEORGHIADE, Chicago, USA Patrick JOURDAIN, Pontoise, FRA - Ursula-Henrike WIENHUES-THELEN, Roche Diagnostics, GER Keld KJELDSEN, Copenhagen, DEN - Damien LOGEART, Paris, FRA - Aldo MAGGIONI, Firenze, ITA Alice MASCETTE, Bethesda, USA - Christian MüELLER, Basel, SUI - Ileana PIÑA, Cleveland, USA Bernard SWYNGHEDAUW, Paris, FRA - Patrick ROSSIGNOL, Nancy, FRA - Hani SABBAH, Detroit, USALuigi TAVAZZI, Cotignola, ITA - Harald SCHMIDT, Maastricht, NED - Stephan VON HAEHLING, Berlin, GER David WHELLAN, Philadelphia, USA - Faiez ZANNAD, Nancy, FRA - Christian ZAUGG, Roche Diagnostics, SUIU2Nd, 2010

16:30-19:00 SALoN oRSAY NoRD RooM ExPERT WoRKSHoP MYoCARDIAL INNERvATIoN IMAGING. FRoM PRoGNoSTICATIoN To GUIDING THERAPY Chairmen: Denis AGOSTINI, Caen, FRA - Ileana PIÑA, Cleveland, USA Myocardial imaging for assessment of cardiovascular risk in heart failure patients. From retrospective observations to prospective validation (ADMIRE-HF) Paolo G. CAMICI, London, GBR



MIBG myocardial imaging to predict ventricular arrhythmias and cardiac outcome Arnold JACOBSON, GE Healthcare, USA

Cardiac MIBG imaging guided therapy in heart failure patients. Time for a trial? Ileana PIÑA, Cleveland, USA

ExPERT WoRKSHoP How to turn a prognostic factor into a therapeutic decision and monitoring tool? Design and methodological issues.

l Where are the unmet needs? What is the target population? Discussant: John CLELAND, Hull, GBR l Mechanistic plausibility: What medication for poor sympathetic neuronal integrity? Discussant: Bertram PITT, Ann Arbor, USA

l Clinically meaningful endpoints. What will convince the doctor? Discussant: James JANUZZI, Boston, USA Panellists: Stefan AGEWALL, Stockholm, SWE - Denis AGOSTINI, Caen, FRA - Paolo G. CAMICI, London, GBR John CLELAND, Hull, GBR - Kenneth DICKSTEIN, Stavanger, NOR - Daniela DOBRE, Nancy, FRA Lawrence FINE, Bethesda, USA - Mihai GHEORGHIADE, Chicago, USA - Arnold JACOBSON, GE Healthcare, USA James JANUZZI, Boston, USA - Henry KRUM, Melbourne, AUS - Keld KJELDSEN, Copenhagen, DEN,- Alice MASCETTE, Bethesda, USA - John McMURRAY, Glasgow, GBR - Marc PFEFFER, Boston, USA - Ileana PIÑA, Cleveland, USA - Bertram PITT, Ann Arbor, USA - Frank RUSCHITZKA, Zurich, SUI - Aldo MAGGIONI, Florence, ITA - Atul PATHAK, Toulouse, FRA - Luigi TA VAZZI, Cotignola, ITA - Patrick ROSSIGNOL, Nancy, FRA - David WHELLAN, Philadelphia, USA - Faiez ZANNAD, Nancy, FRA

16:30-18:30 SALoN oRSAY SUD RooM PLENARY SESSIoN RISK GUIDED CARDIovASCULAR PREvENTIvE DRUG THERAPY - FRoM INDIvIDUAL RISK FACToRS To RISK SCoRING Chairmen: Luis RUILOPE, Madrid, ESP - Faiez ZANNAD, Nancy, FRA Cardiovascular preventive drug therapy, advantages and limitations of the current paradigm Heribert SCHUNKERT, Lübeck, GER

The impact of recent clinical trials on the future of CvD assessment and risk management Transition to “risk score guided” strategies Wolfgang KOENIG, Ulm, GER Clinical utility of biomarkers and bioimaging as tools to identify patients who need drug therapy Matthias LORENZ, Frankfurt, GER

Combined lipid lowering and blood pressure lowering in high risk patients. Rationale and design of the HoPE-3 trial Eva LONN, Hamilton, CAN

Risk scoring. Beyond Framingham Jay COHN, Minneapolis, USA

18:30-19:15 FoYER oRSAY NoRD RooM ESC WoRKING GRoUP oN PHARMACoLoGY AND DRUG THERAPY NUCLEUS BUSINESS MEETING

FRIdAY dECEmbER 3Rd, 2010

08:30-10:30 SALoN oRSAY SUD RooM ExPERT WoRKSHoP DEvICE THERAPY FoR MILD To MoDERATE HEART FAILURE Chairmen: John CLELAND, Hull, GBR - Jean Yves LE HEUZEY, Paris, FRA MADIT-CRT, RAFT and heart failure device trials. Accumulating evidence Jean ROULEAU, Montreal, CAN

CRT and ICD therapy: How early in the disease process? Johannes HOLZMEISTER, Zurich, SUI Debate: From trial to approval to guidelines and adoption. How device trials will stand the journey?

l Weighing the level of evidence. Consistency, validity and mechanistic plausibility of trial results Discussant HF: Kenneth DICKSTEIN, Stavanger, NOR Discussant EP: Jean-Yves LE HEUZEY, Paris, FRA l Updating the guidelines. Have we hit the Ia target? Discussant EP: Malcolm ARNOLD, London, CAN Discussant HF: John CLELAND, Hull, GBR

l How to identify/refer patients eligible for device therapy? Can a “Get With The Guidelines” (GWTG) type initiative help? Discussant HF: Faiez ZANNAD, Nancy, FRA Panellists: William ABRAHAM, Columbus, USA - John CLELAND, Hull, GBR - Jay COHN, Minneapolis, USA Martin COWIE, London, GBR - Kenneth DICKSTEIN, Stavanger, NOR - Mihai GHEORGHIADE, Chicago, USA Johannes HOLZMEISTER, Zurich, SUI - Henry KRUM, Melbourne, AUS - Jean-Yves LE HEUZEY, Paris, FRA Marc PFEFFER, Boston, USA - Frank RUSCHITZKA, Zurich, SUI - Aldo MAGGIONI, Firenze, ITA Franco NACCARELLA, Bologna, ITA - Willem reMMe, Rhoon, NED - Bernd SCHUBERT, Boston Scientific, BEL Jean ROULEAU, Montreal, CAN - Luigi TAVAZZI, Cotignola, ITA - Alphons VINCENT, Medtronic, NED Malcolm ARNOLD, London, CAN - David WHELLAN, Philadelphia, USA - Faiez ZANNAD, Nancy, FRA

08:30-10:30 SALoN oRSAY NoRD RooM11:00-12:30 PLENARY SESSIoN TRIALS oF NEW ANTI-DIABETIC DRUGS A SHIFT IN PARADIGM Chairmen: Angeles ALONSO, Madrid, ESP - William C. CUSHMAN, Memphis, USA

The value of the surrogate glycemic control and HbA1 C, the usual endpoint on which approval of diabe-tes drugs is based is being strongly challenged. Mega and long duration trials are currently undertaken in type 2 diabetes. They may be required to obtain significant improvements in macrovascular outcomes. However, to date, no benefits on macrovascular outcomes have been demonstrated. Ultimately, as at least 50% of the complications associated with type 2 diabetes are microvascular in nature, it may be more appropriate to focus on microvascular outcomes. Also, targeting disease progression rather than events may be appropriate.Because of recently published CV safety issues with the new anti-diabetic agents, the FDA produ-ced proscriptive industry guidelines requesting the evaluation of CV risk in all new anti-diabetic therapies. Such measures create ethical and economic challenges.

What to expect from a new anti-diabetic drug? Endpoint related issues

l HbA1 C, a failed surrogate? William C. CUSHMAN, Memphis, USA

l Micro vs. macrovascular disease progression endpoints Peter SLEIGHT, Oxford, GBR



l Hard endpoints: MACE and Mortality John McMURRAY, Glasgow, GBR

The metabolic memory of HbA1c, how useful as a surrogate ? Hens WEDEL, Gothenburg, SWE

Debate: Are the current megatrials addressing the unmet needs?

Panellists: Eric ABADIE, Paris, FRA - Stefan AGEWALL, Oslo, NOR - Angeles ALONSO, Madrid, ESPJohn CLELAND, Hull, GBR - Robert CODY, Merck,, USA - William C. CUSHMAN, Memphis, USA Jeffrey FRIEDMAN, Boehringer Ingelheim, GER - Nancy GELLER, Bethesda, USADavid GORDON, Bethesda, USA - Yasser KHDER, Boehringer Ingelheim, FRA - Wolfgang KOENIG, Ulm, GER Basil LEWIS, Haïfa, ISR - Giuseppe MANCIA, Monza, ITA - John McMURRAY, Glasgow, GBR - Eva LONN, Hamilton, CAN Prem PAIS, Bangalore, IND - Alfonso PEREZ, Takeda, USA - Bertram PITT, Ann Arbor, USA - Stuart POCOCK, London, GBR - James REVKIN, Boehringer Ingelheim, USA - Eberhardt RITZ, Heidelberg, GER - Yves ROSENBERG, Bethesda, USA Luis RUILOPE, Madrid, ESP - Heribert SCHUNKERT, Lübeck, GER - Daryl SLEEP, Takeda, USA - Peter SLEIGHT, Oxford, GBR - Christian TORP-PEDERSEN, Copenhagen, DEN - Hans-Jürgen WOERLE, Boehringer Ingelheim, GER Hens WEDEL, Gothenburg, SWE - Faiez ZANNAD, Nancy, FRA

11:00-12:30 SALoN oRSAY SUD RooM ExPERT WoRKSHoP MANAGEMENT oF HEART FAILURE PATIENTS GUIDED BY REMoTE HEMoDYNAMIC MoNIToRING IS THE CoNCEPT PRovEN?

Chairmen: Martin COWIE, London, GBR - William ABRAHAM, Columbus, USA

Why do we need telemonitoring solutions for the heart failure patient? Martin COWIE, London, GBR

What to monitor? Defining the right signals which would prompt action. A review of the existing monitoring devices. Haran BURRI, Geneva, SUI

Who should deal with the telemonitoring information? Practical issuesCarlos MORAIS, Amadora, PORmbER 3Rd, 2010Criteria for trial validation of telemedicine devices for heart failure patients? Critical appraisal of recent and ongoing trials (CoMPASS; DoT-HF; DECoDE; PARTNERS-HF; PRECEDE-HF; SENSE-HF; TELE-HF)

David WHELLAN, Philadelphia, USA

Debate: How to generate evidence? Designing telemonitoring trials

Panellists: William ABRAHAM, Columbus, USA - Haran BURRI, Geneva, SUI - Martin COWIE, London, GBR Kenneth DICKSTEIN, Stavanger, NOR - Jay COHN, Minneapolis, USA - Lawrence FINE, Bethesda, USA Mihai GHEORGHIADE, Chicago, USA - Gerasimos FILIPATTOS, Athens, GRE - Henry KRUM, Melbourne, AUS Alice MASCETTE, Bethesda, USA - Aldo MAGGIONI, Firenze , ITA - Sandrine MASSET, Boston Scientific, BELCarlos MORAIS, Amadora, POR - Marc PFEFFER, Boston, USA - Ileana PIÑA, Cleveland, USA - Bertram PITT, Ann Arbor, USA - Willem reMMe, Rhoon, NED - Frank RUSCHITZKA, Zurich, SUI - Bernd SCHUBERT, Boston Scientific, BEL Jean ROULEAU, Montreal, CAN - Luigi TAVAZZI, Cotignola, ITA - Alphons VINCENT, Medtronic, GERDavid WHELLAN, Philadelphia, USA - Faiez ZANNAD, Nancy, FRA

12:30-13:45 FoYER oRSAY NoRD RooM MEET AND EAT WITH THE ExPERT SESSIoN SAFETY ISSUES RELATED To SERUM PoTASSIUM IN CARDIovASCULAR TRIALS - FALLING FRoM CHARY BDE To SCYLLA? Chairmen: Keld KJELDSEN, Copenhagen, DEN - Luis Miguel RUILOPE, Madrid, ESP

The pathophysiology of serum potassium in cardio-renal disease Eberhardt RITZ, Heidelberg, GER


Targets for serum potassium in hypertension and heart failure; Preventing and managing hyperkalemia Luis Miguel RUILOPE, Madrid, ESP

Serum potassium and cardiorenal outcomes in cardiovascular clinical trials of RAAS therapy Faiez ZANNAD, Nancy, FRA

opportunities to prevent/treat hyperkalemia with potassium-binders. objectives and design of the PEARL-HF trial Bertram PITT, Ann Arbor, USA

12:30-13:45 SALoN oRSAY SUD RooM MEET AND EAT WITH THE ExPERTS SESSIoN Cv PREvENTIoN: oNE DRUG, MULTIDRUGS oR PoLYPILL? Chairman: Eva LONN, Hamilton, CAN - Marc PFEFFER, Boston, USA

Polypill and primary Cv prevention. Indian Polycap Study (TIPS) Prem PAIS, Bangalore, IND

Polypill and secondary prevention: the FoCUS trial Felipe MARTINEZ, Cordoba, ARG

The Red Heart multidrug pill Indo European UMPIRE trial Simon THOM, London, GBR

The Regulatory approach. Approvability issues of the polypill Angeles ALONSO, Madrid, ESP

14:00-16:00 SALoN oRSAY SUD RooM ExPERT STATISTICIANS AND TRIALISTS DISCUSS THE MAJoR TRIALS oF THE YEAR Chairmen: Bertram PITT, Ann Arbor, USA - Mohamed SOBHY, Alexandria, EGY

Medicine deals with treatments that work often but not always, so treatment success must be based on probability. This unique session is meant to be educational and possibly controversial. Interpreting trial results requires a good understanding of statistics and trial metho-dology. Senior statisticians and clinical trialists debate their own views as well as tips and tricks for understanding the most recent trials of the year.

Speaker: Stuart POCOCK, London, GBRDiscussant: Roxana Mehran, New York, USA

Panellists: Corine BERNAUD, AstraZeneca, BEL - Robert CODY, Merck, USA - Lawrence FINE, Bethesda, USA Nancy GELLER, Bethesda, USA - David GORDON, Bethesda, USA - Steen HUSTED, Arhus, DEN Yasser KHDER, Boehringer Ingelheim, FRA - Eva LONN, Hamilton, CAN - Gerasimos FILIPATTOS, Athens, GRE Damien LOGEART, Paris, FRA - Josep MASIP, Barcelona, ESP - Marco METRA, Brescia, ITA Christian MüELLER, Basel, SUI - Semir Nouira, Mahdia, TUN - Hani SABBAH, Detroit, USA - Alice MASCETTE, Bethesda, USA - Giuseppe MANCIA, Monza, ITA - Roxana MEHRAN, New York, USA - Atul PATHAK, Toulouse, FRA Marc PFEFFER, Boston, USA - Bertram PITT, Ann Arbor, USA - Stuart POCOCK, London, GBR - Yves ROSEN-berG, Bethesda, USA - Patrick ROSSIGNOL, Nancy, FRA - Victor SEREBRUANY, Towson, USA - Harry SHI, Pfizer, USA Mohamed SOBHY, Alexandria, EGY - Christian TORP PEDERSEN, Copenhagen, DEN - Hans WEDEL, Gothenburg, SWE - Andrew ZALEWSKI, Novartis, USA - Faiez ZANNAD, Nancy, FRA.

FRIdA14:00-16:00 SALoN oRSAY NoRD RooM PLENARY SESSIoN HEART RATE REDUCTIoN WITH IvABRADINE: FRoM CLINICAL TRIALS To CLINICAL PRACTICE Chairmen: Michael BÖHM, Homburg, GER - Faiez ZANNAD, Nancy, FRA

Body of evidence of the importance of heart rate reduction Martin COWIE, London, GBR

Management of heart rate in CAD: lessons from the BEAUTIFUL study Jeffrey S. BORER, New York, USA



Management of heart rate in HF: lessons from the SHIFT study Michael böhM, Homburg, GER

Heart rate management in clinical practice with ivabradine Giuseppe ROSANO, Roma, ITA

Debate: The challenge of optimization of heart failure therapy. Is there a limit to polypharmacy?

Panellists: Stefan AGEWALL, Oslo, NOR - Michael böhM, Homburg, GER - Jeffrey S. BORER, New York, USA Martin COWIE, London, GBR - Jay COHN, Minneapolis, USA - Mihai GHEORGHIADE, Chicago, USA Mona FIUZAT, Durham, USA - Wolfgang KOENIG, Ulm, GER - Henry KRUM, Melbourne, AUS - Guy LEREBOURS, Servier, FRA Felipe MARTINEZ, Cordoba, ARG - John McMURRAY, Glasgow, GBR - Willem reMMe, Rhoon, NED Giuseppe ROSANO, Roma, ITA - Heribert SCHUNKERT, Lübeck, GER - Kurt STOSCHITZKY, Graz, AUT Luigi TAVAZZI, Cotignola, ITA - Faiez ZANNAD, Nancy, FRA

16:30-19:00 SALoN oRSAY SUD RooM ExPERT WoRKSHoP METHoDoLoGICAL, PRACTICAL AND REGULAToRY FRAMEWoRK FoR CoNDUCTING AN ANTI-THRoMBoTIC THERAPY oUTCoME TRIAL IN ATRIAL FIBRILLATIoN Chairmen: Sidney GOLDSTEIN, Detroit, USA - Christian TORP-PEDERSEN, Copenhagen, DEN

Rationale: Several new anti-thrombotic agents and interventional therapies have been subjected to or are being assessed in large mortality and morbidity atrial fibrillation trials. Several challenges and issues are related to designing, conducting and interpreting the results of an anti-thrombotic trial. Understanding these issues is critical for an optimal implementation of the results of these trials into daily clinical practice.

objectives:l Discussing the strengths and limitations of the recent and ongoing mortality-morbidity trials with anti-thrombotic therapy in atrial fibrillation. l Understanding the methodological, practical (environment) and regulatory framework for conducting an anti-thrombotic therapy outcome trial.l Discussion among experts with the aim of improving future anti-thrombotic therapy in atrial fibrillation.

Lectures:Limitations of warfarin anticoagulation and unmet needs in atrial fibrillation stroke prevention.Gregory LIP, Birmingham, GBR

New anti-thrombotic agents versus Warfarin in Patients with Atrial Fibrillation. An update on recent and ongoing trials. Lars WALLENTIN, Uppsala, SWE

Debate: Defining the target population and reshaping the guidelines.

Dosing issues in thrombosis trials. e.g. Progression from Phase 2 to Phase 3 trials with new oral anti-thrombotic agents Discussant: Yasser KHDER, Boehringer Ingelheim, FRA

PRoBE vs. Double Blind study designs in thrombosis trialsDiscussant: Gregory LIP, Birmingham, GBR

What is a clinically meaningful benefit? All cause vs cause specific eventsDiscussant: Freek VERHEUGT, Amsterdam, NED

Panellists: Corine BERNAUD, AstraZeneca, BEL - Alain GAY, Bayer, FRA - Sidney GOLDSTEIN - Detroit, USA - Yasser KHDER, Boehringer Ingelheim, FRA - Stuart KUPFER, Takeda, USA - Andrea LASLOP, Innsbruck, AUT- Gregory LIP, Birmingham, GBR - Basil LEWIS, Haïfa, ISR - Franco NACCARELLA, Bologna, ITA - Yves ROSENBERG, Bethesda, USA Ogun SAZOVA, AstraZeneca, BEL- Luigi TAVAZZI, Cotignola, ITA - Christian TORP-PEDERSEN, Copenhagen, DEN Freek VERGHEUGT, Amsterdam, NED - Lars WALLETIN, Uppsala, SWE - Hans-Jürgen WOERLE, Boehringer Ingelheim, GER - Faiez ZANNAD, Nancy, FRA


16:30-18:30 SALoN oRSAY NoRD RooM ALDoSTERoNE RECEPToR BLoCKERS ACRoSS THE HEART FAILURE SPECTRUM Chairmen: John McMURRAY, Glasgow, GBR - Kenneth DICKSTEIN, Stavanger, NOR

A historical perspective of evidence based therapy in heart failureJay COHN, Minneapolis, USA

EMPHASIS-HF : Extending the indication of eplerenone to mild heart failure Faiez ZANNAD, Nancy, FRA

Aldosterone receptor blockers across the heart failure spectrum. Practical issues and updating the guidelines Henry KRUM, Melbourne, AUS

Anti-aldosterone therapy. New drugs and new trialsBertram PITT, Ann Arbor, USA

18:30-19:30 Meeting with the steering committee

SATURdAY dECEmbER 4Th, 2010

08:00-10:30 SALoN oRSAY NoRD RooM11:00-12:30 «HoW To» WoRKSHoP HoW To SToP A TRIAL PREMATURELY FoR ExCESS oF BENEFIT Chairmen: John McMURRAY, Glasgow, GBR - Stuart POCOCK, London, GBR

Rationale: There are obvious ethical reasons for stopping a trial prematurely when protecting the study patients against excess of harm when a premature evidence of excess adverese events is detected by the data safety and monitoring committee. It may be also ethically important not to keep the study going when patients in the control group appear to be at highr risk of events than the active study group. However stopping a trial prematurely exposes to possible bias and several other interpretation issues. In addition, because they are usually unplanned, the logistical challenges after the decision to stop and until study close out and beyond may be very important. There is no magic solution, but lessons on how to optimize stopping rules and the close out of a study that is stopped prematurely may be learnt from recent experiences.This session is of interest to all investigators, regulators, ethicists, and industry scientists and project managers invol-ved in steering clinical trials and/or in Data Safety and Monitoring Committees.

objective:Discussion among experts on stopping rules, interpretation issues and how to optimize the close out of a study that is stopped prematurely.

Format:Short 10 min presentations followed respectively by 20 min discussion among experts and interaction with an open audience.

Introduction:Case study. My experience with stopping trials prematurely (RALES, CIBIS 2, EMPHASIS-HF and other trials)Faiez ZANNAD, Nancy, FRA

Why to stop – what endpoint? Bertram PITT, Ann Arbor, USA When to stop – what level of statistical certainty? Stuart POCOCK, London, GBR

How to stop – how quickly? Collecting further events? Open label treatment if stopping for efficacy? John McMURRAY, Glasgow, GBR

How did I handle expedited event adjudication? Critical event committee issues Willem REMME, Rhoon, NED



Panellists: Jeffrey S. BORER, New York, USA - Jay COHN, Minneapolis, USA - Henry DARGIE, Glasgow, GBR Lawrence FINE, Bethesda, USA - Gerasimos FILIPATTOS, Athens GRE - Nancy GELLER, Bethesda, USAMihai GHEORGHIADE, Chicago, USA - David GORDON, Bethesda, USA - Yasser KHDER, Boehringer Ingelheim, FRA Wolfgang KOENIG, Ulm, GER - Aldo MAGGIONI, Florence, ITA - Alice MASCETTE, Bethesda, USA Roxana MEHRAN, New York, USA - John McMURRAY, Glasgow, GBR - Marco METRA, Brescia, ITAMarc PFEFFER, Boston, USA - Bertram PITT, Ann Arbor, USA - Stuart POCOCK, London, GBR Willem REMME, Rhoon, NED - Yves ROSENBERG, Bethesda, USA - Harry SHI, Pfizer, USA Maarten SIMOONS, Rotterdam, NED - Christian TORP-PEDERSEN, Copenhagen, DEN - John VINCENT, Pfizer, USA Hans WEDEL, Gothenburg, SWE - David WHELLAN, Philadelphia, USA - Andrew ZALEWSKI, Novartis, USA Faiez ZANNAD, Nancy, FRA

08:00-10:30 SALoN oRSAY SUD RooM11:00-12:30 ExPERT WoRKSHoP CARDIAC RESYNCHRoNIZATIoN THERAPY BEYoND LBBB AND WIDE QRS Chairmen: Johannes HOLZMEISTER, Zurich, SUI - William abrahaM, Columbus, USA

Rationale and design of the Echo-CRT trialFrank RUSCHITZKA, Zurich, SUI

Debate: From proof of concept to a large scale morbidity and mortality trial. Design challenges. Bearing results implementation in mind.

• Where are the unmet needs? What is the target population? Trial population vs. real life patientsDiscussant HF: William abrahaM, Columbus, USA

• Clinically meaningful endpoints. Composite/cause-specific or all-cause? What will convince the doctors? Discussant EP: Johannes HOLZMEISTER, Zurich, SUIDiscussant HF: Henry KRUM, Melbourne, AUS

• What is adequate statistical power? Discussant Statisticiant: Stuart POCOCK, London, GBRDiscussant HF: Faiez ZANNAD, Nancy, FRA

Panellists: William Abraham, Columbus, USA - Malcolm ARNOLD, London, GBR - John CLELAND, Hull, GBR Kenneth DICKSTEIN, Stavanger, NOR - Johannes HOLZMEISTER, Zurich, SUI - Henry KRUM, Melbourne, AUS Stuart POCOCK, London, GBR - Alphons VINCENT, Medtronic, GER - Frank RUSCHITZKA, Zurich, SUI Faiez ZANNAD, Nancy, FRA

09:00-10:30 FoYER oRSAY NoRD RooM11:00-12:30 ExPERT WoRKSHoP MAxIMIZING THE BENEFITS FRoM ANGIoTENSIN RECEPToR ANTAGoNISTS - ENHANCED PoTENCY AND CoMBINATIoN THERAPY Chairmen: Angeles ALONSO, Madrid, ESP - Giuseppe MANCIA, Monza, ITA

Are all angiotensin receptor blockers alike? Are maximized potency and ancillary effects clinically relevant? Luis RUILOPE, Madrid, ESP

How to cook a good combo recipe? What is the ideal diuretic to combine?Stuart KUPFER, Takeda, USA

Is combination therapy to become the rule? Insight from hypertension outcome trials and recent guidelinesGiuseppe MANCIA, Monza, ITA

How to prove/claim added value conferred by ancillary properties?Angeles ALONSO, Madrid, ESP

How to prove/claim superiority of a new combo drug?William C. CUSHMAN, Memphis, USA


Debate: Approvability of new anti-hypertensive agents.

Panellists: Angeles ALONSO, Madrid, SPA - William C. CUSHMAN, Memphis, USA - Stuart KUPFER, Takeda, USA Eva LONN, Hamilton, CAN - Giuseppe MANCIA, Monza, ITA - Alfonso PEREZ, Takeda, USA - Bertram PITT, Ann Arbor, USA Patrick ROSSIGNOL, Nancy, FRA - Vladimir POPOV, Moscow, RUS - Luis RUILOPE, Madrid, SPA - Darryl SLEEP, Ta-keda, USA - Faiez ZANNAD, Nancy, FRA

12:30-13:45 SALoN oRSAY NoRD RooM PLENARY GUEST LECTURE CHALLENGING HYPoTHESES To BE TESTED IN FUTURE TRIALS The Cv Trialists «FoRUM»

«fo•rum (fôrm, fr-) n. pl. fo•rums also fo•ra (fôr, fr)

• The public square or marketplace of an ancient Roman city that was the assembly place for judicial activity and public business.

• A public meeting place for open discussion.

• A medium for open discussion or voicing of ideas, such as a newspaper, a radio or television program, or a website.

• A public meeting or presentation involving a discussion usually among experts and often including audience participation.

• a court of law; a tribunal.»

Clinical trials are humbling experiences. Drug discovery is not a linear process. Many drugs have failed to demonstrate the benefits that were expected from their pharmacological profile. Interestingly, many others have “apparently unexpected” benefits which were not originally predicted from their pharmacodynamic effects. Pleiotropic effects and off target effects have been sometime used to explain these non-linear findings. In this CVCT “Forum” session a tribune is given to an experienced trialist to present new “out of the box” challenging ideas that could be subjected to new trials. He should stand the criticisms of plebeian trialists, sceptical scientists and hard to convince sponsors.

Carte blanche to: Marc PFEFFER, Boston, USA

Panellists: Kirkwood ADAMS, Chapel Hill, USA - Jeffrey S. BORER, New York, USA - Jay COHN, Minneapolis, USA Peter CLEMMENSEN, Copenhagen, DEN - John CLELAND, Hull, GBR - Kenneth DICKSTEIN, Stavanger, NOR Nancy GELLER, Bethesda, USA - Sidney GOLDSTEIN, Detroit, USA - Mihai GHEORGHIADE, Chicago, USA David GORDON, Bethesda, USA - Lawrence FINE, Bethesda, USA - Yasser KHDER, Boehringer Ingelheim, FRA Wolfgang KOENIG, Ulm, GER - Henry KRUM, Melbourne, AUS - Stuart KUPFER, Takeda, Chicago, USA Andrea LASLOP, Innsbruck, AUT - Eva LONN, Hamilton, CAN - Felipe MARTINEZ, Cordoba, ARGAlice MASCETTE, Bethesda, USA - Alexandre MEBAZAA, Paris, FRA - Roxana Mehran, New York, USAJohn McMURRAY, Glasgow, GBR - Marc PFEFFER, Boston, USA - Ileana PINA, Cleveland, USA - Betram PITT, Ann Arbor, USA - Stuart POCOCK, London, GBR - Vladimir POPOV, Moscow, RUS - Willem reMMe, Rhoon, NED - James REVKIN, Boehringer Ingelheim, USA - Yves ROSENBERG, Bethesda, USA - Harry SHI, Pfizer, USA Maarten SIMOONS, Rotterdam, NED - Bernard SWYNGHEDAUW, Paris, FRA - Christian TORP-PEDERSEN, Copenhagen, DEN John VINCENT, Pfizer, USA - Hans WEDEL, Gothenburg, SWE - David WHELLAN, Philadelphia, USA Faiez ZANNAD, Nancy, FRA



14:00-16:00 SALoN oRSAY SUD RooM 16:30-18:00 CvCT WoRKSHoP STUDY DESIGN ISSUES IN THRoMBoSIS TRIALS Chairmen: Peter CLEMMENSEN, Copenhagen, DEN - Roxana Mehran, New York, USA

There is no clear relationship between anti-coagulant or anti-platelet activity and clinical endpoint event rates. The single dose that is taken into phase III studies provides inadequate evidence of the optimal use of the drug. The FDA preferred approach is to take multiple doses into phase III and avoid over-valuing bleeding. Different defini-tions of bleeding across trials and variations in the way that bleeding data are captured make comparisons between studies difficult. Harmonization of collection and reporting of bleeding data in trials of anti-thrombotic drugs would be welcomed. ‘Net clinical benefit’ is not a substitute for benefit-risk. Time has an effect. One component can drive the results. Using more endpoints is not always better and results vary depending on the combination of endpoints. Combining safety and efficacy endpoints can make interpretation of study outcomes problematic.

Areas for experts’ discussion:

Risk benefit issues in progressing to Phase III.Speaker: Sidney GOLDSTEIN, Detroit, USA Do surrogates and/or adaptive design help? Speaker: Roxana MEHRAN, New York, USADiscussant: Sidney GOLDSTEIN, Detroit, USA

Combining efficacy and safety in composite endpointsSpeaker: Andrea LASLOP, Innsbruck, AUT PRoBE vs Double Blind study design in antithrombotic trialsSpeaker: Hans WEDEL, Gothenburg, SWEDiscussant: Christian TORP-PEDERSEN, Copenhagen, DEN Bleeding outcomes: Definitions and adjudication issues Speaker: Maarten SIMOONS, Rotterdam, NEDDiscussant: Peter CLEMMENSEN, Copenhagen, DEN

Faculty: Peter CLEMMENSEN, Copenhagen, DEN - Alain GAY, Bayer, FRA - Sidney GOLDSTEIN, Detroit, USA Yasser KHDER, Boehringer Ingelheim, FRA - Stuart KUPFER, Takeda, USA - Andrea LASLOP, Innsbruck, AUT John McMURRAY, Glasgow, GBR - Roxana MEHRAN, New York, USA - Prem PAIS, Bangalore, IND - James REV-KIN, Boehringer Ingelheim, USA - Yves ROSENBERG, Bethesda, USA - Maarten SIMOONS, Rotterdam, NED Daryl SLEEP, Takeda, USA - Mohamed SOBHY, Alexandria, EGY - Christian TORP-PEDERSEN, Copenhagen, DEN-Hans WEDEL, Gothenburg, SWE - Faiez ZANNAD, Nancy, FRA.


