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6th GlobalCardioVascularClinical Trialists ForumCourse Directors: Faiez Zannad, Nancy – FRA & Bertram Pitt, Ann Arbor – USA

3-5 December 2009PARIS, Pullman Tour Eiffel, FRANCE

FINAL PROGRAM & ABSTRACTS BOOK

www.globalcvctforum.com

CVCT_couverture_exe_OK:Mise en page 1 25/11/09 15:54

CVCT_couverture_exe_OK:Mise en page 1 25/11/09 15:54

GENERAL PRESENTATION

Drug Therapy, CVCT Forum is a meeting specifically and totally dedicated to the discussion of cardiovascular disease.

CVCT Forum is attended by experts principally engaged in cardiovascular clinical trials (hence its name). Participants are among the group of major international opinion leaders and come from various functions linked with primary care, the pharmaceutical industry, pharmaceutical regulatory bodies, and publishing houses from around the world (US, Canada, Asia, Europe, and Japan).

CVCT’s outstanding faculty members are committed to disseminating concise data from controlled clinical trials that contribute to better clinical care and to discussing and identifying issues and relevant information, such as how to design better clinical trials, how to satisfy regulatory authorities, and most importantly, how to improve cardiovascular health care.

The CVCT meetings are ‘grass root’ meetings, attended by individuals who are eager to communicate with one another and to share experiences with primary care physicians and the people that create and analyze major trials.

CVCT meetings are primarily oriented toward discussion between participants as opposed to lectures to a broad audience. Thought processes count and communication (during the meeting, but more importantly informal discussions outside the meeting) is an important agenda, as opposed to dictating doctrine. The format of the meeting is set to fulfil these aims. Beyond plenary sessions the meeting is structured with a variety of small interactive brainstorming workshops, expert discussions, how-to sessions and consensus building workshops.

The discussion takes place with a selected audience of opinion leaders, clinical trialists, pharmaceutical industry partners, regulators, investigators and cardiologists.

CVCT Forum aims to: ■ 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■ 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 do hope that you will share with us the excitement of this unique learning experience and we are very happy to welcome you to Paris.

Pr. Faiez ZANNAD Pr. Bertram PITT

Endorsed by the European Society of Cardiology Working Group on Cardiovascular Pharmacology andclinical trials in

Synopsis• Scientifi c program Thursday .............................................................................. 7 Friday ................................................................................... 9 Saturday ............................................................................ 13

• Acknowledgements .............................................................. 15

• Abstracts ................................................................................ 17

• Posters ................................................................................... 49

ACCREDITATION

The “6th Global CVCT Forum” is accredited by the European Board for Accreditation in Cardiology for 17 hours of external CME credits (EBAC). Each participant should claim only those hours of credit that have actually been spent in the educational activity. EBAC works in cooperation with the European Accreditation Council for Continuing Medical Education (EACCME), which is an institution of the European Union of Medical Specialists (UEMS).

PROGRAM AT A GLANCESalon Orsay Nord Foyer Orsay Nord Salon Orsay Sud Salon Vendôme BC

Thur

sday

Dec

embe

r 3R

D, 2

009

10:00 10.00-13.00ESC Working Group

Nucleus Business Meeting11:0013:45

Workshop and lunch session

Clinical trials in cardiovascular critical care

13:45 Coffee Break and visit of the posters area

14:0016:00

Workshop sessionUnderstanding the results

of the MADIT-CRT. Key elements for an optimal

implementation of CRT-Din clinical practice

ESC Working GroupYoung CardioVascular Clinical

Trialists (YCVCT) Course


16:3018:00

Understanding the results of the MADIT-CRT. Key

elements for an optimal implementation of CRT-D

in clinical practice

Frid

ay D

ecem

ber 4

TH, 2

009

08:3010:00 Biomarkers in clinical trials Targeting the aldosterone

pathwayCardiovascular Trials Going

Global


10:3012:00 Biomarkers in clinical trials Targeting the aldosterone

pathwayCardiovascular Trials Going

Global

12:1513:45

Meet and Eat with the ExpertsManagement of atrial

fibrillation : Trials that are rapidly changing the

landscape

Lunch roundtableNon Industry sponsored trials and the role of NHLBI and EU public

institutions

Meet and Eat with the ExpertsVentilatory therapy for sleep

disordered breathing (SDB) in heart failure and CV

disease. From proof of concept to evidence based medecine


14:0016:00

Coronary artery disease management: Breaking new

ground with ivabradine

Workshop sessionArterial stiffness and central

blood pressure as endpoints in hypertension trials


16:3019:00

The future of anti-thrombotic therapy in coronary

syndromes at the acute and post-acute phases

The cardioRenal Forum - European Society of Cardiology

(ESC) Working-Group on

Pharmacology and Drug TherapyOptimising Care at the Cardio-Renal Interface

20:30 ConGrESS DinnEr

Sat

urda

y D

ecem

ber 5

TH, 2

009

08:0010:30

Workshop sessionAntithrombotic Acute

Coronary Syndromes trials. Methodological and interpretation issues


10:4513:00

Antithrombotic Acute Coronary Syndromes trials.

Methodological and interpretation issues

13:00 Lunch Buffet

13:4515:05

Workshop sessionData Safety and Monitoring

Committees (DSMC) in CV trials


15:2516:45

Data Safety and Monitoring Committees (DSMC) in CV trials

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Thursday december 3rd, 2009

10:00-13:00 FOYER ORSAY NORD ESC WG on CV pharmacology and Drug Therapy Nucleus Business Meeting

Stefan AGEWALL, Stockholm - SWE – Angeles ALONSO, Madrid - SPA – Céline SERIO, Sophia Antipolis - FRA Wiek VAN GILST, Groningen - NED – Finn GUSTAFSSON, Copenhagen - DEN

Keld KJELDSEN, Copenhagen - DEN – Luis RUILOPE, Madrid - SPA – Kurt STOSCHITZKY, Graz - AUT Faiez ZANNAD, Nancy - FRA

11:00-13:45 SALON ORSAY NORD CVCT EXPERTS WORKHOP Clinical trials in cardiovascular critical care Chairmen: Alexandre MEBAZAA, Paris - FRA – Birhan Mehmet YILMAZ, Sivas - TUR

Format: Short presentations (no lecturing) in order to set the stage for a large expert panel discussion

l What are the unmet needs? - The clinician point of view: Alexandre MEBAZAA, Paris - FRA

l Industry point of view - Hemodynamic monitoring: Frederic MICHARD, Edwards Lifesciences, Nyon - SWI - Trade off in heart failure: why clinical trial on ADHF should focus on quality of life Piero POLLESELLO, Orion Pharma, Espoo - FIN l What are the optimal endpoints? - The emergentist point of view: Patrick RAY, Paris - FRA - The intensivist (ICU/CCU) point of view: Birhan Mehmet YILMAZ, Sivas - TUR - The cardiac surgeon point of view: Antonis PITSIS, Tessaloniki - GRE Panellists: Xavier BAERMANN, Argenteuil - FRA – Abdel BELLOU, Rennes - FRA Enrique CASALINO, Paris - FRA – Jean CASSAGNES, Clermont Ferrand - FRA – Bernard CHOLLEY, Paris - FRA Alain COHEN SOLAL, Paris - FRA – Jean Emmanuel de La COUSSAYE, Nimes - FRA Nicolas DEYE, Paris - FRA – Pierre GIBELIN, Nice - FRA – Corinna HEINISCH, Bâle - SWI Guillaume JONDEAU, Paris - FRA – Said LARIBI, Paris - FRA – Alexandre MEBAZAA, Paris - FRA Frederic MICHARD, Edwards Lifesciences - SWI – Atul PATHAK, Toulouse - FRA Antonis PITSIS, Tessaloniki - GRE – Patrick PLAISANCE, Paris - FRA Piero POLLESELLO, Orion Pharma, Espoo - FIN – Patrick RAY, Paris - FRA Guillaume Der SAHAKIAN, Paris - FRA – Jane-Lise SAMUEL, Paris - FRA – Franck SIBELLAS, Lyon - FRA Eric WIEL, Lille - FRA – Birhan Mehmet YILMAZ, Sivas TUR – Faiez ZANNAD, Nancy - FRA 14:00-18:00 SALON ORSAY NORD EXPERT WORKSHOP Understanding the results of MADIT-CRT. Key elements for an optimal implementation of CRT-D in clinical practice

Objectives: l Discussing the opportunities and challenges of an optimal implementation of the results of the device trials l Discussing the strengths and limitations of the device trials in heart failure

Patient population and outcome issues: What is the clinical significance of the results of MADIT-CRT Chairman: Karl SWEDBERG, Göteborg - SWE l What are the patients eligible for CRT-D? How to estimate the size of the eligible population? Speaker: Mihai GHEORGHIADE, Chicago - USA Discussant: Aldo MAGGIONI, Florence - ITA

l The relative contribution of preventing death and preventing HF hospitalization Speaker: Frederic ANSELME, Rouen - FRA Discussant: Faiez ZANNAD, Nancy - FRA

l The Clinician point of view: Generalizability of the results of recent trials (MADIT-CRT) Gunter BREITHARDT, Münster - GER

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Thursday december 3rd, 2009 Mechanistic issues: How does CRT-D work for the prevention of HF hospitalization? Chairman: Daniel GRAS, Nantes - FRA l Consistency within the trial subgroups, consistency with other CRT and ICD trials Cecilia LINDE, Stockholom - SWE

l Mechanistic plausibility. Insight from pathophysiology – importance of improvement of LV function across all trials Mark ESTES, Boston - USA

Registerability and implementation issues Chairman: Faiez ZANNAD, Nancy - FRA l Is “Prevention of HF events” in mild HF patients with large QRS and low EF an approvable new indication for CRT-D? Bernd LEMKE, Lüdenscheid - GER Discussant: Daniel GRAS, Nantes - FRA

l Updating the guidelines and overcoming implementation issues/barriers Karl SWEDBERG, Göteborg - SWE

Panellists: Kirkwood ADAMS, Chapell Hill - USA – Angeles ALONSO, Madrid - SPA Frederic ANSELME, Rouen - FRA – Olivier BARTHEZ, Dijon - FRA – Gunter BREITHARDT, Münster - GER Mark ESTES, Boston, USA – Mihai GHEORGHIADE, Chicago - USA – Daniel GRAS, Nantes - FRA Jean-Yves LE HEUZEY, Paris - FRA – Bernd LEMKE, Lüdenscheid - GER – Cecilia LINDE, Stockholm - SWE Aldo MAGGIONI, Florence - ITA – Edmond ROLAND, EMEA, Paris - FRA – Karl SWEDBERG, Götborg - SWE Faiez ZANNAD, Nancy - FRA

14:00-16:00 SALON VENDôME BC European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy Young CardioVascular Clinical Trialists (YCVCT) Course Chairmen: Thibaut DAMY, Créteil - FRA – Patrick ROSSIGNOL, Nancy - FRA

l The young CVCT initiative: Time to rejuvenate CV clinical trialists Bertram PITT, Ann Arbor - USA

l Maximizing scientific knowledge from randomized clinical trials data. Opportunities for young CVCT fellows Gilles DAGENAIS, Quebec - CAN

l How to teach trial methodology to young clinicians? Eric VICAUT, Paris - FRA

l Responsibilities, role and functioning of trial committees (Steering committee, DSMC, Event committee) Sidney GOLDSTEIN, Detroit - USA

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FrIday december 4Th, 2009

08:30-12:00 SALON ORSAY NORD PLENARY SESSION Biomarkers in clinical trials Chairmen: Angeles ALONSO, Madrid - SPA – Kirkwood ADAMS, Chapell Hill - USA

l How evidence based is the current risk stratification guided CV preventive drug therapy? Luis RUILOPE, Madrid - SPA

l The challenge of designing a biomarker trial Faiez ZANNAD, Nancy - FRA

l Biomarker guided therapy: Trial design and interpretation issues Kirkwood ADAMS, Chapell Hill - USA

Debate: Design of Biomarkers for CV trials The industry viewpoint. Ursula-Henrike WIENHUES-THELEN, Roche Diagnostics - GER

The regulator viewpoint Bruno FLAMION, European Medicines Agency - EMEA, Brussels - BEL

Panellists: Kirkwood ADAMS, Chapell Hill - USA – Enrico AGABATI-ROSEI, Brescia - ITA Alain COHEN SOLAL, Paris - FRA – Finn GUSTAFSSON, Copenhagen - DEN – Wim HOUDIJK, Biomérieux - FRA Patrick JOURDAIN, Paris - FRA – Alexandre MEBAZAA, Paris - FRA Patrick ROSSIGNOL, Nancy - FRA – Luis RUILOPE, Madrid - SPA – Nancy SEYMOUR, Inverness, Biosite - USA Dominique SURUN, Aterovax - FRA – Wiek VAN GILST, Groningen - NED Ursula-Henrike WIENHUES-THELEN, Roche Diagnostics - GER

08:30-12:00 SALON ORSAY SUD PLENARY SESSION Targeting the aldosterone pathway Chairmen: Aldo MAGGIONI, Florence - ITA – Mihai GHEORGHIADE, Chicago - USA

l Aldosterone: a culprit hormone in cardiovascular disease Johann BAUERSACHS, Würzburg - GER

l Which is to blame? Is it aldosterone or mineralocorticoid receptor activation? Frederic JAISSER, Paris - FRA

l Pharmacology of agents interfering with the aldosterone pathways Michel AZIZI, Paris - FRA

l Update on aldosterone trials Faiez ZANNAD, Nancy - FRA

l Practical use of agents acting on the aldosterone system. Where to fit into the RAAS drug armamentarium? Bertram PITT, Ann Arbor - USA

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08:30-12:00 SALON VENDôME BC PLENARY SESSION Cardiovascular Clinical Trials. Going Global Chairmen: Felipe MARTINEZ, Cordoba - ARG – Jean MORGAN, Quintiles

l Overview of international cardiovascular clinical trials and current regulatory requirements for clinical trials in Russia and Ukraine Vladimir POPOV, Moscow - RUS

l Middle East and the Arab world, emerging to CardioVacular trials. Cultural, organisational and regulatory aspects Mohamed SOBHY, Alexandria - EGY

l Regional Risk Factors and Cardiovascular trials: no influence or high impact? Felipe MARTINEZ, Cordoba - ARG

12:15-13:45 SALON VENDôME BC MEET AND EAT WITH THE EXPERTS Ventilatory therapy for sleep disordered breathing (SDB) in heart failure and CV disease. From proof of concept to evidence based medicine Chairmen: Luc HITTINGER, Paris - FRA – Guillaume JONDEAU, Paris - FRA

l Introduction and overview: Why does sleep disordered breathing deserve the cardiologist’s attention? Christiane ANGERMANN, Würzburg - GER

l Future clinical evidence needs? Design of the SERVE-HF protocol Luc HITTINGER, Paris - FRA

l How to screen and manage patients with SDB in the clinical cardiology routine? Olaf OLDENBURG, Bad Oeynhausen - GER

12:15-13:45 SALON ORSAY SUD TRANSATLANTIC TRIALISTS Lunch Rountable Non industry sponsored trials and the role of NHLBI and EU public institutions Chairmen: Michael LAUER, Bethesda - USA – Faiez ZANNAD, Nancy - FRA

l Cardiovascular clinical trials under the EU Research Framework Programmes? A good start or a missed opportunity? Faiez ZANNAD, Nancy - FRA

l National Heart Lung and Blood Institute cardiovascular drug trials - future directions? Michael DOMANSKI, Bethesda - USA

Debate: Going global. Is an NHLBI-EU joint cardiovascular trial initiative at all feasible? Panellists: Kirkwood ADAMS, Chapell Hill - USA – Enrico AGABATI-ROSEI, Brescia - ITA Christian BOITARD, Inserm, Paris - FRA – Gérard BRÉART, Paris - FRA Virginija DAMBRAUSKAITE, EU, Brussels - BEL – Jacques DESMOTES, ECRIN, Bordeaux - FRA Michael DOMANSKI, NHLBI, Bethesda - USA – Nancy GELLER, NHLBI, Bethesda - USA Mihai GHEORGHIADE, Chicago - USA – David GORDON, NHLBI, Bethesda - USA Michael LAUER, NHLBI, Bethesda, USA – Alexandre MEBAZAA, Paris - FRA Bertram PITT, Ann Arbor - USA – Philippe G. STEG, Paris - FRA – Faiez ZANNAD, Nancy - FRA

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12:15-13:45 FOYER ORSAY NORD ME T AND EAT WITH THE EXPERTS (2) Management of atrial fibrillation: Trials that are rapidly changing the landscape Chairmen: Dan ATAR, Oslo - NOR – Karl SWEDBERG, Göteborg - SWE

l Will new drugs and new trials shift the rate vs. rhythm control paradigm (Dronedarone, Vernakalant)? Gunter BREITHARDT, Münster - GER

l New anti-thrombotic trials in atrial fibrillation (RE-LY) and possible consequence on anti-thrombotic strategies Gregory LIP, Birmingham - GBR

l Ablation in atrial fibrillation: Reassessing the evidence Etienne ALIOT, Nancy - FRA

Debate: Revisiting the rate vs. rhythm control debate in the light of the new pharmacological environment

Panellists: Etienne ALIOT, Nancy - FRA – Angeles ALONSO, Madrid - SPA – Dan ATAR, Oslo - NOR Gunter BREITHARDT, Münster - GER – Alain COHEN SOLAL, Paris - FRA Finn GUSTAFSSON, Copenhagen - DEN – Patrick JOURDAIN, Paris - FRA – Keld KJELDSEN, Copenhagen - DEN Gregory LIP, Birmingham - GBR – Aldo MAGGIONI, Florence - ITA Kurt STOSCHITZKY, Graz - AUT – Karl SWEDBERG, Göteborg - SWE – Wiek VAN GILST, Groningen - NED Faiez ZANNAD, Nancy - FRA

14:00-16:00 FOYER ORSAY NORD CVCT EXPERT WORKSHOP Arterial stiffness and central blood pressure as endpoints in hypertension trials Chairmen: Enrico AGABATI-ROSEI, Brescia - ITA – Luc VAN BORTEL, Ghent - BEL

l Clinical significance of lowering central BP and arterial stiffness Athanas BENETOS, Nancy - FRA

l Central BP and arterial stiffness as clinical endpoints in large scale trials. Metrological and methodological issues Stéphane LAURENT, Paris - FRA

l Currently available drugs and new agents that decrease central BP and arterial stiffness. Insight from recent trials Luc VAN BORTEL, Ghent - BEL

Panellists: Enrico AGABATI-ROSEI, Brescia - ITA – Michel AZIZI, Paris - FRA Athanas BENETOS, Nancy - FRA – Luc VAN BORTEL, Ghent - BEL – Alain COHEN SOLAL, Paris - FRA Finn GUSTAFSSON, Copenhagen - DEN – Stéphane LAURENT - Paris - FRA – Atul PATHAK, Toulouse - FRA Bertram PITT, Ann Arbor - USA – Patrick ROSSIGNOL, Nancy - FRA – Luis RUILOPE, Madrid - SPA Michel SAFAR, Paris - FRA – Wiek VAN GILST, Groningen - NED – Charalambos VLACHOPOULOS, Athens - GRE Ursula-Henrike WIENHUES-THELEN, Roche Diagnostics - GER

14:00-16:00 SALON ORSAY NORD MAIN PLENARY SESSION Coronary artery disease management: Breaking new grounds with ivabradine Chairmen: Philippe G. STEG, PARIS - FRA – Ake HJALMARSON, Göteborg - SWE

l Introduction Ake HJALMARSON, Göteborg - SWE

l Heart rate reduction in clinical practice Ake HJALMARSON, Göteborg - SWE

l New results with Ivabradine Jeffrey BORER, New York - USA

l Coronary artery disease management: A step further with ivabradine Philippe G. STEG, Paris - FRA

E

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16:30-19:00 SALON ORSAY NORD MAIN PLENARY SESSION The future of anti-thrombotic therapy in coronary syndromes at the acute and post-acute phases Chairmen: Nicolas DANCHIN, Paris - FRA – Dan ATAR, Oslo - NOR

l The pharmacology of modern anti-thrombotic drugs: how to maximize the benefit-to-bleed risk ratio? Tabassome SIMON, Paris - FRA

l Resistance to antiplatelet agents: biological fantasy or clinical reality? Gilles MONTALESCOT, Paris - FRA

l How the results of the most recent trials will change the anti-thrombotic strategy in acute coronary syndromes? Nicolas DANCHIN, Paris - FRA

l Post acute coronary syndromes. Risk and management of anti-thrombotic therapy in the ambulatory patient Philippe G. STEG, Paris - FRA

Debate: unclot with little bleed. Unravelling the Gordian knot

Panellists: Dan ATAR, Oslo - NOR – Nicolas DANCHIN, Paris - FRA Efthymios DELIARGYRIS, Athens - GRE – Pascale GAUSSEM, Paris - FRA – Antoine LAFONT, Paris, FRA Gregory LIP, Birmingham - GBR – Gilles MONTALESCOT, Paris - FRA – Bertram PITT, Ann Arbor - USA Stuart POCOCK, London - GBR – Tabassome SIMON, Paris - FRA – Philippe G. STEG, Paris - FRA Faiez ZANNAD, Nancy - FRA

16:30-19:00 FOYER ORSAY NORD JOINT SESSION The CardioRenal Forum - European Society of Cardiology (ESC) Working-Group on Pharmacology and Drug Therapy Optimising Care at the Cardio-Renal Interface Chairman: Alexandre MEBAZAA, Paris - FRA – Bengt FELLSTROM, Uppsala - SWE

l Cardiovascular outcomes in chronic kidney disease, Rationale for future clinical trials Faiez ZANNAD, Nancy - FRA

l Cardiovascular protection trials in end stage renal disease Bengt FELLSTROM, Uppsala - SWE

l Clinical trials targeting renal protection in heart failure and cardiovascular disease Marco METRA, Brescia - ITA

Debate: What endpoints for a renoprotective agent in cardiovascular disease?