14:00-16:00 SALoN oRSAY NoRD RooM16:30-18:00 ExPERT WoRKSHoP ACUTE HEART FAILURE TRIALS. HoW To ovERCoME ENRoLLMENT CHALLENGES Chairmen: Mihai GHEORGHIADE, Chicago, USA - Faiez ZANNAD, Nancy, FRA

Rationale: A fundamental problem in performing heart failure (HF) trials relates to multiple issues including:

• The heterogeneous nature of the patients presenting with HF• The large variability of patients presenting to teaching, academic and tertiary centres versus those presenting to community hospitals and private clinics• Lack of cooperation between cardiology, heart failure, medicine and emergency room care providers• Lack of infrastructure geared specifically at the site level towards HF research combined with lack of expertise of coordinators in HF• Long start up periods related to difficulties in negotiating the complex regulatory environment and long/convoluted contracting process• Sponsors as well as CROs and AROs need to work jointly in developing a network of trained acute heart failure trial investigators based on the diversity of the trial settings. The fundamentals of such a network should include:• Representation from academics, private, teaching and community centres• Common scientific goal to better define “real life” HF – concentrating on acute HF, systolic HF and diastolic HF• A global outreach – looking at HF in different continents, countries and regions• Create an infrastructure at the site level that would provide the coordinators and scientific platform on which clinical research can be built later• Create a common legal and regulatory platform which would enable fast and seamless start up towards clinical studies• Clear delineation at each site level which type of HF patients can be assessed by the site – acute, chronic systolic, chronic diastolic, etc.• Create a long term training program that would ensure the ethics and quality of HF research at the sites

objectives:• Identify barriers to conducting HF studies that would represent “real life” patients• Identify barriers to rapid patient enrollment in AHF trials • Define the scientific goals of the network• Discuss opportunities for sponsors, CROs and AROs to work jointly in training and setting a durable network of AHF trials investigators.

Programme (each topic will be followed by a 30 min discussion):Introduction:Experience with recent trials in acute and chronic HF. Enrollment challenges and regional differences Mihai GHEORGHIADE, Chicago, USA

Lessons from the largest Acute Heart Failure Trials: ASCEND HF Chris O’CONNOR, Durham, USA

How to set up a HF research centre that can enroll “real life” patients in all HF research areas

Experience from Central EuropeEwa JANKOWSKA, Wroclaw, POL

Experience from Western EuropeMarco METRA, Brescia, ITA

Experience from the USAMihai GHEORGHIADE, Chicago, USA


ACKNOWLEdGEmENTS TO ALL PARTNERS


Experience from South AmericaFelipe MARTINEZ, Cordoba, ARG

Experience from AfricaSemir NOURIA, Mahdia, TUN

Experience in AsiaPrem PAIS, Bangalore, IND

organizational aspects of better HF studies: what should the common mechanism be? The «nuts and bolts» of regulatory packages and contractsGad COTTER, Durham, USA

Understanding the heterogeneity of the syndrome: The need for a global registry of HF patientsFaiez ZANNAD, Nancy, FRA

How can we do better studies? Lothar ROESSIG, Bayer, GER

Panel discussion: Opportunities for training and setting a durable network of HF trials investigators.

Panellists: William ABRAHAM, Columbus, USA - Kirkwood ADAMS, Chapel Hill, USAAlain COHEN SOLAL, Paris, FRA - Jay COHN, Minneapolis, USA - Gad COTTER, Durham, USA Martin COWIE, London, GBR - Kenneth DICKSTEIN, Stavanger, NOR - Gerasimos FILIPPATOS, Athens, GRE Mihai GHEORGHIADE, Chicago, USA - Mona FIUZAT, Durham, USA - Ewa JANKOWSKA, Wroclaw, POLAldo MAGGIONI, Firenze, ITA - Josep MASIP, Barcelona, ESP - Felipe MARTINEZ, Cordoba, ARGAlexandre MEBAZAA, Paris, FRA - Marco METRA, Brescia, ITA - Christian MüELLER, Basel, SUI Semir NOUIRA, Mahdia, TUN - Chris O’CONNOR, Durham, USA - Prem PAIS, Bangalore, IND Marc PFEFFER, Boston, USA - Ileana PIÑa, Cleveland, USA - Bertram PITT, Ann Arbor, USA Willem reMMe, Rhoon, NED - Lothar ROESSIG, Bayer, GER - Frank RUSCHITZKA, Zurich, SUI Hani SABBAH, Detroit, USA - Norman STOCKBRIDGE, Rockville, USA - Luigi TAVAZZI, Cotignola, ITA Andrew ZALEWSKI, Novartis, USA - Faiez ZANNAD, Nancy, FRA.


ABST

RAC

TS


ABSTRACT

New reversible antiplatelet drugs. Pharmacology and potential advantages.Steen Husted, Aarhus University Hospital, DenmarkDual antiplatelet therapy with aspirin and clopidogrel or prasugrel is currently the stan-dard treatment for patients with acute coronary syndromes (ACS). Despite the proven efficacy of clopidogrel and prasugrel ACS is still associated with significant morbidity and mortality. Furthermore, adding a thienopyridine that binds irreversibly to the platelet P2Y12 receptor to aspirin significantly increases the risk of major bleedings. Thus, there is still a need for new therapies to improve outcomes in ACS.Three reversibly-binding P2Y12 inhibitors ticagrelor, cangrelor and elinogrel are in phase3 development. These 3 drugs belong to different classes and have important pharmacologic differences as well as important similarities. They bind directly and reversibly to the receptor and do not need metabolic activation. Drug withdrawal results in a rapid restoration of platelet activity. They all provide additional P2Y12 inhibition as compared to that achieved by clopidogrel.Cangrelor is an intravenously-administered ATP analogue that inhibits platelet activity to a high degree with normalisation of platelet function within one hour of discontinuation. The plasma half-life of the drug is less than 10 min. Cangrelor bound to the receptor inhibits binding of the thienopyridine active metabolites. The drug was tested in the phase 3 CHAMPION trials.Ticagrelor can be orally administered and belongs to the class cyclo-pentyl-triazolo-py-rimidine. The drug binds to a separate site than ADP on the receptor, but inhibits the binding of ADP to the receptor and ADP-induced platelet activation. Ticagrelor has a rapid onset of action with maximum inhibition seen after approximately 2 hours and the inhibitory effect far exceeds the mean level of inhibition seen with a high loading dose of clopidogrel (ONSET-OFFSET trial). During maintenance therapy ticagrelor achieves a more consistent and greater mean level of platelet inhibition compared with standard treatment with clopidogrel both in patients with stable coronary artery disease (DISPER-SE trial) and ACS (DISPERSE 2 trial). The half-life of ticagrelor is 8-12 hours and the inhibitory effect after treatment discontinuation declines rapidly over 72 hours with nor-malization of platelet function after 5 days. For comparison clopidogrel-treated patients obtaining a high degree of platelet inhibition normal platelet function is seen after 10 days. It has been demonstrated in an animal model that ticagrelor has a non-P2Y12-media-ted inhibitory effect on adenosine reuptake and can enhance coronary flow in response to adenosine. In the PLATO trial including ACS patients ticagrelor reduced the risk of cardiovascular death, myocardial infarction and stoke without an increased risk of major bleeding complications. Furthermore, cardiovascular mortality as well as total mortality were significantly reduced. Elinogrel is a reversible-binding P2Y12 inhibitor, which can be administered both orally and intravenously. The drug competitively inhibits ADP-induced platelet activation. The half-life of the drug is approximately 12 hours. The drug has been evaluated in phase 2 trials ERASE MI pilot trial and INNOVATE-PCI trial. A major phase 3 trial including patients with coronary artery disease is being planned. Antagonism of the platelet thrombin receptor protease-activated receptor-1 (PAR-1) represents a new strategy to reduce residual ACS cardiovascular risk. Selective PAR-1 antagonists are likely to prevent a fraction of vascular events occurring via thromboxane A2 (TXA2)- and ADP-independent platelet activation pathways. Reinforcement of platelet activation by thrombin occurs after initiation of clot formation by collagen, suggesting that PAR-1 an-tagonists may be associated with a lower bleeding risk. Dose-dependent antithrombotic effects have been shown with the PAR-1 antagonist vorapaxar, but current data are not sufficient to provide information on bleeding rates. Vorapaxar is being tested for clinical efficacy and safety in the ongoing phase 3 TRACER and TRA2-P trials.TXA2/prostaglan-din H2 (TP) receptor antagonists are also currently under investigation. Terutroban is a potent, selective TP receptor antagonist with early onset of action (30-60 minutes), dose-dependent reversibility within 24-96 hours, and limited interindividual variability in platelet response. However, the PERFORM trial, which assessed the superiority of terutroban versus aspirin in stroke was terminated early after results indicated the primary efficacy endpoint was unlikely to be achieved.

RECoMMENDED READING1. Chamorro A. TP receptor antagonism: a new concept in atherothrombosis and stroke prevention. Cerebrovasc Dis 2009;27 (suppl. 3):20-7.2. Ferreiro JL, Ueno M, Angiolillo DJ. Cangrelor: a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther 2009;7:1195-201.3. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopido grel in patients with stable coronary artery disease Circulation 2009;120:2577-85.4. Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmaco kinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27:1038-47.5. Husted S, van Giezen JJ. Ticagrelor: the first reversible binding oral P2Y12

receptor antagonist. Cardiovasc Ther 2009;27:259-74.6. Macaulay TE, Allen C, Ziada KM. Thrombin receptor antagonism – the potential of antiplatelet medication SCH530348. Expert Opin Pharmacother 2010;11:1015-22.7. Ueno M, Rao SV, Angiolillo DJ. Elinogrel: pharmacological principles, preclinical and early phase clinical testing. Future Cardiol 2010;6:445-53.8. Wallentin L. P2Y12 inhibitors: Differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J 2009;30:1964-77.

The mechanisms of the mortality benefit of ticagrelor therapy. Adenosine mediated mechanisms beyond antiplatelet effectVictor Serebruany, Towson, USA

victor Serebruany, Towson, USAProfessional Experience :2006 – present Associate Professor of Medicine, Johns Hopkins University2000 - present Owner, HeartDrug Research, LLCAwards and Honors:2002: Pfizer Established Investigator Award1991: Bristol-Myers Squibb Stipend1990: International Pediatric Nephrology Association Award1989: Bristol-Myers Squibb Young Investigator AwardProfessional Societies :American Medical AssociationAmerican Federation for Clinical ResearchAmerican Heart Association (Council for Arteriosclerosis,Thrombosis and Vascular Biology )International Society on Thrombosis and HaemostasisWorking Group on Cardiovascular Pharmacology, ESCWorking Group on Thrombosis, ESCConsultant :DAKO, PharMingen, Becton Dickinson, Pfizer, Bristol-Myers Squibb, Sanofi Aventis, Novartis, Boehringer Ingelheim, McNeil, Merck, Eisai, Cardax, Regado, Ikaria, XomaEditorial Boards: 8 Journals Reviewer : 22 JournalsResearch : over 50 projectsPatents: 12 issued or pending applicationsPublications: over 250 peer-reviewed

ABSTRACT

Objectives – To hypothetize on the potential mechanism explaining surprising mortality benefit of ticagrelor in the PLATO trial.Background - In PLATO, the mortality reduction (107 deaths) numerically exceeds the MI prevention benefit (89 events), making it a hitherto unmatchable achievement of tica-grelor over active comparator. If confirmed, such an impressive mortality advantage will be critical for the further success of ticagrelor to compensate for its otherwise unfavora-ble safety profile. In fact such an impressive survival represents an entirely unexpected benefit, which will serve as a key point in the drug approval process and subsequent use in clinical practice. Methods – Potential association of ticagrelor as a promoter of blood adenosine serving as adenosine agonist is assessed.Results - Multiple properties of adenosine, which can be closely matched with both clinical benefits, and adverse events after ticagrelor, suggest that this novel pyrimidine is not a pure antiplatelet agent. Unquestionably, ticagrelor potently inhibits platelet activity via established mechanism of P2Y12 receptor blockade, and probably chronically increasing blood adenosine levels, ultimately contributing to the vascular outcome benefit observed in PLATO. Conclusions - Future randomized trials of ticagrelor in acute heart failure, sudden death prevention, treatment of atrial fibrillation are warranted, and will expand our understanding of the potential role of adenosine in the outcome benefit after pyrimidines.

THURSDAY DECEMBER 2, 14:00 – 16:00

PLENARY SESSIoNoPTIMIZING THE RISK To BENEFIT RATIo WITH NEW REvERSIBLE ANTIPLATELET THERAPIES IN ACUTECoRoNARY SYNDRoMESChairmen: Dan ATAR, Oslo, NOR - Lars WALLENTIN, Uppsala, SWE

Dan Atar, oslo, NoR

Dan Atar, MD, (51) is Head of Cardiology B at Oslo University Hospital Ulleval, Oslo, Norway, and holds a full Professorship in Cardiology at the University of Oslo, Norway, along with a Visiting Associate Professorship at the Johns Hopkins Unversity, Baltimore, Maryland, USA.Dan Atar trained in Denmark, Switzerland, and the United States before receiving his board certification in Internal Medicine and Cardiology in 1995. His research fo-cuses on myocardial biomarkers, myocardial function, heart failure and cardiovas-cular pharmacology. He has written >100 articles and book chapters and holds the fellowship-titles FESC, FACC, and inaugural FAHA. Dan Atar is the past-Chair-man of the ESC Working Group-3 (Cardiovascular Pharmacology and Drug The-rapy), and Associate Editor of the international peer-reviewed journal “Cardiology” (Karger). He was on the writing committee for the 2007 ESC “Cardiovascular Di-sease Prevention Guideline”, the 2008 ESC “Guideline on acute and chronic Heart Failure”, the “2010 ESC Guideline on Atrial Fibrillation”, and serves on the ESC/AHA/ACC 2011 guideline “New Definition of Myocardial Infarction” and the ESC-2012 guideline on STEMI. He was chairing the FIRE.-trial, a multicenter study in patients with STEMI to reduce ischemia/reperfusion injury, published in 2009. Cur-rently he chairs the ARCTIC-AF trial as well as the TROPHOS/MITOCARE-clinical research consortium, a EU-FP7 grant to study reperfusion injury in pPCI.

Lars Wallentin, Uppsala, SWE

Lars Wallentin became the first Professor of Cardiology at Uppsala University Hos-pital, Uppsala, Sweden in 1991 and was Head of the Department of Cardiology from 1991 to 1999. He founded the Cardiothoracic Center at Uppsala, becoming its first Chairman in 1994 - 1995, and going on to serve as Vice Chairman from 1995 to 1999. In 1992 he started and became the first chairman of the Swedish Registry of Acute Cardiac Care (RIK-HIA). In 2001, Professor Wallentin founded the Uppsala Clinical Research Center, where was the first Director until 2008. In 2002, he founded and became the first Director of the First Swedish Competence Center for national Quality Registers in Health Care until 2008 which now is res-ponsible for more than 20 registries in different areas of health care in Sweden and internationally.

Over the last 20 years professor Wallentin has been the chairman and princi-pal investigator of many national and international clinical trials of new treatment concepts in cardiac diseases. Currently he is the chief researcher of cardiovascu-lar disease at UCR and the leader of several global clinical trials including more than 60.000 patients investigating not only concerning the effects of new phar-maceutical agents but also the genetic and biochemical basis for cardiovascular diseases.

The group of Lars Wallentin has developed many new concepts concerning pa-thogenesis, diagnosis, risk stratification, and antithrombotic and interventional treatments in acute coronary artery diseases. Over the last 20 years, they have pioneered the use of molecular biomarkers and new treatments concepts in acute coronary artery diseases.Prof Wallentin has published more than 350 papers in peer-reviewed international journals, in addition to a large numbers of other publications and book chapters and has received several prestigious research awards. He is a member of nume-rous research councils, medical societies, task forces, working groups and edito-rial boards, and is an expert for the Swedish Board of Health and Welfare. From 1998 to 1999, Professor Wallentin was President of the Swedish Cardiac Society, and from 2000 to 2002, he founded and served as President of the Swedish Heart Association. He has also got several prestigious research award and was in 2010 honored with the European Society of Cardiology Gold Medal for his outstanding contributions to the science and practice of cardiology.

Current guidelines and unmet needs in the management of thrombotic events in acute coronary syndromesNicolas Danchin, Paris, FRA

New reversible antiplatelet drugs. Pharmacology and potential advantagesSteen Husted, Arhus, DEN

Steen Husted, Arhus, DEN

Steen Husted is the chief of the Department of Medicine and Cardiology at Århus University Hospital in Århus, Denmark. He is also associate professor of Clinical Pharmacology at the University. Professor Husted served as president of the Da-nish Society on Thrombosis and Haemostasis 1993–1997, and remains an active member of the Board.

He is also a board member of the Danish Stroke Association, and participates in a number of working groups for the Danish Society of Cardiology and the European Society of Cardiology. Professor Husted is a member of the European Society of Cardiology’s task forces on antiplatelet therapy and anticoagulant therapy in heart patients, and was a co-author of the 2007 position paper for the latter entitled ‘Anticoagulants in heart disease: current status and perspectives’.His research interests include invasive and clinical cardiology, clinical pharmaco-logy (particularly antithrombotic drugs), platelet physiology and functions in throm-bosis formation, and animal models of thrombosis formation. He has published over 250 original and review articles in the areas of receptor pharmacology, cli-nical pharmacology of antithrombotic drugs, platelet function, clinical studies with antithrombotic drugs and haemostatic markers for vascular thrombosis. Professor Husted was the lead investigator for the DISPERSE trial, and a member of the executive steering committee for DISPERSE2. He currently serves as a member of the executive steering committee for the PLATO trial and at the moment in the steering committee for a number of phase 3 trials of antithrombotic drugs in acute coronary syndrome, atrial fibrillation and venous thromboembolism.


RECoMMENDED READING1. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Sto-rey RF, Harrington RA; the PLATO Investigators. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 361: 1045-1057.2. Jacobson KA, Mamedova L, Joshi BV, Besada P, Costanzi S. Molecular reco-gnition at adenine nucleotide (P2) receptors in platelets. Semin Thromb Hemost 2005;31:205-216.3. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27:1038-1047.4.Linden J. Molecular approach to adenosine receptors: receptor-mediated me-chanisms of tissue protection. Ann Rev Pharmacol Toxicol 2001; 41:775-787. 5.Fredholm BB, AP IJ, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001; 53:527-552.6.Jacobson KA. Introduction to adenosine receptors as therapeutic targets. Handb Exp Pharmacol 2009;193:1-24.

PLATelet inhibition and patient outcomes with ticagrelor or Clopidogrel (PLATo). Practical consideration.Lars Wallentin, Uppsala , SWE

ABSTRACTAcute coronary syndrome (ACS) remains one of the most common reasons for acute hos-pital care and mortality in developed countries, and its prevalence is rising in developing countries. Over the last 20 years, the rapid development of new and effective treatments has reduced short-term mortality by half and led to an increase in long-term survival in patients with ACS. (1-4)Platelet inhibition is since around 20 years a mainstay in the prevention of myocardial infarc-tion and death in patients with acute coronary syndrome.(1-4) Aspirin therapy yields consis-tent inhibition of platelet thromboxane A2 release. However, inhibiting this pathway only modestly attenuates platelet activation without any influence e.g. on ADP induced platelet activation. Aspirin treatment provides a relative reduction of the risk of myocardial infarction and death by 30 – 50 % as compared to placebo in patients with acute coronary syndrome. However, aspirin alone has no convincing effect on prevention of stent thrombosis. There-fore also other pathways needs to be inhibited in the highly prothrombotic of acute coronary syndrome. The P2Y12 receptor plays a major role in the ADP mediated amplification of platelet response regardless of the stimulus. Clopidogrel and Prasugrel are thienopyridine prodrugs acting on this receptor by almost identical active metabolites which irreversibly bind to the receptor. Slow and variable active metabolite generation leads to clopidogrel having a slow onset of action and wide inter-individual variability in the pharmacodynamic response.(5) However, as compared to aspirin alone, clopidogrel provides around a relative 20% reduction in myocardial infarction and also a substantial reduction in stent thrombosis in patients with acute coronay syndrome as shown in the CURE trial.(6) The thienopyridine prasugrel has a more efficient active metabolite generation than clopidogrel with a rapid onset of action, more pronounced platelet inhibition and no clinically important variability in response. These features therefore lead to a further around 20% reduction in myocardial infarction and around halving of the risk of stent thrombosis in the TRITON-TIMI 38 trial randomizing patients with acute coronary syndrome to prasugrel versus clopidogrel in asso-ciation with a planned PCI procedure.(7) However, both the addition of clopidogrel to aspirin and the use of prasugrel instead of clopidogrel was associated with a significant increase in major bleeding.(6-7)Ticagrelor, the first reversibly binding oral P2Y12 receptor antagonist, does not require metabolic activation, has a rapid onset of action, and can disassociate from the receptor, permitting restoration of platelet function without the need for production of new platelets. In pharmacodynamic studies, ticagrelor have demonstrated greater, more rapid, and more consistent ADP induced platelet inhibition as compared to clopidogrel and more rapid offset of action following cessation of therapy. In the PLATO Study 18 624 patients with acute co-ronary syndrome were randomized within 24 hours after symptom onset to ticagrelor versus clopidogrel. The results showed a 16% relative reduction of the composite of CV death, myocardial infarction and stroke, a 22 % reduction in total mortality and also a reduction in stent thrombosis. Ticagrelor was not associated with any increase in overall bleeding but during long-term treatment there were more non-procedural bleeding with ticagrelor. (8) In conclusion, several new alternatives providing more rapid and consistent platelet inhibition than clopidogrel are currently introduced for routine treatment of patients with acute coronary syndrome. These new treatments seem to provide additional benefits to the patients without undue increments in the risk of bleeding if used for the appropriate patients. Within the

next few years even more treatment alternatives might be available to even further improve outcomes of the large patient population with acute coronary syndrome.

RECoMMENDED READING1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for

the management of patients with unstable angina/non-ST-elevation myocardial infarction. Circulation 2007;116:803-77.

2. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myo-cardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collabo-ration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008;117:296-329.

3. Bassand JP, Hamm CW, Ardissino D, et al; for the Task Force for theDiagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syn-dromes of European Society of Cardiology. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598–1660.

4. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarc-tion of the European Society of Cardiology. Eur Heart J 2008;29:2909-45.

5. Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms ofaction and potential consequences for clinical use. Eur Heart J 2009;30:1964-77.

6. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes wi-thout ST-segment elevation. N Engl J Med 2001;345:494-502.

7. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. The New England journal of medicine. 2007 Nov 15;357(20):2001-15.

8. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndro-mes. The New England journal of medicine. 2009 Sep 10;361(11):1045-57.


ExPERT WoRKSHoP BIoMARKERS To GUIDE THERAPY IN HEART FAILURE PATIENTS. IS THE CoNCEPT PRovEN? Chairmen: Lawrence Fine, Bethesda, USA - Alain Cohen Solal, Paris, FRA

Lawrence J. Fine, Bethesda, USALawrence J. Fine, M.D., Dr. P.H. is the branch chief of the Clinical Applications and Prevention Branch in the Division of Cardiovascular Sciences at NHLBI. He is currently Project Officer of the SPRINT trial. Current scholarly interests range from the prevention of coronary heart disease, efficacy studies treatment of hypertension and heart failure, better methods for patient reported outcomes and effectiveness studies of evidence based cardiovascular medicine. Prior to NHLBIhe worked at the Office of Behavioral and Social Sciences Research, in the Office of the Director of NIH. . Between 1988 and 2001, Dr. Fine spent 14 years with the National Institute for Occupational Safety and Health, (NIOSH) as Acting Director of the Institute and as Director of the Division of Surveillance, Hazard Evaluations, and Field Studies (DSHEFS). NIOSH is one of the centers in the Centers for Disease Control and Prevention (CDC). Dr. Fine was the Director of the Occupational Health Program in the at the University Of Michigan School Of Public Health from 1985 to 1988. Prior to 1985 was on the faculties of the University of Michigan and the Harvard School of Public Health. He is board certified in Internal Medicine and Occupational Medicine.

Why do we need biomarkers in the heart failure patient?Stephan von Haehling, Berlin, GER

What to monitor? Defining the right biomarker to prompt actionJames Januzzi, Boston, USA

James Januzzi, Boston, USA

Dr. James Januzzi is an Associate Professor of Medicine at Harvard Medical School and Director of the Cardiac Intensive Care Unit at the Massachusetts General Hos-pital. After graduating as the top ranked student from New York Medical College in 1994, Dr. Januzzi completed training in Internal Medicine at the Brigham and Wo-men’s Hospital and Cardiology at the Massachusetts General Hospital. Dr. Januzzi joined the MGH staff in 2000.Dr. Januzzi has published more than 180 peer reviewed manuscripts, review arti-cles, and book chapters, with a main area of research in cardiac biomarker testing, where he has published two text books on the topic. Notably, Dr. Januzzi has made numerous seminal observations regarding applications of NT-proBNP for diagnosis, prognosis, and management of heart failure. He was the principal investigator of the PRIDE and ICON studies, which set world-wide standards for application of NT-proBNP for acute heart failure diagnosis and prognosis. Most recently Dr. Januzzi was the principal investigator of the PROTECT study of aggressive heart failure care guided by NT-proBNP, indicating value of biomarker “guided therapy” in patients with left ventricular systolic dysfunction.Dr. Januzzi is on the editorial board of numerous journals, and is the chairman of the heart failure section of the Universal Definition of MI task force. He participates in numerous educational committees for the American Heart Association and Ame-rican College of Cardiology, and is an internationally recognized speaker on the subject of biomarker testing.

ABSTRACT

Several biomarkers have been identified that may independently predict the likeli-hood for adverse cardiovascular outcome. However, although the fact that a bio-marker independently predicts risk is an important finding, the relevant challenge at present is to better understand the potential value of such a discovery. Can this biomarker inform decisions regarding the need to therapy adjustment? Can the risk predicted by this biomarker be reduced by such therapy adjustments? Can a candidate biomarker tell us about discrete pathophysiologies in heart failure, such as risk for ventricular remodeling or risk for arrhythmia? If so, we will we ultimately be using a panel of markers to “guide” therapy, rather than a single test? Although the possibility of “guided therapy” using natriuretic peptides is likely to be realized, the experience with BNP and NT-proBNP testing in heart failure therapy is a cautionary one with respect to novel biomarkers, as the story appears to be more complex than initially suspected: which patients should be “guided” with natriuretic peptides, and which are less likely to benefit? Is this a “one-size fits all” opportunity, or are some heart failure patients not benefited (e.g. HFpEF or el-derly patients)? Should we be focusing our therapeutic interventions in natriuretic peptide guided therapy on specific drug types, such as those with specific benefits such as that seen on remodeling due to application of aldosterone blockers? Are natriuretic peptides too non-specific in their pathophysiologic associations to be of value to “guide” therapy, once we begin to further identify markers that are more focused with respect to what they predict (e.g. sST2 or gal-3)?It is clear that while we have made progress, numerous advances are yet needed: candidate novel biomarkers must be vetted carefully above and beyond the gold standard already present, specifically BNP and NT-proBNP. If novel markers are no different than an updated BNP or NT-proBNP, little value is likely from them. On the other hand, if a novel biomarker is additively predictive of risk to that iden-tified by BNP or NT-proBNP, potential value is present, however the same stan-

dards that were applied for the natriuretic peptides must be met: what is this novel marker predicting, and what should we do about it? Can we change the risk?Some novel markers have been identified that are additively prognostic to natriu-retic peptides, and some (such as remodeling markers) have potential mechanistic associations that support a possible therapeutic response with drugs specifically targeting the pathophysiology leading to their release. However, most (if not all) novel biomarkers are far behind the natriuretic peptides with respect to the un-derstanding of their biology and pathophysiology. Focused efforts with the best leading candidates in the novel biomarker field are crucially important to optimize the likelihood for progress in this complex area.

RECoMMENDED READING1. Berger R, Moertl D, Peter S, et al. N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chro-nic heart failure a 3-arm, prospective, randomized pilot study. J Am Coll Cardiol 2010;55:645-53.2. Bhardwaj A, Rehman SU, Mohammed A, Baggish AL, Moore SA, Januzzi JL, Jr. Design and methods of the Pro-B Type Natriuretic Peptide Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study. Am Heart J 2010;159:532-8 e1.3. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol 2007;49:1733-9.4. Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53-60.5. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009;301:383-92.6. Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR, Januzzi JL. Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure. Eur J Heart Fail;12:826-32.7. Van Kimmenade RR, Januzzi JL, Jr., Ellinor PT, et al. Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol 2006;48:1217-24.8. Bayes-Genis A, Pascual-Figal D, Januzzi JL, et al. Soluble ST2 Monitoring Provides Additional Risk Stratification for Outpatients With Decompensated Heart Failure. Rev Esp Cardiol;63:1171-8.9. Shah RV, Januzzi JL, Jr. ST2: a novel remodeling biomarker in acute and chro-nic heart failure. Curr Heart Fail Rep;7:9-14.10. Rehman SU, Mueller T, Januzzi JL, Jr. Characteristics of the novel interleu-kin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol 2008;52:1458-65.11. Boisot S, Beede J, Isakson S, et al. Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure. J Card Fail 2008;14:732-8.

What is the evidence that biomarker guided therapy is useful?Hans Peter Brunner La Rocca, Maastricht, NED

Hans Peter Brunner La Rocca, Maastricht, NED

Study of medicine in Zurich, Switzerland: 1982-1988Training Internal Medicine: 1989-1994Training in Cardiology, University Hospital Zurich: 1994-1997Post-doc on interaction of neurohumoral systems at Baker Medical Research Institute and Alfred Hospital, Melbourne, Australia: 1997-1999Cardiologist and senior research fellow (heart failure and transplantation):


University Hospital Zurich, 1999-2002Head Heart Failure and Transplant Services: University Hospital Basel, Switzerland, 2002-2009Director of Heart Failure Clinic, Maastricht University Medical Centre, the Netherlands, since 2009Professor of Cardiology and Internal Medicine, Basel Switzerland 2008, Professor of Cardiology, Maastricht, the Netherlands 2010, Original publications in journals with IF: 109, reviews: 30, Selected publications: JAMA 2009;301:383-392. JACC 2001;37:1221-1227.Lancet 2007;370:1552-1559. Lancet 2005;366:921-929. EHJ 2007;28:719-725. AJRCCM 2009;180:346-352. Ann Intern Med 2006;145:497-505. Circ 2005;112:1106-1112. Citations app. 3’000; h-index 25Fellow of European Society of Cardiology

ABSTRACT

Current practice in treating heart failure (HF) patients is based on large randomized treatment trials, as reflected in current guidelines. However, there are several reasons why only considering guidelines may not be best for all patients. Thus, premises are not the same in all patients and most likely patients do not respond in a uniform way to therapy and a more individualized approach might be superior. As a consequence, the question arises if there are better approaches than to give “everything to everybody”. This is particularly relevant since treatment in many patients in clinical practice is not according to the guidelines, i.e. not all recommended therapy is used and if used often not in recommended doses. As reason, intolerability is often claimed and it seems very appealing to individually treat patients with the treatment that is best for them. In some ways, individualized medicine is already applied in HF management as it may depend on underlying cause (e.g. coronary artery disease), complications of HF (e.g. severe mitral regurgitation) and adverse events of therapy (e.g. renal failure) influence therapy, too. Also, prognostic factors are being used to guide therapy (e.g. indication for transplanta-tion by VO2max, LVEF for ICD-indication). However, the majority of the recommenda-tions does not depend on individual assessment. There are several factors not mentioned above related to prognosis in HF. These fac-tors are potential candidates to guide therapy based on the assumption – which does not necessarily have to be true – that positively influencing these factors also results in an improvement of prognosis. Among these prognostic factors, biomarkers are appea-ling candidates. Although the term “biomarker” is used in different ways, in the present context the understanding is that biomarkers refer to circulating molecules that represent neurohumoral stimulation, reflect tissue injury, inflammation or remodeling processes. Their advantage is the fact that they are not only linked to prognosis, but also play a role in the pathophysiology of the disease. Furthermore, they can be measured often relatively easy, not requiring invasive of potentially harmful procedures, require little time and are relatively cheap.However, until now, there is basically only one biomarker that plays a specific role in HF, i.e. B-type natriuretic peptide (BNP) or the N-terminal part of its precursor peptide (NT-proBNP). Its role in the diagnosis of acute dyspnoe and acute HF, respectively, is well established and it is also cost-effective in this setting to measure BNP or NT-proBNP. Moreover, after discharge from hospital or in the chronic setting they are superior to most other prognostic factors. In this context, it may be beneficial to measure BNP or NT-pro-BNP not only once, but to also see if it is possible to reduce their levels. Patients where this is not possible have a very poor prognosis and require special attention.Less clear is if such an approach may also be used to guide therapy, i.e. that (medical) therapy should be intensified based on repeated measurement of BNP or NT-proBNP (the approach of stopping uptitration or even reducing therapy based on BNP-results has not yet been tested). Several trials have addressed this prospectively. However, a large trial is still missing, since the largest study so far (TIME-CHF) included 499 patients only. Since not a single therapy was studied but different uptitration schemes of HF medication, direct comparisons are more difficult than with standard treatment trials. The results of the trials were somewhat controversial, although recent metanalyses revealed positive effects of this approach. This seems to be particularly true in the patients that were also included in the large treatment trials (i.e. patients <75 years of age with little co-morbidities). Thus, guiding therapy, i.e. uptitrating medical therapy, based on BNP or NT-proBNP levels cannot yet be generally recommended. Nevertheless, repeated measurement of BNP or NT-proBNP may help as a reminder to intensify therapy, parti-cularly in those showing highest risk based on these results.

RECoMMENDED READING1.Pfisterer M, Buser P, Rickli H, Gutmann M, Erne P, Rickenbacher P, Vuillomenet A, Je-ker U, Dubach P, Beer H, Yoon SI, Suter T, Osterhues HH, Schieber MM, Hilti P, Schin-

dler R, Brunner-La Rocca HP. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA. 2009;301:383-392.2.Maeder MT, Mueller C, Pfisterer ME, Buser PT, Brunner-La Rocca HP. Use of B-type natriuretic peptide outside of the emergency department. Int J Cardiol. 2008;127:5-16.3.Felker GM, Hasselblad V, Hernandez AF, O’Connor CM. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am Heart J. 2009;158:422-430.4.Lainchbury JG, Troughton RW, Strangman KM, Frampton CM, Pilbrow A, Yandle TG, Hamid AK, Nicholls MG, Richards AM. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol. 2010;55:53-60.5.Hlatky MA, Greenland P, Arnett DK, Ballantyne CM, Criqui MH, Elkind MS, Go AS, Harrell FE, Hong Y, Howard BV, Howard VJ, Hsue PY, Kramer CM, McConnell JP, Normand SL, O’Donnell CJ, Smith SC, Jr., Wilson PW. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Associa-tion. Circulation. 2009;119:2408-2416.6.Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardio-logy. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-2442.

DebateThe challenge of designing biomarker guided therapy trials. Optimization algorithms, endpoint and blinding issues, safety concerns.


ExPERT WoRKSHoP MYoCARDIAL INNERvATIoN IMAGING. FRoM PRoGNoSTI-CATIoN To GUIDING THERAPY Chairmen: Denis Agostini , Caen, FRA - Ileana Piña, Cleveland, USA

Denis Agostini , Caen, FRA

Titres Hospitalo-Universitaires2009. Vice-Doyen Faculté de Médecine Caen2008 : PU-PH 1ER C 2003-2008 : PU-PH 2nd C 2000-2002 : MCU-PH 1ère C 1996-1999 : MCU-PH 2ème C1993-1996 : AHU, Biophysique - Médecine Nucléaire, Caen1986-1991 : Internat, CHU CaenMobilité Nationale :1987-1988 : DEA de physiologie à Orsay1988-1989 : Service de Cardiologie, CHU MondorInternationale :1991-1993 : Post-Doc à Akita, Japon (TEP cardiologie) 1993 : Stages à Hammersmith, Bruxelles (TEP cardiologie)Diplômes2008 : PUPH 1er C 2003 : Professeur des Universités-Praticien Hospitalier (PUPH 2C, CNU 43-01)2000 : HDR, Université de Caen2000 : Thèse d’Université de Caen, option Médecin1999 : DES de Médecine Nucléaire1996 : Maîtrise de Biophysique1996 : DESC de Médecine Nucléaire1991 : Thèse de Médecine 1991 : DES de Cardiologie1987-1988 : DEA de Physiologie, Paris V-Orsay

Activité HospitalièreRéalisation des Epreuves d’effort (500/an)Interprétations des Scintigraphies Cardiaques (2400/an), pulmo¬naires et des TEP en oncologie (800/an)Activités de Recherche2009. Président du Comité Scientifique du CHU au sein de la DRCI2008 : Membre de l’équipe EA 3212 : Cœur et Ischémie de l’UFR de médecine, Caen 2007-2008 : Directeur des Investigations Humaines TEP et IRM à CYCERON2004-2007 :Directeur d’une Equipe d’Accueil EA 3916 de l’UCBN : Imagerie fonction-nelle et métabolique en oncologiePublications : n=62- à comité de lecture : anglais (39), français (23)- didactique et chapitres de livres : 16

Principales publications1 – Flotats A et al. Proposal for standardisation of 123-I-metaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM cardiovascular Committee and the European Council of Nuclear Cardiology. Eur J Nucl Med Mol Imaging 2010; 37:1802-1812.2 – Manrique A et al. Diagnostic and prognostic value of myocardial perfusion gated SPECT in orthotopic heart transplant recipients. J Nucl Cardiol 2010 ; 3 - Jacobson AF, Senior R, Cerqueira M et al. Myocardial iodine-123-meta-iodoben-zylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (Adreview myocardial imaging for risk evaluation inherit failure) study. J Am Coll Cardiol 2010 ;55:2212-22214 – Aide N et al. High throughput static and dyanmic small animal imaging using clinical PET/CT: potential preclinical applications. Eur J Nucl Med Mol Imaging 2010; online. 5 – Agostini D et al. How to use cardiac MIBG scintigraphy in chronic heart failure. Eur J Nucl Med Mol Imaging 2009; 36:555-559. 6 – Bax JJ et al..123 I-mIBG scintigraphy to predict inducibility of ventricular arrhyth-mias on cardiac electrophysiology testing: a prospective multicenter pilot study. Circ Cardiovasc Imaging. 2008 Sep;1(2):131-407 - Agostini D et al. Cardiac 123I-MIBG scintigraphy in heart failure. Q J Nucl Med Mol Imaging 2008; 52:369-377.8 – Manrique A et al. Prognostic value of sympathetic innervation and cardiac asyn-chrony in dilated cardiomyopathy. Eur J Nucl Med Mol Imaging 2008; 35:2074-2081.9 - Agostini D et al. I-123-MIBG myocardial for assessment of risk for a major cardiac event in heart failure : insights from a retrospective European multicenter study. Eur J Nucl Med Mol Imaging 2008; 35:535-546.10 - Verberne HJ et al. Variations in (123)-I-MIBG late heart mediastinal ratios in chro-nic heart failure : a need for standardization and validation. Eur J Nucl Med Mol Imaging 2008; 35: 547-553.11 – Hamon M et al. Prognostic impact of right ventricular involvement in patients with acute myocardial infaction: meta-analysis. Crit Care Med 2008; 36:2023-2033.12 – Hamon Mi et al. Diagnostic performance of 16-and 64-section spiral CT for coro-nary artery bypass graft assessment :meta-analysis. Radiology 2008;247:679-686.13 – Levy B et al. Impaired tissue perfusion : a pathology common to hypertension, obesity, and diabetes melllitus. Circulation 2008;118:968-976.2008 : Membre de l’Editor Board de l’EJNMMI Lecteur pour Heart, Arch Mal Cœur, Heart Disease and Heart Failure, J Nucl Med, Eur J Nucl Med, Eur J Heart Fail, Med Nucl Mol ImagSociétés Savantes2005 - 2007 Président du Groupe de Travail de la Société Française de Cardiologie Nucléaire et IRMMembre des : Société Internationale de Cardiologie Nucléaire (ICNC)Société de Biophysique et de Médecine NucléaireSociété Européenne de Médecine Nucléaire (EANM)Société Américaine de Médecine Nucléaire (SNM)

Myocardial imaging for assessment of cardiovascular risk in heart failure patients. From retrospective observations to pros-pective validation (ADMIRE-HF) Paolo G. Camici , London, GBR

MIBG myocardial imaging to predict ventricular arrhythmias and cardiac outcome.Arnold Jacobson, GE Healthcare, USA

Cardiac MIBG imaging guided therapy in heart failure patients. Time for a trial?

Ileana Piña, Cleveland, USA

Dr. Piña, a cardiologist and heart failure/transplant expert, received her MD at the Uni-versity of Miami in 1976. She continued her education and received her Masters of Pu-blic Health in 2009 after completing a 3 year Fellowship in Quality at the Cleveland VA. She has served as Director of the Exercise Laboratory at the University of Miami, of Heart Failure and Cardiac Rehabilitation at Hahnemann University, of Cardiomyopathy at Temple University and Heart Failure/Transplantation at University Hospitals Health System at Case Medical Center. Dr. Piña is the Principal Investigator of as well as has participated in many studies focused on improving heart failure and rehabilitation. She serves as an advisor/consultant to the US Food and Drug Administration’s (FDA) Center for Devices and Radiological Health and the Division of Epidemiology which allows her to assist in evaluation and review cardiovascular medical devices, epide-miologic research studies while working with the FDA staff. Dr. Piña is internationally recognized for her research in rehabilitation and recovery of heart failure patients. She has over 70 publications and is a world-renown speaker on this subject. She has been a recurrent presenter/speaker in the World Congress of Cardiology in Spain, Argentina, Berlin, and Beijing. She is also a National Spokes-person for Go Red for Women and the Heart Truth of Ohio in which she is dedicated to finding out why and coming up with solutions for women who suffer from Heart Disease, which will enable them to live healthier, longer, lives.In 1995, Dr. Piña established and initiated The National Heart Failure Training Program(N-Heft™) at Case Western Reserve University with Hector Ventura of Ochsner Medi-cal Center in New Orleans, Louisiana which is a program that seeks to educate physi-cians and other healthcare professionals in best practices for treating heart failure. Dr. Piña is a recipient of many Outstanding Service Awards and Best Doctors recogni-tion Awards 2010. She sits on numerous committees and chairs countless scientific sessions and meetings and is currently a member for the AHA (American Heart As-sociation) Writing Group Women’s Cardiovascular Diseases Prevention Guidelines. She also representes the AHA at the Electronic Health Inititaive (eHI) and AHRQ Task Force on Workplace.

Where are the unmet needs? What is the target population? Discussant: John Cleland, Hull, GBR

John Cleland, Hull, GBRDegrees & DiplomasM.B. Ch.B. with Commendation. 1977 M.R.C.P. / F.R.C.P. (Glasgow and London) 1980 / 1991 / 1994 M.D. / F.E.S.C. / F.A.C.C. 1990 / 1992 / 1995Current Post: Professor of Cardiology, University of Hull


1.Career Historya)Professor of Cardiology, University of Hull. 1999-b)Senior lecturer (BHF Funded), Clinical Research Initiative in Heart Failure, Glas-gow. 1994-98.c)Senior Lecturer in Cardiology, Hammersmith Hospital, London. 1989 – 1994.Past chairman of the Working Group on Heart Failure of the ESCFounding Editor of the European Journal of Heart Failure (an official journal of the ESC).Member of the data standards committee on heart failure for the AHA/ACC Task ForcePast-chairman of the British Society for Heart Failure

Selected Publications of original research or major reviews in journals with impact factor >9 since 20011.Cleland JG, Charlesworth A, Swedberg K et al. Comparison of the Effects of Carvedilol and Metoprolol on ‘Well-being’, Morbidity and Mortality (The Patient-Journey) in Patients with Heart Failure. JACC 2006; 47: 1603-16112.Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L, for the Cardiac Resynchronization – Heart Failure (CARE-HF) Study Investigators. The Effect of Cardiac Resynchronization on Morbidity and Mortality in Heart Failure. NEJM. 2005; 352: 1539-49.3.Cleland JG, Louis AA, Rigby AS, et al. Noninvasive home telemonitoring for patients with heart failure at high risk of recurrent admission and death: the Trans-European Network-Home-Care Management System (TEN-HMS) study. JACC. 2005;45:1654-64.4.Radford MJ, Arnold JM, Bennett SJ, Cinquegrani MP, Cleland JG, et al. ACC/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with chronic heart failure. Circulation. 2005;112:1888-916. 5.Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JG. Carvedi-lol alone or in combination with digoxin for atrial fibrillation in patients with heart failure? JACC 2003;42:1944-51.6.Cleland JGF, Pennell DJ, Ray SG, Coats AJ, MacFarlane PW, Murray GD, Dalle Mule J, Vered Z, Lahiri A, on behalf of the CHRISTMAS investigators. Myocardial viability as a determinant of the ejection fraction response to carvedilol in patients with heart failure. Lancet 2003; 362:14-21.7.Poole-Wilson PA, Swedberg K, Cleland JG, et al. Carvedilol Or Metoprolol Eu-ropean Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol Eu-ropean Trial (COMET). Lancet. 2003;362:7-13.8.Cleland JG, Cohen-Solal A, Aguilar JC, et al. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey. Lancet. 2002;360:1631-99.Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosi-mendan compared with dobutamine in severe low-output heart failure (the LIDO study). Lancet. 2002;360:196-20210.Cleland JG, Taylor J, Tendera M. Prognosis in heart failure with a normal ejec-tion fraction. NEJM 2007; 357:829-830.11.Kjekshus, E. Apetrei, V. Barrios, M. Bohm, Cleland JG et al. Rosuvastatin in Older Patients with Systolic Heart Failure. NEJM 357:ePub, 2007.12.Mozaffarian D, Anker S, Anand I, Linker DT, Sullivan MD, Cleland JG et al. Prediction of Mode of Death in Heart Failure: the Seattle Heart Failure Model. Circulation 2007; 116: 392-398. 13.Cleland JG, Freemantle N, Ghio S, et al Predicting the Long-Term Effects of Cardiac Resynchronisation Therapy on Mortality from Baseline Variables and the Early Response: A Report from the CARE-HF Trial. J Am Coll Cardiol 2008 Aug 5;52(6):438-45. 14.Torabi A, Cleland JGF, Khan NK, Loh PH, Clark AL, Alamgir F, Caplin JL, Rigby AS, Goode K. The timing of development and subsequent clinical course of heart failure after a myocardial infarction. Eur Heart J 2008 Apr;29(7):859-70.15.Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG for the WATCH Trial Investigators. Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Pa-tients With Chronic Heart Failure. The Warfarin and Antiplatelet Therapy in Chro-nic Heart Failure(WATCH) Trial. Circulation. 2009 Mar 31;119(12):1616-24.

Mechanistic plausibility: What medication for poor sympathetic neuronal integrity? Discussant: Bertram Pitt, Ann Arbor, USA

Bertram PITT, Ann Arbor – USA

Professor of Internal Medicine1949-53 B.S., Cornell University, New York,1953-59 M.D., University of Basel, Switzerland1959-60 Intern, Beth Israel Hospital, New YorkPositions and Honors.Postdoctoral Training1960-62 Assistant Resident, Beth Israel Hospital, Boston, Mass1961-62 Teaching Fellow in Medicine, Harvard,University Boston1962-63 Chief Resident, Medicine, Beth Israel Hospital, Boston, Mass1962-63 Assistant in Medicine, Harvard University Teaching Fellow in Medicine,Tufts University1966-67 National Heart Institute Special Fellow, Department of Medicine,Division of Cardiology, Johns Hopkins University Academic Appointments1967-68 Instructor in Medicine, Johns Hopkins University1968-72 Assistant Professor Medicine, Johns Hopkins University1972-77 Associate Professor of Medicine, Johns Hopkins University1977-91 Professor of Internal Medicine, Director, Division of Cardiology, Universityof Michigan School of Medicine1991-99 Professor of Internal Medicine, Associate Chairman for Academic andIndustrial Programs, Department of Internal Medicine, University of MichiganSchool of Medicine1999-Pres Professor Internal Medicine, University of Michigan School of MedicineHonors and Awards1976-66 Bronze Award, American Heart Association – Maryland Affi liate1977 Haille Selassie Lecturer, British Heart Foundation1978 Outstanding Cardiology Staff – University of Michigan2000 Johns Hopkins University Society of Scholars2001 Forest Dewey Dodrill Award for Excellence – American Heart Association2002 Paul Dekruif Lifetime Achievement Award – University of MichiganResearch Support.Co-Investigator, Angiotensin Receptor Blockade in Age Dependent EndothelialDysfunction (Prevailed II) – Understand the changes that occur in blood vesselsto develop strategies to combat cardiovascular disease –Novartis Co-Investigator, A multi-center, double-blind, randomized studyto evaluate the effects of valsartan and the combination of valsartan andsimvastatin on blood pressure (ambulatory and standard cuff) and on selectedbiochemical markers of endothelial function, safety and tolerability – To assessand compare the effects of valsartan, and the combination of valsartan andsimvastatin – Novartis

Clinically meaningful endpoints. What will convince the doctor? Discussant: James JANUZZI, Boston, USA

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PLENARY SESSIoNRISK GUIDED CARDIovASCULAR PREvENTIvE DRUG THERAPY.FRoM INDIvIDUAL RISK FACToRS To RISK SCoRINGChairmen: Luis Ruilope, Madrid, ESP - Faiez Zannad, Nancy, FRA

Luis Ruilope, Madrid, ESP

Ruilope is Associate Professor of Internal Medicine at Complutense University and Head of the Hypertension Unit at the 12 de Octubre Hospital in Madrid, Spain. His principal area of interest is hypertension and the kidney. Professor Ruilope recei-ved his MD degree from the University of Madrid and completed his residency and fellowship in nephrology at the Jiménez Díaz Foundation in Madrid.A member of the Scientific Council of the International Society of Hypertension and an International Fellow of the Council of High Blood Pressure Research, Professor Ruilope is on the editorial boards of the Journal of Hypertension, Blood Pressure, High Blood Pressure & Cardiovascular Prevention, Medicina Clinica, Nephrology Dialysis Transplantation, and the Journal of Human Hypertension.He is a board member of the Spanish Society of Hypertension and a member of the Council on the Kidney in Cardiovascular Disease (American Heart Associa-tion). He served on the ISH 2000 International Scientific Program Committee and was a member of the Steering Committee in the studies Hypertension Optimal Treatment (HOT), INtervention aS a Goal In HyperTension (INSIGHT), Study on Cognition and Prognosis in the Elderly (SCOPE), and Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE).

Faiez Zannad, Nancy, FRA

Faiez Zannad, MD, PhD is Professor of Therapeutics at the Medical Faculty of the Henri Poincaré University of Nancy. He obtained his MD as a Cardiology specialist in 1979 from the Faculté de Médecine de Nancy. In 1981 he served as a Research Fellow at the Clinical Pharmacology Medical Research Unit of Oxford University, UK and in 1986 he obtained his PhD in cardiovascular clinical pharmacology at the University of Lyon. He is currently Head of the Division of Heart Failure, Hyperten-sion and Preventive Cardiology/ department of Cardiovascular Disease of the aca-demic 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 at an INSERM Unit (U961, Cardiac Fibrosis, Stiffness and cardiovascular risk) at the Faculté de Médecine. He is national coordinator of the network of 15 Clinical Investigation Centres working in the cardiovascular field in France. He is coordinating a Joint Research Program on transition from Hypertension to Heart Failure, in the 6th FP EU funded Network Excellence “InGeniousHyperCare”. He conducts his research, in the area of physiopathology and pharmacotherapeutics of hypertension and heart failure. Dr Zannad is Past Chairman of the Board of the French Society of Hypertension, Fellow of the European Society of Cardiology (ESC), Chairman of the ESC Working group on pharmacology and drug therapy

as well as Board member of the ESC Heart Failure Association. He is currently Co- Editor in chief of Fundamental and Clinical Pharmacology, the official journal of the European Federation of Pharmacological Societies (EPHAR) and a member of the Editorial boards of a number of journals in the field of Cardiology, Hypertension and Cardiovascular Pharmacology. He has contributed more than 300 scientific publications and published several books on cardiovascular pharmacotherapy and on Heart Failure. He is chairman and organizer of several international mee-tings: “CardioVascular Clinical Trialists (CVCT) Forum and Workshop” (Cannes and Paris, with Bertram Pitt and Desmond Julian); “Acute Heart Failure Syndro-mes” (Cannes and Chicago, with Mihai Gheoghiade) and “Biomarkers in Heart Failure” (Cannes, with Kirkwood Adams). Dr. Zannad is involved in a number of major cardiovascular clinical trials, as a Principal Investigator and/or as a chair or member of several Steering Committees, Critical Event Committees and Data Safety and Monitoring Boards. : Executive Steering committee member: CIBIS 11, RALES VALIANT, RECOVER, MOXCON, EPHESUS,, EVEREST, AURORA, EXAMINE, ASTRONAUT, AXIOM-ACS, SERVE-HF, HF-ACTION; NECTAR-HF, PEARL-HF, ALBATROSS, REMINDRE, FOSIDIAL (Chairman), EMPHASIS-HF (Chairman) Steering Committee membership: APSI, FIRST, CIBIS I, ASCEND-HF, CAPRICORN, , Critical Event Committee: CAPRICORN, RESPECT, SCOUT, EchoCRT Data and Safety Monitoring Board HEAAL, ASPIRE.

Cardiovascular preventive drug therapy, advantages and limita-tions of the current paradigm.Heribert Schunkert, Lübeck, GER

Heribert Schunkert, Lübeck, GER

Heribert Schunkert, MD is Professor of Cardiology and Director of the Department of Internal Medicine at Universitätsklinikum, Lübeck. He is a graduate of Staat-sexamen, West Germany and Rheinisch-Westfälisch Technische Hochschule, Aachen, FRG. Dr. Schunkert completed a research fellowship in medicine at Bri-gham and Women’s Hospital, clinical fellowships in cardiology at Beth Israel Hos-pital and Universitätsklinikum, Regensburg, and interventional cardiology at Mas-sachusetts General Hospital. He was appointed to the faculty at Harvard Medical School before returning to Universitätsklinikum, Regensburg, where he attained the rank of Professor. Dr. Schunkert conducts research in the molecular biology and genetics of multifactorial cardiovascular disease and the induction of cellular growth by angiotensin II. He coordinates the EU sponsored project Cardiogenics and the BMBF sponsored project Atherogenomics within the NGFN to identify the genetic roots of myocardial infarction. He lists awards from the German Society of Cardiology, the German Society of Hypertension (has been elected in their board of directors), and the German Society of Preventive and Rehabilitative Medicine as well as the Travel , Research- and Heisenberg Grants from the Deutsche Fors-chungsgemeinschaft and Research Grants from the Bundesministerium für Fors-chung and Technologie. Professional society memberships include the Deutsche Gesellschaft für Innere Medizin, Deutsche Gesellschaft für Kardiologie - Herz- und Kreislaufforschung and the International Society of Hypertension. Dr. Schunkert serves on the editorial boards of Clinical and Experimental Hypertension, Cardio-vascular Drugs and Therapy, Basic Research in Cardiology, Pharmacogenetics and Genomics, European Heart Journal, Circulation Cardiovascular Genetics and is editor of Cardiovasc. He is the author of more than 300 publications in interna-tional journals.

ABSTRACT

The past three decades witnessed a constant decline in age-adjusted morbidity and mortality from coronary artery disease. In order to elucidate the causes of this steady decline, the multinational epidemiological study MONICA (monitoring trends and determinants in cardiovascular disease) was initiated in the 1970th. The main finding of this study was that a lower burden of traditional risk factors may explain only a part of the decreasing incidents of cardiovascular events. Another important factor was the steadily improving quality of early detection and better therapy of ST elevation and non-ST elevation myocardial infarctions. Sub-sequently, secondary prevention, largely based on management of cardiovascular risk factors, also improved over the last 30 years further decreasing the death-roll of cardiovascular disease.


However, there is still a substantial “residual burden” of cardiovascular morbidity and mortality. Indeed, cardiac and vascular diseases continue to be the leading causes of death worldwide. Therefore, there is urgent need to identify better pre-ventive strategies a) to slow down the epidemics of obesity and diabetes mellitus and b) the often inapparent development of atherosclerosis and left ventricular dysfunction. There is great hope that the recent success in identifying genetic fac-tors affecting these conditions may help to further elucidate the functional mecha-nisms leading to disease and thereby novel targets for better prevention and therapy.

The impact of recent clinical trials on the future of CvD assess-ment and risk management. Transition to “risk score guided” strategies

Wolfgang Koenig, Ulm, GER

Wolfgang Koenig, MD, PhD, FRCP, FESC, FACC, FAHA is a Professor of Me-dicine/Cardiology at the Department of Internal Medicine – II Cardiology at the University of Ulm Medical School, Ulm, Germany. He graduated from the Univer-sity of Munich and received his MD from the University of Heidelberg and his PhD from University of Ulm. He is Board certified in internal medicine, cardiology, and in intensive care medicine with special interest in interventional cardiology. He also trained in cardiovascular disease epidemiology and is a former Director of the WHO-MONICA Augsburg Myocardial Infarction Register. Previous Hospital Appointments include: Director of the ER 1995-2000; Deputy Director, Depart-ments of Internal Medicine 1995-2000; Director of the ICU 2003-2004, Director of Cardiovascular Laboratories 2004-2005. At present he serves as a Consultant in Cardiology, is the Director of the Cardiovascular Outpatient Clinics, the Preventive Cardiology Program, and the Clinical Cardiovascular Research Program (CTU). Dr. Koenig`s research interests involve the molecular basis of atherothrombo-genesis including genetics with particular interest in the interrelations between hemostasis, inflammation and atherothrombotic complications / type 2 diabetes, the metabolic syndrome, the clinical pharmacology of cardiovascular active com-pounds, and the clinical epidemiology of cardiovascular disorders, focusing on the identification and evaluation of new biomarkers for cardiometabolic diseases.Dr. Koenig has published more than 450 research papers and reviews in journals including Nature, NEJM, JAMA, The Lancet, Circulation, Diabetes, BMJ, ATVB, and the Eur Heart J. He is a member of the Editorial Board of Clinical Chemistry and Associate Editor of Atherosclerosis. In 1999, he served as a Visiting Profes-sor at the Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, USA. Presently he serves on the Steering Committee of various large international randomized clinical studies testing innovative targets in cardiovascular medicine.

ABSTRACT

The traditional perspective to management of cardiovascular diseases was based on the individual treatment of independent risk factors to certain targets derived from large scale randomized controlled clinical trials. During recent years this concept has changed to a global risk perspective using various scores like Fra-mingham Risk Score (FRS) or the European Society of Cardiology SCORE provi-ding 10 year absolute risk derived from complex algorithms based on results from representative epidemiological cohort studies. Although the integration of the individual risks from independent risk factors into a global risk reflecting a subject`s total risk certainly represents a major step forward, still to date we mainly advise to “treat to target” concerning elevated individual risk factors. The alternative would consist in an approach that takes into account the

absolute risk and proposes treatment according to the level of measured risk. Indeed, in several countries reimbursement of statin therapy is already based on the presence of a high risk score (either FRS > 20% or SCORE ≥ 5%) and ele-vated LDL-cholesterol. However, there are two main issues here to mention: First, all major scores are based on a limited number of risk factors and, second, the majority of clinical cardiovascular events are coming from those at intermediate or low risk, thus limiting a “risk score guided” strategy, relying purely on existing scores. Based on these shortcomings it has been suggested to include new risk markers, either blood biomarkers or markers of subclinical disease in the triage of subjects at risk for cardiovascular complications. The JUPITER trial represents an interesting and successful example of such an approach. Elevated C-reactive protein (CRP, > 2 mg/L) in the absence of elevated LDL-cholesterol (<130mg/dl) identified a high risk group which strongly benefited from treatment with rosuvas-tatin. This has been documented in the total study population as well as in various high risk groups like the elderly, those with chronic kidney disease, and those with FRS > 20% or SCORE ≥ 5%. Of note, similar risk reductions as in these groups could be demonstrated in those at intermediate risk based on FRS or the Reynolds Risk Score. Approval of rosuvastatin in Europe earlier this year, for the first time, is based on the presence of a high risk as defined above, even in the absence of elevated LDL-cholesterol. Patients after an acute coronary syndrome (ACS) represent a high risk group for a recurrent event. Recently, 5 year follow-up data of those who survived the first 6 months from GRACE (Global Registry of Acute Coronary Events) revealed a strikingly high risk in those with a high GRACE score. In ACS patients, using the TIMI Risk Score, it has been demonstrated, that those at high risk benefited most from anticoagulant or antiplatelet therapy, as well as from an early routine invasive therapy. Thus, risk scores can accurately predict short-term and long-term out-come in ACS patients but also in those with stable disease and identify those with most to gain from novel strategies and therapies.

RECoMMENDED READING1.Koenig W & Ridker PM. Rosuvastatin for primary prevention in patients with Eu-ropean systematic coronary risk evaluation risk ≥5% or Framingham risk >20%: post hoc analyses of the JUPITER trial requested by European health authorities. Eur Hear J 2010 (Epub)2.Morrow DA. Cardiovascular risk prediction in patients with stable and unstable coronary artery disease. Circulation 2010;121:2681-2691 3.Fox KAA et al. Underestimated und under-recognized: the late consequences of acute coronary syndrome (GRACE UK – Belgian Study). Eur Heart J 2010 (Epub)4.Bhatt DL et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;302:1350-1357

Clinical utility of biomarkers and bioimaging as tools to iden-tify patients who need drug therapy.

Matthias Lorenz, Frankfurt, GER

Matthias Lorenz (born 1970 in Schongau, Germany) studied Physics at Tübingen university from 1990-1992 and Medicine at Saarland and Heidelberg universities from 1992-2000. He received a doctoral degree in 2001, specialized in Neuro-logy in 2008 and received the Venia legendi for Neurology in 2009. He holds a degree in medical biometry and statistics (certificate of the German Region of the International Biometric Society). His scientific interests cover cardiovascular epidemiology and (neuro-) vascular ultrasound. His current position is senior physician at the Department for Neurology at Fran-kfurt University (Head: Prof. Helmuth Steinmetz). He is Principal Investigator of

the PROG-IMT project (Individual progression of carotid intima media thickness as a surrogate for vascular risk), a multinational project to assess the associa-tion between IMT progression and clinical endpoints in an individual data based metaanalysis.