Panellists: Kirkwood ADAMS, Chapell Hill - USA – Stefan AGEWALL, Stockholm - SWE – Angeles ALONSO, Madrid - SPA Bengt FELLSTROM, Uppsala SWE – Mihai GHEORGHIADE, Chicago - USA – Felipe MARTINEZ, Cordoba - ARG Alexandre MEBAZAA, Paris - FRA – Marco METRA, Brescia - ITA – Patrick ROSSIGNOL, Nancy - FRA Wiek VAN GILST, Groningen - NED – Faiez ZANNAD, Nancy - FRA

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saTurday december 5Th, 2009

08:00-13:00 SALON ORSAY NORD CVCT EXPERT WORKSHOP Antithrombotic Acute Coronary Syndromes trials. Methodological and interpretation issues Chairmen: Gregory LIP, Birmingham - GBR – Stuart POCOCK, London - GBR

1. Selecting the appropriate design 1.1. Positive control, placebo-controlled trials vs. non inferiority head-to-head comparative trials. Which way to go? Speaker: Stuart POCOCK, London - GBR Discussant: Yasser KHDER, Boehringer Ingelheim, Paris - FRA

1.2. Adaptive design. Strengths and limitation Speaker: Sidney GOLDSTEIN, Detroit - USA Discussant: Michael DOMANSKI, Bethesda - USA

2.Defining the appropriate patient population: ACS, AMI, STEMI/NSTEMI: terminology and definition matters Speaker: David MORROW, Boston - USA Discussant: Marteen SIMOONS, Rotterdam - NED

3. Study drug and comparator drug related issues: Clinical and Regulatory challenges 3.1. What is the optimal “reference” comparator? Speaker: Gregory LIP, Birmingham - GBR

3.2. Timing of randomisation/dosing Speaker: Philippe G. STEG, Paris - FRA Discussant: Nicolas DANCHIN, Paris - FRA

4.Endpoint definition 4.1. Time to first event vs. cumulative events Speaker: Christian TORP-PEDERSEN, Copenhagen - DEN Discussant: Aldo MAGGIONI, Florence - ITA

4.2. Composite events Speaker: John WARREN, London - GBR Discussant: Edmond ROLAND, Paris - FRA

4.3. Balancing benefit vs. risk Speaker: Edmond ROLAND, Paris - FRA Discussant: Gregory LIP, Birmingham - GBR

5. Interpretation issues 5.1. Statistically significant vs. clinically meaningful results? A Statistical Interpretation of Recent Trials Speaker: Stuart POCOCK, London - GBR

Faculty members Academy: Michael ANGIOI, Nancy - FRA – Vidal BENATAR, Saint-Cloud - FRA Laurent BONELLO, Marseille - FRA – Jeffrey BORER, New York - USA – Jean CASSAGNES, Clermond-Ferrand - FRA Gilles DAGENAIS, Quebec - CAN – Nicolas DANCHIN, Paris - FRA – Efthymios DELIARGYRIS, Athens - GRE Gregory DUCROCQ, Paris FRA – Sidney GOLDSTEIN, Detroit - USA – Antoine LAFONT, Paris - FRA Gilles LEMESLE, Lille - FRA – Gregory LIP, Birmingham - GBR – Aldo MAGGIONI, Florence - ITA David MORROW, Boston - USA – Bertram PITT, Ann Arbor - USA – Stuart POCOCK, London - GBR Tabassome SIMON, Paris - FRA – Marteen SIMOONS, Rotterdam - NED – Philippe G.STEG, Paris - FRA Christian TORP-PEDERSEN, Copenhagen - DEN – Eric VICAUT, Paris - FRA – John WARREN, London - GBR Faiez ZANNAD, Nancy - FRA

Faculty members EMEA / AFSSAPS: Eric ABADIE, Paris - FRA – Angeles ALONSO, Madrid - SPA Fernando DE ANDRES, Trelles - ESP – Mira PAVLOVIC, Paris - FRA – Edmond ROLAND, Paris - FRA

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saTurday december 5Th, 2009

Faculty members NHLBI (NIH): Michael DOMANSKI, Bethesda - USA – Nancy GELLER, Bethesda - USA David GORDON, Bethesda - USA Faculty members Industry: Maria-Niki AIGYPTIADOU, Daiichi-Sankyo - GER Gunnar BRANDRUP, AstraZeneca - SWE – Yasser KHDER, Boehringer Ingelheim - FRA Stuart KUPFER, Takeda - USA – Guy LEREBOURS, Servier - FRA – Hubert POULEUR, Pfizer - USA James REVKIN, Boehringer Ingelheim - USA – Magali SARTRAL, Eli-Lilly - FRA

13:45-16:45 SALON ORSAY NORD CVCT EXPERT WORKSHOP Data Safety and Monitoring Committees (DSMC) in CV trials Chairmen: Stuart POCOCK, London - GBR – Bertram PITT, Ann Arbor - USA

1. Data access 1.1. Data Cleaning issues Speaker: Jorgen SELDRUP, Quintiles - FRA Discussant: Robert CODY, Merck - USA

1.2. Adjudicating issues Speaker: Aldo MAGGIONI, Florence - ITA Discussant: Gilles DAGENAIS, Quebec - CAN 1.3. Unblinding issues Speaker: Nancy GELLER, Bethesda - USA Discussant: Phlippe G. STEG, Paris - FRA

2. Stopping rules in adaptive design trials 2.1. Methodological issues Speaker: Stuart POCOCK, London - GBR Discussant: Michael DOMANSKI, Bethesda - USA

2.2. Ethical issues Speaker: Sidney GOLDSTEIN, Detroit - USA Discussant: David GORDON, Bethesda - USA

2.3. Regulatory issue Speaker: Amin KADI, MFF, Paris - FRA Discussant: John WARREN, London - GBR

Faculty members Academy: Kirkwood ADAMS, Chapell Hill - USA – Jeffrey BORER, New York - USA Jan CARLSEN, Lyngby - DEN – Gilles DAGENAIS, Quebec - CAN - Nicolas DANCHIN, Paris - FRA Virginija DAMBRAUSKAITE, EU, Brussels - BEL – Jacques DESMOTES, ECRIN, Bordeaux - FRA Bengt FELLSTROM, Uppsala - SWE – Mihai GHEORGHIADE, Chicago - USA Sidney GOLDSTEIN, Detroit - USA – Luc HITTINGER, Paris - FRA – Guillaume JONDEAU, Paris, FRA Stéphane LAURENT, Paris, FRA – Aldo MAGGIONI, Florence - ITA – Gilles MONTALESCOT, Paris - FRA Bertram PITT, Ann Arbor - USA – Stuart POCOCK, London - GBR – Phlippe G. STEG, Paris - FRA Marteen SIMOONS, Rotterdam - NED – Chris TORP PEDERSEN, Copenhagen - DEN Eric VICAUT, Paris - FRA – John WARREN, London - GBR – Faiez ZANNAD, Nancy - FRA

Faculty members: NHLBI (NIH): Michael DOMANSKI, Bethesda - USA Nancy GELLER, Bethesda - USA –David GORDON, Bethesda - USA

Faculty members Industry and CROs: Michel ABITEBOUL, Quintiles - FRA – Bertrand BEAU, Parexel - FRA Robert CODY, Merck - USA – Amin KADI, MFF - FRA – Yasser KHDER, Boehringer Ingelheim - FRA Stuart KUPFER, Takeda, USA – Michel LEVY, ADDS - FRA – Vladimir POPOV, Esmar - RUS Hubert POULEUR, Pfizer - USA – James REVKIN, Boehringer Ingelheim - USA – Jorgen SELDRUP, Quintiles - FRA

Faculty members EMEA / AFSSAPS: Eric ABADIE, Paris - FRA – Angeles ALONSO, Madrid - SPA Fernando De ANDRES, Trelles - SPA

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acKNOWLedGemeNTs TO aLL ParTNers

15

6th Global CardioVascular

Clinical Trialists Forum

18

6th Global CardioVascular Clinical Trialists Forum • Paris 2009

Thursday December 3rd, 2009, 11 am- 1.45 pm

CVCT EXPERTS WORKHOPClinical trials in cardiovascular

critical careChairpersons: Alexandre Mebazaa,

Birhan Mehmet Yilmaz

What are the unmet needs?The clinician point of view

Alexandre MEBAZAA, Paris – FRADate et lieu de naissance: 21 mai 1960, Tunis – TunisieAdresse professionnelle: Département d’Anesthésie-Réanimation ; Hôpital Lariboisière; Tél : 01.49.95.80.85Email: [email protected]. Titres et Fonctions Universitaires– Diplôme de Docteur en médecine, Université Strasbourg I, 1989– Diplôme d’Etudes Spécialisés en Anesthésie-Réanimation, Univ. Strasbourg I, 1989– Chef de Clinique, Faculté de Lariboisière Saint-Louis, 1989 - 1991– Assistant Professor, Johns Hopkins University, Baltimore, Etats-Unis, de 1991 à 1994– Professeur des Universités en Anesthésie-Réanimation, Paris 7, Septembre 2000– Président du Conseil Pédagogique de la Faculté de Médecine Paris 7 Denis Diderot, depuis Novembre 2005– Professeur Associé Faculté de Médecine de Tunis, depuis juin 2006B. Fonctions Hospitalières– Interne: CHU de Strasbourg, 1984 - 1987, et Assistance Publique-Hôpitaux de Paris, 1988 - 1989– Assistant: Hôpital Lariboisière, Département d’Anesthésie-Réanimation, Novembre 1989- Novembre 1991– Staff Anesthesiologist : Anesthesiology and Critical Care Medicine, Johns Hopkins University, 1991-1993– Praticien Hospitalier: Département d’Anesthésie-Réanimation, hôpital Lariboisière, 1994 à ce jour– Vice-Président du CCM : depuis 2003– Expert - rapporteur sur les recherches biomédicales portant sur les dispositifs médicaux AFSSAPS , 2006C. Scientifi ques– Diplôme d’Etudes Approfondies (DEA), Physiologie et Physiopathologie Cardiaque et Pulmonaire, Paris V, 1989– Guest Researcher, Gerontology Research Center, National Institutes of Health (NIH), Baltimore, 1992-1994– Thèse de Sciences, Paris V, 1994– Habilitation à Diriger les Recherches, Faculté Lariboisière-Saint-Louis, Université Paris VII, 1996D. Principales publicationsMEBAZAA A et al. Activation of cardiac endothelium as a novel component of endotoxin-induced cardiomyopathy: role of endothelin, prostaglandins and nitric oxide. Circulation, 2001; 104:3137-44LANONE S, , MANIVET P, CALLEBERT J, LAUNAY JM, PAYEN D, AUBIER M, BOCZKOWSKI J, MEBAZAA A. Inducible nitric oxide synthase (NOS2) expressed in septic patients is nitrated in selected tyrosine residues: implications for enzymatic activity. Biochem J 2002; 366: 399-404.BENLOLO S, MATEO J, RASKINE L, TIBOURTINE O, BEL A, PAYEN D, MEBAZAA A. Sternal puncture allows an early diagnosis of poststernotomy mediastinitis. J Thorac Cardiovasc Surg. 2003; 125:611-617V. CAILLE, J.D. CHICHE, N. NCIRI, C. BERTON, S. GIBOT, B. BOVAL, D. PAYEN, J.P. MIRA, A. MEBAZAA. Histocompatibility leukocyte antigen-D related expression is specifi cally altered and predicts mortality in septic shock but not in other causes of shock. Shock. 2004;22:521-6.V. FAIVRE, H. KASKOS, J. CALLEBERT, M-R LOSSER, P. MILLIEZ , P. BONNIN, D. PAYEN, A. MEBAZAA. Cardiac and renal effects of levosimendan, arginine vasopressin and norepinephrine in endotoxin-treated rabbits Anesthesiology 2005; 103:514-521.RABUEL C & MEBAZAA A. Septic shock: a heart story since 1960’s. Intensive Care Med 2006; 32 : 799-807