Combined lipid lowering and blood pressure lowering in high risk patients. Rationale and design of the HoPE-3 trialEva Lonn, Hamilton, CAN

Eva Lonn, Hamilton, CAN

Dr. Lonn completed her training in Internal Medicine and Cardiology and a Re-search Fellowship at the University of Toronto and a Master of Science degree in Health Research Methodology, Department of Epidemiology and Biostatistics, at the McMaster University, in Hamilton.She is a Fellow of the Royal College of Physicians and Surgeons of Canada with certification in Internal Medicine and Cardiology and a Diplomate of the American Board of Internal Medicine with certification in Internal Medicine and Cardiovascu-lar diseases. She is currently Professor of Medicine at McMaster University and Director of the Vascular Research Imaging Laboratory at the Population Health Research Institute, McMaster University. Her research interests are in clinical trials in cardiovascular prevention, cardiovascular epidemiology and in ultrasound imaging in atherosclerosis. She has received numerous peer reviewed grants and industry contracts and has led several large international clinical trials in cardio-vascular prevention and in atherosclerosis (HOPE-2, HOPE-3, SECURE, STARR, GRACE) and was or is a member of the Steering Committee of additional large international trials (HOPE, ORIGIN, STABILITY, APOLLO). Dr. Lonn was a mem-ber of the Executive Committee of the Canadian Cardiovascular Society and is currently a member of the CCS Council and the Scientific Program Committee for the Canadian Cardiovascular Congress. Dr. Lonn has published over 350 peer re-viewed manuscripts, abstracts and book chapters and has presented at numerous national and international meetings. References:1. Lloyd-Jones DM, Leip EP, Larson MG, D’Agostino RB, Beiser A, Wilson PW, Wolf PA, Levy D. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113:791-798.2. Ford EA, Ajani UA, Croft JB, Critchley, Ja Labarthe DR, Kottke TE, Giles WH, Capewell S. Explaining the decline in coronary mortality in the United States between 1980 and 2000. N Engl J Med. 2007;356:2388–2398.3. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 coun-tries (the INTERHEART study): case-control study. Lancet. 2004;364:937-952. 4. O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL, Ryglewicz D, Czlonkowska A, Weimar C, Wang X, Yusuf S; on behalf of the INTERSTROKE in-vestigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376:112-123.5. Ford ES, Li C, Zhao G, Pearson WS, Capewell S. Trends in the prevalence of low risk factor burden for cardiovascular disease among United States adults. Circulation. 2009 29;120:1181-1188. Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ. 2002;324:1570-1577.Rose G. Strategy of prevention: lessons from cardiovascular disease. Br Med J 1981;282:1847–1851.6. Cholesterol Treatment Trialists’ (CTT) Collaborators Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Si-mes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117-125.

ABSTRACT

Background and Rationale: Cardiovascular disease (CVD) is the major cause of death and disability worldwide and most events are potentially preventable by re-ducing major CV risk factors. At present, intensive prevention efforts are generally directed at high-risk subjects, such as those with known CVD or with substantial elevations in CV risk factors. However, most CVD events occur in individuals wi-thout previous CV events and with average levels of risk factors, who have a very high lifetime risk of CVD (about 50% in men and 40% in women). At present, the approach to CV prevention in this population remains uncertain. Effective, safe, widely applicable and financially viable prevention strategies are needed. Lifestyle modifications could theoretically reduce risk, however clinical trials of lifestyle in-terventions alone have generally produced disappointing results, largely because sustainable and significant changes in risk factors are difficult to achieve. Choles-terol and blood pressure (BP) are major CV risk factors (account for >70% of the population attributable risk for CVD) and their relationship to CVD is continuous, extending well below average (“normal”) levels. Cholesterol and BP can be effec-tively and safely lowered with statins and with BP lowering drugs, shown also to substantially lower CV event rates within 5 years in high-risk people. However, to date there are only limited data in people at moderate risk. Therefore, the HOPE-3 trial will evaluate potent lipid modification with statin therapy and BP lowering with low dose combination antihypertensive therapy and their combination in a wide range of middle-aged people at intermediate (moderate) CV risk with average cho-lesterol and BP levels and who are all receiving structured lifestyle advice. Study Design: Study Population: Consenting women aged ≥ 65 years and men aged ≥55 years, with at least one CV risk factor in addition to age, no known CVD and wi-thout any clear indication or contraindication for statin and/or angiotensin receptor blockers (ARB) and thiazide diuretics (uncertainty principle) are eligible. Physi-cians will be reminded of local CVD prevention guidelines and lipids, glucose, liver function tests, muscle enzymes and BP will be measured prior to enrolment, to ensure that there is no indication or contraindication for these medications. Study Design: After a 4-week single blind active run-in phase individuals who tole-rate these therapies and have high adherence, will be randomized to rosuvastatin 10 mg/day (expected to lower LDL-C by about 2.0 mmol/L and to raise HDL-C by about 8%) or placebo and to candesartan/HCT 16/12.5 mg/day (expected to lower BP by about 12/8 mmHg) or placebo, utilizing a 2 x 2 factorial design. Participants will receive study medications for an average of 5 years. Study Outcomes: The primary study outcome is the composite of CV death, nonfa-tal myocardial infarction and nonfatal stroke. Effects on additional CV events and cost-effectiveness will also be evaluated, as well as effects on renal and cognitive function and quality of life. Participants’ safety will be carefully monitored. Sample Size: Based on effects on cholesterol and BP, each therapy alone is theo-retically expected to reduce events by about 30-35% and their combination by about 50%-60%. Accounting for non-adherence, drop-ins and the factorial study design and using a conservative approach, the trial is designed to recruit 12,500 study participants and will have 90% power to detect ≥30% proportional reduc-tions in risk for each arm of the factorial design and 90% power to detect ≥ 40% proportional reduction in risk for the combined rosuvastatin plus candesartan/HCT vs. double placebo comparison. The study will complete randomization before the end of 2010. Study Organization: The HOPE-3 trial is conducted 22 countries with representa-tion from North and South America, Western and Eastern Europe, India, China and other countries in the Far East, the Middle East and South Africa and is coordina-ted by the Population Health Research Institute, McMaster University, Canada.

Risk scoring. Beyond FraminghamJay Cohn, Minneapolis, USA

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FRIDAY DECEMBER 3, 08:30 – 10:30

ExPERT WoRKSHoPDEvICE THERAPY FoR MILD To MoDERATE HEART FAILUREChairmen: John Cleland, Hull, GBR; Jean Yves Le Heuzey, Paris, FRA

Jean Yves Le Heuzey, Paris, FRA Professor of CardiologyHôpital Européen Georges Pompidou - Université Paris V René Descartes France Jean-Yves LE HEUZEY, M.D., is Professor of Cardiology and head of the arrhythmia Department in Georges Pompidou Hospital, Paris. Professor LE HEUZEY obtained his medical degree from the University René Des-cartes in 1980 and spent a year of research training in Physiology at the University of Orsay, laboratory of compared Physiology. He became Professor of Cardiology in 1990 at Broussais Hospital.Professor LE HEUZEY has a long-standing research interest in the basic mechanisms of cardiac arrhythmias, coupled with clinical activity in arrhythmology. His dedicated re-search group addresses clinically relevant issues ranging from the cell level to patients management, with an emphasis on the mechanism of atrial arrhythmias. He has been chairman (2000-2001) of the Working Group on Arrhythmias of the French Society of Cardiology and treasurer of the European Heart Rhythm Association (EHRA, 2003-2005). He has served on a variety of national grant review committees, on boards and com-mittees of national and international clinical trials (CIBIS, ACTIVE, AF-CHF, RELY, SHIFT, recordAF, DIONYSOS), and as reviewer for a number of journals including European Heart Journal, Europace, Pacing and Clinical Electrophysiology (PACE) and Circulation.Professor Le Heuzey has given over 300 lectures including 100 lectures to internatio-nal audiences, written near 200 papers and appears on over 500 abstracts.

MADIT-CRT, RAFT and heart failure device trials. Accumulating evidenceJean Rouleau, Montreal, CAN

Jean Rouleau, Montreal, CAN

Named dean of the faculty of medicine of the University of Montreal in June 2003, Dr. Rouleau has first obtained his MD (cum laude) from the University of Ottawa in 1974 and obtained his FRCPC in Internal Medicine and in Cardiology following his training at McGill University. He won the McLaughlin Research Fellowship to the Cardiovas-cular Research Institute at the University of California at San Francisco and returned to Canada where he held a number of key positions in Medicine, Cardiology, Physiology and Pharmacology at McGill University, the University of Toronto and the University of Montreal.Dr. Rouleau is an accomplished clinical cardiologist, having served as Director of the Coronary Care Unit at the Montreal General Hospital, the Hopital du Sacré Coeur in Montreal, and most recently at the University Health Network in Toronto. He has also been Director of the Medical Intensive Care Unit of the Montreal Heart Institute and has served as Director of Cardiology at the University of Sherbrooke, as Associate Director of Research of the Medical ICU at the Montreal Heart Institute, and Director of cardio-logy and the cardiovascular program at the University Health Network and Mount-Sinaï Hospital of the University of Toronto. In addition, he is an excellent teacher having influenced a generation of students in both Cardiology and Medicine. In 1996-97 he won the Best Teacher of the Department of Medicine at the Montreal Heart Institute. He has also been a mentor to over 20 gra-duate and postgraduate research students who have come to study with him.He received the Exceptional Merit Award of the FRSQ, and has been Governor for

Quebec at the American College of Cardiology. He received the Confederation Com-memorative Medal of Canada in 1992, the Prestige Award from the Quebec Medical Association in 2009, and is the recipient of the CSCI/Royal College Henry Friesen Award for the year 2009. However, it is for his research accomplishments that Dr. Rouleau has been best reco-gnized in Canada and throughout the academic world. His research interests include: heart failure, post-infarction, ventricular remodelling, neurohormones, therapeutic inter-ventions, ventricular function and the development of heart failure post-infarction. His work has explored myocardial pathophysiology, pharmacology and molecular biology in animal models and human subjects, and has contributed greatly to our fundamental understanding of myocardial and endothelial function in human disease. He also chai-red the MRC Cardiovascular B Committee. He has made major contributions in clinical research, examining multiple aspects of investigation and intervention in human heart disease. His studies have resulted in 335 peer-reviewed publications in high impact journals, 7 book chapters and 292 published abstracts. For these research accomplis-hments, Dr. Rouleau was awarded the Career Research Achievement Award of the Canadian Cardiovascular Society in 1997, and the Annual Achievement Award from the Canadian Cardiovascular Society in 2005. He has served on several editorial com-mittees, including Circulation (Journal of the American Heart Association), the Cana-dian Medical Association Journal, and the Canadian Journal of Cardiology. He is also Member of the Governing Council, Canadian Institutes for Health Research (CIHR) since 2005, a member of the LCME/CACMS (American and Canadian Medical School Accreditation Committes). He is presently co-chairing the Academic Health Science Centres - National Task Force on Securing the Future of Canada’s Academic Health Sciences Centre. Finally, he is a member of the CIHR President’s Advirosy Board on Patient-Oriented Research.

CRT and ICD therapy: How early in the disease process? Johannes Holzmeister, Zurich, SUI

Johannes Holzmeister, Zurich, SUICardiac Device Program, Cardiology, University Hospital Zurich and Clinical Assistant Professor, Department of Internal Medicine, Division of Cardiovascular Medicine, Ohio State University, OH, USA and is serving as associate editor for cardiac devices for the European Heart Journal. Dr Holzmeister is co-principal investigator of the Echocardio-graphy-guided Cardiac Resynchronization Therapy (EchoCRT) trial, which is the first prospective randomized clinical trial to evaluate the impact of cardiac resynchronization therapy (CRT) in patients with advanced heart failure (NYHA Class III) and a narrow QRS, who show mechanical dyssynchrony as assessed by echocardiography. Another distinguishing feature of the study is that it is a transatlantic partnership between the US Food and Drug Administration and the European Economic Community. With 125 centres including 80 sites in Europe and Australia, and 1250 patients, it is currently one of the biggest ongoing medical device trials. The event-driven trial, which began in August 2008 and runs for approximately 3 years, aims to show that optimal medical therapy plus CRT reduces all-cause mortality, or first hospitalization for worsening heart failure, compared with optimal medical therapy alone. Dr Holzmeister is co-founder and member of the board of directors of Car-diorentis Ltd., a biopharmaceutical company developing and commercializing therapies for the treatment of heart failure focusing on the clinical develop-ment of the natriuretic peptide Ularitide.

DebateFrom trial to approval to guidelines and adoption. How device trials will stand the journey?

Weighing the level of evidence. Consistency, validity and mechanistic plausibility of trial results. Discussant HF: Kenneth Dickstein, Stavanger, NORDiscussant EP: Jean Yves Le Heuzey, Paris, FRA

Kenneth Dickstein, Stavanger, NoR

University of Bergen, Stavanger University Hospital, Stavanger, Norway.Kenneth Dickstein was born in Philadelphia and completed undergraduate education at the Univ. of Pennsylvania. He has medical degrees from the Univ. of London and the Royal College of Surgeons (1977). He was a research fellow at Harvard Medical School (1988-90) and received his PhD at the Univ. of Bergen in 1992. Dr. Dickstein is in charge of the coronary care unit at Stavanger University Hospital, professor of me-dicine at the Univ. of Bergen and coordinator for the medical student teaching program at the hospital. His primary focus is clinical research in heart failure and he is director of the research program at Stavanger Health Research Foundation. Professor Dickstein is Past-President of the Heart Failure Association of the European Society of Cardio-logy. He was Chairman of the Task Forces for both the ESC 2008 Guidelines on Heart Failure and the 2010 Focused Update of ESC guidelines on device therapy in heart failure. He is an active member of numerous editorial boards and steering committees. Prof. Dickstein has published over 250 scientific papers and held over 250 invited lec-tures at international venues. He resides with his wife and 2 sons on the west coast of Norway and spends most of his free time fly fishing.

Updating the guidelines. Have we hit the Ia target?Discussant EP: Malcolm Arnold, London, CANDiscussant HF: John Cleland, Hull, GBR

How to identify/refer patients eligible for device therapy? Can a “Get With The Guidelines” (GWTG) type initiative help?Discussant HF: Faiez Zannad, Nancy, FRA

FRIDAY DECEMBER 3, 08:30 - 10:30 AND 11:00 - 12:30

PLENARY SESSIoNTRIALS oF NEW ANTI-DIABETIC DRUGS A SHIFT IN PARADIGMChairmen: Angeles Alonso, Madrid, ESP - William C. Cushman, Memphis, USA

Angeles Alonso, Madrid, ESPI was born and raised in Madrid, Spain. In 1979 I graduated from the School of Medi-cine at the Universidad Autónoma de Madrid (SM-UAM) and later in 1991 I succes-sfully completed my Ph.D at the Faculty of Medicine. I began my clinical experience as a resident doctor in the Department of Cardiology at the Academic Hospital Puerta de Hierro (Madrid) where I went on to become a member of staff of the Department

of Cardiology Service in 1987 to the present date (Coronary Care Unit, Hospitalisation Unit-Out-office Unit). In 2000 I became a member of the Committee for Ethics and Clinical Investigation and a Member of the Committee for Mortality. I am an Honorary Professor at the Department of Medicine in Cardiology at SM-UAM and have also been Coordinator, Chairman and speaker of several post-degree Ph D Courses at the Aca-demic Hospital Puerta de Hierro de Madrid on Cardiovascular Topics: Hipertensión, Cardiac Emergencies and Heart Failure. I have been a member of the Spanish Society on Cardiology (SEC) since 1986, and an active member of several WGs. I was voted General Secretary of the SEC: 2001-2003 and President of the International Relations Department of the SEC and Member of the Editorial Committee of the Spanish Heart Journal.I have also been a Fellow of the European Society of Cardiology since 2001. At present I am a member of the nucleus of the WG of Cardiovascular Pharmacology and Drug Therapy, Congress Programm Committee (2010-2012), EuroObsevational Over-sight Committee and European Affairs Committee In terms of regulatory experience of the Scientific Advice Working Party of the EMA (2005 to date). My field of expertise is Heart Failure, Cardiovascular Pharmacology and CV Prevention.

William C. Cushman – USA

Dr. Cushman is Chief of the Preventive Medicine Section at the Veterans Affairs (VA) Medical Center in Memphis, Tennessee, the Lead Hypertension Consultant to Medical Service in Central Office of the Department of Veterans Affairs, and Professor of Pre-ventive Medicine, Medicine, and Physiology at the University of Tennessee College of Medicine. He was on the 2004 VA-DoD (Department of Defense) Hypertension Clinical Practice Guideline committee, the Executive Committee for the Seventh (2003) Joint National Committee Report on Prevention, Detection, Evaluation, and Treatment of Hypertension (JNC 7) and is currently on the JNC 8 Panel. In April 2010 Dr. Cus-hman received the John Blair Barnwell Award for outstanding achievement in clinical science, the U.S. Department of Veterans Affairs Clinical Science Research and Deve-lopment’s (CSR&D) highest honor for scientific achievementHe has been an investigator in many clinical studies relating to hypertension, diabetes, and lipid therapy. Dr. Cushman was the VA Principal Investigator for the Antihyperten-sive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a National Heart, Lung and Blood Institute (NHLBI) study comparing cardiovascular events from four major classes of antihypertensive agents in 42,418 patients. He is also Principal Investigator for the VA Clinical Center Network and Chair of the Blood Pressure Wor-king Group of the NHLBI-sponsored Action to Control Cardiovascular Risk in Diabe-tes (ACCORD) trial (2000-2010) and Principal Investigator for the VA Clinical Center Network and Chair of the Intervention Subcommittee of the NHLBI-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) (2009-2018).

What to expect from a new anti-diabetic drug? Endpoint related issues

HbA1 C, a failed surrogate?William C. Cushman, USA

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Micro vs. macrovascular disease progression endpointsPeter Sleight, Oxford, GBR

Peter Sleight, oxford, GBR

Peter Sleight has worked in Oxford since 1964. He was Field Marshal Alexander Pro-fessor of Cardiovascular Medicine in Oxford until 1994, but continues to work as an honorary consultant cardiologist at the John Radcliffe Hospital. He chaired/co-chared the ISIS 1-4, HOPE, & HPS SEARCH, ONTARGET, & TRANSCEND studies. He serves on several DSMBs of large clinical trials.He has a longstanding interest in cardiovascular physiology, particularly on reflex control mechanisms. Since 1992 he has also worked regularly on this subject at the University of Pavia.Awards: Mackenzie Medal, British Cardiac Society. 2004 – Louis Bishop Lecturer American College of Cardiology; 2005 – Alberto Zanchetti Lifetime Achievement Award, Euro-pean Society of Hypertension; 2005 – Lifetime Research Award, Russian Federation of Car-diology 2008 – International Lecturer, American College of Cardiology; 2010 - Gold Medal Eur. Soc. Cardiology

ABSTRACT

I did not choose this title, which however is an interesting question.It is not easy to be certain when these two endpoints were first used together in the analysis of the results of randomised clinical trials. Certainly the sort of trials analysed by the Blood Pressure Lowering Treatment Trials Collaboration (BPLTTC) used only harder (macrovascular) endpoints such as all-cause mortality, cardiovascular death, myocardial infarction, or stroke. All cause mortality is not usually used as a primary endpoint in these trials since it includes many events which are unrelated to bloodpressure lowering, so cardiovascular mortality is preferred since this requires fewer enrolled subjects.The more recent use of microvascular endpoints probably arose because in current trials of BP lowering it is not easy ethically to use a placebo, so a newer agent is com-pared with an older drug. This naturally means that very many more subjects would need to be enrolled, or the trial duration prolonged, in order to achieve a statistically significant result. Either or both of these would render a proposed trial impractical, and/or prohibitively expensive.One problem of using microvascular endpoints is that in practice the choices of these differ between different trials. For example the UKPDS study used a combination of microvascular endpoints - retinopathy requiring photocoagulation, vitreous haemor-rhage, and fatal or non-fatal renal failure. On the other hand the ADVANCE study (Indapamide+Perindopril vs (“Placebo”) used worsening nephropathy (including just albuminuria), and retinopathy (of several types).Another problem is that microvascular endpoints such as albuminuria may not have as much prognostic significance as had previously been thought. This might be because this marker takes longer to impact on hard endpoint such as mortality, & so seems less predictive of harm in trials which are of short duration. The mean time to an endpoint in a 5 year trial is only 2.5 years. In the UKPDS study albuminuria took from 5-8 years to become predictive.In conclusion, although microvascular endpoints may be interesting (and predictive in the longer term) they carry much less clinical (as opposed to statistical) weight.

RECoMMENDED READING1.CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting pa-rallel group randomised trials 2.BMJ. 2010; 340: c869. Published online 2010 March 23.3.Reporting of Methodologic Information on Trial Registries for Quality Assessment: A Study of Trial Records Retrieved from the WHO Search Portal4.Ludovic Reveiz,1* An-Wen Chan,2 Karmela Krleža-Jerić,3 Carlos Eduardo Grana-dos,4 Mariona Pinart,5 Itziar Etxeandia,6 Diego Rada,7 Monserrat Martinez,8 Xavier Bonfill,9 and Andrés Felipe Cardona105.PLoS One. 2010; 5(8): e12484 The 2008 Canadian Hypertension Education Pro-gram recommendations for the management of hypertension: Part 2 – therapyNadia A Khan, Brenda Hemmelgarn, Robert J Herman, Simon W Rabkin, Finlay A McAlister, Chaim M Bell, Rhian M Touyz, Raj Padwal, Lawrence A Leiter, Jeff L Ma-hon, Michael D Hill, Pierre Larochelle, Ross D Feldman, Ernesto L Schiffrin, Norman RC Campbell, Malcolm O Arnold, Gordon Moe, Tavis S Campbell, Alain Milot, James A Stone, Charlotte Jones, Richard I Ogilvie, Pavel Hamet, George Fodor, George Car-ruthers, Kevin D Burns, Marcel Ruzicka, Jacques deChamplain, George Pylypchuk, Robert Petrella, Jean-Martin Boulanger, Luc Trudeau, Robert A Hegele, Vincent Woo, Phil McFarlane, Michel Vallée, Jonathan Howlett, Peter Katzmarzyk, Sheldon Tobe, Richard Z Lewanczuk, and for the Canadian Hypertension Education ProgramCan J Cardiol. 2008 June; 24(6): 465–475.6.Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2diabetes mellitus (the ADVANCE Trial): a randomised controlled trial. Patel A, ADVANCE Collaborative GroupLancet 2007; 370:829–8407.Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Dia-betes: New results from the ADVANCE trialSophia Zoungas, Bastiaan E. de Galan, Toshiharu Ninomiya, Diederick Grobbee, Pa-vel Hamet, Simon Heller, Stephen MacMahon, Michel Marre, Bruce Neal, Anushka Pa-tel, Mark Woodward, John Chalmers, and on behalf of the ADVANCE Collaborative Group8.Diabetes Care. 2009 November; 32(11): 2068–2074. Published online 2009.9.Association of systolic blood pressure with macrovascular and microvascular compli-cations of type 2 diabetes (UKPDS 36): prospective observational study. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD,Turner RC, Holman RR.BMJ 2000;321:412– 41910.Effects of intensive glucose lowering in type 2 diabetes11.Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT.N Engl J Med 2008 358: 2545–255912.Hypertension and Diabetes: Should We Treat Early Surrogates? What are the cons?Nilsson PM13.DIABETES CARE, VOLUME 32, SUPPLEMENT 2 S290-3 2009

Hard endpoints: MACE and MortalityJohn McMurray, Glasgow, GBR

John McMurray, Glasgow, GBR

Professor John McMurray, FESC, is Professor of Medical Cardiology at the University of Glasgow, Deputy Director of the Glasgow British Heart Foundation Research centre and Head of the Section of Academic Cardiology at the University. He is also Lead Consultant Cardiologist at the Western Infirmary, Glasgow. Professor McMurray is currently on sabba-tical as the inaugural Eugene Braunwald Scholar in Cardiovascular Disease at the Brigham and Women’s Hospital, Boston and visiting Professor of Medicine, Harvard University, Bos

ton, Massachusetts USA. He is immediate Past-President of the Heart Failure Association of the European Society of Cardiology (HFA of the ESC). His primary research interests are in heart failure, coronary heart disease, diabetes and atrial fibrillation, with a focus on clinical trials, epidemiology and health-services research. He also has an interest in socioeconomic determinants of health and outcomes. Professor McMurray is, or was, the principal inves-tigator, member of the executive committee or steering committee member in a number of large trials in heart failure and other cardiovascular diseases. He has also run or participated in a number of end-point and safety committees. He has published approximately 400 origi-nal papers, reviews and book-chapters and is the primary author or editor of thirteen books. He was the lead author of the WHO and first SIGN guidelines on the management of heart failure, member of the 2008 ESC heart failure guideline Task-Force and Chair of the 2012 Task-Force. Professor McMurray sits on the Editorial Board of several leading cardiovascu-lar journals, including the European Heart Journal and European journal of Heart failure. The metabolic memory of HbA1c, how useful as a surrogate?Hans Wedel, Gothenburg, SWE

Hans Wedel, Gothenburg, SWEI was born 1940. I have been professor in Epidemiology and Biostatistics at the Nordic School of Public Health, Gothenburg, Sweden since 1982 and I am professor emeritus since 2008. For six years I was a member of the prioritising group for Epidemiology and Social Medicine at the Swedish Medical Research Council. I have been president of the Swedish Epidemiological Society and the Swedish Society of Biostatistics. I was educa-ted as a statistician at Gothenburg University. My special research areas are cardiovas-cular epidemiology and clinical trials in cardiovascular medicine. During 1979-80 I was a visiting-scientist at Biostatistics Branch, NHLBI, Bethesda, Maryland. In 1993 I had a sab-batical year partly at University of Wisconsin, Madison and partly at Stanford University. I have been on the Steering Committee or DSMB for several large clinical trials. I was the statistician on the Steering Committee for HAPPY, MIAMI, HOT, 4S, MERIT, CONSEN-SUS-2, OPTIMAAL, LIFE, DIGAMI I+II, ASCOT, CORONA and ALECARDIO.I was a member of the DSMB for STOP-I, STOP-II, ATLAS, FRISCII, LOWASA, IDEAL, ALERT, EXPRESS, CARE-HF, ESSENTIAL, HEAAL, DIRECT, AURORA, SCAST, NOCTET, DOT-HF and AMPLIFY. My reference list consists of more than 200 scientific publications. During the period 2002-2009 I have been co-author in 87scientific peer reviewed papers. Three of these have been published in New England Journal of Medicine, 5 in Lancet and 2 in JAMA.

DebateAre the current megatrials addressing the unmet needs?

FRIDAY DECEMBER 3, 11:00 - 12:30

ExPERT WoRKSHoPMANAGEMENT oF HEART FAILURE PATIENTS GUIDED BY REMoTE HEMoDYNAMIC MoNIToRING. IS THE CoNCEPT PRovEN?Chairmen: Martin Cowie, London, GBR - William Abraham, Columbus, USA Why do we need telemonitoring solutions for the heart failure patient?Martin Cowie, London, GBR -

Martin Cowie, London, GBR

Professor Martin Cowie is Professor of Cardiology at the National Heart & Lung Insti-tute, Imperial College, London, UK and Honorary Consultant Cardiologist at the Royal Brompton Hospital, London. A founding member and past-chairman of the British So-ciety for Heart Failure, Professor Cowie has also been a Board member (and Chair of the Education Committee) of the Heart Failure Association of the European Society of Cardiology (ESC). He advises the National Institute for Clinical Excellence (NICE) on the management of chronic heart failure, and the Quality Care Commission on its heart failure audit work. He sits on the Cardiovascular Round Table and the EU Affairs Committee of the European Society of Cardiology.Professor Cowie’s studies and reviews have been featured in a variety of peer-reviewed journals, including The Lancet, European Heart Journal, British Medical Journal, Heart, European Journal of Heart Failure, J American College of Cardiology and Journal of Cardiac Failure. He is a member of the editorial board of Heart, The British Journal of Diabetes and Vascular Diseases, and Cardiovascular Diabetology. He has contributed chapters to many books, and has written a book for patients entitled ‘Living with Heart Failure – a guide for patients’. His research interests centre on remote monitoring and new diagnostic and treatment technologies.

ABSTRACT

Multidisciplinary disease management programs have developed to optimise the management of chronic conditions, such as heart failure (HF). Such programs are often co-ordinated by a nurse specialist in secondary care. They provide education to facilitate self-care (including self-monitoring), ensure appropriate up-titration of drug therapy, and facilitate collaboration within the multiprofessional team. They have been shown in many randomised trials to reduce the risk of hospitalisation and mortality compared with the traditional approach of periodic clinic review after a hospitalisation,1 and are recommended in international guidelines.2 The typical HF patient is elderly, often with decreased mobility and social support. This can make clinic attendance difficult. Local review by the family doctor can be easier, but the primary care team may lack the specialist knowledge and experience to monitor the HF optimally. Home visits by a specialist nurse are helpful, but are expensive, and few healthcare systems can provide this for any length of time.Telehealth (‘healthcare at a distance’) has the potential to widen access to high-quality disease management. As part of this, telemonitoring (TM) has developed rapidly in the past decade.3There is increasing evidence that remote monitoring of heart failure patients using information technology can help improve the outcome and experience of care.4 Integrating such TM into existing healthcare practice is challenging, not least because of the change in working practice for healthcare professionals. The monitoring technology varies from simple to complex, but data transmission to the healthcare team is straightforward. The best method of displaying the data to ensure the most appropriate decision making is yet to be determined, as is the best combination of variables to monitor. Patient acceptability is rarely a problem, but reimbursement is often a barrier to implementation.The signs and symptoms of deterioration of HF are typically increasing fluid re-tention, breathlessness, and effort intolerance. In many, but not all, patients and episodes deterioration is gradual and it should be possible to detect such decom-pensation. The ideal variable to monitor would be simple and convenient to measure, repro-ducible, sensitive and specific to changes in the control of heart failure, and would change sufficiently rapidly to give an early warning of deterioration. No such va-riable has been identified, and in practice several measurements are relied upon. Increasingly, commercial platforms integrate information from multiple variables to provide a ‘risk indicator’ for the healthcare professional, allowing them to triage patients into low, medium and high risk categories. This prevents the healthcare professional being swamped with data, and assists them in the accurate identifi-cation of patients who require attention. Not all patients will require remote monitoring continuously. Most programmes have focused on higher-risk individuals – particularly those recently hospitalised, or those with severe symptoms. It is perhaps surprising that remote access to data and expertise has taken so long to take off in healthcare: this is likely to change rapidly in the coming decade, at least for the increasing number of people living with HF in Europe.


RECoMMENDED READING1.Roccaforte R, Demers C, Baldassarre F et al. Effectiveness of comprehensive di-sease management programmes in imporving clinical outcomes in heart failure pa-tients. Eur J Heart Failure 2005; 7: 1133-44.2.Dickstein K, Cohen-Solal A, Filippatos G et al. European Society of Cardiology Gui-delines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2008; 29: 2388-2442.3.Riley JP, Cowie MR. Telemonitoring in heart failure. Heart 2009; 95: 1964-8.4.Inglis SC, Clark RA, McAlister FA et al. Structured telephone support or telemonito-ring programmes for patients with chronic heart failure. Cochrane Database Syst Rev 2010 Aug 4; 8: CD007228.

What to monitor? Defining the right signals which would prompt action. A review of the existing monitoring devices.Haran Burri, Geneva, SUI

Haran Burri, Geneva, SUIAssociate Professor Electrophysiology Unit, Cardiology Service, University Hospital of Geneva, Switzerland Qualifications: FMH in Cardiology (Switzerland), European Heart Rhythm Association, (EHRA) competency in Cardiac pacing and in Electrophysiology Clinical activity: Cardiac pacing (pacemakers, ICD and CRT implantation and follow-up, lead extractions); Catheter radiofrequency ablation; Echocardiography Academic activity: Privat Docent and Chargé de Cours at the Medical Faculty of the University of Geneva, > 70 publications (scientific journals and book chapters) and >100 abstractsMain focus of research: Cardiac Pacing and Resynchronisation Therapy, Remote Monitoring Board membership: Swiss working group on cardiac pacing and electrophysiology, EHRA Education board, EHRA Health Economics board

ABSTRACT

Heart failure is associated with high patient mortality and morbidity, and is a major bur-den on the healthcare system. Remote monitoring of these patients has the potential to prevent cardiac decompensation leading to hospitalization. Randomized studies such as TENS-HMS trial1 have evaluated the utility of remotely monitoring parameters such as blood pressure and body weight, with encouraging results in terms of reduction of hospital stay and mortality, but results of such trials have been unequivocal. Many heart failure patients also qualify for cardiac resynchronization therapy and implantable cardioverter defibrillators, that have automatic wireless remote monitoring capabili-ties.2 In addition to monitoring cardiac arrhythmias, these devices are able to track a number of heart failure parameters such as heart rate, heart rate variability, respiratory rate, and lung fluid overload. The interpretation of these parameters in individual pa-tients may be difficult, and their efficacy in improving patient outcome in the setting of remote monitoring remains to be firmly established by trials such as MORE-CARE.3 Nevertheless, it is likely that evaluation of these parameters, especially when combined together,4 may serve to risk stratify patients and guide their clinical management. Ad-ditionally, technological advances have been made in miniaturizing pressure sensors that can be implanted in the right ventricle, the left atrium (via a transseptal puncture), or in the pulmonary artery. Initial results of trials such as HOMEOSTASIS5 have shown promising results in terms of reduction of heart failure hospitalization. Physicians involved with remote monitoring of heart failure patients are faced with the difficulty of making clinical decisions without having the benefit of being able to inter-rogate and examine their patients in person. The different parameters outlined above may indeed prove to be useful to guide decisions, but the interpretation of these signals needs to be better defined before they can be applied to routine clinical practice.

RECoMMENDED READING1. Cleland JGF, Louis AA, Rigby AS, et al. Noninvasive Home Telemonitoring for Pa-tients With Heart Failure at High Risk of Recurrent Admission and Death: The Trans-European Network-Home-Care Management System (TEN-HMS) study. Journal of the American College of Cardiology 2005;45:1654-64.2. Burri H, Senouf D. Remote monitoring and follow-up of pacemakers and implantable cardioverter defibrillators. Europace 2009;11:701-9.3. Burri H, Quesada A, Ricci RP, et al. The MOnitoring Resynchronization dEvices and CARdiac patiEnts (MORE-CARE) study: rationale and design. Am Heart J 2010;160:42-8.4. Whellan DJ, Ousdigian KT, Al-Khatib SM, et al. Combined heart failure device dia-gnostics identify patients at higher risk of subsequent heart failure hospitalizations:

results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) study. J Am Coll Cardiol 2010;55:1803-10.5. Ritzema J, Melton IC, Richards AM, et al. Direct Left Atrial Pressure Monitoring in Ambulatory Heart Failure Patients: Initial Experience With a New Permanent Implanta-ble Device. Circulation 2007;116:2952-9.

Who should deal with the telemonitoring information? Practical issues.Carlos Morais, Amadora, POR

Criteria for trial validation of telemedicine devices for heart failure patients? Critical appraisal of recent and ongoing trials (CoMPASS; DoT-HF; DECoDE; PARTNERS-HF; PRECEDE-HF; SENSE-HF; TELE-HF)David Whellan, Philadelphia, USA

David Whellan, Philadelphia, USADavid J. Whellan, MD, is Associate Professor of Medicine in the Division of Cardio-logy at Jefferson Medical College and Director of the Jefferson Coordinatint Center for Clinical Research.( http://www.jefferson.edu/jmc/medicine/coordinating_center/ ), an academic research organization.He received his BS from the University of Pennsylvania, his Master of Health Sciences from Duke University, and MD degree from Washington University School of Medicine. He is board certified in internal medicine and cardiology. He completed a residency in Medicine at the Hospital of the University of Pennsylvania and a fellowship in Clinical Cardiology at Duke University and the Duke Clinical Research Institute. Dr. Whellan has participated in the design and implementation of a number of multi-center clinical trials. He was the Co-Principal Investigator of the HF-ACTION study, a $37 million National Heart, Lung, and Blood Institute grant for research in heart failure and exercise training and the Principal Investigator for the PARTNERS HF, which eva-luated the ability of device diagnostics to predict future clinical events. He currently sits on the steering committee for the ASCEND and TRACER-ACS trials.He has published over 80 peer reviewed manuscripts. In addition, he is an associate editor for American Heart Journal; and a reviewer for Archives of Internal Medicine, Medical Care, and American Journal of Cardiology.

ABSTRACT

Background The goals of heart failure disease management (HFDM) programs are to improve outcomes and reduce resource utilization through the implementation of novel care processes. HFDM consists of providing multidisciplinary interventions such as intensive self management counseling, pharmacological management by protocol, device based diagnostics, communication with specialized HF physicians and HF tele-phone-directed care. Studies evaluating HFDM have provided inconsistent benefits for HF patients. Newer generation implantable devices provide continuous monitoring of HF patients. Recent clinical trials evaluating the potential use of device diagnostic data as part of HFDM intervention have clinical trials strategies including remote monito-ring (telemonitoring) and device based managements. The PARTNERS, COMPASS, CHAMPION, and REDUCE studies published both positive and negative results and newer studies such as TELE- HF and SENSE-HF are ongoing. TELE-HF, the most recent study of non-device HFDM intervention using voice response technology Critical issues in trial design and criteria, including subject risk, usual care, intervention intensity and outcomes for trials, need to be considered when evaluating clinical trials in remote monitoring. The goal of this presentation is to generate discussion on whether a standard clinical design should be implemented in the disease management of HF patient with remote hemodynamic monitoring.

RECoMMENDED READING1. David J. Whellan, MD, MHS et al: Combined Heart Failure Device Diagnostics Identify Patients at Higher Risk of Subsequent Heart Failure Hospitalizations Re-sults From PARTNERS HF (Program toAccess and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) Study. (J Am Coll Cardiol 2010;55:1803–10)2. Robert C. Bourge, William T. Abraham et al: Randomized Controlled Trial of an Implantable Continuous Hemodynamic Monitor inpatients with Advanced Heart Failure( The COMPASS-HF Study. J. Am. Coll. Cardiol. 2008;51;1073-10793. Phillip Adamson, MD, FACC, William T Abraham, MD. CardioMEMS Heart Sen-sor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) Trial Rationale and Design: The Long-Term Safety and Clinical Efficacy of a Wireless Pulmonary Artery Pressure Monitoring System. J Cardiac Fail 2010;1-84. Martin R. Cowie, MD, Vivanne Conraads, MD, Rationale and Design of a Pros-pective Trial to Assess the Sensitivity and Positive Predictive Value of Implantable Intrathoracic Impedance Monitoring in the Prediction of Heart Failure Hospitaliza-tions: The SENSE-HF Study. J Cardiac Fail 2009;15:394e4005. Sarwat I. Chaudry, MD, Barbara Barton , RN, MPH. Randomized Trial of Tele-monitoring to Improve Heart Failure Outcomes (Tele-HF): Study Design . J Car-diac Fail 2007;13:709e714 6. Frieder Braunschweig, Ian Ford. Can monitoring of intrathoracic impedance reduce morbidity and mortality in patients with chronic heart failure? Rationale and design of the Diagnostic Outcome Trial in Heart Failure (DOT-HF). European Journal of Heart Failure 10 (2008) 907–916.7. John G. F. Cleland, MD, Amala A. Louis, MD. Noninvasive Home Telemonitoringfor Patients With Heart Failure at High Risk of Recurrent Admission and Death. The Trans-European Network–Home-Care Management System (TEN-HMS) Study. JACC Vol. 45, No. 10, 2005

DebateHow to generate evidence? Designing telemonitoring trials


MEET AND EAT WITH THE ExPERT SESSIoNSAFETY ISSUES RELATED To SERUM PoTASSIUM IN CAR-DIovASCULAR TRIALS. FALLING FRoM CHARYBDE To SCYLLA?Chairmen: Keld Kjeldsen, Copenhagen, DEN - Luis Miguel Ruilope, Madrid, ESP

Keld Kjeldsen, Copenhagen, DEN

Keld Kjeldsen: MD. Dsc. Specialist in clinical cardiology. Chief physician, Head of Potassium Research Laboratory, Copenhagen University Hospital (Rigshospi-talet). Vice chairman of European Society of Cardiology Working Group on Car-diovascular Pharmacology and Drug Treatment. Author of 196 papers – her of 119 peer reviewed – and 2 books. Citations in WOS 3301. H-index 33. Research areas: Molecular cardiology with emphasis on Na,K-ATPase, general cardiology, cardiovascular pharmacology and immunology. Supervisor of 6 theses. Expe-rience with evaluation of theses and research projects. Extensive experience as peer reviewer and as editorial board member at international journals. Extensive teaching experience in clinical cardiology, cardiovascular pharmacology and re-search methodology for students and academic personnel. Extensive experience as organizer and chairmen of courses for medical doctors as well as of internatio-nal meetings and congresses. Censor for medical students. [email protected]

The pathophysiology of serum potassium in cardio-renal diseaseEberhardt Ritz, Heidelberg, GER

Eberhardt Ritz, Heidelberg, GER

He was born on January 23rd, 1938, in Heidelberg and studied medicine in the Medical Schools of Heidelberg, Munich and Montpellier. He worked at the Depart-ment Internal Medicine Zürich (Switzerland) and subsequently as an NIH postdoc-toral fellow at the Department of Biochemistry, Washington, University of St. Louis.Since 1967 he worked in the Department of Internal Medicine, University of Hei-delberg, where he was promoted to become Professor of Internal Medicine in 1974 and then chief of the Division of Nephrology in 1977.He is professor emeritus since April 2003.His main interests concern calcium metabolism in renal failure, hypertension and the kidney, diabetic nephropathy and cardiac problems in renal failure.He is past president of the «Gesellschaft für Nephrologie» and past council mem-ber of the European Renal Association and council member of the International Society of Nephrology. He was president of the World Congress of Nephrology, June 2003 in Berlin. He is honorary member of the European Renal Associa-tion (ERA/EDTA) and of the Australian, British, Czech , French, Italian, Polish, Spanish and South African Societies of Nephrology. He is member of the Ame-rican College of Physicians and the Royal College of Physicians in London and Edinburgh respectively. He is recipient of the distinguished investigator medal of the National Kidney Foundation, the «Wissenschaftspreis der Deutschen Hochdruckliga» and the «Bundesverdienstkreuz» of the German government. He is Dr.h.c. of the Silesian School of Medicine, the Pomerian School of Medicine and of Semmelweis Univer-sity Budapest/Hungary and recipient of the Jacob Henle medal of the University Goettingen.He received the John P. Peters award of the American Society of Nephrology 2003. He was congress president of the World Congress of Nephrology Berlin, June 8-12th, 2003.He is editor-in-chief emeritus of Nephrology Dialysis Transplantation and past as-sociate editor of the Journal American Society of Nephrology.He is currently president of the International Society of Nephrology.

ABSTRACT

Although aldosterone has been shown, both in experimental and clinical studies, to be involved in cardiovascular damage accompanying chronic kidney disease (CKD) as well as in progression of chronic kidney disease, only scanty information is available on the effect of mineralocorticoid receptor blockade, although aldos-terone mediated stimulation of the mineralocorticoid receptor has been shown to play a major role in the progression of CKD, both in experimental studies (heart: Micea, Hypertension (2008) 52:295; kidney: Green, Journal Clinical Investigation (1996) 98:1063). The major reason for the absence of interventional studies was the concern about hyperkalemia as a side effect. The first step in the treatment to halt progression is blockade of the RAS but this is counteracted in a large proportion of patients by the «escape» phenomenon, i.e. return of proteinuria to the pre-treatment level. Escape can be reversed by aldosterone or eplerenone (Chrystomou, NEJM(2001) 345:925 and its efficacy and safety has meanwhile been confirmed in numerous studies in diabetic and non-diabetic nephropathy with proteinuria.


Despite interesting experimental evidence, no effort has been made to replicate the cardio-protective action of mineralocorticoid receptor blocka de in patients with CKD. Recent studies (Gross, American Journal of Kidney Disease (2005) 46:94) show that even in anuric hemodialysis patients, spironolactone may not cause major hyperkalemia. Given appropriate safeguards (potassium content of diet, avoidance of co-medication aggravating hyperkalemia…) mineralocorticoid receptor blockade appears to be feasible. The rationale of mineralocorticoid re-ceptor blockade is amplified by recent observations that salt, by mineralocorticoid independent mechanism, further activates the mineralocorticoid receptor(Shibata, Nat.Med.(2008) 14:1370).

Targets for serum potassium in hypertension and heart failure; Preventing and managing hyperkalemia.Luis Miguel Ruilope, Madrid, ESP

Serum potassium and cardiorenal outcomes in cardiovascular clinical trials of RAAS therapyFaiez Zannad, Nancy, FRA

opportunities to prevent/treat hyperkalemia with potassium-binders. objectives and design of the PEARL-HF trialBertram PITT, Ann Arbor, USA


Cv PREvENTIoN: oNE DRUG, MULTIDRUGS oR PoLYPILL?Chairmen: Eva Lonn, Hamilton, CAN - Marc Pfeffer, Boston, USA Polypill and primary Cv prevention. Indian Polycap Study (TIPS)Prem Pais, Bangalore, IND

Polypill and secondary prevention: the FoCUS trial.Felipe Martinez, Cordoba, ARG

Felipe Martinez, Cordoba, ARG

Profesor de medicina internauniversidad nacional de cordobaPositionsProfessor of Medicine. Cordoba National University (since 1994)Director. Instituto Damic and Fundacion Rusculleda. (since 1993)Outstanding achievementsFormer President. Argentinean Federation of Cardiology (2002-2003)Co Chairman. Scientific Program. World Congress of Cardiology (2008)Governor for Argentina. International Society of Cardiovascular Pharmacology (since 2007)Scientific societies / cometeesBoard Member. World Heart Failure SocietyFellow. American College of CardiologyMember of 18 Steering Com. Of International TrialsScientific activitiesPublications 129Invited Speaker in more than 200 International Meetings, in 21 Countries.

ABSTRACT

Cardiovascular disease, including coronary heart disease (CHD) and stroke, is the ma-jor cause of premature deaths in adults in Europe and The Americas.The magnitude of this public health problem worsens in developing countries. WHO estimated that there are more than 176 million persons at high risk of suffering a cardiovascular event in the next 10 years, a large proportion of them living in emerging regions such as Asia and South America. A number of randomized controlled trials and the results of seve-ral meta-analyses have clearly demonstrated that long term administration of aspirin, statins, beta-blockers, and agiontensin converting enzyme inhibitors (ACEI) improve prognosis in high risk patients, particularly those recovering from an acute coronary event. The European Society of Cardiology guidelines, among others, recommend their routine use for secondary prevention in these patients.However, several factors, including wide variability in the pattern of prescription among physicians, limited acces-sibility and affordability to expensive drugs in emerging countries, and poor adherence to medication determine a deficient use of these drugs and that constrain the efficacy of cardiovascular prevention.The FOCUS trial (Fixed Dose Combination Drug for Se-condaryCardiovascular Prevention ) is the first study using a polypill in Secondary Pre-vention.The aim of FOCUS is to test the Fixed Dose Combination (aspirin,sinvastatin and ramipril) for cardiovascular prevention in populations of different socio-economic characteristics. At the same time, FOCUS aims to understand the factors determining inappropriate prescribing for secondary cardiovascular prevention and those for poor adherence to treatment. This will allow FOCUS to establish recommendations for a better use of medication in patients with ischemic heart disease. In addition, after a successful completion of FOCUS, secondary prevention medication will be available and affordable for a large number of patients in both developed as well as developing countries.The Study will be performed in two European Countries (Italy and Spain) and three in South Ameríca (Argentina, Brasil and Paraguay). And it is devided in two Phases:• Phase 1 is a descriptive, non-interventional study. Its aim is to provide a comprehen-sive analysis of potential factors precluding adequate secondary prevention, including Health system characteristics, drugs affordability and availability, as well as patients’ characteristics. • Phase 2 is an interventional, randomized trial with prospective economic evaluation. It will be organised as a two-arm,(Polypill vs the three drugs separately) randomised, parallel, multinational study. Will recruit patients completing the Phase 1, and fulfilling inclusion/exclusion criteria .• Initial Results are expected in 2012.

The Red Heart multidrug pill Indo European UMPIRE trial Simon Thom, London, GBR

Simon Thom, London, GBRInternational Centre for Circulatory HealthNational Heart and Lung Institute, St Mary’s Hospital & Imperial College LondonSimon Thom is Professor of Cardiovascular Medicine & Pharmacology at Imperial College London. He is a Consultant Physician at St Mary’s Hospital, Paddington and Co-director of the Peart-Rose Cardiovascular Disease Prevention Clinic based in the International Centre for Circulatory Health. He is also co-director of the NW London Diabetes Research Network – part of the UK national Clinical Research Network.He trained at St Mary’s Medical School and subsequently in Bath, Newcastle-upon-Tyne and London. He is a Fellow of the Royal College of Physicians, holds an MD from the University of London and was recently a member of the Executive Committee of the British Hypertension Society and the national hypertension guidelines group.His clinical interests include general medicine, hypertension, cardiovascular disease prevention and hypertensive complications in pregnancy. Research interests include vascular pharmacology and physiology, structure and mechanics of the circulation and

haemodynamics in relation to vascular disease. He leads clinical trials of cardiovascu-lar treatments – currently the multi-centered UMPIRE trial evaluating a “cardiovascular polypill” that includes collaborators and participants in India, Australia, the Netherlands, Ireland and UK. Research support comes from the British Heart Foundation, the Wel-lcome Trust, the European Commission, the Engineering & Physical Sciences Re-search Council and the pharmaceutical industry.

ABSTRACT

UMPIRE - Use of a Multidrug Pill In Reducing cardiovascular Events; a rando-mised controlled trial of fixed-dose combination medication and usual care in those at high risk of cardiovascular disease.Background. A combination once daily polypill including a statin, aspirin and 2 an-tihypertensive agents may be a useful strategy to address some of the barriers to effective CVD prevention. Such a pill, the Red Heart Pill (RHP), has been formu-lated by Dr Reddy’s Laboratories in India. The RHP is inexpensive. The UMPIRE trial aims to evaluate whether provision of a cardiovascular polypill compared with usual medications improves adherence to therapies and clinical outcomes among high-risk patients. The results will be used to develop recommendations for equi-table access relevant to both Europe and India. Parallel polypill projects running in Australia and New Zealand will afford the opportunity of pooling data to assess effects on cardiovascular events. Trial design. Open label, randomised, controlled trial (n = 2000 participants, in-cluding 1000 in Europe [UK + Ireland + the Netherlands] and 1000 in India) of the RHP compared to usual care in individuals at high risk of cardiovascular disease.Aim. To assess whether provision of the RHP (compared to usual CV medica-tions) improves adherence to indicated medicines and clinical outcomes in high-risk patients at end of trial follow-up. Patient recruitment. Participants at high risk of CVD (including those with a history of CHD or stroke) will be recruited through general practices and hospital out-pa-tient departments. Randomisation and trial medication. Eligible participants will be randomised to at least 12 months treatment with the polypill or to continued usual care:Polypill:RHP version 1: - aspirin 75mg, simvastatin 40mg, lisinopril 10mg, atenolol 50mg; RHP version 2: - aspirin 75mg, simvastatin 40mg, lisinopril 10mg, hydrochloro-thiazide 12.5mg.The choice of polypill version will be at the discretion of the local physician. Usual care: Usual cardiovascular preventive medications (e.g. antiplatelet, BP lowering and cholesterol lowering as separate medicines) as prescribed by the treating doctor.Data collection & follow-up. Participants will be followed up until one year after the last participant is randomised. Average follow-up is anticipated to be about 18 months. BP and fasting lipids will be measured at baseline and 12 months, and at 24 months or at the end of the trial. Self-reported adherence will be assessed at all trial visits. During trial contacts, the research nurse/investigator will ask about barriers to adherence, quality of life, cardiovascular and other SAEs, and reasons for stopping cardiovascular medications. Outcomes. Primary outcomes: Adherence to indicated medications (defined as self-reported current use of antiplatelet, statin and combination (≥2) BP lowering therapy), change in BP, change in LDL-cholesterol, at end of trial. Secondary out-comes: Dispensing of statin and ≥ 2 BP lowering agents, self-reported barriers to adherence, SAEs, cardiovascular events, reasons for stopping cardiovascular me-dications, quality of life, change in total-cholesterol and other lipid fractions (HDL-cholesterol and triglycerides), and comparison of results in Europe and India. Registration. http://clinicaltrials.gov/ct2/show/NCT01057537?term=umpire&rank=1http://www.ctri.in/Clinicaltrials/index.jsphttp://www.spacecollaboration.org

RECoMMENDED READING1. Reddy KS, Shah B, Varghese C, Ramadoss A. Responding to the threat of chronic diseases in India. Lancet 2005; 366: 1744-1749.2. Joshi R, Jan S, Wu Y, MacMahon S. Global inequalities in access to cardiovas-cular health care. J Am Coll Cardiol 2008; 52:1817-1825.3.WHO. Secondary prevention of non-communicable disease in low & middle income countries through community-based & health service interventions. WHO-Wellcome Trust report, August 2001, Geneva. 2002

4.Yusuf S. Two decades of progress in preventing vascular disease. Lancet 2002; 360: 2-35.Wald N, Law M. A strategy to reduce cardiovascular disease by more than 80%. BM J, 2003; 326: 1419-1424.

The Regulatory approach. Approvability issues of the polypillAngeles Alonso, Madrid, ESP


ExPERT STATISTICIANS AND TRIALISTSDISCUSS THE MAJoR TRIALS oF THE YEARChairmen: Bertram Pitt, Ann Arbor, USA - Mohamed Sobhy, Alexandria, EGY

Speaker: Stuart Pocock, London, GBRDiscussant: Roxana Mehran, New York, USA


PLENARY SESSIoN HEART RATE REDUCTIoN WITH IvABRADINE: FRoM CLINICAL TRIALS To CLINICAL PRACTICE Chairmen: Michael Böhm, Hamburg, GER - Faiez Zannad, Nancy, FRA

Body of evidence of the importance of heart rate reduction Martin Cowie, London, GBR

ABSTRACT

Heart failure is associated with an increase in resting heart rate and chronotropic incompetence during exercise. The heart rate increase is partly due to chronic activation of the sympathetic nervous system and partly due to reduction in vagal activity, identified by blunting of vagal reflexes and reduced heart rate variability in response to the respiratory cycle.Elevated resting heart rate is associated with both all-cause and cardiovascular mortality in the general population and in patients with cardiovascular disease. Risk increases linearly with increasing heart rate above approximately 60 bpm. Sub-analysis from the BEAUTIFUL Study corroborates this, with an increase in the risk of cardiovascular events in patients with a heart rate above 70-80 beats per min. More specifically, increased heart rate was significantly associated with the risk of death, and cardiovascular death or hospitalization in patients with left ventricular dysfunction.1 It has long been believed that lowering heart rate could be beneficial for cardiac function and clinical outcomes in heart failure patients. Pathophysiologically, benefits may include improved left ventricular filling, an increase in myocardial perfusion, and a decrease in myocardial oxygen consumption.2 A recent meta-analysis confirms that heart rate lowering is central to the prognostic benefit of beta-blockade in patients with heart failure.3 There is, therefore, much interest in the therapeutic potential of pharmacologi-cal heart-rate reduction beyond beta-blockade. The recently published SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) provides strong evidence that heart rate reduction per se is a reasonable target for treat-ment in patients with left ventricular dysfunction and heart failure. 4,5

RECoMMENDED READING1. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R on behalf of the BEAUTI-FUL Investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial.2. Reil J-C, Custodis F, Swedberg K et al. Heart rate reduction in cardiovascular disease and therapy. Clin Res Cardiol 2010 (epub ahead of print). 3. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009; 150: 784-94.4. Swedberg K, Komajda M, Bohm M, et al, on behalf of the SHIFT Investigators. Iva-bradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. Lancet 2010; 376: 875-85.5. Bohm M, Swedberg K, Komajda M, et al, on behalf of the SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomized placebo-controlled trial. Lancet 2010; 376: 886-94.



ExPERT WoRKSHoPMETHoDoLoGICAL, PRACTICAL AND REGULAToRY FRA-MEWoRK FoR CoNDUCTING AN ANTI-THRoMBoTIC THE-RAPY oUTCoME TRIAL IN ATRIAL FIBRILLATIoNChairmen: Sidney Goldstein, Detroit, USA - Christian Torp-Pedersen, Copenhagen, DEN

Lectures: Limitations of warfarin anticoagulation and unmet needs in atrial fibrillation stroke prevention Gregory Lip, Birmingham, GBR

Gregory Lip, Birmingham, GBR

Professor Lip is an academic clinical cardiologist based in a busy city centre teaching hospital, and leads a large multidisciplinary research group [including clinical and la-boratory-based components] at the Centre for Cardiovascular Sciences, University of Birmingham (United Kingdom), where he is Professor of Cardiovascular Medicine. He is also Visiting Professor of Haemostasis Thrombosis and Vascular Sciences in the School of Life & Health Sciences at the University of Aston in Birmingham (United Kingdom).Half of his time is spent as a clinician, and he practises the full range of cardiovascular medicine, including outpatient clinics [with large atrial fibrillation and hypertension spe-cialist clinics] and coronary care units. He also undertakes coronary intervention, and assists in a 24/7 primary angioplasty rota for ST elevation MIs.As an academic, he provides strategy and research direction for his group, with many local/national/international collaborations in progress. He has been involved in national and international guidelines and working groups [see later section], mostly at European level.Professor Lip is a member of the scientific documents committee of the European Heart Rhythm Association [EHRA], and serves on the Nucleus of the Working Group on Thrombosis of the European Society of Cardiology [ESC]. He is also a member of EHRA and the European Association of Percutaneous Coronary Revascularisation.Professor Lip has acted as Clinical Adviser for the UK National Institute for Health & Clinical Excellence [NICE] guidelines on atrial fibrillation [AF] management. He was on the writing committee for the 8th American College of Chest Physicians [ACCP] Antithrombotic Therapy Guidelines for Atrial Fibrillation, as well as various guidelines and/or position statements from EHRA including the EHRA statement on defining endpoints for AF management, EHRA guidelines for antithrombotic therapy during ablation. He recently Chaired an ESC Task Force writing a Working Group of Throm-bosis Consensus Document on Antithrombotic therapy use in atrial fibrillation patients presenting with an acute coronary syndrome and/or undergoing percutaneous coro-nary intervention/stenting (2009). He is also on the writing committee of the new ESC Guidelines on Atrial Fibrillation (2010) and is Deputy Editor (‘content expert’) for the 9th ACCP guidelines on antithrombotic therapy for AF (due 2011).Professor Lip is involved at senior editorial level for major international journals e.g. Journal of Human Hypertension (Editor in Chief), Thrombosis & Haemostasis (Editor in Chief [Clinical Studies]), Europace (Associate Editor), Circulation (Guest Editor), etc.

ABSTRACT

Oral anticoagulation is the most effective drug for stroke prevention in atrial fibrillation (AF). Until recently, the only oral anticoagulant drug class available for our clinical use is the Vitamin K antagonists (VKAs, eg. warfarin). Nonetheless, warfarin use is limited by significant inter- and intra- patient variability, as well as the dis-utility of needing an-ticoagulation monitoring (to keep within a narrow therapeutic range) and the diet/drug/alcohol restrictions associated with these drugs. Thus, prior stroke risk stratification guidelines have tried to artificially divide patients into low, moderate and high stroke risk strata, eventhough these categories do not have good predictive ability.

Given the dis-utility associated with the VKAs, uptake of oral anticoagulation is also limited, with high rates of discontinuation after initiation. With the availability of new oral anticoagulant drugs, a paradigm shift has been made towards getting better at identi-fying ‘truly low risk’ patients who do not need any antithrombotic therapy, whilst those patients with one or more stroke risk factors can be considered for oral anticoagulation. This approach is recommended within the new 2010 European Society of Cardiology guidelines for the management of AF.

RECoMMENDED READING1. Lip GY, Halperin JL. Improving stroke risk stratification in atrial fibrillation. Am J Med. 2010 Jun;123(6):484-8.2. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrilla-tion: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010 Oct;31(19):2369-429.3. Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, Lip GY, Manning WJ; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):546S-592S.

New anti-thrombotic agents versus Warfarin in Patients with Atrial Fibrillation. An update on recent and ongoing trials.Lars Wallentin, Uppsala, SWE

ABSTRACT

Warfarin is effective for stroke prevention in atrial fibrillation but has downsides be-cause of variability in response and a raised risk of bleeding. The efficacy and safety of warfarin is related to the time in therapeutic range (TTR) with International normalized ration (INR) 2.0-3.0 with a raised risk of stroke and death and INR < 2 and of bleeding at INR >3. However, the risk of bleeding, including intracranial bleeding, is present also in patients within this target range. This limits the indication for warfarin to patients with an intermediate to high risk of stroke.(1,2)The development of new oral anticoagulants aims to be at least effective as warfarin and with a better safety allowing its use also in lower risk populations. The new alter-natives provide more specific inhibition of the coagulation cascade i.e. by inhibition of thrombin (dabigatran) or FXa (apixaban, rivaroxaban, edoxaba, betrixaban etc.). Currently the final results prospective trials comparing these new treatment alternatives to warfarin in patients with atrial fibrillation and a raised risk of stroke are only available concerning dabigatran (D) However, the prospective double-blind trials comparing res-pectively apixaban and rivaroxaban to warfarin i will be presented within the next year. The RELY trial (3) randomized 18,113 patients with atrial fibrillation in 951 sites to blinded fixed doses of D110 mg or D150 mg twice daily versus unblinded warfarin dose adjusted to INR 2.0-3.0. Median follow-up was 2.0 years. Rates of the primary outcome were 1.70% per year on warfarin versus 1.55% per year on D110 mg (p non-inferiority<0.001) and 1.11% per year on D150 mg (p superiority<0.001). Rates of major hemorrhage were 3.46% per year on warfarin versus 2.74% per year on D110 mg (p=0.002) and 3.22% per year on D 150 mg (p=0.32). Rates of hemorrhagic stroke were 0.38% per year on warfarin versus 0.12% per year on D110 mg (p<0.001) and 0.10% per year on D150 mg (p<0.001). The continued analyses have investigated the relative effects of D in relation to the average TTR (cTTR) in each centre’s warfarin po-pulation (4) and to CHADS2 score 85). The quartiles of cTTR for the warfarin patients were <57%, 57%-65%, 65%-73% and >73%. There were no significant interactions with cTTR concerning the superiority of D150 or the non-inferiority of D110 versus war-farin regarding prevention of stroke and systemic embolism and both doses superiority concerning intracranial bleeding. Recently the AVERROES trial (5) presented the results comparing the factor Xa in-hibitor apixaban 5 mg b.i.d. versus aspirin 80 – 325 mg/day for stroke prevention in patients with atrial fibrillation and ≥1 risk factor for and unsuitable for oral anticoa-gulation. The trial was prematurely terminated because of apixaban being superior to aspirin concerning the primary end-point. There was a 54% reduction (p<0.001) in the primary efficacy endpoint of stroke and systemic embolism. There was no signi-ficant difference in major bleedin or any other major safety endpoint. Apixaban was even better tolerated than aspirin, with less discontinuations with apixaban compared to aspirin.In patients with atrial fibrillation direct thrombin inhibition with dabigatran as compared to warfarin provided, with the lower dose D110 mg similar rate of stroke and systemic embolism and lower rates of major haemorrhage and, with the higher dose D150 mg, a lower rate of stroke and systemic embolism and similar rates of major haemorrhage.