Industry point of viewHemodynamic monitoring

Frederic MICHARD, Edwards Lifesciences, Nyon – SWI

Trade off in heart failure: why clinical trial on ADHF should focus on quality of life:

Piero POLLESELLO, Orion Pharma, Espoo – FINPiero Pollesello has a Ph.D. in biochemistry (University of Trieste, Italy) and is adj.Prof. in biochemistry (Faculty of Medicine, University of Helsinki, Finland). Specialist in the application of Nuclear Magnetic Resonance Spectroscopy to bio- and medical sciences and to drug discovery, he worked on a broad range of research topics such as the characterization of human pathologies, the determination of the phosphorylation potential on perfused tissues and organs, the detection

and quantifi cation of metabolites, the determination of protein structure and protein-ligand interaction (e.g. on troponin C and phospholamban), and fi nally the pharmacological characterization of a new fi rst-in-class cardiovascular drug. He has been head of cardiovascular pharmacology and drug discovery at Orion Pharma (Espoo, Finland), where he substantially contributed to the discovery, patenting, development, registration and launch of SIMDAX® (Levosimendan), a novel inodilator for the treatment of acutely decompensated heart failure. In his publication list there are 65 peer-reviewed papers, several book chapters and ten patents. He has been a member of the Editorial Board of J.Cardiovasc.Pharmacol. from 2005. He cooperated as evaluator in the European Union framework FP6 in the years 2003-2005. In 2007 he was appointed Critical Care Global Brand Manager at Orion Pharma for the proprietary products Levosimendan and Dexmedetomidine. He is Knight of the Italian Republic (O.S.S.I.).

ABSTRACTThe incidence and prevalence of heart failure (HF), a pathologic condition associated with signifi cant morbidity and mortality, are increasing in the Western population (1,2). Steward et al. (3) have shown that HF affects quality of life (QoL) more profoundly than many other chronic diseases. It is therefore straightforward that QoL should be taken into consideration when selecting the HF treatments and when developing new ones. New parameters such as health-related quality of life (HRQoL) and quality-adjusted life year (QALY) have been developed and used to measure reliably QoL (4). A distinction, however, should be made between HF and acutely decompensated HF patients, who are per defi nition hospitalised. An observation was recently made on the preferences of the patients after hospitalisation for AHF as it regards trading length of life for QoL (5). A bimodal distribution of the preferences was noticed making more diffi cult to prioritise the weight of one of the two when assessing the effect of therapies. Since it is objectively diffi cult to defi ne and assess QoL in the acutization of HF, some clinical studies included as end points some surrogate parameters such as patient self assessed symptoms, or even the “patient journey”, which is a composite consisting of repeated symptom assessments, worsening heart failure and mortality in a period of time of months after the event of decompensation (6). Other studies preferred a simpler “day alive and out of hospital” end-point (7). In a recent regulatory clinical study (8) on Levosimendan (REVIVE) the primary end point was on a composite with some QoL components (patient self assessment at different time points, in addition to doctor assessment of symptoms, biomarkers, etc.). The primary end-point in that study was successfully reached in front of a non signifi cant neutral outcome on the mortality at 90 days. The open question is how to weight the success of QoL end-points over a long term mortality end-point in an ADHF clinical study. As a fi nal consideration, it should be remembered that QoL parameters are often overlapping to health economic parameters, such as day-in-hospital and re-hospitalization (8), of paramount utility when planning clinical studies on new therapeutics in HF.


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LIST OF SUGGESTED READINGS: (1) Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93:1137-46. (2) Alla F, Zannad F, and Filippatos G. Epidemiology of acute heart failure syndromes. Heart Fail Rev. 2007;12:91-5.(3) Stewart AL et al. Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA 1989;262: 907–13.(4) Alehagen U et al. Quality-adjusted life year weights among elderly patients with heart failure. Eur J Heart Failure 2008;10:1033–1039(5) Stevenson LW et al. Changing Preferences for Survival After Hospitalization With Advanced Heart Failure. JACC 2008;52:1702–8(6) Nieminen MS et al. Oral levosimendan in patients with severe chronic heart failure --the PERSIST study. Eur J Heart Fail. 2008;10:1246-54.(7) Follath F et al. Effi cacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002;360:196-202(8) de Lissovoy G et al. Hospital costs for treatment of acute heart failure: economic analysis of the REVIVE II study. Eur J Health Econ. 2009 Jul 7. [Epub ahead of print]

What are the optimal endpoints? The emergentist point of view

Patrick Ray, Paris – FRA

The intensivist (ICU/CCU) point of view

Mehmet Birhan YILMAZ, MDAssociate Professor of CardiologyHe was born in Izmir in 1974. He graduated from Hacettepe University Faculty of English Medicine in 1998. He fi nished his residency in Türkiye Yuksek Ihtisas Education and Research Hospital, Cardiology Clinic in 2003. He started Department of Cardiology of Cumhuriyet University School of Medicine as a consultant and as an academic staff in 2005. He has become Associate Professor of Cardiology in 2006. He has been academic staff and a consultant in the same

department since then. He has been interested in valvular heart disease since 2003 and heart failure since 2005. He will be in INSERM U 942, in Laribosiere Hospital for one year with a grant from TUBITAK for research on biomarkers in heart failure. Dr.Yilmaz is a member of Working Group on Heart Failure of Turkish Society of Cardiology, and Working Group on Valvular Heart Disease of European Society of Cardiology.

ABSTRACTClinical trials in cardiovascular critical care: What are the optimal endpoints? Cardiac Intensivist Point of View: Mehmet Birhan YILMAZ (Sivas, TUR)Optimal end point is the one that takes every measurable impact of a therapeutic option into account. Every measurable means positive-negative impact both in the form of hard end points (mortality, disease-related mortality) and soft end points, which are quantifi able and comparable within different centres in a large trial. By saying optimal, there are at least two options: First is optimal endpoint during the critical care, the second is the optimal endpoint after the critical care, which is relatively well defi ned in many trials (hard endpoints: death, MI etc.) A)After critical care: Shall we look at cancer studies? Possible candidates for soft end points: 1-Acceptably high quality life days, gained up on therapy, 2-How many days does the patient spend without dyspnea or without exacerbation of my dyspnea?, 3-How many days did the patient gain without signifi cant angina (CCS II, or less than III), 4-How many days did the patient gain without palpitation? 5-How many days can the patient sleep without signifi cant dyspnea? (sleep quality indices?). Though, half of the life is in sleep, sleep quality is not thoroughly considered among trials. HF signifi cantly disturbs sleep, and sleep problems are unacceptably high among patients with HF.

6-Time to occurrence of specifi c-soft but relevant end-points (adjudicated): a)Time to occurrence of fi rst attack which causes the patient to admit emergency department (there must be requirement of the ED physician to report this as a serious admission in order to adjudicate it as an event): For example for a patient with HF: if there is admission to ED, there must be at least one criterion proving that the patient was sicker than before. (BNP, renal function, liver function, echocardiography, chestXray, questionnaires indicating worsening for HF), b) Admission free interval (any admission to health care facility), c) Combination of organ function end points with quality of life end points: If two are present or absent, 3 points, if one is present or absent 1 point in either direction. Organ function end-points could be in the form of natriuretic peptides, left ventricular remodelling, intima-media thickness, fl ow-mediated vasodilatation, creatinine, eGFR, liver dysfunction (enzymes). Organ function end points must be validated consistently before use in clinical trials. In general, all can be put into the category of “progression free survival”, end-point of oncology trials. On the other hand, if disease-free survival for CV disease is shown to predict overall survival in the meta analyses, then disease free survival can be put instead of overall survival.B) During critical care: End points could possibly be focusing more specifi cally. 1-Acute change in symptomatic status: both resting and with provocation, 2-Acute change in critical-organ function: compared to baseline (at admission) or to levels during stable phase or to the best value before

SUGGESTED READINGS:Cohn J et al. Unconventional end points in cardiovascular clinical trials: should we be moving away from morbidity and mortality? J Card Fail. 2009 ;15(3):199-205Anand IS. Surrogate end points in Heart Failure. J Am Coll Cardiol. 2002 ;39(9):1414-21Sargent DJ et al. J Clin Oncol. 2007; 25(29):4569-74.End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group.Quinn TJ. Time spent at home poststroke: «home-time» a meaningful and robust outcome measure for stroke trials. Stroke. 2008;39(1):231-3. Ferreira-González I et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334(7597):786.

The cardiac surgeon point of viewAntonis A. PITSIS, Thessaloniki, GREECEAntonis Pitsis is Head of the Department of Cardiothoracic Surgery at St. Luke’s Hospital and also the director of Thessaloniki Heart Institute (Thessaloniki, Greece). He is a British trained cardiothoracic surgeon. From 1992 – 1997 he undertook his residency in cardiothoracic surgery at Papworth Hospital (Cambridge), South Cleveland Hospital (Middleborough), University Hospital of Wales (Cardiff). From 1997 – 1999 he served as a Consultant and Senior Lecturer in cardiac surgery at the Bristol Royal Infi rmary

and University of Bristol (Bristol). His thesis was on percutaneous ventricular assist devices. He was appointed in his current post at St. Luke’s Hospital in 1999. His main fi elds of interests are mechanical circulatory support and heart failure surgery.

ABSTRACTThe mortality of acute heart failure (AHF) remains high despite advances in treatment. Mechanical circulatory support (MCS) can be applied in AHF, refractory to conventional measures, to improve outcomes. This presentation aims to stimulate discussion on the current and the prospective role of MCS in the treatment of AHF. The support strategies and the indications of MCS are continuously evolving, including clinical scenarios considered as contraindications in the past. Appropriate patient selection, advanced device technology and improved patient management have contributed to the substantially improved results. Evolution in device technology results in evolution of the clinical applications of MCS.

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Earlier application of MCS, with novel, fl exible and individualized support strategies is now feasible. Bridging to recovery is the most intriguing support strategy and bridging to future treatments is feasible with long-term support. The progressively expanding role of MCS in the treatment of heart failure is not refl ected in the existing guidelines. Being reserved for refractory heart failure, MCS has been applied to the sickest patients who were less amenable to randomization. This partly explains the lack of robust evidence, but also highlights the value of the progressively improving results. The anticipated wider application of MCS should be better defi ned, systematically recorded, and guided.3

LIST OF SUGGESTED READINGS: 1: Holman WL, Pae WE, Teutenberg JJ, Acker MA, Naftel DC, Sun BC, Milano CA, Kirklin JK. INTERMACS: interval analysis of registry data. J Am Coll Surg. 2009 May;208(5):755-61; discussion 761-2. Epub 2009 Feb 1. 2: Stevenson LW, Pagani FD, Young JB, Jessup M, Miller L, Kormos RL, Naftel DC, Ulisney K, Desvigne-Nickens P, Kirklin JK. INTERMACS profi les of advanced heart failure: the current picture. J Heart Lung Transplant. 2009 Jun;28(6):535-41. 3: Pitsis AA, Visouli A. Mechanical circulatory support in the ICCU. Acute Card Care. 2009 Sep 9:1-12. 4: Visouli AN, Pitsis AA. Will modern miniaturized left ventricular assist devices offer a viable alternative to heart transplantation? Hellenic J Cardiol. 2008 Sep-Oct;49(5):335-48. 5: Pitsis AA, Visouli AN. Update on ventricular assist device management in the ICU. Curr Opin Crit Care. 2008 Oct;14(5):569-78.

Thursday December 3rd, 2009, 2 pm- 6pm

EXPERT WORKSHOPUnderstanding the results of MADIT-CRT.

Key elements for an optimal implementation of CRT-D in clinical practice

Patient population and outcome issues: what is the clinical signifi cance of the results of MADIT-CRT Chairperson: Karl Swedberg, Göteborg – Swe

What are the patients eligible for CRT-D? How to estimate the size of the eligible population?

Mihai GHEORGHIADE, Chicago – USADr Gheorghiade currently serves as Professor of Medicine and Surgery, Associate Chief of the Division of Cardiology, Chief of the Cardiology Clinical Service, and the Director of the Telemetry Unit at Northwestern University’s Feinberg School of Medicine and Northwestern Memorial Hospital. He was recently appointed Adjunct Professor of Medicine at Duke University and also Section Editor for Heart Failure Reviews Journal. He graduated Magna Cum Laude from the University of Rome Medical School in 1972 and did his residency and fellowship in cardiology at Brown University. He then moved to Virginia, where he was Chief of Cardiology at the Salem VA Medical Center and Associate Professor of Medicine at the University of Virginia. In 1985, Dr Gheorghiade became Chief of the Cardiac Care Unit at the Henry Ford Hospital in Detroit and Associate Professor of Clinical Medicine at the University of Michigan. During his tenures in Virginia and Michigan, he received numerous teaching awards from both medical students and residents. In 1992, he joined Northwestern University.Dr Gheorghiade has served as a visiting professor in the United States and abroad. He has served as a visiting professor in the United States and abroad. He has chaired or co-chaired more than 150 national and international meetings and has given more than 500 invited lectures. He has served or is currently serving on the editorial board of several journals including The American Heart Journal, The American Journal of Cardiology, Journal of the American College of Cardiology, and Circulation Heart Failure Journal. He has also served as guest editor on several occasions for The American Journal of Cardiology, The American Heart Journal, and The American Journal of Medicine. He has chaired many international trials in heart failure including OPTIME-HF, ACTIV-HF, IMPACT, PRESERVD, STEP-CHF and HORIZON Trials. He has co-chaired the global EVEREST Trial and the ECLIPSE Trial, and was a member of the Steering Committee of RADIANCE, FIRST, CARS, RITZ 4, and EPHESUS Trial. In addition, Dr Georghiade was an active member of the Steering Committee in the OPTIMIZE-HF and IMPACT-HF registries. He currently serves as Chair of the international ASTRONAUT, RENO-DEFEND, and Co-chair of the IGNITE trials. Dr Gheorghiade has authored more than 500 peer-reviewed publications and more than 300 abstract presentations at national and international meetings. He is the co-editor for two comprehensive textbooks on acute heart failure syndromes and has written several chapters in many textbooks including Kelley’s Textbook of Internal Medicine, and Heart Failure: A Companion to Braunwald’s Heart Disease. He was recently invited to write a chapter on acute heart failure syndromes in the upcoming edition of Braunwald’s Heart Disease.In 2004, Dr Georghiade founded the Acute Heart Failure Syndromes International Group, comprised of physicians, scientists, clinicians, and regulatory and governmental agencies from North America and Europe to advance the knowledge and care of patients with acute heart failure syndromes through clinical research. This group has met annually, producing several consensus documents published in Circulation, Journal of the American College of Cardiology, and European Heart Journal.At present, Dr Gheorghiade is actively involved in the management of patients undergoing solid organ transplantation at Northwestern Memorial Hospital, and remains actively involved in animal and human research for the development of novel compounds for acute heart failure syndromes. He dedicates signifi cant time and energy to the mentorship of medical students, residents and junior faculty as attested by their primary authorship of more than 100 peer-reviewed publications in recent years. Improving outcomes of hospitalized patients with heart failure through research and education remains his top priorities.


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Professor Aldo MAGGIONI, Florence – ITAANMCO Research Centre, Florence, ItalyProfessor Aldo Maggioni received his medical degree in 1974 from the University of Milan’s School of Medicine, Italy, where he subsequently completed his fellowship in internal medicine. He undertook a residency in cardiology at the University of Padua (1975–1978) before becoming a clinical cardiologist at the General Hospital ‘G. Fornaroli’ and progressing to Vice-Head of

the Division of Cardiology at G. Fornaroli and later, the Division of Cardiology at General Hospital Fatebenefratelli ed Oftalmico, both in Milan.Professor Maggioni is a member of the GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico) Coordinating Centre and Director of the Research Centre of the Italian Association of Hospital Cardiologists (ANMCO) in Florence. Professor Maggioni has served on the steering committees, event evaluation committees, and data and safety monitoring boards of more than 40 clinical trials within the fi elds of arrhythmia, myocardial infarction, unstable angina, secondary prevention, stroke and congestive heart failure.Professor Maggioni is author of more than 250 papers on peer-reviewed journals. He is also a member of the Editorial Board of the following journals: Journal of Cardiovascular Medicine, Cardiovascular Drugs and Therapeutics, Evidence Based Cardiovascular Medicine, European Heart Journal, European Journal of Heart Failure, Circulation Quality and Outcomes, BMJcases.

The relative contribution of preventing death and preventing HF hospitalization

Frédéric ANSELME, Rouen – FRA Date de naissance : 30 juin 1965 Nationalité : FrançaiseDiscipline : Cardiologie et Maladies Vasculaires Numéro de l’Ordre des Médecins: 76/5002Professeur d’Université- Praticien Hospitalier dans le service de Cardiologie du Pr Cribier depuis Septembre 2006Responsable de l’unité de rythmologie dans le service du Pr Cribier à Rouen depuis 2000Responsable du DIU de Rythmologie et de Stimulation Cardiaque à l’université de Rouen.Activités administratives et responsabilités collectives:Membre titulaire de la Société Française de CardiologieMembre du bureau du groupe de Rythmologie et de stimulation cardiaque de la Société Française de CardiologiePrésident de l’Association de Cardiologie de Haute Normandie (membre du conseil d’administration de la Fédération Française de Cardiologie)Stage à l’étranger: Laboratoire d’Electrophysiologie du Pr M.E. Josephson, au Beth Israël Hospital de Boston, Harvard Medical School, Massachusetts, USA (1994-1995).PUBLICATIONS RECENTESAnselme F. Macro-reentrant atrial tachycardia: physiopathological concepts. Heart Rhythm, June 2008 5 (6):S18-S21.Anselme F, Mletzko R, Bowes R, Mabo P, Sadoul N, Schoels W, Seidl K, Schwab J, Iscolo N, Nitzsche R. Prevention of Inappropriate Shocks in ICD Recipients: A Review of 10,000 Tachycardia Episodes. Pacing Clin Electrophysiol. 2007 Jan;30(s1):S128-S133. Schwab JO, Gasparini M, Anselme F, Mabo P, Peinado R, Lavergne T, Bocchiardo M, Mascioli G, Passardi M, Mainardis M. Right Ventricular versus Biventricular Antitachycardia Pacing in the Termination of Ventricular Tachyarrhythmia in Patients Receiving Cardiac Resynchronization Therapy: The ADVANCE CRT-D Trial. J Cardiovasc Electrophysiol. 2006 May;17(5):504-7. Anselme F, Gahide G, Savoure A, Gerbaud E, Mabru M, Cribier A, Dacher JN. MR evaluation of pulmonary vein diameter reduction after radiofrequency catheter ablation of atrial fi brillation. Eur Radiol. 2006 Apr 26. Meune C, Van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden cardiac death in patients with lamin A/C gene mutation. N Engl J Med. 2006 Jan 12;354(2):209-210.Sadoul N, Mletzko R, Anselme F, Bowes R, Schoels W, Kouakam C, Castaigneau

G, Luise R, Iscolo N, Aliot E. Incidence and clinical relevance of slow ventricular tachycardia in ICD recipients. An international multicenter prospective study. Circulation. 2005 Aug 16;112(7):946-53Saoudi N, Ricard P, Rinaldi JP, Yaïci K, Darmon JP, Anselme F. Methods to determine bi-directional block of the cavo-tricuspid isthmus in radiofrequency ablation of typical atrial fl utter. J Cardiovasc Electrophysiol. 2005 Jul;16(7):801-3.

Faiez ZANNAD, Nancy – FRAFaiez 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, Hypertension and Preventive Cardiology/

department of Cardiovascular Disease of the academic hospital of Nancy, and Director of the Clinical Investigation Center (CIC), mutually funded by the academic hospital and the INSERM and of a research group at an INSERM Unit (U684, Cardiac Fibrosis, Stiffness and cardiovascular risk) at the Faculté de Médecine.He is coordinator of a Joint Research Program on transition fromHypertension to Heart Failure, in the EU funded Network Excellence“InGeniousHyperCare”. He conducts his research, in the area ofphysiopathology and pharmacotherapeutics of hypertension and heart failure. Dr Zannad is Fellow of the European Society of Cardiology (ESC), Vice-chairman of the ESC Working group on pharmacology and drug therapy, Chairman of the Board of the French Society of Hypertension as well as a member of a large number of international societies in cardiology, hypertension, pharmacology and therapeutics. He is currently Co- Editor inchief of Fundamental and Clinical Pharmacology, the offi cial journal of the European Federation of Pharmacological Societies (EPHAR) and a member of the Editorial boards of a number of journals in the fi eld of Cardiology, Hypertension and Cardiovascular Pharmacology. He has contributed more than 300 scientifi c publications and published several books on cardiovascularpharmacotherapy and on Heart Failure. He is chairman and organizer of several international meetings: “CardioVascular Clinical Trialists (CVCT) Forum and Workshop” (Cannes and Paris, with Bertram Pitt and Desmond Julian); “Acute Heart Failure Syndromes” (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 severalSteering Committees, Critical Event Committees and Data Safety and Monitoring Boards. Steering Committee membership: APSI, FIRST, CIBIS I and II (Executive committee), RALES (Executive committee), CAPRICORN, FOSIDIAL (Chairman), VALIANT, RECOVER, MOXCON, EPHESUS (Executive committee), AURORA(Executive committee), EVEREST (Executive committee), EMPHASIS-HF (Chairman), Critical Event Committee: CAPRICORN, RESPECT, SCOUT, Data and Safety Monitoring Board HEAAL, Protocolwriting groups RALES, CAPRICORN, CIBIS II and EPHESUS, EVEREST.