Management of heart rate in CAD: lessons from the BEAUTIFUL studyJeffrey S. Borer, New York, USA

Management of heart rate in HF: lessons from the SHIFT studyMichael Böhm, Hamburg, GER

Heart rate management in clinical practice with ivabradineGiuseppe Rosano, Roma, ITA

Giuseppe Rosano, Roma, ITA

1988: MD in Medicine and Surgery, University of Rome «La Sapienza» with full honors1992: Specialization in Cardiology, University of Rome «La Sapienza» with full honors1997: PhD in Medical Sciences, University of London 1990- 1994 :Research Registrar at the Royal Brompton Hospital, London.1994-1997: Lecturer, Chair of Clinical Pharmacology, University of Reggio Calabria1997- 2000: Senior Lecturer Department of Cardiology Istituto H San Raffaele, Milano 2000: Director, Center of Clinical and Experimental Medicine, IRCCS San Raffaele, RomaMay 2006: Vice Chairman Member of the S.A.G. Cardiovascular of the European Medicine AgencyJanuary 2007: Adjunct Professor in Cardiology, TUFTS University of Boston, USAMarch 2010: Member of the Scientific Committee of the Italian Space AgencyApril 2010: Director of the Department of Medical Sciences IRCCS San Raffaele RomaAreas of Scientific Interest: Cardiovascular Pharmacology, Cardiac metabolism, Car-diovascular disease in the elderly and in women, Cardiovascular effect of sex hormo-nes, Vascular Physiology, Ischemic heart disease, Heart failureFellow: European Society of Cardiology, Italian Federation of Cardiology ,American College of CardiologyScholar of the Italian Society of CardiologyVice-Chairman of the Task Force on Gender Differences in Cardiovascular Disease of the European Society of Cardiology, Member of the Nucleus of the WG on Pharma-cology of the ESCAuthor of 4 books and of 26 chapters in books and over 200 publications in peer re-viewed Journals

ABSTRACT

Ivabradine is a new innovative treatment for cardiovascular disease. Although it has initially been suggested to be a pure HR-reducing agent, modulating the rate of spontaneous diastolic depolarization through selective If current inhibition in sinoatrial pacemaker nodal cells, it is now clear that its mechanism of action include also im-provement of coronary blood flow, reduction of myocardial oxygen consumption both with preservation of cardiac physiology. Furthermore, it has been shown that coronary artery perfusion during increased cardiac demands is with ivabradine 30%-40% grea-ter than that obtained with beta-blockers. Therefore, the degree of improvement of myocardial ischemia/reduction of HR is much greater with Ivabradine compared with beta-blockers. A significant and dose-dependent improvement in total exercise capacity, as well as a significant decrease in the number of anginal episodes and use of short-acting nitrates, has been observed with ivabradine. The anti-ischemic effect of Ivabradine has been proven to be similar to that of Atenolol in the randomized parallel study INITIATIVE conducted in 939 patients with CAD and stable angina. The study showed that for simi-lar degree of HR reduction the anti-ischemic effect of ivabradine was more pronounced (up to twofold) than that of Atenolol. The ASSOCIATE study showed that unlike nitrates and calcium channel blockers the adjunct of Ivabradine to Atenolol improves exercise time, time to angina and ischemic threshold compared to atenolol alone. Therefore, Ivabradine is, along with trimetazidine, the only drug capable of an additive effect on angina and myocardial ischemia in ischemic patients receiving beta-blockers.

The BEAUTIFUL study had already shown that HR reduction with ivabradine improves ischemia-related endpoints in patients with coronary artery disease and left ventricular dysfunction. The analysis of 1507 patients with limiting angina at baseline included in the BEAUTIFUL study showed that treatment with ivabradine was associated with a 24% reduction in risk for the primary endpoint and a 42% reduction in the risk for hospitalization for fatal and nonfatal MI. More recently, the SHIFT study showed that in patients with heart failure and left ven-tricular dysfunction Ivabradine improves event free survival. Two recent randomised studies have shown that Ivabradine alone or in association with beta-blockers is more effective than full dose beta-blockade in improving exercise capacity in patients with coronary artery disease and in those with heart failure. The clinical experience gathered from randomised clinical studies suggest a place in therapy for Ivabradine as first line therapy alone or in association with beta-blockers in all patients with coronary artery disease and in those with heart failure.

RECoMMENDED READING1. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010 Sep11;376(9744):875-85. 2. Rosano GM, Vitale C, Volterrani M. Heart rate in ischemic heart disease. Theinnovation of ivabradine: more than pure heart rate reduction. Adv Ther. 2010Apr;27(4):202-10. Epub 2010 May 20. Review3. Koester R, Kaehler J, Ebelt H, Soeffker G, Werdan K, Meinertz T. Ivabradine incombination with beta-blocker therapy for the treatment of stable angina pectorisin every day clinical practice. Clin Res Cardiol. 2010 Oct;99(10):665-72. 4. Tendera M, Borer JS, Tardif JC. Efficacy of I(f) inhibition with ivabradine indifferent subpopulations with stable angina pectoris. Cardiology.2009;114(2):116-25. Epub 2009 May 26. 5. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators.Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Sep 6;372(9641):807-16. 6. Heusch G, Skyschally A, Gres P, van Caster P, Schilawa D, Schulz R.Improvement of regional myocardial blood flow and function and reduction ofinfarct size with ivabradine: protection beyond heart rate reduction. Eur HeartJ. 2008 Sep;29(18):2265-75. Epub 2008 Jul 10

DebateThe challenge of optimization of heart failure therapy. Is there a limit to polypharmacy?

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The benefits of D150 reducing stroke, D110 reducing bleeding, and both doses re-ducing intracranial bleeding as compared to warfarin were consistent irrespective of the centres’ quality of INR control. These benefits should translate into substantial advantages when dabigatran etexilate is implemented as a new treatment alterna-tive for stroke prevention in patients with atrial fibrillation. Also factor Xa inhibition with apixaban provides better stroke prevention than aspirin and probably at least similar stroke prevention as warfarin in patients with atrial fibrillation. Therefore there are great hopes that several new treatment alternatives will be available for stroke prevention in atrial fibrillation.

RECoMMENDED READING1. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): develo-ped in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257–e354.2. Singer DE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:546S–592S.3. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Commit-tee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. . N Engl J Med. 2009 Sep 17;361(12):1139-51. Epub 2009 Aug 30.4. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ; RE-LY investigators Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrilla-tion: an analysis of the RE-LY trial. Lancet. 2010 Sep 18;376(9745):975-83. 5. Connolly s, Eikelboom J, Flaker G, Kaatz S, Avezum A, PiegasL, Hermosillo A, Hohnlose S, Golitsyn S ,Yusuf S. AVERROES: Apixaban versus Acetyl salicyclic acid to prevent strokes. European Society of Cardiology, Stockholm, 31 August 2010.

DebateDefining the target population and reshaping the guidelines

Dosing issues in thrombosis trials. e.g. Progression from Phase 2 to Phase 3 trials with new oral anti-thrombotic agentsDiscussant: Yasser Khder, Boehringer Ingelheim, FRA

Yasser Khder, Boehringer Ingelheim, FRA

Dr Yasser KHDER obtained his medical degree and his speciality in internal me-dicine from Damascus University, in 1986, subsequently he was graduated as specialist in cardiovascular pathology from Nancy Medical School, France in 1992. Between 1992 and 1996 Yasser worked as non-invasive cardiologist. Meanwhile, he also had a partial-time academic research assignment in the National Insti-tute of Health and Medical Research (INSERM). During this period Yasser was successfully graduated as a BSc in clinical pharmacology, an MSc in clinical epi-demiology, methods in clinical research and a DSc in human biology from the Nancy University and accomplished several scientific works in the vascular bio-logy arena. Yasser is working as a Scientific Director Cradiology in Boehringer-Ingelheim, Pa-ris, France since June 2008. Earlier, Yasser worked 7 years in Novartis Pharma AG, Basel as a Global Phase IV Leader for Diovan®, European Clinical Team Leader for Aliskeren, Protocol Review Committee Cardiovascular Scientific Direc-tor and Global Program Leader for a NCE in hypertension/heart failure.

Before joining Novartis, he worked 5 years in Merck KGaA, where he led several development programs such as bisoprolol in silent myocardial ischemia, nicorandil in cardiac surgery and PCI as well as Na+/H+ exchanger inhibitor at the acute phase of myocardial infarction.

ABSTRACT

Several new antithrombotic agents are either registered or currently underdevelo-pment for the prevention of thromboembolic events in patients with atrial fibrillation (AF). Unlike warfarin, these agents do not require routine monitoring of of the phar-macodynamic response. Development and successful registration of these drugs necessitate large-scale, outcome trial(s). Since a rather steep relationship between bleeding events and dose-levels has always been described with these agents, it is essential to select dose(s) with a good safety profile without hampering efficacy for further testing in the phase 3 program. Full understanding of the pharmaco-logical profile of the new therapy is essential to support the determination of the dosing-interval and the appropriate dose-range for further assessments. Phase 2, dose-ranging studies usually compare several doses and/or dosing-intervals of the new therapy to warfarin and/or placebo in the target population. Primary outcome is always safety (bleeding events). Biomarkers, indicators of efficacy such as D-dimer and coagulation parameters are also evaluated. It is important to ensure that the phase 2, dose-ranging study population is representative of the target population in term of age, gender, ethnicity, concomitant medications and associated clinical conditions. Population PK assessment and evaluation of the exposure-response analysis may also be helpful to select the most appropriate dose and dosing interval. Subsequently, one or two doses may be selected for further assessment in the phase 3 program. Most often, antithrombotic agents are developped for other indications, such as prevention and treatment of venous thromboembolism, acute coronary syndromes and severe medical illness. The dose-selection for the phase 3 program should integrate all available safety and efficacy results including data from other indi-cations. Occasionally, the experience gained in other indications may be used as basis for dose-selection for the phase 3 program in AF; without conducting a proper dose-ranging study in the target population. This approach may be helpful to streamline the clinical development program but not without a theoretical risk of suboptimal dose-selection.In summary: appropriate dose selection for phase 3 program of the new antithrom-botic agents begins with the clinical pharmacology studies in health volunteers, in elderly and in subjects with renal and hepatic impairment. A phase 2, dose-ranging study in the target population is always essential for dose-selection. Integration of all available safety and efficacy information in different indications is required as well. Population PK assessment and concentration-response analysis are also important methodological tools to improve dose-selection of new antichrombotic agents for the phase 3 program in atrial fibrillation.

RECoMMENDED READING1. Camm AJ, Kirchhof P, Lip GYH, et al: Guidelines for the Management of Atrial Fibrillation. The Task Force for the Management of Atrial Fibrillation of the Euro-pean Society of Cardiology. Eur Heart J 2010; 31:2369-2429.2. Ezekowitz MD, Reilly PA, Nehmiz G, et al: Dabigatran with or without concomi-tant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrilla-tion (PETRO Study). Am J Cardiol 2007;100:1419-26. 3. Weitz JI, Connolly SJ, Patel I, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010;104:633-41. 4. Buller H, Deitchman D, Prins M, Segers A for Botticelli Investigators, Writing Committe: Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008;6:1313-8. 5. Fisher WD, Eriksson BI, Bauer KA, et al: Rivaroxaban for thromboprophy-laxis after orthopaedic surgery: pooled analysis of two studies. Thromb Haemost 2007;97:931-

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PRoBE vs. Double Blind study designs in thrombosis trialsDiscussant: Gregory Lip, Birmingham, GBR

What is a clinically meaningful benefit? All cause vs Cause specific events.Discussant : Freek Verheugt, Amsterdam, NED

Freek verheugt, Amsterdam, NED

University Hospital, The NetherlandsFreek W.A, Verheugt, M.D., F.E.S.C. , F.A.C.C., F.A.H.A. (62) is Professor of Car-diology at the Heart-Lung Centre of the University Medical Centre of Nijmegen and Chairman of the Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG) in Amsterdam, The Netherlands.Professor Verheugt gradua¬ted from the University of Amsterdam in 1974 and wrote a thesis on platelet and granulo¬cyte antigens and antibodies. He trained in cardiology at the Thoraxcenter of the Erasmus University in Rotterdam. He has been a Professor at the University of Colorado Health Sciences Center in Denver, U.S.A., and at the Free University in Amsterdam. He was President of the Nether-lands Society of Cardiology between 1999 and 2001.Professor Verheugt has published over 400 papers in peer-reviewed international journals including New England Journal of Medicine, Lancet, Circulation, Journal of the American College of Cardiology and European Heart Journal, of which is an Editorial Board Member. He is an editorial adviser of Lancet, New England Journal of medine and Circulation. He has over14,000 citations. His main fields of scientific interest are pharmacological and interventional treatments of acute coronary syndromes and atrial fibrillation

ABSTRACT

The objective of anti-thrombotic therapy in atrial fibrillation is prevention of systemic thromboembolism and stroke. The latter is considered a devastating complication of atrial fibrillation. Proper oral anticoagulation can prevent strokes in up to 70% of cases when compared to control treatment.1 Oral antiplatelet therapy hardly modifies this risk.1 The flip side of oral anticoagulation therapy is the catastrophic complication of cerebral haemorrhage. Ischemic stroke and cerebral hemorrhage, therefore, are currently the most severe complications of atrial fibrillation. When targeting left atrial thrombosis in prevention of stroke in atrial fibrillation the benefit of oral anticoagulation should be balanced against the risk of intracranial bleeding.2 Or, in other words, how many ischemic strokes can be prevented at the cost of how many excess intracerebral bleeds? In general, total stroke rate of a specific strategy is more logical than giving cause-specific events like ischemic stroke versus hemorrhagic strokes. Yet, the conse-quences of the two types of strokes may be very different. Ischemic stroke may be mild or life-threatening, whereas hemorrhagic strokes usually are fatal, especially when they occur in patients on (adequate) oral anticoagulation therapy. A more focussed approach can be the disability score associated with strokes occurring on anti-thrombotic therapy for stroke prevention in atrial fibrillation. Usually, the modified Rankin scale is used, where Rankin scales 0-2 represent a no, minimal or moderate disability, whereas Rankin scale 3-5 represent severe disability or fatal outcome (6). The Rankin scale circumvents cause-specificity of the stroke and may better corroborate with clinical practice and clinical outcomes. Thus, when evaluating anticoagulation therapy for stroke prevention in atrial fi-brillation cause-specific events are important for a scientific purpose, but all-cause stroke events are more appropriate for the clinical benefit of a certain strategy in stroke prevention in atrial fibrillation.

RECoMMENDED READING1. Lip GY, Hart RG, Conway DS. Antithrombotic therapy for atrial fibrillation.BMJ 2002;325:1022-10252. Camm J, Kirchhof P, Lip GYH et al. Guidelines for the management of atrial fibrillation. Task force of the management of atrial fibrillation of the European So-ciety of Cardiology (ESC). Eur Heart J 2010;31:2369-2429


ALDoSTERoNE RECEPToR BLoCKERS ACRoSS THE HEART FAILURE SPECTRUMChairmen: John McMurray, Glasgow, GBR - Kenneth Dickstein, Stavanger, NOR

A historical perspective of evidence based therapy in heart failureJay Cohn, Minneapolis, USA

EMPHASIS-HF : Extending the indication of eplerenone to mild heart failureFaiez Zannad, Nancy, FRA

Aldosterone receptor blockers across the heart failure spectrum. Practical issues and updating the guidelinesHenry Krum, Melbourne, AUS

Anti-aldosterone therapy. New drugs and new trials Bertram Pitt, Ann Arbor, USA

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SATURDAY DECEMBER 4, 08:00 - 10:30 AND 11:00 - 12:30

” HoW To” WoRKSHoPHoW To SToP A TRIAL PREMATURELY FoR ExCESS oF BENEFIT Chairmen: John McMurray, Glasgow, GBR - Stuart Pocock, London, GBR

Introduction: Case study. My experience with stopping trials prematu-rely (RALES, CIBIS 2, EMPHASIS-HF and other trials)Faiez Zannad, Nancy, FRA

Why to stop – what endpoint? Bertram Pitt, Ann Arbor, USA

When to stop – what level of statistical certainty?Stuart Pocock, London, GBR

How to stop – how quickly? Collecting further events? open label treatment if stopping for efficacy?John McMurray, Glasgow, GBR

How did I handle expedited event adjudication? Critical Event Commit-tee issues.Willem Remme, Rhoon, NED

Willem Remme, Rhoon, NED

Professor Willem J. Remme, “Sticares” Cardiovascular Research Institute, Rot-terdam-Rhoon, The Netherlands. Director and CEO, Sticares-InterACT NV, Rot-terdam-Rhoon, The Netherlands. 1st Chairman of the Working Group on Heart Failure of the European Society of Cardiology.Chairman World Heart Failure So-ciety. Chairman SHAPE - Study group on Heart failure Awareness and Perception in Europe. Chairman GAPS-HF: Global Awareness and Perception Study in Heart FailureHonorary Membership: French Society of Cardiology, Romanian Society of Car-diologyRomanian Society of Internal MedicineEditorial Boards: Editor-in-Chief of Cardiovascular Drugs and Therapy.

ABSTRACT

When a study is stopped before the scheduled deadline and database closure or, in the case of an event-drive study, before the required events have been adjudi-cated, quite a few reported events are still waiting for the final adjudication process due to missing data and unresolved queries. In addition, events will continue to occur until final data base closure.Together, these make for an unexpected challenge for all parties involved in event data collection, including the investigator site, CRAs, event data base organization and the Critical Event Committee.As to be expected, the possibility that all information will be collected in time does not exist. Following agreement with the Steering Committee several deci-sions may be reached regarding data collection, ranging from omitting data with low priority to accepting all available data as sent by the investigator without any subsequent queries. In extreme conditions towards the end of the study these may only concern specific event-related forms without supporting data. With less and less information the task of the Critical Event Committee obviously becomes more difficult, but still doable while staying within the limits of its Charter. It very much depends on the precision of the event definitions and that of the spe-cific event forms which should capture all pertaining information of each specific event.

These should normally suffice and not necessitate supporting information, althou-gh under normal study conditions the latter is always present for support and to check the information of the investigator. When insufficient or questionable information is present, and no way to rectify this, the Committee as a whole (or those who can be reached in a hurry when ne-cessary) may decide on the case during a teleconference or by e-mail using their clinical expertise. That way, events can be adjudicated or declared unsolvable/unknown in the pre-defined way following the Committee’s Charter, even until the very last hours before database closure.


ExPERT WoRKSHoPCARDIAC RESYNCHRoNIZATIoN THERAPY BEYoND LBBB AND WIDE QRS Chairmen: Johannes Holzmeister, Zurich, SUI - William Abraham, Columbus, USA

Rationale and design of the Echo-CRT trialFrank Ruschitzka, Zurich, SUI

DebateFrom proof of concept to a large scale morbidity and mortality trial. Design challenges. Bearing results implementation in mind.

Where are the unmet needs? What is the target population? Trial population vs. Real life patients.Discussant HF: William Abraham, Columbus, USA

Clinically meaningful endpoints. Composite/Cause specific or all cause? What will convince the doctors?Discussants EP: Johannes Holzmeister, Zurich, SUIDiscussant HF: Henry Krum Melbourne, AUS

What is adequate statistical power? Discussant Statician: Stuart Pocock, London, GBRDiscussant HF: Faiez Zannad, Nancy, FRA


ExPERT WoRKSHoPMAxIMIZING THE BENEFITS FRoM ANGIoTENSIN RECEPToR ANTAGoNISTS. ENHANCED PoTENCY AND CoMBINATIoN THERAPYChairmen: Angeles Alonso, Madrid, ESP - Giuseppe Mancia, Monza, ITA

Are all Angiotensin receptor blockers alike? Are maximized potency and ancillary effects clinically relevant?Luis Ruilope, Madrid, ESP

How to cook a good combo recipe? What is the ideal diuretic to combine?Stuart Kupfer, Takeda, USA

Stuart Kupfer serves as executive medical director in cardiovascular clinical scien-ce at Takeda Global Research and Development in Deerfield, IL, USA. His areas of research have included hypertension, thrombosis, diabetes, dyslipidemia, and growth disorders. Dr. Kupfer previously served on the medical school faculties of Washington University in St. Louis, MO, USA and University of North Carolina in Chapel Hill, NC, USA where he conducted basic research in gene regulation of steroid hormone receptors and bone metabolism. Dr. Kupfer’s clinical training includes pediatrics and endocrinology.

ABSTRACT

The combination of a thiazide-type diuretic and a renin-angiotensin-aldoseterone sys-tem (RAAS) blocker, such as an angiontensin converting enzyme inhibitor (ACEi) or angointensin receptor blocker (ARB), is commonly used for the treatment of hyper-tension because of complementary mechanisms of action and potentiation of blood pressure reduction. Hydrochlorothiazide (HCTZ) is the most common diuretic utilized in fixed-dose combinations (FDC) of RAAS blockers; however, the weight of clinical evidence suggests that other thiazide-type diuretics, such as chlorthalidone or indapa-mide, may be more effective than HCTZ. At the typical low doses used in FDCs (12.5 – 25 mg), HCTZ is half as potent as chlorthalidone in lowering blood pressure, in part because of chlorthalidone’s longer half-life. More importantly, in contrast to chlorthali-done or indapamide, HCTZ-based regimens have not been consistently effective in reducing major cardiovascular events in large outcome trials compared with an ACEi or calcium channel blocker, despite similar blood pressure reduction. These data suggest that alternative thiazide-type diuretics should be considered for combination therapy with RAAS blockers in patients with hypertension in order to optimize cardiovascular risk reduction.

RECoMMENDED READING1. ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The antihypertensive and lipid-lowering treatment to prevent heart attack Trial (ALLHAT). JAMA 2002; 288(23):2981-97.2. Beckett NS, Peters R, Fletcher AE, Staessen JA, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358(18):1887-98. Epub 31 March 2008. 3. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evi-dence supporting their interchangeability. Hypertension 2004; 43(1):4-9.4. Elliot WJ, Grimm RH Jr. Using diuretics in practice: one opinion. J Clin Hypertens (Greenwich) 2008; 10(11):856-62.5. Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359(23):2417-28.6. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systo-lic hypertension in the elderly program (SHEP). JAMA 1991; 265(24):3255-64.7. Wing LM, Reid CM, Ryan P, Beilin LJ, et al; Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting-en-zyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 200313; 348(7):583-92.

Is combination therapy to become the rule? Insight from hypertension outcome trials and recent guidelines.Giuseppe Mancia, Monza, ITA

How to prove/claim added value conferred by ancillary properties?Angeles Alonso, Madrid, ESP

How to prove/claim superiority of a new combo drug?William C. Cushman, Memphis, USA

SATURDAY DECEMBER 4, 12:30 - 13:45

CHALLENGING HYPoTHESES To BE TESTED IN FUTURE TRIALSTHE Cv TRIALISTS “FoRUM” Marc Pfeffer, Boston, USA

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__SATURDAY DECEMBER 4, 14:00 - 18:00

CvCT WoRKSHoPSTUDY DESIGN ISSUES IN THRoMBoSIS TRIALSChairmen: Peter Clemmensen, Copenhagen, DEN - Roxana Mehran, New-York, USA

Peter Clemmensen, Copenhagen, DEN

Professor Peter Clemmensen completed his medical training at the University of Copenhagen, and currently holds the positions of Associate Professor of Cardio-logy, Copenhagen University Hospitals, and Chief physician, The Heart Centre, Department of Cardiology, Rigshospitalet, Denmark. He has been a board mem-ber of the International Society of Electrocardiology and the Danish Heart Foun-dation, of which he presides since 2008. Vice-chair of the ESC Working Group on Acute Cardiac Care. Professor Clemmensen has published over 100 scientific papers and chapters in international textbooks. The research has mainly been on assessment of re-perfusion therapies in patients with ST segment elevation myocardial infarction, including non-invasive methods to estimate the effects of thrombolytic therapy, primary and rescue PTCA on infarct size. A recent focus of the research has been risk stratification in patients with non-ST elevation acute coronary syndromes, in-cluding cardiac markers and electrocardiology. The research has resulted in an equal number of abstracts and lectures at scientific meetings. Professor Clem-mensen has also acted as a mentor on 9 completed and ongoing dissertations in Cardiology. He has served on several national and international end-points committees and working groups including the Joint ESC/ACC Committee for redefinition of myo-cardial infarction 2000, and its 2004-2010 GLOBAL MI Task Force. He is also a referee for 10 international journals.

Areas for experts’ discussion: Risk benefit issues in progressing to Phase IIISpeaker: Sidney Goldstein, Detroit, USA

Do surrogates and/or adaptive design help?Speaker: Roxana Mehran, New York, USA Discussant: Sidney Goldstein, Detroit, USA

Combining efficacy and safety in composite endpointsSpeaker: Andrea Laslop, Innsbruck, AUT

Andrea Laslop, Innsbruck, AUT

Andrea Laslop joined AGES PharmMed, the Austrian Medicines Agency, upon its foundation on January 2nd, 2006. She is heading there the Institute Science and Information, which deals with the different types of centralized European proce-dures during drug development and marketing authorization applications as well as the approval of clinical trials on a national level and various aspects of public relations.


Prior to this Andrea Laslop worked as an associate professor of pharmacology and toxicology at the Medical University of Innsbruck, Austria. During her engage-ment at the university she was appointed as member to several working groups of the European Medicines Agency (EMA), e.g. the Efficacy Working Party in 1998, the Scientific Advice Working Party and the Paediatric Expert Group in 2003. In June 2007, she became alternate member of the Committee for Human Medicinal Products of the EMA, where she is representing Austria now as the full member since January 2009.Andrea Laslop studied medicine at Innsbruck University where she earned her MD and later on specialized as a pharmacologist. Her professional career included se-veral sojourns for joint research projects at the NIMH in Bethesda, the Albert Eins-tein College of Medicine in New York and the Clinical Research Institute of Montreal.

PRoBE vs Double Blind study design in antithrombotic trialsSpeaker: Hans Wedel, Gothenburg, SWEDiscussant: Christian Torp Pedersen, Copenhagen, DEN

Hans Wedel, Gothenburg, SWE

ABSTRACT

For antithrombotic studies with placebo as the control it is agreed that blind de-sign should be the norm. PROBE design has been discussed mainly in studies with warfarin as the control. Those studies are mainly AF studies. Examples of PROBE open designs are: SPORTIF III and RE-LY. Examples of blinded design are: SPORTIF V, ARISTOTLE, AMPLIFY.Problems with openness if warfarin is control drug. Warfarin treatment requires a close follow up.More visits are generated in the warfarin group compare to modern antithrombotic treatment Endpoints like DVT and SE are detected easier in the those patients with many visitsI mean that this bias is present also when the Endpoint committee works blinded.How to blind when warfarin is the treatment in the control group?Today there are computer programs, which simulates similar INR values (sham values) in the new treatment group. The simulated INR-value is calculated for each person in the Active group based on experience from wafarin treatment,.An overestimation of some percentage could affect the overall judgement and the health economy. I believe that there is a positive effect of dabigatran strategy at 150 mg in RE-LY no doubt but I do not accept that the arguments for open design should have an impact on future studies.I hope to see more double blind studies in AF patients when warfarin is the control drug.It is technically feasible with sham values and design gives unbiased estimates of the effect as far as possible.

RECoMMENDED READING1.SPORTIF III, LANCET 2003;362:1691-16982. SPORTIF V, JAMA 2005; 293:690-6983. RE_LYNEJM 361; 1139-11514. RE-LY Clinicaltrials.gov NCT00262600 NDA 22-5125. RE-LY fda.gov UCM226704, fda.gov dabigatran clinical review6. RE-LY fda.gov dabigatran Advisory Committee Briefing Document

Bleeding outcomes: Definitions and adjudication issuesSpeaker: Maarten Simoons, Rotterdam, NEDDiscussant: Peter Clemmensen, Copenhagen, DEN

SATURDAY DECEMBER 4, 14:00 - 18:00

ExPERT WoRKSHoP ACUTE HEART FAILURE TRIALS. HoW To ovERCoME ENRoLLMENT CHALLENGES.Chairmen Mihai Gheorghiade, Chicago, USA; Faiez Zannad, Nancy, FRA

Introduction: Experience with recent trials in acute and chronic HF. Enrollment challenges and regional differences. Mihai Gheorghiade, Chicago, USA

Lessons from the largest Acute Heart Failure Trials: ASCEND HFChris O’Connor, Durham, USA

ABSTRACT

Background:Acute decompensated heart failure (ADHF) is a major public health burden with significant mortalityand morbidity. Nesiritide is a recombinantly produ-ced intravenous formulation of human B-type natriuretic peptide thatpromotes va-sodilation and increases salt and water excretion, which results in reduced cardiac filling pressures. Prior studieshave shown that dyspnea is improved in patients with ADHF 3 hours after nesiritide infusion with significant dose-relatedreductions in cardiac filling pressures and systemic vascular resistance without significant arrhythmias. However, the effect ofnesiritide on dyspnea at 6 or 24 hours is unk-nown, and no clinical outcome trials have been done to provide a reliable estima-teof the effect of nesiritide on morbidity and mortality.Methods: ASCEND-HF is a phase III study evaluating the efficacy and safety of nesiritide in patients with ADHF. Patients hospitalized for heart failure were ran-domly assigned to receive either intravenous nesiritide or matching placebo for 24 hours to 7 days. The 2coprimary end points were (1) assessment of acute dyspnea at 6 or 24 hours and (2) death or rehospitalization for heart failure within 30 days. Over 7,000 patients were enrolled worldwide between 2007 and 2010.Conclusions The data from the ASCEND-HF trial will establish whether nesiritide safely improves acute dyspnea as wellas morbidity and mortality at 30 days. The results of this trial will be presented at the American Heart Assocation (AHA) 2010 Scientific Sessions.

RECoMMENDED READING1. Hernandez et al. Rationale and design of the Acute Study of Clinical Effective-ness of Nesiritide in Decompensated HeartFailure Trial (ASCEND-HF)Am Heart J 2009;157:271-7.2. The VMAC Investigators. Intravenous nesiritidevs nitroglycerin fortreatment of decompensated congestive heart failure: a randomizedcontrolled trial. JAMA 2002;287:1531-40.3. Aaronson KD, Sackner-Bernstein J. Risk of death associated withnesiritide in patients with acutely decompensated heart failure. JAMA2006;296:1465-6.

Experience from Central EuropeEwa Jankowska, Wroclaw, POL

Experience from Western Europe Marco Metra, Brescia, ITA

Experience from the USAMihai Gheorghiade, Chicago, USA

Experience from South AmericaFelipe Martinez, Cordoba, ARG

ABSTRACT

Global approach is expanding to Medicine, and the cardiovascular therapeutics are not the exception. Multicentric international trials with pharmacologic interven-tions are being performed in the five continents. Heart Failure Trials are not the exception, and and the performance and results may vary among Regions.. This is the justified interest on the regional analysis. A large amount of multinational Heart Failure Trials have been done or are on going in South America, and in comparisson with other regions of the world., enrollment and key issues may be influenced by the following regional factors:1)Differences in gender and mean age of included patients. In general a higher number of women and younger population.2)Some differences in type and magnitude of risk factors. More cigarrette consumption, salty diet and saturated fat intake3)Longer hospitalization timelines in all types of heart failure4)Specific differences in diseases severity 5)Lower indication of interventional procedures and use of devices6)Ssome “regional” differences appear in Registries with “real world” patients.Interventions in the RAAS show higher numbers compared with the rest of the world. The opposite is observed with beta blockers and different dosing of statins.7) The impact of some endemic diseases affecting the cardiovascular system like Chagas , or the still mild incidence of rheumatic fever in some areas.On the other hand, there are some Regional “benefits and advantages” favouring enrollmrnt of heart failure patients such as:1)Closer relationship/interaction between phisycians and patients2)Strong family support3) Most areas with accurate weather4)Possitive attitude for Clinical TrialsAn accurate analysis of such observations may help Cardiologists and local Public Health Authorities, to facilitate enrollment and improve quality of studies in heart failure in the Region.

Experience from AfricaSemir Nouira, Mahdia, TUN

Semir Nouira, Mahdia, TUN

ABSTRACTThe prevalence of cardiovascular disease is growing in developing nations. Al-though most research participants continue to be recruited from the USA and Eu-rope, African participants are not sufficiently involved in international countries. Their inclusion in such clinical studies is a crucial step for running clinical trials in the modern era. Although, this issue has not been well addressed in the literature, the recruitment may be more challenging when the study involves people from low income countries. Indeed, the conduct of clinical research in developing countries setting involves unique challenges. Examining the capacity to participate in clinical trials shows that there are structural constraints and cultural impediments that affect both investigators and participants. First, investigators in developing countries may not be trained in good clinical prac-tices and data collection can be difficult with regard to the lack of specific research assistants. Some issues are related to logistical issues because the concept of a research team is not well developed while the clinical nurse is rarely actively involved in conducting research. Second, differences in socioeconomic status, ethnicity, education, or language between participants and researchers may pre-sent challenges to research participation and understanding of the purpose of the research leading to therapeutic misconception. Often, in low-income countries the individuals believe they may receive better treatment when participating in research. Third, weakness of financial management systems is another barrier to develop clinical trials. Official institutions are frequently unable to spend grant funds effectively, leading to administrative delays for research projects. In addition, they have not sufficient highly trained staff available to commission, interpret or evaluate research and in some countries promotion of researchers has nothing to do with their productivity. Fourth, there is usually a communication gaps between international planners and local investigators. Understanding these constraints is important if we want to improve low-income countries contribution in international clinical trials. Local researchers are to be sustained over time and effort must be invested in their training. Technical assistance should be provided at numerous stages in the research process as early as the preliminary steps of problem iden-tification. Investigators, sponsors, and regulators should ensure that the research question is relevant to the population studied and that the population is in a position to benefit from the results of the research. We also need to carefully consider potential participants’ rights and ensure that sound ethical principles underpin the trial. In conclu-sion, the involvement of low income countries, such African ones, in multinational trials should be encouraged, language, education, culture, beliefs, and decision-making sty-les are not potential barriers to obtain significant contribution in clinical trials. Clinicians from these countries could yield other interesting, and possibly different, results which is crucial to developing a realistic longer-term perspective.