The clinician point of view: generalizability of the results of recent trials (MADIT-CRT)

Gunter BREITHARDT, Münster – GER

Mechanistic issues: How does CRT-D work for the prevention of HF hospitalisation?

Chairperson: Daniel Gras, Nantes – FRA

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Consistency within the trial subgroups, consistency with other CRT and ICD trials.

Cecilia LINDE, Stockholom –SWE

Mechanistic plausibility. Insight from pathophysiology – importance of improvement of LV function across all trials

Mark ESTES, Boston – USA

Registerability and implementation issues.

Chairperson: Faiez Zannad

Is “Prevention of HF events” in mild HF patients with large QRS and low EF an approvable new indication for CRT-D?

Bernd LEMKE, Lüdenscheid – GER

Updating the guidelines.and overcoming implementation issues/barriers

Karl SWEDBERG, Göteborg – SWE

Thursday December 3rd, 2009, 2 pm- 4pm

EUROPEAN SOCIETY OF CARDIOLOGY Working Group on Cardiovascular Pharmacology

and Drug Therapy Young CardioVascular Clinical Trialists

(YCVCT) Course

Chairperson: Thibaud Damy, Patrick Rossignol

Thibaud DAMY, Créteil – FRA Doctor Thibaud Damy qualifi ed in medicine at the University of Paris XI in 1996. After a period of postgraduate cardiology training in several Parisian hospitals and a PhD on the effect of nitric oxide on heart failure at the University Paris VII, he was appointed fi rst as a senior registrar at Paris V University (2004), then at Paris XII (2005-2006) and subsequently in 2007 as a senior lecturer in cardiology and honorary consultant cardiologist at Henri Mondor Hospital, Creteil, France.

In August 2008, he obtained a secondment for 16 months as a senior research fellow at the Academic Cardiology Department of Professor John G Cleland at the University of Hull (UK).Doctor Damy’s main fi eld of interest is heart failure, extending from its epidemiology and physiopathology through to its diagnosis and treatment. Particular current interests include the role of the nitric oxide pathway, neurohumoral systems, sleep apnoea syndrome, right ventricule function, and pulmonary artery pressure in heart failure.

Patrick ROSSIGNOL, Nancy – FRABorn 15 April 1969, FrenchProfessional address: Centre d’Investigation Clinique de NancyHOPITAL JEANNE D’ARC, BP 90303, F-54201 TOUL CEDEXTel :+33 3 83 65 66 25 /fax +33 3 83 65 66 19/ E-mail: [email protected] (degrees, dates, universities)Master degree in Biology and Pathology of the epithelia, 1998, University of Paris VI « Pierre et Marie Curie »

Medical Doctorate, specialty nephrology, 2000, University of Paris V « Necker-Enfants Malades »Complementary fellowship in Vascular medicine : 2004, University of Paris V « Necker-Enfants Malades »Ph. D. “Biology and pharmacology of hemostasis” : 2005, University of Paris VII “Denis Diderot”Professional/research experience11/2000-31/10/2002 : Ph. D. student, INSERM Unit 460, Dr Michel, Paris.11/2002-31/10/2003 : fellowship in vascular biology, Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven (Belgium) : Pr Lijnen, Pr Collen11/2003-04/2006 : Chief-Assistant, then Assistant Professor (05/2006-04-2007) : Vascular Medicine and Hypertension department, Pr Fiessinger, Hôpital Européen Georges Pompidou (Assistance Publique-Hôpitaux de Paris), Paris, and Faculté de Médecine René Descartes-Paris V ; associate researcher, INSERM 765 (formerly U 428), Pr Emmerich.05/2007- : Assistant-Professor (Therapeutics), delegate physician of the Nancy University Hospital & INSERM Clinical Investigation Centre (Coordinating physician : Pr Zannad) ; associate researcher, INSERM 961, Dr Lacolley.Main publications over the last 5 yearsIraqi W, Rossignol P, Angioi M, Fay R, Nuée J, Ketelslegers JM, Vincent J, Pitt B, Zannad F. Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: Insights from the EPHESUS study. Circulation 2009 ;119 :2471-9


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Joly L, Perret-Guillaume C, Kearney-Schwartz A, Salvi P, Mandry D, Marie PY, Karcher G, Rossignol P, Zannad F, Benetos A. Pulse wave velocity assessment by external non-invasive devices and phase-contrast magnetic resonance imaging in the obese. Hypertension 2009, Jun 8 [Epub ahead of print]Ortiz-Muñoz G, Houard X, Martín-Ventura JL, Ishida BY, Loyau S, Rossignol P, Moreno JA, Kane JP, Chalkley RJ, Burlingame AL, Michel JB, Meilhac O. HDL anti-elastase activity prevents smooth muscle cell anoikis, a potential new anti-atherogenic property. FASEB J 2009, May 5 [Epub ahead of print]Rossignol P*, Kearney-Schwartz A, Bracard S, Felblinger J, Fay R, Boivin JM, Benetos A, Zannad F. Vascular structure and function is correlated to cognitive performance and white matter hyperintensities in older hypertensive patients with subjective memory complaints. Stroke. 2009;40:1229-1236. *co-fi rst authorHouard X, Touat Z, Ollivier V, Louedec L, Philippe M, Sebbag U, Meilhac O, Rossignol P, Michel JB. Mediators of neutrophil recruitment in human abdominal aortic aneurysms. Cardiovasc Res. 2009; 82:532-41Rossignol P, Cambillau M, Mouradian D, Plouin PF, Chatellier G, Jacob MP. Variations with time of plasma concentrations of matrix metalloproteinases 2 and 9 and tissue inhibitors of matrix metalloproteinases 1 and 2. Thromb Res. 2007; 119 : 261-3 Martin-Ventura JL, Leclercq A, Blanco-Colio LM, Egido J, Rossignol P, Michel JB, Meilhac O. Low plasma levels of HSP 70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation. Atherosclerosis 2007;194:334-341. Rossignol P, Luttun A, Martin-Ventura JL, Lupu F, Carmeliet P, Collen D, Anglès-Cano E, Lijnen H-R. Plasminogen activation : a mediator of vascular smooth muscle cell apoptosis in atherosclerotic plaques. J. Thromb Haemost 2006, 4 : 664-670.Caligiuri G, Rossignol P, Julia P, Groyer E, Mouradian D, Urbain D, Misra N, Ollivier V, Sapoval M, Boutouyrie P, Kaveri S.V, Nicoletti A, Lafont A. Reduced immunoregulatory CD31+ T cells in patients with atherosclerotic abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 2006, 26: 618-23.Rossignol P, Bouton MC, Bryckaert M, Jacob M-P, Bezeaud A, Jandrot-Perrus M, Guillin MC, Michel JB, Meilhac O. A paradoxical pro-apoptotic effect of thrombin on vascular smooth muscle cells. Exp Cell Res. 2004 ;299:279-85.Rossignol P, Ho-Tin-Noé B, Vranckx R, Bouton MC, Meilhac O, Lijnen H.R, Guillin MC, Michel JB, Anglès-Cano E. Protease-nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells J. Biol Chem 2004;279:10346-56

The young CVCT initiative: Time to rejuvenate CV clinical trialists

Bertram PITT, Ann Arbor – USAProfessor of Internal Medicine1949-53 B.S., Cornell University, New York,1953-59 M.D., University of Basel, Switzerland1959-60 Intern, Beth Israel Hospital, New York

Positions 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, University of Michigan School of Medicine1991-99 Professor of Internal Medicine, Associate Chairman for Academic and Industrial Programs, Department of Internal Medicine, University of Michigan School of Medicine1999-Pres Professor Internal Medicine, University of Michigan School of Medicine

Honors 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 Michigan Research Support.Co-Investigator, Angiotensin Receptor Blockade in Age Dependent Endothelial Dysfunction (Prevailed II) – Understand the changes that occur in blood vessels to develop strategies to combat cardiovascular disease –Novartis Co-Investigator, A multi-center, double-blind, randomized study to evaluate the effects of valsartan and the combination of valsartan and simvastatin on blood pressure (ambulatory and standard cuff) and on selected biochemical markers of endothelial function, safety and tolerability – To assess and compare the effects of valsartan, and the combination of valsartan and simvastatin – Novartis

Maximizing scientifi c knowledge from randomized clinical trials data. Opportunities for young CVCT fellows.

Gilles DAGENAIS, Quebec – CANA graduate from the Medical School of the Université de Montréal, Dr Dagenais pursued his training in research at McGill University and subsequently in Internal Medicine at the Université de Montréal. He did his training in cardiology and research at the Johns Hopkins Hospital and University and in clinical trial during a one-year sabbatical at the University of Oxford.From 1979 to 1987, Dr Dagenais was the Director of the Quebec Heart Institute and the Cardiology Program at the Université Laval where he was a Professor of

Medicine. From 1991 to 1999, he was Professor and Chairman of the Department of Medicine at the Université de Montréal. Professor emeritus at the Université de Montréal and at the Université Laval, he continues his career in clinical cardiology and research at the Quebec Heart Institute.Dr Dagenais’ main research interest is on ischemic cardiovascular diseases and their prevention. He is the principal investigator of the Quebec Cardiovascular Study, co-chair of the HOPE and HOPE TOO trials, and member of the steering committee of the DIG, DREAM/Epi-DREAM, ONTARGET-TRANSCEND, BARI-2D, ORIGIN, HOPE-3, TIDE clinical trials as well as the international epidemiological PURE study.Dr Dagenais is involved in several national and international societies and professional associations. He has been President of the Canadian Cardiovascular Society, member of the College of Cardiology Board, Associate-editor of the Canadian Journal of Cardiology, President of the Canadian Association of Professors and Chairmen of Department of Medicine, President of the 4th International Conference on Preventive Cardiology and fi rst Vice-president of the Inter-American Society of Cardiology.

ABSTRACTIt is what we think we know already that often prevents us from learning. Claude Bernard What we know and what we think that our fellows know about randomized clinical trials (RCTs) may be summarized as follows. Some RCTs have contributed to improving the survival and the quality of life of high-risk patients; GISSI, ISIS-2, SOLVD and SAVE are good examples. Other RCTs have shown that despite encouraging surrogate fi ndings and assumptions, the medications evaluated were deleterious (ILLUMINATE, CAST). Other RCTs have shown that the medication evaluated was not different from the placebo or the comparator agent (BARI 2D, HOPE-TOO). Some trials have generated hypotheses; for example, ACE-inhibitors or angiotensin receptor blockers decreased the risk of type 2 diabetes; however, these trials were not designed to assess type 2 diabetes as primary outcome but they generated the hypothesis that was or is being tested (DREAM, NAVIGATOR). A variety of methodologies have been used in RCTs alone or in pseudo-amalgams of RCTs-database registries. These different trials with theirs

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methods constitute an extraordinary dataset covering a wide spectrum of information that is useful to improve knowledge on RCTs and beyond.1-4 Although several RCTs are model trials and others had limitations; did we, young and less young fellows, learn from these trials? Analyzing some of these trials in more details may enrich the training of fellows. For example raising questions such as: how relevant is the question to be answered by the trial? Was the question or the objective based on observational studies, mechanistic and/or surrogate studies? Was the design of the study adequate to answer the question? Was the trial performed according to the submitted protocol? How was the interpretation of the data? The implications of such questions in the training of fellows will be highlighted during this presentation.RCT analyses are important methods of improving knowledge of fellows in the fi eld of clinical trials but they should be incorporated into a global training program including facilities for mentorship, basic epidemiological training, exchanges with colleagues in a productive milieu, the opportunities to generate a small or pilot clinical trial and if possible to participate in a large RCT. Finally, RCT knowledge facilitates critical appraisal and should be integrated at an early stage of the training such as in the curriculum of health care students.5-7

References1. Zwarenstein M, Treweek S. What kind of randomized trials do patients and clinicians need? EBM 2009; 14: 101-32. Shaw SM, Yonan N, Williams SG, Fildes JE. The interpretation of clinical trial data-wrongly ACCLAIM’ed? Am Heart J 2009; 158: 149-51.3. Swedberg K Fallacies in clinical cardiovascular trials. Heart 2009; 95: 1464-8.4. Pfeffer MA, Sacks FM Leapfrogging data. No shortcuts for safety or effi cacy information. Circulation 2008; 118: 2491-4.5. Witte CL, Witte MH, Kerwin A. Ignorance and the process of learning and discovery in medicine. Control Clinical Trials 1994; 15: 1-4. 6. Haidet P, Hunt D, Coverdale J. Learning by doing: teaching critical appraisal of randomized trials by performing an in-class randomized trial. Acad Med 2002; 27: 1161. 7. Rangachari PK. Student-designed clinical trails: evaluating self-directed learning in pharmacology. Arch Pharmacol 2002; 366: 44-7.

How to teach trial methodology to young clinicians?Eric VICAUT, Paris – FRA

Responsibilities, role and functioning of trial committees (Steering committee, DSMC, Event committee).

Sidney GOLDSTEIN, Detroit – USA

Division Head, Emeritus, of the Division of Cardiovascular Medicine at Henry Ford Hospital in Detroit, Michigan. Dr. Goldstein received his B.A. at Cornell Univesity and his medical education at Cornell University Medical Colege. He completed both his internship and residency at the New York Hospital – Cornell Medical Center. Following this, he was a research fellow sponsored by the New York Heart Association at New York Hospital – Cornell Medical Center. Before going to Henry Ford Hospital, he was head of the cardiology division at Rochester General Hospital in Rochester, New York and Associate Professor of Medicine at the University of Rochester. Dr. Goldstein’s major areas of basic and clinical research have been in the areas of ischemic heart disease, the mechanism and prevention of sudden cardiac death and the treatment of heart failure. He served as chairman of the steering committee of the Beta-Blocker Heart Attack Trial and was a principal investigator in the Aspirin Myocardial Infarction Study, the Cardiac Arrhythmia Suppression Trial and the Asymptomatic Cardiac Ischemia Pilot Study. He has carried out extensive research on the mechanism and prevention of sudden death supported by the National Heart, Lung and Blood Institute. His current research interests are directed at understanding the basic mechanism of heart failure. He was Co-Principal Investigator of Metoprolol CR Randomized Interventional Trial in Heart Failure (MERIT-HF).Widely published, he is the author or co-author of more than 250 peer-reviewed articles, in addition to numerous editorials and book chapters. He is co-editor of Heart Failure Reviews, a journal examining the spectrum of research in heart failure from basic science to clinical research. He is medical editor of

Cardiology News and currently serves on the editorial boards of the American Journal of Cardiology, American Journal of Geriatric Cardiology and Internal Medicine NewsDr. Goldstein is a fellow of the American College of Cardiology and a past member of its board of trustees and chairman of the Workforce and Credential Committees. He is a member of the Council of Clinical Cardiology and Epidemiology of the American Heart Association and a fellow of the American College of Physicians, and a member of the American Federation for Clinical Research and the Central Society for Clinical Research and the Association of University Cardiologists.

Sidney Goldstein, M.D., is Professor of Medicine at Wayne State University and


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Friday December 4th, 2009, 9.00 am – 12.00 am

PLENARY SESSIONBiomarkers in clinical trials

Chairpersons: Angeles Alonso, Kirkwood Adams

Angeles ALONSO, Madrid – SPA I was born and raised in Madrid, Spain. In 1979 I graduated from the School of Medicine at the Universidad Autónoma de Madrid and later in 1991 I successfully completed my Ph.D at the Faculty of Medicine. I began my clinical experience with as a resident doctor in the Intensive Care Unit at the Hospital La Paz (Madrid) and then 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). In 2000 I became a member of the Committee for Ethics and Clinical Investigation and a Member of the Committee for Mortality. Two years later I was promoted to Senior Consultant of the Cardiology Department at the Hospital Universitario Puerta de Hierro (Majadahonda).I am an Honorary Professor at the Department of Medicine in Cardiology at the Faculty of Medicine, Universidad Autónoma de Madrid and have also been Coordinator, Chairman and speaker of several post-degree Ph D Courses at the Academic Hospital Puerta de Hierro de Madrid on Cardiovascular Topics: Hipertensión, Cardiac Emergencies, Heart Failure and Cardiac pacing. I have been a member of the Spanish Society on Cardiology (SEC) since 1986, a member of the Heart Failure, Ischemic Diseases, Women and CV Disease, Pharmacology Working Groups of the Spanish Society of Cardiology, General Vice-Secretary elect of the Spanish Society of Cardiology: 1999-2001, General Secretary of the Spanish Society of Cardiology: 2001-2003 and President of the International Relations Department of the Spanish Society of Cardiology 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, a member of the WG of Heart Failure and Acute Heart Diseases of the European Society of Cardiology ESC, a member of The Euro Heart Survey Committee of the European Sociey of Cardiology ESC from 2002-2004, National Coordinator of the Euro Heart Survey Program of the European Society on Cardiology 2000-2004, a member of the Clinical Practice Guidelines Committee of the European Society of Cardiology ESC 2000-2004, a member of the Task Force of Stable Angina Guideline of the ESC 2006, a member of the Regulatory Committee of the ESC until the present date and a member of the General Coordinating Committee of The Euro Heart Survey Programm until the present date.In terms of regulatory experience, I am a member of the Cardiovascular Group of the Effi cacy Working Party of the European Medicines Agency EMEA (2000 to date) and a member of the Scientifi c Advice Working Party of the EMEA (2005 to date).

How evidence based is the current risk stratifi cation guided CV preventive drug therapy?

Luis RUILOPE, Madrid – SPALuis Ruilope is currently Associate Professor of Internal Medicine at Complutense University and Head of the Hypertension Unit at the 12 de Octubre Hospital in Madrid, Spain. Dr Ruilope received his MD degree from the University of Madrid and completed his residency and fellowship in nephrology at the Jiménez Diaz Foundation in Madrid. His principal area of interest is hypertension and the kidney.Dr Ruilope is a member of the editorial boards of several journals including Journal of Hypertension,

Blood Pressure, Hypertension and The Journal of Human Hypertension. In addition, he was President of the Spanish Hypertension Society and Chairman of the 16th European Society on Hypertension in Madrid . Between 1998 and

2009, Dr Ruilope was a member of the Scientifi c Committee of the European Society of Cardiology. He is also an International Fellow of the Council for High Blood Pressure Research and the Council of the Kidney in CV Disease for the American Heart Association.

ABSTRACTClinical evidence is required in order to develop guidelines of treatment in different areas in medicine. In CV disease evidence is usually based in trials where differences in outcome is obtained while comparing different therapeutical attitudes. In the particular case of arterial hypertension, evidence was fi rstly obtained in studies where active therapy was compared to placebo and later obtained comparing different therapies in most cases monotherapies. Now-a-days an adequate risk stratifi cation is required to initiate the adequate type of therapy which will always consist of an adequate life-style accompanied by physical activity and whe required by pharmacological therapy. This scheme is used by the ESH-ESC Guidelines for the treatment of hypertension and contributes to facilitate not only BP control but also the correction of the very frequently associated CV risk factors other than elevated BP.References-1- Mancia G et al. Reappraisal of European guidelines on hypertension management: a ESH Task Force document. J Hypertens 2009. (epub ahead of print)2- Zanchetti A. Bottom BP or bottom CV risk? How far can CV risk be reduced. J Hypertens 2009. 27: 1509-15203- Segura J, Ruilope LM. Treatment of prehypertension in diabetes and metabolic syndrome: what are the prost?. Diabetes Care 2009. 32 (suppl 2): S284-S289.

The challenge of designing a biomarker trial.

Faiez ZANNAD, Nancy – FRA

Biomarker guided therapy: Trial design and interpretation issues

Kirkwood ADAMS (Chapell Hill, USA)

Debate: Design of biomarkers for cardiovascular trials

The industry viewpoint

Ursula-Henrike WIENHUES-THELEN, Roche Diagnostics – GERUrsula Henrike Wienhues-Thelen´s background is a molecular biologist. She obtained her PhD in the Institute of Genetics at the University of Cologne. After a three years postdoctoral fellowship in the Institute of Physiology at the University of Munich she moved to the R&D Department of Boehringer Mannheim Diagnostics, therafter Roche Diagnostics in Penzberg. She is now involved as a senior scientist in the early assessment of novel diagnostic marker candidates.

ABSTRACT Recent progress yielded in the availability of large databases as tools for biomarker identifi cation. Several transcriptomic and proteomic profi ling experiments concern progressive heart failure. Targeted biomarker extraction to fi lter candidates for development of assays for CV trials is discussed. -list

LIST OF SUGGESTED READINGS: Circ Res 2006 (98) 309J Am Coll Cardiol 2006 (48) 1733Molecular and Cellular Proteomics 2008 (7.3) 520

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The regulator viewpoint

Bruno FLAMION, European Medicines Agency-EMEA, Brussels – BELBruno Flamion, MD, PhD, is a Belgian national. He graduated from the Medical School of the University of Brussels and specialized in internal medicine and nephrology, then obtained a PhD in Physiological Sciences in 1992 and worked at the National Institutes of Health (USA) in Bethesda, MD, between 1988 and 1992 and for the Belgian National Fund for Scientifi c Research, 1992-1996. He is now Full Professor in Physiology and Pharmacology at the University of Namur, Belgium where he heads the Laboratory of Physiology and Pharmacology. His main research interest is in hyaluronidases.Since 1999 Bruno Flamion has been a medical and pharmacological expert for what has become the Belgian Federal Agency for Medicinal and Health Products (FAMHP). At the European Medicines Agency (EMEA) in London, he has been a member of the CHMP, the Effi cacy Working Party and the Therapeutic Group on Pharmacokinetics, as well as vicechairman of the Pharmacogenetics Working Party, since 2001 and has become a member of the new Committee for Advanced Therapies (CAT) which started its activities in January 2009.Bruno Flamion was appointed chairman of the Scientifi c Advice Working Party (SAWP) of the CHMP in April 2005 and was reelected in April 2008 for another 3-year term. Through SAWP, the CHMP gives more than 300 scientifi c advices per year to large and small companies on drug development in all therapeutic areas.Bruno Flamion is also a member of the Regulations Advisory Board of the Centre for Medicines Research (CMR), International Institute for Regulatory Science.His continued activities in basic research and teaching make Bruno Flamion a strong supporter of increased scientifi c interactions between pharma leaders, regulatory bodies and the academia.