RECoMMENDED READING1. Roberto Jun Arai, Max Senna Mano, Gilberto de Castro Jr, Maria Del Pilar Es-tevez Diz, Paulo Marcelo Gehm Hoff. Building research capacity and clinical trials in developing countries. The Lancet Oncology 2010; 11: 712-713.2. M Hussain Gambles, B Leese, K Atkin, J Brown, S Mason, P Tovey. Involving South Asian patients in clinical trials. Health Technology Assessment 2004; 8: 42.3. Trostle J, Simon J. Building applied health research capacity in less developed countries: problems encountered by the ADDR project. Soc. Sci. Med. 1992; 35: 11.4.Kass NE, Maman S, Atkinson J. Motivations, understanding, and voluntariness in international randomized trials. IRB 2005; 27:1-8. 5.Mapstone J, Elbourne D, Roberts I. Strategies to improve recruitment to re-search studies (review). The Cochrane Collaboration. 2007; 2:1-15. 6.Ellis E, Biegel B, Hamon M, Carlson B, Jimenez S, Parkington S. The challen-ges of conducting clinical research: one research team’s experiences. Clin Nurse Spec. 2001;15:286-294.

Experience in AsiaPrem Pais, Bangalore, IND

organizational aspects of better HF studiesWhat should the common mechanism be – the “nuts and bolts” of regulatory packages and contractsGad Cotter, Durham, USA

Gad Cotter, Durham, USA

Gad cotter MD – Born 1964, received his medical education in Israel and specia-lized in cardiology with a special interest in heart failure. In 2004 moved to the US where he served as an attending physician in Duke and worked as a researcher at DCRI. Since 2007 the head of Momentum-Research a consulting clinical research company specializing in heart failure and acute cardiac conditions. Was involved with multiple clinical studies in the field of acute HF such as RITZ, VERITAS, Protect and Relax AHF. Beyond clinical research Dr. Cotter has published subs-tantially in the field of HF, adherence research and is interested in the diversity of HF around the globe

ABSTRACT

OutlineOne of the most important limitations of Acute HF research is the lack of uni-fying definition and patient’s selection. AS recently described by Pang et al (ref) patients enrolled in clinical AHF studies differ dramatically by region. Some of this divergence may relate to the fact that HF is caused by different diseases in different areas (HTN is the lead cause of HF in Africa while IHD causes < 5% of the disease). However, in some cases the wide variability leads to a “sampling error”. I.e, despite the fact that in many countries and regions HF is caused by similar processes patients enrolled in clinical studies are different. This “sampling error” may be the result of multiple processes. One important process is the site selection for clinical studies. Sites that participate in clinical studies are motivated differently in different regions of the world. In some, financial incentives are more important while in others the scientific mission behind research is an important driving force. The first, will bias studies towards investigators in less-well-to-do hospitals to be more motivated to enroll patients, skewing the patients’ population towards lower economical class, less compliant patients while the second will bias studies towards academcial centers where patients tend to have more severe advanced chronic disease and patients in higher socioeconomical strata. The other major factor in conducting clinical research is the complexity of study “start up” i.e., how much effort and time will the site have to invest into starting the study. In regions where the effort is substantial study start up is prolonged, making sites less represented in the clinical study first, since many will drop out during the process and second, since those who will finally participate will have less time to contribute. How can we address these issues? A potential way forward would be to create a dedicate network of sites that can perform clinical studies. Such network will ideally have a weighted representation from different types of centers (community, metropolitan, private, academcial, etc) representing the real life distribution of acute HF patients. By creating a priori criteria for ratios of patients in each “sub group” the studies would become more representative and their application to real life would be simplified. Importantly such distribution should be carefully determined on regional basis to represent well not sub-populations of patients by region. Second, the network would allow a set up of contracts and regulatory packages that would simplify and shorten subs-tantially the start up period enabling a fast ramp up of clinical studies regardless of local barriers.In conclusion clinical AHF research would benefit from establishing a network of research sites which would represent real life patients and enable smooth perfor-mance of studies.


RECoMMENDED READING1. Collins SP, Pang PS, Lindsell CJ, Kyriacou DN, Storrow AB, Hollander JE, Douglas Kirk J, Miller CD, Nowak R, Frank Peacock W, Tavares M, Mebazaa A, Gheorghiade M. International variations in the clinical, diagnostic, and treatment characteristics of emergency department patients with acute heart failure syndro-mes. Eur J Heart Fail. 2010; 12: 1253-60.2. Blair JE, Zannad F, Konstam MA, Cook T, Traver B, Burnett JC Jr, Grinfeld L, Krasa H, Maggioni AP, Orlandi C, Swedberg K, Udelson JE, Zimmer C, Gheorghia-de M; EVEREST Investigators. Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program. J Am Coll Cardiol. 2008; 52:1640-8.3. Akkerhuis KM, Deckers JW, Boersma E, Harrington RA, Stepinska J, Mahaffey KW, Wilcox RG, Lincoff AM, Keltai M, Topol EJ, Califf RM, Simoons ML. Geo-graphic variability in outcomes within an international trial of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes. Results from PURSUIT.. Eur Heart J. 2000; 21: 371-81.4. Simes RJ, O’Connell RL, Aylward PE, Varshavsky S, Diaz R, Wilcox RG, Arms-trong PW, Granger CB, French JK, Van de Werf F, Marschner IC, Califf R, White HD; HERO-2 Investigators Unexplained international differences in clinical out-comes after acute myocardial infarction and fibrinolytic therapy: lessons from the Hirulog and Early Reperfusion or Occlusion (HERO)-2 trial. Am Heart J. 2010; 159: 988-97.5. Collins SP, Levy PD, Lindsell CJ, Pang PS, Storrow AB, Miller CD, Naftilan AJ, Thohan V, Abraham WT, Hiestand B, Filippatos G, Diercks DB, Hollander J, Nowak R, Peacock WF, Gheorghiade M. The rationale for an acute heart failure syndromes clinical trials network. J Card Fail. 2009; 15: 467-74.

Understanding the heterogeneity of the syndrome: The need of a global registry of HF patients.Faiez Zannad, Nancy, FRA

How can we do better studies? Lothar Roessig, Bayer, GER

Lothar Roessig, Bayer, GER

Lothar Roessig received his MD form the Hannover Medical School, Germany. He is board certified in Cardiology and in Internal Medicine, and serves as a Lecturer in Medicine at the Goethe University of Frankfurt, Germany. A senior cardiologist and member of the faculty at the University Hospital Frankfurt, he participated as clinical investigator in numerous cardiovascular trials, including ENABLE (Endo-thelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) and the European Heart Survey until 2007, when he moved into clinical reasearch indus-try. Since October 2009 he is appointed at Bayer HealthCare as Global Clinical Leader for the development program of a soluble guanylate cyclase stimulator in left heart failure. Lothar Roessig authored more than 30 international scientific publications, peer reviews for various cardiovascular journals including Circula-tion, and was finalist of the American Heart Association Samuel A. Levine Young Clinical Investigator Awards.

ABSTRACT

Within the past decade numerous new molecules with various pharmacodyna-mic actions have been investigated for the treatment of patients with acute heart failure syndromes, but none of these trials demonstrated clinical benefit in terms of improved outcomes. While these failures may indicate inappropriate mechanis-tic approaches or insufficient efficacy of the tested compounds, both design and conduct of trials to enroll the appropriate patients entered central stage of drug development. Future strategies to explore novel drug candidates will, therefore, need to ensure from the early stages of development on that the relevant patho-

physiological mechanism(s) upstream of the clinical manifestation of congestion are targeted and a complete cardiovascular pharmacodynamic effect and safety profile is characterized in each relevant group of patients, before clinical outco-mes are evaluated in the appropriate target population. We do not need larger studies, but a focussed approach to target mechanisms of highest relevance in dedicated risk populations of patients. To acknowledge the emerging role of renal and cardiac injuries that drive heart failure worsening, their underlying mecha-nisms could perhaps provide a more promising target than principles aiming at the compensation of their deleterious consequences. Of paramount importance for the implementation of these principles, however, drug characterization should not remain limited to elaborate pre-clinical and early clinical assessment before undergoing default clinical development programs. Instead, a dedicated approach has to accommodate each individual molecule of interest throughout the entire clinical investigation plan. As the execution of the chosen trial concept is central to succesful exploration of clinical efficacy and safety, a close and early interaction between clinical investigators and trialists has to underly protocol design as part of the overall development plan to warrant a feasible and valid conduct. Robust positioning of any novel compound to target causal pathophysiological mecha-nisms of worsening heart failure will, therefore, require immediate, interactive, and prospective integration of this profile into every detail not only of the protocols, but also the associated logistic and administrative aspects of clinical trial conduct.

RECoMMENDED READING1. Pang PS, Komajda M, Gheorghiade M. The current and future management of acute heart failure syndromes. Eur Heart J. Apr 2010;31(7):784-7932. Bueno H, Ross JS, Wang Y, et al. Trends in length of stay and short-term out-comes among Medicare patients hospitalized for heart failure, 1993-2006. JAMA. Jun 2 2010;303(21):2141-21473. Felker GM, Pang PS, Adams KF, et al. Clinical trials of pharmacological thera-pies in acute heart failure syndromes: lessons learned and directions forward. Circ Heart Fail. Mar 2010;3(2):314-3254. Fonarow GC, Adams KF, Jr., Abraham WT, et al. Risk stratification for in-hospi-tal mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA. Feb 2 2005;293(5):572-5805. Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation. Jun 15 2010;121(23):2592-2600

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INdUSTRY INFORmATION

ASTRAZENECA

AstraZeneca is a global, innovation-driven, integrated bio-pharmaceutical company. Our mission is to develop inno-vative and effective new medicines that fulfil unmet medical needs in important areas of healthcare. AstraZeneca has been at the forefront of cardiovascular re-search since pioneering the development of beta-blockers more than 50 years ago.Our cardiovascular R&D focus is on discovering and deve-loping effective treatments for the major cardiovascular risk factors and in particular type 2 diabetes, obesity, atheroscle-rotic cardiovascular disease, thrombosis and arrhythmias. The corporate headquarters of AstraZeneca are in the UK, and the company has R&D and manufacturing sites throu-ghout the world. The R&D headquarters for cardiovascular medicine are situated in Mölndal, Sweden.

ASTRAZENECA S-431 83 MölndalSwedenTel: +46 31 7761000 Fax: +46 31 7763806Web site: www.astrazeneca.com

BIoTRoNIKExcellence for Life – BIoTRoNIK Company Profile

Company BIOTRONIK is a leading European manufacturer of medical technology with worldwide market presence and an unwavering patient focused philosophy. The company develops, manufactures and sells devices for cardiac rhythm management and vascular intervention. Its products aid the physician in saving lives and improving the quality of life for both patients and their families. BIOTRONIK maintains R&D and production sites in Europe and North America, and mar-kets its products in more than 100 countries on all continents.

BIoTRoNIK SE & Co. KGWoermannkehre 112359 BerlinTel: +49 (0) 30 68905-1400Fax: +49 (0) 30 68905-1940www.biotronik.com

GE HEALTHCARE

GE Healthcare is dedicated to helping you transform heal-thcare delivery by driving critical breakthroughs in biology and technology. Our expertise in medical imaging and in-formation technologies, diagnostics, patient monitoring sys-tems, drug discovery, and biopharmaceutical manufacturing technologies is enabling healthcare professionals around the world discover new ways to diagnose and treat disease earlier. We call this model “Early Health”. Our goal is more targeted treatments, so they can help their patients live their lives to the fullest.

GE HEALTHCAREChalfont, St. GilesBuckinghamshireUK+ 44 1494 544000+ 44 1494 498234www.gehealthcare.com

BoSToN SCIENTIFICBoston Scientific is a worldwide developer, manufacturer and marketer of medical devices with approximately 25,000 em-ployees and revenue of $8.118 billion in 2009. For more than 30 years, Boston Scientific has advanced practice of less-inva-sive medicine by providing a portfolio of innovative products, technologies and services across a wide range of medical spe-cialties among which Cardiac Rhythm Management. Company’s mission is to improve quality of patientcare & pro-ductivity of healthcare through development and advocacy of less-invasive medical devices & procedures, accomplished through continuing refinement of existing products and proce-dures and investigation of new technologies which can reduce risk, trauma, cost, procedure time and need for aftercare.

GUIDANT EURoPE A Boston Scientific CompanyLambroekstraat 5D1831 DiegemBelgiumwww.bostonscientific-international.com.


NovARTISANovartis provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving gene-ric pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only com-pany with leading positions in these areas. In 2009, the Group’s continuing operations achieved net sales of USD 44.3 billion, while approximately USD 7.5 billion was inves-ted in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100.000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

MEDTRoNIC

At Medtronic, we’re committed to Innovating for Life by pushing the boundaries of medical technology and actually changing the way the world treats chronic disease. Driven by our deep understanding of the human body and our close partnerships with physicians, we’re transforming technology to treat patients across the entire care continuum. Our in-novations help physicians diagnose diseases early, treat patients with the least amount of disruption possible, and minimize symptoms throughout the patient’s life. Today, we’re improving the lives of millions of people worldwide each year across numerous conditions—including heart di-sease, diabetes, neurological disorders, spinal conditions, and vascular diseases. But it isn’t enough. So we’re innova-ting beyond products. We’re breaking down barriers, chal-lenging assumptions, and looking beyond the status quo—to continually find more ways to help people live better, longer.

Medtronic was founded in 1949 as a medical equipment re-pair company by Earl Bakken and his brother-in-law, Palmer Hermundslie. Today, we’re the world’s largest independent medical technology company. We employ 38,000 people worldwide - serving physicians, clinicians, and patients in more than 120 countries.

RELYPSARelypsa is a clinical-stage biopharmaceutical company lea-ding the discovery and development of novel non-absorbed polymeric drugs for important applications in cardiovascular and renal diseases. Relypsa’s lead product candidate is RLY5016, a non-absorbed potassium binder for the treat-ment of hyperkalemia. RLY5016 is also a safe method for eliminating the substantial risk of hyperkalemia that cur-rently prevents the prescription of the most effective CKD and heart disease medications. Relypsa is dedicated to the discovery of additional product candidates through use of its proprietary polymer platform.

RELYPSA INC.Dr. Gerrit Klaerner 5301 Patrick Henry DriveSanta ClaraCA 95054 USATel: +1 408.200.9555 [email protected] www.relypsa.com

PFIZER INC.Pfizer Inc.: Working together for a healthier world™

At Pfizer, we apply science and our global resources to improve health and well-being at every stage of life. We strive to set the standard for quality, safety and value in the discovery, development and manufacturing of medicines for people and animals. Our diversified global health care port-folio includes human and animal biologic and small mole-cule medicines and vaccines, as well as nutritional products and many of the world’s best-known consumer products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treat-ments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as the world’s leading biopharmaceutical company, we also collaborate with health care providers, governments and local commu-nities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfi-zer has worked to make a difference for all who rely on us.



SERvIERServier is a private independent pharmaceutical company.

The Company has developed drugs for the treatment of hy-pertension, cardiac ischemia, and heart failure. Procoralan (ivabradine), Vastarel MR (trimetazidine), Coversyl (perin-dopril), Coveram (perindopril-amlodipine), Preterax (perin-dopril-indapamide) and Natrilix SR (indapamide) are six of our major cardiovascular drugs.

Procoralan (ivabradine), the first If inhibitor on the market, is indicated for the symptomatic treatment of chronic stable angina. Servier is currently developing new drugs in the cardiovas-cular field, which accounts for 60% of its turnover.

www.servier.com

TAKEDABased in Deerfield, Ill., Takeda Global Research & De-velopment Center, Inc. is a subsidiary of Takeda Phar-maceutical Company Limited, the largest pharmaceutical company in Japan. The company seeks to bring innova-tive products to patients through a pipeline that includes compounds in development for diabetes, cardiovascular disease, gastroenterology, neurology and other conditions. To learn more about Takeda, visit www.takeda.com.

RoCHE

Headquartered in Basel, Switzerland, Roche is a leader in re-search-focused healthcare with combined strengths in phar-maceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in on-cology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible impro-vements in the health, quality of life and survival of patients. In 2009, Roche had over 80’000 employees worldwide and invested almost 10 billion Swiss francs in R&D. The Group posted sales of 49.1 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Ro-che has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.

POSTERS

POST

ERS


SILDENAFIL AS A TREATMENT FoR HEART FAILURE

Oswald Londono SánchezSusana Pacreu, Luis Paredes

INTRoDUCTIoNWe realized a follow-up with 30 patients after Hospital discharged for heart failure for a couple of weeks. These group have a peculiar characteristic: are patient between 55 and 65 years old with a wonderful quality of life before actual disease, that for different reason came into heart failure for ischeamic disease (myocardial infarction, atrial fibrillation and hypertensive crisis).We random them with sildenafil and 15 patients asigned to placebo, with 3- and 6- month assesments fo cardiopulmonary treadmile test, echo-cardiography doppler procedures.

oBJECTIvESWe really know that nitric oxide represents a challenge for recovering pulmonary capacity leading to improve the ejection fraction in patients with heart failure at the Intensive Care Units. We gave 50mg of sildenafil twice per day in this group of patients.

RESULTSSildenafil improved pulmonary capacity and ejection fraction. These findings suggested us the potential benefits of sildenafil in heart failure improving pulmonary capacity through the endothelium modulation of the muscle due to exercise.In the group treated with sildenafil we observed reduction of systolic pulmonary atery pressure (from 30,3 tol 23,6 mmHg and 21,5 mmHg), ergoflex effect on ventilation (from 5,7 to 3,1 l.min-1 and 1.9 l.min-1), ventilation to CO2 production slope (VE/Vco2, from 33.5 to 31,8 and 29.7), and brethlessness (score) (from 21.5 to 17,1 and 18.2), and an increase of FMD (from 8.5% to 13.4% and 14.2%), peak Vo2 (from 12.8 to 19,2 ml.min-1.kg-1 and 17.7 ml.min-1) and ratio of Vo2 to work rate changes (from 6.7 to 9.6 and 10.1) All changes were significant at p<0.01.No adverse effects were observed.

CoNCLUSIoNSIn patients with heart failure, sildenafil improves exercise ventilation and aerobic capacity and is sustained and is significntly related with an endothelium-mediated attenuation of exercising muscle oversignaling. Chronic use of sildenafil is a wonderful tool for heart failure treatment.

oRACLE-RF REGISTRY

Alexander G. AruytyunovDaria D. Pashkevich

First Open Registry of a cute decompensated heart faiLure syndrome and concomitant diseases in Russian Federation – epidemiological study ORACLE-RF

This registry do not have the aim to analyze the prevalence of chronic heart failure in Russian Federation, the trials ”EPOCH” and “EPOCH about HF” fully answer this questions.

The primary study objective of this registry is to investigate only the acute decompensated heart failure syndrome (ADHF) and therapeutics comorbidity on patient population in Russian Federation in different regions. None of such data is available for Russian Federation.

Important point is that in this registry ADHFS will be investigated like stand alone syndrome and correlation with concomitant disease and conditions will come through further analyze.

First aims are to collect information of prevalence of ADHFS, rehospitalization and death rate, concomitant medication.

The aims are also to investigate the main cause of ADHF. Important is to determine the dominating risk factors leading to decompensation and to investigate the role of other risk factors in future prognosis.

Special position in this registry is investigation the role of chronic and acute infection in pathophysiologycal mechanisms of decompensation. All concomitant disease and concomitant medication will be marked in the CRF.

Registry starts 05.09.2010

Enrollment period 1 year, follow up period - 1 year.


EFFECT oF CARvEDILoL, IvABRADINE AND THEIR CoMBINATIoN oN ExERCISE CAPACITY IH HEART FAILURE

Maurizio Volterrani, MD Giuseppe Marazzi, MD, PhD Francesco Pelliccia, MD, PhD Gennaro Cice, MD Cristiana Vitale, MD, PhD Michele Gabriele, MD Giuseppe Caminiti, MD Giuseppe M.C. Rosano, MD, PhDGennaro Cice, MD Cristiana Vitale, MD, PhD Michele Gabriele, MD Giuseppe Caminiti, MD Giuseppe M.C. Rosano, MD, PhD

Patients with heart failure have a limited exercise capacity. ACE-inhibitors and beta-blockers improve survival and quality of life in patients with heart failure. However, in clinical practice beta-blockers are seldom used at doses that have been shown to reduce events and are often under-used. Furthermore, studies have yielded conflicting results on the effect of adequate beta-blockade on exercise capacity in patients with heart failure. Ivabradine is effective in reducing cardiovascular events in patients with left ventricular dysfunction of ischaemic origin and elevated heart rate and when administered in combination with atenolol it has been shown to be more effective than atenolol alone in improving exercise tolerance in patients with ischemic heart disease.

Aim of the present study was to assess the effect of heart rate reduction with Carvedilol, Ivabradine and their combination on exercise capacity in 120 patients with heart failure (NYHA Class II-III) receiving maximal ACE-inhibitor dose.

After a run-in phase during which patients underwent two 6 minute walking test (6MWT) patients were randomised into 3 groups: Carvedilol up to 50 mg/day, Ivabradine up to 15 mg/day, Carvedilol-Ivabradine up to 25/10 mg/day. Drug therapy was up-titrated at 2 weeks intervals. Only patients with a 6MWT exercise tolerance between 200 and 400 m and with a variability between the two baseline tests <10% were included.

Maximal dose of study drug/combination was more frequently tolerated by patients allocated to Ivabradine (36/40) compared to those allocated to Carvedilol (18/40) or to combination therapy (32/40) (p<0.01 Ivabradine vs Carvedilol). The most frequent reason for sub-optimal up-titration was excessive blood pressure reduction (26 patients).

Exercise capacity improved significantly more in patients allocated to Ivabradine compared to those receiving Carvedilol or Ivabradine-Car-vedilol (38% vs 15% vs 27%, %change compared to baseline, p<0.01 ivabradine vs carvedilol; p<0.05 ivabradine vs combination therapy; p<0.05 combination therapy vs carvedilol). Similar improvement in exercise tolerance assessed by MVO2 and in quality of life were observed.

CoNCLUSIoNSIvabradine alone or in combination with carvedilol is more effective than carvedilol alone at improving exercise tolerance and quality of life in patients with heart failure. RELATIoNSHIP BETWEEN PLASMA NEURoPEPTIDE Y AND CIRCADIAN BLooD PRESSURE CHANGES IN HYPERTENSIvE PATIENTS

Vizir V.A.,Voloshyna I.M. Zaporozhye State Medical University,UkraineBulanova N.A. ., Popov V.V Moscow Medical Academy named after I.M. Sechenov, Moscow, Russia

oBJECTIvESTo evaluate the level of plasma neuropeptide Y (NPY) in hypertensive patients with and without stroke and to estimate its relationship with circadian blood pressure (BP) changes.

MATERIALS AND METHoDSSixty four hypertensive patients (36 men, 28 women) aged 54±2,7 years and 32 healthy normotensive volunteers (18 men and 15 women) aged 50±4,2 years were included in this study. Twenty-four hours blood pressure measurements («Cardiotens» monitor, Meditech, Hungary) were made to all subjects withcalculations of 24-hour systolic and diastolic BP, 24-hour heart rate, 24-hour systolic BP variability and nocturnal BP dipping (NBPD). Plasma concentrations of NPY and noradrenalin were determined by immunoassay method.

RESULTSThe mean value of NPY in hypertensive patients was 44, 2±5,8 pg/ml, the mean for noradrenalin was 205,1±2,8 pg/ml that were significantly higher comparing with healthy normotensive volunteers (NPY - 9,3±1,9 pg/ml, noradrenalin - 168,3±5,3 pg/ml, p<0,001). The correlation between NBPD and level of noradrenalin was -0,45 (p<0,001), between NBPD and level of NPY it was revealed to nonlinear dependence as an U-curve which was described by equalization of regression: NPY = 53,3998 - 1,5257∙NBPD, (p=0,0047). Patients with night BP rising had the largest levels of plasma noradrenalin (223,6± 6,7 pg/ml), NPY (98,3± 13,5 pg/ml) and systolic BP variability (17,2±0,9 mm Hg) compered with the healthy subjects (n=32, NPY - 9,3±1,9 pg/ml, noradrenalin - 168,3±5,3 pg/ml, BP variability - 11,3±1,2 mm Hg) and hypertensive patients with BP profiles dipper (n=17, NPY - 11,2±2,5 pg/ml, noradrenalin - 197,6±5,7 pg/ml, BP variability - 13,4±1,1 mm Hg). Non-dipper patients had the same BP variability like piker subjects (n=24, BP variability - 16,1±0,8 mm Hg) but significantly lower levels of sympathetic me-diators (NPY – 30,7±3,7 pg/ml, noradrenalin - 207,3± 3,7 pg/ml). In sub-groups of over-dipper (7 patients) the levels of plasma NPY was 102,4±17,1 pg/ml like in piker patients but the noradrenalin level was normal (173,7±2,4 pg/ml).

CoNCLUSIoNSHypertensive patients with night BP rising had significant simultaneous elevation of NPY and noradrenalin plasma levels that was less expressed in non-dipper patients. The association of significant elevation plasma NPY with normal level of noradrenalin was observed in over-dipper sub-jects.

DAILY STRUCTURE oF ARTERIAL BLooD PRESSURE AT PATIENTS WITH RHEUMAToID ARTHRITIS AND ITS INFLUENCE

Dr. Elina MikhaylovaProfessor Vladimir Popov, Dr. Nataliya BulanovaCardiology Department, Yaroslavl Regional Clinical Hospital, Yaroslavl, Russia.

INTRoDUCTIoNBackground: During past years success was achieved in a therapy of rheumatoid arthritis (RA), but in a meantime, it didn’t decrees the death rate mostly because of cardiovascular diseases. These have been shown to be associated with functional abnormality of the arterial wall.

oBJECTIvESTo study daily structure of arterial blood pressure (ABP) in patients with RA and its influence on cerebral circulatory dynamics, with IMT (intima media thickness) evaluation in a common carotid artery.

METHoDS 92 (65%) patients with RA, 50 (35%) patients with arterial hypertension (AH) and 30 controls matched on age, sex, and ethnicity. The group of RA was divided it to two groups: those who had RA+AH- 55 (59, 7%) and those who didn’t suffer that disease: RA without AH- 37 (40, 3%).

MEASUREMENTS Daily monitoring of ABP; common carotid and cerebral arteries ultrasonography.

RESULTS RA with AH group: the reduction of patients with adequate decrease of BP at night revealed: the profile type non-dipper, was defined at 47 % of cases, in group of healthy population their percent has made - 13. At patients with arterial hypertension is 56 %.In a group of RA with AH there were patients with night hypertension profile type night-peacker in 26,5 % cases, in group of patients with AH-17 %. The configuration of profile at patients with RA without AH essentially differed from controls and repeated group of patients with AH. Among patients with R without AH the profile type non-dipper met in 73 % of cases.At comparison of cerebral haemodynamics and the daily BP measurements at RA with AH patients, inverse relationship between average speed of haemodynamics in a common carotid artery to a systolic BP for a day and for a night, average arterial diastolic BP for a night. For intracranial arteries similar terms are established.At patients with RA without AH, despite normal figures of BP, the similar correlations were revealed of daily BP measurements, with indicators of cerebral haemodynamics that testifies the increase in system vascular resistance at patients with RA in comparison with controls. At the research of a common carotid artery, at patients with RA, irrespective of presence or absence of AH, a thickness of IM is authentic more than in controls: 0,10±0,04 mm vs 0,05±0,01 mm.

CoNCLUSIoN The formation of AH is connected with abnormal relaxing function of the endothelium which effects the increase of the wall thickness of cerebral arteries and the increase of peripheral vascular resistance of cerebral arteries. The drop of the speed parameters of a blood-groove and rising load by the pressure, changes in the circadian rhythm of ABP may lead to AH formation and, as a result, to the increase of cardiovascular morbidity and mortality. This closely has to be explored with lengthy, prospective and controlled studies, which are currently lacking.


CoMPLIANCE WITH TREATMENT AND CARDIovASCULAR CoMPLICATIoNS RISK IN PATIENTS SURvIvED ACS

Nikita F. PuchinyanNikolay V. Furman, Lidia I Malinova, Polina V. Dolotovskaya, Yakov P. Dovgalevsky

GoAL oF THE STUDYTo estimate platelets functional activity in patients with coronary heart disease during clopidgrel medication (75 mg a day.) and possible influence of incomplete platelets aggregation activity inhibition on rethrombosis events risk.

MATERIALS AND METHoDS271 patients with acute coronary syndrome in consecutive order hospitalized in urgent cardiology department were involved in the study. All participants according to clinical guidelines were treated with antiplatelet agents, -adrenic bloching agents, ACE- inhibitors, statins. Frequency of potentially improving coronary heart disease clinical course medication administration was analyzed. Phone contacts with patients (relatives) were performed at 1, 3, 6, 12 months points (since baseline). Cardiovascular complications including death, myocardial infarction, stroke, unstable angina pectoris and heart failure decompensation were followed up during 12 months period. Compliance with recommended treatment was estimated.

RESULTS Aspirin was recommended after discharge from the hospital in 98%, -adrenic bloching agents –in 95%, ACE- inhibitors in 97%, statins – in 44%. At 12 months point only in 73% patients continued aspirin medication, in 66% - -adrenic bloching agents medication, in 74% - ACE- inhibitors medication, and in 44% - statins medication.Within patients discontinued recommended medication (on any possible purpose) frequency of rehospitalization caused by clinical state worse-ning was significantly higher: 80% (32 patintes) vs 24% (55 patients). The main reason of hospitalization included heart failure decompensation (46%), angina pectoris clinical signs resumption (32%), and iterative acute coronary syndrome (19%).

CoNCLUSIoNSignificant part of patients (about 1/3) discontinues recommended therapy within 12 months after acute coronary syndrome. Unsatisfactory low compliance with recommended therapy mostly caused by subjective reasons and was associated with threefold increase of cardiovascular complications risk (OR = 3.27, CI 2.49-4.30, p level = 0.05).

CLoGPIDoGREL RESISTANCE AND CASES oF NoN SUCCESSIvE TREATMENT

Nikita F. PuchinyanNikolay V. Furman, Lidia I. Malinova, Yakov P. Dovgalevsky

GoAL oF THE STUDYTo estimate compliance with recommended therapy in patients survived acute coronary syndrome (ACS) and cardiovascular complications risk within 12 months since discharge from the hospital, to evaluate possible reasons of unsatisfactory low compliance with recommended therapy.

MATERIALS AND METHoDS87 patients under clopidogrel medication (in standard dose of 75 mg a day) were included in the study (39 were after acute coronary syndrome, 48 – patients with stable angina pectoris II and III functional class). All patients were undergoing full clinical investigation with addition of platelets aggregatometry. Induced ADP (5 mcm/l) platelets aggregation was performed.

ADP induced platelets aggregation exceeding 50% during clopidogrel medication was considered as high residual platelets activity.

Combined end point included sudden death, myocardial infarction, ishaemic stroke and verified stent thrombosis to estimate influenceof high residual platelets aggregation activity upon rethrombotic events risk. Following up period was 24-32 months (28,34±8,7).

RESULTSAAPD induced platelets aggregation in studied group was under normal variation. There were 15 rethrombotic evens in the whole group: 9 cases of myocardial infarction and 6 stent thrombosis within 12 patients.

In all patients with high residual platelets activity during clopidogrel medication rethrombotics events were associated with stent thrombosis.

CoNCLUSIoNPatients with hight residual platelets functional activity were of increased relative risk rethrombosis events comparing to with adequate reaction upon antiplatelets therapy (CI 95% 4,39; 17,84 =0,05).

CoNNECTIoN BETWEEN THE HEART RATE, INDECES oF ERF AND ovERWEIGHT IN YoUNG PEoPLE

Slepchenko N.S.Sidorov A.A., Mostovoy Y.M.

THE AIM oF THE STUDY was to estimate the influence of overweight (body mass index (BMI)=25-29,9 kg/m²) on parameters of electrocardiogram (ECG) monitoring for 24 hours, on indices of external respiration function (ERF) and parameters of quality of life in people of young age. During the study we also tried to find correlation between the BMI, indices of ERF and parameters of day’s monitoring of ECG.

METHoDS523 young people including 175 (33,8%) males and 342 (66,2%) were enrolled into clinical-and-anthropometric study. All these persons comple-ted special questionnaire concerning physical activity, height and weight were measured, BMI was calculated. After that 2 groups were separated from all the persons who were enrolled. The first group consists of young people (n=45) with overweight (BMI=28,1±1,5 kg/m²), average age is 23,5±2,7 years. The second group consists of young persons (n=45) with normal weight (BMI=21,6±1,9 kg/m² ), average age is 22,7±2,9 years. There is the same amount of people in each group for providing maMonitoring of ECG for 24h and studying of ERF at rest and after 6-minute walk were performed. All the people in each group completed questionnaire MOS SF-36 to estimate the quality of life. Statistic program SPSS 16.0 was used for working with data.

RESULTS16,3% of the people who were included had overweight, but no obesity. Regular physical activity was absent more frequently in people with overweight (71% vs 64,3%, p<0,05). No considerable changes in forced exhalation volume for the first second (FEV1) and forced vital capacity (FVC) were noticed at rest. After physical activity decrease of FEV1 by 7,5±1,7% was seen in 9 (20%) of 45 people with overweight. Daily heart rate was higher in people with overweight (81,4±3,3 per minute vs 74,9±4,7 per minute). Overweight persons were found to have significantly decrease indices of physical activity, social activity, psychic health and state of health as compared with the same indices in the people with normal weight. Decreased indices were demonstrated both in male and female, but females had lower indices of psychological status than ma-les (72,3±3,5 vs 86,2±5,7). There is a direct correlation between the BMI and heart rate (r=0,41). There is no correlation between the BMI and indices of ERF. Correlation is absent between the heart rate and indices of ERF.

CoNCLUSIoNIn young age overweight is associated with subclinical functional changes of cardiovascular and respiratory systems. These data show that overweight in young age may be discussed as a predictor of combined cardiopulmonary pathology in mature age. Overweight also leads to substantial decreasing of quality of life, especially in women.

INFLUENCE oF SMoKING AND PRE-oBESITY oN CARDIoRESPIRAToRY PARAMETERS IN PEoPLE oF YoUNG AGE

Sidorov A.A.Slepchenko N.S., Mostovoy Y.M.

AIMWe decide to estimate the prevalence of combination of pre-obesity and smoking among the people of young age (18-25 years) and their cumulative influence on day’s heart rate and indices of external respiration function (ERF).

METHoDS523 young people were asked to complete the special questionnaire. Anthropometric examination also was performed. After that three groups of people were separated from all included persons. The first group consists of the nonsmoking people (n=41) with normal weight ( body mass index (BMI)=22,5±1,8 kg/m²). The second one was formed of the nonsmoking people (n=42) with overweight (BMI=28,6±1,2 kg/m²). The third group consists of the smoking people (n=33) with overweight (BMI=27,8±1,3 kg/m²). Day’s monitoring of the electrocardiogram (ECG) and spirometry were performed to all the persons in three groups. Statistic program SPSS 16.0 was used for working with data , which were received.

RESULTSThe prevalence of the overweight is 16,3%, the prevalence of the smoking is 27,3%. The combination of this two risk factors occurs in 6,4% of the people. The day’s heart rate was 73,5±3,7 per minute in nonsmoking people with normal weight, it was 82,3±4,8 per minute in nonsmoking people with overwei-ght (82,3±4,8 vs 73,5±3,7, p=0,043). This parameter was 84,8±5,1 per minute in smoking people with overweight (84,8±5,1 vs 82,3±4,8, p>0,05). There were no statistically reliable difference between the forced vital capacity (FVC), forced exhalation volume for the first second (FEV1) and other indices of ERF among the 3 groups. But it was tendency to worsening of FEV1. In the first group it was 105,2±6,7%, in the second one – 101,3±7,1%, in the third group – 96,4±5,9%. We have find a correlation between the BMI and heart rate (r=0,41). Correlation also presents between the severity of nicotine dependence and day’s heart rate (r=0,43). There was no difference in frequency of supraventricular and ventricular extrasystoly in all groups.

CoNCLUSIoNSOn the whole smoking leads to strengthening all negative tendencies which are connected with overweight. Combination of these factors may be more hard predictor of the combined cardiopulmonary pathology in mature age than the each factor alone.


ovERvIEW oF INTERNATIoNAL CARDIovASCULAR CLINICAL TRIALS IN RUSSIA

Arkhipchuk OlgaBulanova Natalia, Popov Vladimir

Cardiovascular diseases are the most common diseases all over the world. Therefore there is an obvious demand to search new medical products and treatments for this patient’s population.Clinical trials in cardiology are widely distributed throughout the world. Russia ranks not the last place in the list of participants countries international multicenter clinical trials phase I-IV.

The aim of the presentation is to review the development of CVT and regulatory requirements for clinical trials in Russia over the last 2009-2010 years. And thus to proceed the comparative statistical survey published last year.Data from the US clinical trials are registered in www.ClinicalTrials.gov and Federal Service on Surveillance in Healthcare and Social Development trials are registered in www.roszdravnadzor.ru and are analyzed to study the magnitude of contribution by Russia to the Global CVTs arena, based on registered industry sponsored phase I-IV trials. From the 4th quarter of 2009, there has been a significant reduction in the number of ongoing international clinical trials in Russia in the cardiovascular field. Thus in the first half of 2009, 46 international multi-center CVT were initiated in Russia, which it takes about 20% of the total amount of trials conducted in reporting period. In the second half of 2009, 18 CVCT were conducted, and in two quarters 2010 a number of initiated studies makes up 18, which is equivalent about of 7% of total number of trials. Nevertheless a total number of initiated studies has also been reduced approximately by 7% over 2009 year. Total number of clinical trials initiated in CEE and Russia fell 18 per cent year-on-year in 2009, ending a period of growth. ClinicalTrials.gov lists 2380 clinical trials which were initiated in 2008 in Central and Eastern Europe (CEE) and Russia. A year later by ClinicalTrials.gov number of trial initiation fell to 1951. The relation between foreign and inland producers has changed significantly. Percentage of clinical trials conducted by foreign manufacturing companies in Russia decreased from 67% to 51% while the share of Russian trials has increased by 16% and amounts 49% of the total number of studies.During the period from III quarter 2009, the companies of 23 countries get sponsors of trials. First place, still, keep inland producers with 37 CT, after follow American sponsors with 8 trials, then Germany - 6 CT, France - 5 CT, Italy 3 CT, Britain and Switzerland by 2 new trials. Percentage rating of clinical trials in phases has also changed over the reporting period. Still, as per CT in Russia both in cardiology and in other medicine areas top position belongs to Novartis. French pharmaceutical company Servier is a leader in the number of recruited patients (1950). Main cardiovascular trials areas were: Essential Hypertension, Myocardial Infarction, Acute Coronary Syndrome, Atrial Fibrillation. During the reporting period the inspection by FDA has not been conducted in Russia.Despite the clearly expressed a downward trend of IMCT during the reporting period, held in Russia, Russia remains one of the leaders in rate and number of patients included into the study, that do not affect the quality of the data.References:

http://www.roszdravnadzor.ru, http://www.clinicaltrials.org, http://www.moz.gov.ua, http://www.fda.gov , http://www.ClinicalTrialMagnifier.com; http://www.outsourcing-pharma.com

EFFECTS oF SIMvASTATIN oN AoRTIC vALvE STENoSIS IN THE ELDERLY PATIENTS WITH CHRoNIC HEART FAILURE A

O. Mytrokhina, Dnipropetrovsk state medical academyO. Kuryata, Dnipropetrovsk state medical academy O. Vlasova, Dnipropetrovsk state medical academy

C-reactive protein (CRP) and hypercholesterolemia predicts progression and severity of aortic stenosis (AS) in the elderly patients (pts) with chronic heart failure (CHF). Statins have shown pleotropic effects, however the role of statins in pts with CHF and AS remains debatable.

We aimed to evaluate the effects of simvastatin 10 mg/day on progression of AS in the elderly pts with CHF and preserved systolic function. 46 pts (28 M, 18 F, mean age - 76,83±3,65 years) with CHF NYHA I-III class and preserved systolic function and with asymptomatic AS were enrolled. Aortic valve area (AVA) was calculated by Doppler echocardiography in all pts. Total cholesterol (TC) and CRP levels weredetermined in the blood. 20(43,5%) pts received only the standard treatment (1 group), 26(56,5%) (2 group) – received the standard treatment and simvastatin 10 mg/day for 24 weeks.

Increased CRP and TC levels correlated to AS (r=0,44 and r=0,35; <0,05). After 24 weeks of treatment with simvastatin,TC and CRP levels in 25% pts (<0,01) had been decreased in 2 group; in 1 group in 13% pts (<0,01) respectively. Decrease in TC and CRP levels correlated to AS (r=0,38; <0,05 and r=0,45; <0,05). 2 group had significantly less stenotic progression, than 1 group (average decrease in AVA, 0,19 cm2 versus 0,12 cm2, respectively (p=0,01)).

Simvastatin may retard progression of AS and safe and effective for patients with CHF and preserved systolic function. Its administration may provide benefits for the reduction of mortality and hospitalizations in its population.

EFFECTIvENESS oF CARDIovASCULAR PREvENTIoN PRoGRAMS IN PRIMARY CARE, PRECARDIo

Claes NereeNele Jacobs, Els Clays, Ward Schrooten

PURPoSE Cardiovascular is a major cause of mortality and morbidity and its prevalence is set to increase. While the benefits of medical and lifestyle interventions is established, the effectiveness of interventions which seek to improve the way preventive care is delivered in primary care is less so. The purpose was to study the effectiveness of 2 intervention programs in reducing cardiovascular risk factors within primary care.

METHoDSA randomized controlled trial conducted in Belgium 2007-2010 with 295 participants allocated to a medical (=MP) and a medical + behavioral (=MBP) program. The MP consisted of medical assessments (screening and follow-up) by a general practitioner. The BP was a tailored behavior change program (web-based and individual coaching). The dose of the coaching was chosen by the participants. Primary outcome measures were total cholesterol, blood pressure, and body mass index (BMI). The secondary outcomes were smoking status, fitness-score, totalcardiovascular risk and events.

RESULTSThe median age was 40 years (IQR 32– 49), 75 participants were female, 6 had a personal cardiovascular event and 3 had diabetes. The median total cholesterol was 181,5 mg/dl (IQR 165 – 207), median systolic pressure 130 mmHg (IQR 120 – 140), median diastolic blood pressure 83 mmHg (IQR 75 - 90) and median BMI was 25 kg/ m² (IQR 22 - 27). Being a smoker was reported by 48 of the participants. There were no significant differences in baseline characteristics between MP and MBP. Our drop-out after three years of intervention was 13%. There was a significant decrease in total cholesterol (median difference: -4,5 mg/dl; p<0,001), systolic blood pressure (-1 mmHg; p=0,016), and diastolic blood pressure (-16,5 mmHg; p<0,001). There was a significant increase in BMI (+0,3 kg/m²; p<0,001). There were no significant differences found between MP and MBP in primary outcomes. At baseline, 48 participants were smoker compared to 29 at the study end-point. Overall there was a significant decrease in fitness-score (median difference: -2; p=0,035). Calculation of the total cardiovascular risk for participants gave a median score of 0,35 (IQR 0,11 – 1,19) at baseline and 0,34 (IQR 0,091 – 1,11) at end-point (p<0,001). During the study period one participant in the MBP had a cardiovascular event.

CoNCLUSIoNBoth intervention programs are effective in reducing cardiovascular risk factors. In our population the combined medical and behaviouralprogram was not superior to the medical program.


EFFECTS oF IvABRADINE oN CARDIovASCULAR EvENTS IN PATIENTS WITH LIMITING ANGINA:THE PoST HoC ANALYSIS FRoM THE BEAUTIFUL* STUDY

Kim Fox1, Ian Ford2, P. Gabriel Steg3, Michal Tendera4, Michele Robertson2, and Roberto Ferrari5 on behalf of the BEAUTIFUL investigators

1- Royal Brompton Hospital, London, UK2- Robertson Centre for Biostatistics, Glasgow, UK3- Hôpital Bichat-Claude Bernard, Paris, France4- Medical University of Silesia, Katowice, Poland5- Chair of Cardiology, University of Ferrara, S. Maugeri Foundation, Ferrara, Italy

(*morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction)

AIMS The BEAUTIFUL study was designed to evaluate the effects of the If inhibitor ivabradine on outcome in patients with stable coronary artery disease and left ventricular systolic dysfunction receiving optimal medical therapy. The BEAUTIFUL study was an international, randomized, double blind, placebo-controlled, parallel-group trial performed in 781 centres in 33 countries. The main study found no impact of ivabradine on outcomes in the whole population, however in patients with an elevated heart rate (>70 bpm) ivabradine has resulted in 36% and 30% reduc-tions in relative risk of hospitalization for fatal and non-fatal MI and coronary revascularization, respectively. A post hoc analysis of the effect of ivabradine in BEAUTIFUL patients whose limiting symptom at baseline was angina, particularly in terms of coronary outcomes was performed.

METHoDS AND RESULTSOf the BEAUTIFUL population, 13.8% had limiting angina at baseline (734 ivabradine, 773 placebo); of these, 712 patients had heart rate 70 bpm. Median duration of follow-up was 18 months. Ivabradine was associated with a 24% reduction in the primary endpoint (cardiovascular mortality or hospitalization for fatal and non-fatal myocardial infarction [MI] or heart failure) (HR, 0.76; 95% CI, 0.58–1.00) and a 42% reduction in hospitalization for MI (HR, 0.58, 95% CI, 0.37–0.92). In patients with heart rate 70 bpm, there was a 73% reduction in hospitalization for MI (HR, 0.27, 95% CI, 0.11–0.66) and a 59% reduction in coronary revascularization (HR, 0.41, 95% CI, 0.17–0.99). Ivabradine was safe and well tolerated.

CoNCLUSIoNOur analyses raises the possibility that ivabradine may be helpful to reduce major cardiovascular events in patients with stable CAD and LVSD who present with limiting angina.

EFFICACY oF THE IF CURRENT INHIBIToR IvABRADINE IN PATIENTS WITH CHRoNIC STABLE ANGINA RECEIvING BETA-BLoCKER THERAPY: A 4-MoNTH, RANDoMIZED, PLACEBo-CoNTRoLLED TRIAL Jean-Claude Tardif 1, Piotr Ponikowski 2,3, Thomas Kahan 4 for the ASSOCIATE study investigators

1- Montreal Heart Institute, Montreal, Quebec, Canada 2- Clinical Military Hospital, Wroclaw, Poland; 3- Wroclaw Medical University, Wroclaw, Poland4- Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden

oBJECTIvESIvabradine, the first If inhibitor approved for clinical use, acts specifically on the pacemaker activity of the sinoatrial node, providing a pure heart rate reduction. Ivabradine has demonstrated anti-ischaemic and anti-anginal efficacy in a placebo-controlled trial and has been shown to be as effective as atenolol or amlodipine in two large trials. The aim of this study was to evaluate the anti-anginal and anti-ischaemic efficacy of the selective If current inhibitor ivabradine in patients with chronic stable angina pectoris receiving beta-blocker therapy.

METHoDSIn this double-blind, parallel-group, international trial, 889 patients with documented CAD and a history of stable angina already treated with atenolol 50 mg od were randomised to receive, in addition to the beta-blocker, either ivabradine (5 mg bid for 2 months up-titrated to 7.5 mg bid for two additional months) or placebo for 4 months. Patients underwent treadmill exercise tests at the trough of drug activity using the standard Bruce protocol for randomization and at 2 and 4 months. Main outcomes measures were the changes in total exercise duration (TED), time to limiting angina (TLA), time to angina onset (TAO) and time to 1-mm ST segment depression (TST) at trough of drug activity.

RESULTSBaseline HR was 67±7 bpm and that addition of ivabradine reduced HR by 9±10 bpm (vs 1±10 bpm in placebo group). Total exercise duration at 4 months increased by 24.3+65.3 s in the ivabradine group, compared with 7.7+63.8 s with placebo (P , 0.001). Ivabradine was superior to placebo for all exercise test criteria at 4 months (P , 0.001 for all) and 2 months (P-values between ,0.001 and 0.018). Ivabradine in combination with atenolol was well tolerated. Only 1.1% of patients withdrew owing to sinus bradycardia in the ivabradine group.

CoNCLUSIoNThe combination of ivabradine 7.5 mg b.i.d. and atenolol at the commonly used dosage in clinical practice in patients with chronic stable angina pectoris produced additional efficacy with no untoward effect on safety or tolerability.

EFFECTS oF IvABRADINE oN CARDIovASCULAR EvENTS IN PATIENTS WITH MoDERATE-To-SEvERE CHRoNIC HEART FAILURE: THE SHIFT* STUDY

1- Karl Swedberg1, Michel Komajda2, Michael Böhm3, Jeffrey S. Borer4, Ian Ford5, and Luigi Tavazzi6

1- Department of Emergency and Cardiovascular Medicine, University of Gothenburg, Gothenburg, Sweden 2- Department of Cardiology, La Pitié-Salpétrière Hospital, Paris, France3- Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany4- Division of Cardiovascular Medicine and the Howard Gilman Institute for Heart Valve Disease, New York, USA5- Robertson Centre for Biostatistics, University of Glasgow, Scotland, UK6- GVM Hospitals of Care and Research, Cotignola, Italy

* Systolic Heart failure treatment with the If inhibitor ivabradine Trial

AIMSThe SHIFT study was designed to evaluate the effect of heart rate reduction with ivabradine, in addition to guideline-based treatment, on cardiovascular outcomes, symptoms and quality of life in patients with chronic heart failure and systolic dysfunction.

METHoDSSHIFT is a randomized, double-blind, placebo controlled, parallel-group study in patients with symptomatic chronic heart failure (NYHA class II–IV), left-ventricular ejection fraction 35%, a prior hospitalization for worsening heart failure within the previous 12 months and a resting heart rate at baseline 70 bpm. Patients were randomly assigned ivabradine titrated to a maximum of 7•5 mg twice daily or matching placebo.The primary endpoint is the composite of the time to first event of cardiovascular death or hospitalization for worsening heart failure.

RESULTSA total of 6558 patients were included with a median follow-up of 22.9 months. The primary endpoint was significantly reduced by 18% (HR 0.82, 95% CI 0.75-0.90, p<0.0001). The effects were principally driven by reductions in death due to heart failure (HR 0.74, 0.58-0.94, p=0.014) and hospitalization for worsening heart failure (HR 0.74, 0.66-0.73, p<0.0001). Serious adverse events occurred less frequently in the group receiving ivabradine (p<0.0001). Symptomatic bradycardia and visual symptoms were reported in 150 (5%) and 89 (3%) of ivabradine patients, versus 32 (1%) and 17 (1%) in the placebo group respectively.

CoNCLUSIoNThese results show that heart rate reduction with ivabradine improves clinical outcomes in patients with chronic heart failure and support the role of heart rate in the physiopathology of the disorder.

RLY5016: A NovEL, NoN-ABSoRBED, THERAPEUTIC PoLYMER FoR THE CoNTRoL oF SERUM PoTASSIUMI. Huang1, T. Blok2, M. Burdick1, J. Cope1, S. Halfon1, K. Mellinger3, C. Park1, J. Vanderlugt2, D. Bushinsky4 & D. Albrecht11Relypsa, Santa Clara, CA; 2 Jasper Clinic, Kalamazoo, MI; 3 Battelle, Richland, WA; 4U. Rochester, Rochester, NY

oBJECTIvERLY5016 is a novel, high-capacity, non-absorbed, cation exchange polymer being developed for the control of serum potassium (K+). RLY5016 is administered as a calcium salt and consists of smooth, spherical beads (~100 um) that are free-flowing and low-swelling. Here we present data from two Phase 1 clinical trials evaluating: 1) the dose-response effects of 3 to 60g/day RLY5016 on fecal K+ excretion and 2) the effects of 30g/day RLY5016 administered in three different dosing regimens.

METHoDIn study RLY5016-101, following single-dose and baseline periods, 31 healthy subjects received 1g, 5g, 10g, or 20g three times a day (TID) of RLY5016 (3, 15, 30, or 60g/day) or placebo orally for 8 days in a double-blind, randomized, parallel-group design. In study RLY5016-102, 12 healthy subjects received 30g/day RLY5016 orally for a total of 18 days in a crossover design administered as 10g TID, 15g twice a day (BID), or 30g once a day (QD).

RESULTSIn study RLY5016-101, a dose-dependent increase in mean daily fecal K+ excretion and a corresponding decrease in urinary K+ excretion compared to baseline were observed (Figure). RLY5016 isolated from collected feces demonstrated that the in vivo K+ binding capacity of this polymer exceeded 1mEq/g. RLY5016 was well tolerated in all dose groups and AEs were all mild to moderate in severity.

In study RLY5016-102, no significant differences were observed between the dose regimens in mean daily fecal or urinary K+ excretion. All AEs were mild to moderate and were reported for 1, 5, and 7 subjects in the TID, BID, and QD periods, respectively.

CoNCLUSIoNAdministration of RLY5016 resulted in a significant dose-dependent increase in mean daily fecal K+ excretion and decrease in urine K+ excretion indicating appreciable intestinal K+ binding. It was effective when administered in several dosing regimens, and was well tolerated.


Figure: Dose-Dependent Effect of RLY5016 on Mean Daily Fecal and Urinary K+ Excretion in Healthy Volunteers in Study RLY5016-101

RLY5016: A NovEL, EFFECTIvE, NoN-ABSoRBED, oRAL PoLYMER FoR THE CoNTRoL oF SERUM PoTASSIUM IN HF AND CKD D. Bushinsky1, I. Huang2, S. Anker3, D. Kitzman4, F. Zannad5 and B. Pitt6.1U. Rochester, Rochester, NY; 2Relypsa, Santa Clara, CA; 3Charite, Berlin, Germany; 4Wake Forest U., Winston-Salem, NC; 5CHU, Nancy, France and 6U. Michigan, Ann Arbor, MI

oBJECTIvETo investigate the ability of a new oral potassium (K+) binding polymer, RLY5016, to control serum K+ in HF patients at risk of developing hype-rkalemia because of CKD and RAAS blockade .

METHoDIn this study (RLY5016-202), 104 chronic HF patients with a serum K+ of 4.3-5.1 mEq/L and clinically indicated to receive spironolactone were evaluated. Patients with: 1) CKD (eGFR< 60mL/min) on one or more HF therapies (ACEIs, ARBs, BBs) and/or 2) documented history of hype-rkalemia within the last six months leading to discontinuation of an AA, ACEI, ARB, or BB, were given spironolactone 25 mg/d and randomized to either 30 g/d of RLY5016 (55 pts) or placebo (49 pts) for 4 wks. After two weeks, if serum K+ was ≤ 5.1 mEq/L, the spironolactone dose was increased from 25 mg/d to 50mg/d. The primary endpoint was change from baseline serum K+ at the end of the double-blind treatment period. The secondary endpoints included the proportion of patients with hyperkalemia (K+ >5.5 mEq/L), and the proportion whose spironolactone dose could be increased to 50 mg/d.

RESULTSTreatment groups had similar baseline characteristics and serum potassium (~4.7 mEq/L). RLY5016 significantly decreased mean serum K+ from baseline compared to placebo (-0.45 mEq/L, p<0.001; Figure), reduced the incidence of hyperkalemia compared to placebo (7% vs. 25%, p=0.015) and increased the proportion of patients whose spironolactone dose could be increased (91% vs. 74%, p=0.019). RLY5016 was well tolerated; study withdrawal due to an AE was 7% on RLY5016 vs. 6% on placebo and there were no drug-related serious AEs.

CoNCLUSIoNThe oral K+ binding polymer RLY5016 effectively controlled serum K+ in patients with HF and CKD given spironolactone and may allow the increased use of RAAS inhibitors in these patients.

Figure: Least Squares Mean SerumK+ for the placeboand RLY5016treated groups in study RLY5016 202

PRoGNoSTIC SIGNIFICANCE oF 123I-MIBG MYoCARDIAL SCINTIGRAPHY IN HEART FAILURE PATIENTS: RESULTS FRoM THE PRoSPECTIvE MULTICENTER INTERNATIoNAL ADMIRE-HF TRIAL

Arnold F Jacobson, GE Healthcare, Princeton, NJ; Roxy Senior, Northwick Park Hospital, Harrow, UK; Fred Weiland, Sutter Roseville Hosp, Roseville, CA; Harish Chandna, Victoria Heart, Victoria, TX; Denis Agostini, CHU Cote de Nacre, Caen, France; for the ADMIRE-HF investigators.

ADMIRE-HF is the integration of 2 prospective multicenter international Phase 3 trials designed to demonstrate the prognostic value of scintigraphy with the norepinephrine analog 123I-mIBG as an indicator of risk for major adverse cardiac events (ACE).in subjects with heart failure (HF).

METHoDS962 subjects with NYHA class II (82%) and III (18%) HF (66% ischemic, 34% non-ischemic) and left ventricular ejection fraction (LVEF) ≤35% (mean 27.2%) underwent early (15 minute) and late (4 hour) planar and SPECT 123I-mIBG myocardial imaging and were then followed for a maxi-mum of 2 years. The composite endpoint was time to first occurrence of either NYHA HF class progression, potentially life-threatening arrhythmic event (including appropriate ICD discharge), or cardiac death, as determined by an independent adjudication panel. The primary analysis employed a Cox proportional hazards model to compare outcomes in subjects with heart/mediastinum ratios (H/M) of <1.60 and ≥1.60 on late planar imaging. A multivariable Cox proportional hazards analysis incorporated SPECT imaging and clinical variables into a prediction model for ACEs.

RESULTS238 subjects (25%) experienced ACEs during a mean follow-up of 18 months. First events were heart failure progression in 162 subjects, arrhythmic events in 52, and 24 cardiac deaths. 29 additional cardiac deaths occurred as later events. 2-year event-free survival was 85% in subjects with H/M≥1.60 compared with 59% for those with H/M<1.60 (p<0.001). Hazard ratio for occurrence of an ACE was 4.5 (p<0.002). 51 cardiac deaths occurred in the low H/M group, compared with 2 in the high H/M group (hazard ratio 6.0 (p<0.001)). Negative predictive value of a high H/M for an arrhythmic ACE or cardiac death was 96% (178/185). The only significant contributors to the multivariable model were late H/M, LVEF, and NYHA class.

CoNCLUSIoN123I-mIBG cardiac imaging can identify a subpopulation of NYHA Class II/III HF patients with low 2-year risk of a fatal cardiac event and may aid in defining a cohort with increased likelihood of HF progression, ventricular arrhythmias, or cardiac death. These results may have implications for decisions regarding ICD and CRT therapy.

HoW To CooK A GooD CoMBo RECIPE – FINDING THE IDEAL “DIURETIC” INGREDIENT

Stuart Kupfer, MD. Takeda Global Research & Development Center, Inc.The combination of a thiazide-type diuretic and a renin-angiotensin-aldoseterone system (RAAS) blocker, such as an angiontensin converting enzyme inhibitor (ACEi) or angointensin receptor blocker (ARB), is commonly used for the treatment of hypertension because of complementary mechanisms of action and potenti-ation of blood pressure reduction. Hydrochlorothiazide (HCTZ) is the most common diuretic utilized in fixed-dose combinations (FDC) of RAAS blockers; however, the weight of clinical evidence suggests that other thiazide-type diuretics, such as chlorthalidone or indapamide, may be more effective than HCTZ. At the typical low doses used in FDCs (12.5 – 25 mg), HCTZ is half as potent as chlorthalidone in lowering blood pressure, in part because of chlorthalidone’s longer half-life. More importantly, in contrast to chlorthalidone or indapamide, HCTZ-based regimens have not been consistently effective in reducing major cardiovascular events in large outcome trials compared with an ACEi or calcium channel blocker, despite similar blood pressure reduction. These data suggest that alternative thiazide-type diuretics should be considered for combination therapy with RAAS blockers in patients with hypertension in order to optimize cardiovascular risk reduction.

REFERENCESALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or cal-cium channel blocker vs diuretic: The antihypertensive and lipid-lowering treatment to prevent heart attack Trial (ALLHAT). JAMA 2002; 288(23):2981-97.Beckett NS, Peters R, Fletcher AE, Staessen JA, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358(18):1887-98. Epub 31 March 2008. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension 2004; 43(1):4-9.Elliot WJ, Grimm RH Jr. Using diuretics in practice: one opinion. J Clin Hypertens (Greenwich) 2008; 10(11):856-62.Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359(23):2417-28.SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP). JAMA 1991; 265(24):3255-64.Wing LM, Reid CM, Ryan P, Beilin LJ, et al; Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-conver-ting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 200313; 348(7):583-92.M≥1.60 compared with 59% for those with H/M<1.60 (p<0.001). Hazard ratio for occurrence of an ACE was 4.5 (p<0.002). 51 cardiac deaths occurred in the low H/M group, compared with 2 in the high H/M group (hazard ratio 6.0 (p<0.001)). Negative predictive value of a high H/M for an arrhythmic ACE or cardiac death was 96% (178/185). The only significant contributors to the multivariable model were late H/M, LVEF, and NYHA class.

CoNCLUSIoN123I-mIBG cardiac imaging can identify a subpopulation of NYHA Class II/III HF patients with low 2-year risk of a fatal cardiac event and may aid in defi-ning a cohort with increased likelihood of HF progression, ventricular arrhythmias, or cardiac death. These results may have implications for decisions regarding ICD and CRT therapy.


EvALUATIoN oF CARDIovASCULAR SAFETY oF AN ANTI-DIABETIC AGENT: THE PIoGLITAZoNE CASE

Alfonso Perez, MDTakeda Global Research & Development Center, Inc.

oBJECTIvETo evaluate the risk of major adverse cardiovascular events (MACE) in the composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke in subjects with T2 DM treated with pioglitazone versus different comparators.

METHoDUse of all randomized controlled clinical trials in the pioglitazone clinical database. Primary analysis was the time (days) from first study dose to the first occurrence of an event at any time in the MACE composite, using the Cox proportional hazards models, based on individual subject data. All analysis included all subjects randomized to treatment who took at least one dose of study drug.

RESULTSA total of 22,718 subjects received pioglitazone (n=12,506) or a comparator (n=10,212) in all controlled studies. Approximately 75% of subjects in both pioglitazone and comparator groups completed the study. All baseline characteristics were well-balanced between treatment groups.

For the MACE end-point, the pioglitazone/comparator hazard ratio (HR) was 0.82 (95% CI: 0.71 – 0.95) p=0.0073. Similar results were observed in sensitivity analysis including only events that occurred within 30 days of last dose (HR=0.83) 95% CI=0.71-0.97) and excluding studies with no MACE HR = 0.82 (95% CI = 0.71 – 0.95).

DISCUSSIoNMeta-analysis of clinical data can help to interpret the cardiovascular safety of an anti-diabetic agent, in this particular case, a specific study (PROactive) was conducted in subjects with T2 DM and previous macrovascular event (high risk) with a total number of 570 MACE events (10.9%) were observed. In the “low risk” group, a total number of 176 MACE events (1.0%) were reported. Beside the different in MACE events between these two groups, they have an HR ratio that is similar (0.822 versus 0.828) indicating the risk of MACE events was independent of the Cardiovascular risk of the patients.

CoNCLUSIoNThe CV safety of pioglitazone evaluated by MACE gave a good indication in the pool of patients with low risk typically observed in the develop-ment of anti-diabetic agents as far than the total number of events are between 150-200, when compared with specific trials in outcome studies with total MACE events in excess of 550 observed in the PROactive trial.

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