PLENARY SESSIONTargeting the aldosterone pathway

Chairpersons: Aldo Maggioni, Mihai Gheorghiade

Aldosterone: a culprit hormone in cardiovascular disease

Johann BAUERSACHS, Wurzburg – GERMedizinische Klinik und Poliklinik I Universitätsklinikum Würzburg Josef-Schneider-Str. 2, 97080 WürzburgE-Mail: [email protected] Curriculum vitae13.12.1993 Thesis (M.D.) at the University of Freiburg, Department of Physiology1993-1995 Residency and Fellowship in Internal Medicine, University Hospital Frankfurt

1995-1996 Postdoctoral / Research Associate, Center of Physiology, University of Frankfurt1996-1999 Residency and Fellowship in Internal Medicine, University Hospital Mannheim 1999-2003 Residency and Fellowship in Internal Medicine and Cardiology, Department of Medicine, University of Würzburg1999-2004 Scientifi c Secretary DFG Special Research Program SFB 355 23.08.00 Board of Internal Medicine Certifi cation2001 Habilitation, Member of the Faculty, senior lecturer, Dept. of Medicine, Division of Cardiology, University of Würzburg31.01.2002 Board of Cardiology Certifi cationsince 2003 Consultant Internal Medicine/Cardiology, University Hospital Würzburg since 2006 Scientifi c Secretary DFG Special Research Program SFB 688since 2008 Associate Professor, Dept. of Medicine, Division of Cardiology, University Hospital WürzburgSpecial achievements/honors2001 Oskar-Lapp- Award of the „Deutsche Gesellschaft für Kardiologie“ 2004 Albert-Fraenkel- Award of the „Deutsche Gesellschaft für Kardiologie“2006 Parmley-Award of the American College of Cardiology

ABSTRACTActivation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of cardiovascular disease. High levels of aldosterone impair cardiac and vascular function and predict mortality risk of patients with acute myocardial infarction or heart failure. Patients with primary hyperaldosteronism display a higher incidence of myocardial infarction and stroke. Large clinical trials (RALES, EPHESUS) have shown mineralocorticoid receptor (MR) blockade to decrease mortality in heart failure with reduced ejection fraction (Greenberg et al., 2006). While numerous studies suggest that MR blockade is also effective in heart failure with preserved ejection fraction, defi nitive evidence will come from ongoing randomised, placebo-controlled studies. In a large proportion of patients with resistant hypertension MR blockade reduces blood pressure even in the absence of primary hyperaldosteronism (de Souza et al., 2009).In contrast to the classical notion that mineralocorticoids were only involved in body electrolyte and water homeostasis mediated by the kidney, aldosterone exerts important direct (patho)physiological effects on the cardiovascular system. MR expression has been repeatedly documented in cardiovascular cells such as cardiomyocytes, cardiac fi broblasts, endothelial cells and smooth muscle cells leading to cardiac hypertrophy, fi brosis and vascular injury. MR expression in the heart is increased in heart failure explaining detrimental effects of aldosterone even in the absence of markedly elevated circulating levels of aldosterone. MR activation increases cardiomyocyte as well as vascular endothelial and smooth muscle cell reactive oxygen species formation (Lombes et al., 1995; Fraccarollo et al., 2003).Under certain pathophysiological circumstances, also glucocorticoids may act


27

as agonists on the MR (Mihailidou et al., 2009). In the Würzburg heart failure registry including consecutive heart failure patients with either preserved or reduced LV function, higher serum levels of both cortisol and aldosterone were independent predictors of increased mortality risk conferring complementary and incremental prognostic value. (Guder et al., 2007). The predictive value of cortisol in heart failure has recently been confi rmed by Yamai et al. (Yamaji et al., 2009).Evidence has also been accumulated linking aldosterone levels/MR activation to the metabolic syndrome and its single components, especially abdominal obesity and insulin resistance, which may be driven by renin-independent stimulation of aldosterone secretion (Guo et al., 2008; Sowers et al., 2009).

LIST OF SUGGESTED READINGSde Souza, F, Muxfeldt, E, Fiszman, R, Salles, G (2009) Effi cacy of Spironolactone Therapy in Patients With True Resistant Hypertension. Inter-American Society of Hypertension. Hypertension, in press.Fraccarollo, D, Schäfer, A, Hildemann, S, Galuppo, P, Ertl, G, Bauersachs, J (2003) Additive Improvement of Left Ventricular Remodeling and Neurohormonal Activation by Aldosterone Receptor Blockade With Eplerenone and ACE Inhibition in Rats With Myocardial Infarction. J Am Coll Cardiol 42: 1666-1673.

Greenberg, B, Zannad, F, Pitt, B (2006) Role of aldosterone blockade for treatment of heart failure and post-acute myocardial infarction. Am J Cardiol 97(10A): 34F-40F.

Guder, G, Bauersachs, J, Frantz, S, Weismann, D, Allolio, B, Ertl, G, Angermann, CE, Stork, S (2007) Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure. Circulation 115(13): 1754-1761.

Guo, C, Ricchiuti, V, Lian, BQ, Yao, TM, Coutinho, P, Romero, JR, Li, J, Williams, GH, Adler, GK (2008) Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinfl ammatory adipokines. Circulation 117(17): 2253-2261.

Lombes, M, Alfaidy, N, Eugene, E, Lessana, A, Farman, N, Bonvalet, JP (1995) Prerequisite for cardiac aldosterone action. Mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase in the human heart. Circulation 92: 175-182.

Mihailidou, AS, Loan Le, TY, Mardini, M, Funder, JW (2009) Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction. Hypertension 54(6): 1306-1312.

Sowers, JR, Whaley-Connell, A, Epstein, M (2009) Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med 150(11): 776-783.

Yamaji, M, Tsutamoto, T, Kawahara, C, Nishiyama, K, Yamamoto, T, Fujii, M, Horie, M (2009) Serum Cortisol as a Useful Predictor of Cardiac Events in Patients With Chronic Heart Failure: The Impact of Oxidative Stress. Circ Heart Fail 2(6): 608-615.

Which is to blame? Is it aldosterone or mineralocorticoid receptor activation?

Frederic JAISSER, Paris – FRAFrédéric Jaisser is Research Director at the Unit 872 of INSERM (Institut National de la santé et de la Recherche Médicale). He is Professor at the Faculty of Medicine of REIMS where he coordinates different courses such « Animal Models and Physiopathological Mechanisms.He is MD, specialist in Nephrology, has a University degree in Biological and Medical Engineering. He joined the INSERM in 1996. His fi elds of expertise are mainly renal and cardiovascular pathophysiology,

development of transgenic animal models for pathophysiologic studies or human disease models, mainly in the fi eld of aldosterone pathophysiology. He is also the coordinator of several multicentric projects.He is an Editorial Board Member of Endocrinology and an expert for several others peer-review journals such as Circulation or Hypertension. He is currently the President of ESAC-France (European Section of the Aldosterone Council).

Pharmacology of agents interfering with the aldosterone pathways.Michel AZIZI, Paris – FRADr Azizi received his MD from René Descartes University and his PhD from Pierre et Marie Curie University, Paris, France. He is Professor in Vascular Medicine in Paris Descartes University and Head of the Clinical Investigation Center at the Hôpital Européen Georges Pompidou of Paris. Dr Azizi was member of the Clinical Research Commission of INSERM (Institut National de la Santé et de la Recherche Médicale) and of APHP (Assistance Publique des Hôpitaux de Paris) until 2008. He has received the Jean Hamburger prize for Medical Research in 2007. His main research interests include the physiology, genetics and pharmacology of the renin–angiotensin–aldosterone system, and of the haematological peptide, AcSDKP. Dr Azizi is a member of the French Society of Cardiology and of the European Society of Hypertension. He has published more than 100 papers in peer reviewed journals. Selected publications:1. Azizi M, Boutouyrie P, Bissery A, Agharazii M, Verbeke F, Stern N, et al. Arterial and renal consequences of partial genetic defi ciency in tissue kallikrein activity in humans. J Clin Invest 2005;115(3):780-7.2. Azizi M, Bissery A, Peyrard S, Guyene TT, Ozoux ML, Floch A, Menard J. Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans. Clin Pharmacol Ther 2006;79(1):49-61.3. Azizi M, Menard J, Peyrard S, Lievre M, Marre M, Chatellier G. Assessment of Patients’ and Physicians’ Compliance to an ACE Inhibitor Treatment Based on Urinary N-Acetyl Ser-Asp-Lys-Pro Determination in the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study. Diabetes Care 2006;29(6):1331-1336.4. Azizi M, Iturrioz X, Blanchard A, Peyrard S, De Mota N, Chartrel N, Vaudry H, Corvol P, Llorens-Cortes C. Reciprocal Regulation of Plasma Apelin and Vasopressin by Osmotic Stimuli. J Am Soc Nephrol 2008;19:1015-24.5. Azizi M, Chedid A, Oudard S. Home blood-pressure monitoring in patients receiving sunitinib. N Engl J Med 2008;358(1):95-7.6. Wuerzner G, Peyrard S, Blanchard A, Lalanne F, Azizi M. The lactotripeptides isoleucine-proline-proline and valine-proline-proline do not inhibit the N-terminal or C-terminal angiotensin converting enzyme active sites in humans. J Hypertens. 2009;27:1404-1409.

ABSTRACTUp to now, blockade of the biological effects of aldosterone has been achieved with the two available mineralocorticoid receptor (MR) antagonists, spironolactone and eplerenone which are effective in the treatment of congestive heart failure, proteinuric nephropathies and hypertension. Both drugs are especially effective in those forms of hypertension where aldosterone is the main participant, such as in primary hyperaldosteronism, low-renin hypertension, and resistant hypertension. Their use may however be limited by two facts. First, spironolactone has a low tolerance profi le as long term treatment with is associated with a large, dose-related incidence of gynecomastia in males, sexual dysfunction and menstrual irregularities that is not shared by eplerenone at marketed doses. Second, both drugs induce a counter-regulatory rise in plasma renin and aldosterone concentrations which may limit the effi cacy of MR blockade and stimulate the MR-independent effects of aldosterone. Aldosterone synthase inhibition has thus emerged as a new option aiming at decreasing hormone concentrations in both plasma and tissues and consequently at reducing both MR-dependent and –independent effects at the level of the renal epithelial cells and other target organs. The consequences of this very specifi c and targeted pharmacological approach have not yet been tested in humans, although the use of various adrenal inhibitors of steroidogenesis, such as aminoglutethimide (P450 side chain cleavage enzyme inhibitor), metapyrone (11ß hydroxylase inhibitor) and trilostane (3 ß hydroxysteroid deshydrogenase inhibitor) has been reported in small series of hypertensive patients with or without primary aldosteronism. These drugs have potential safety drawbacks due to inhibition of early steps of steroidogenesis involved in both the glucocorticoid and mineralocorticoid axis and are usually not effi cient in controlling BP in the long-term. More recently, the availability of fadrozole an aromatase inhibitor with inhibitory properties against 11 ß-hydroxylase and corticosterone methyloxidase type II enzymes and its dextroenantiomer, in animal models have shown that the neutralization of aldosterone’s effects with its benefi cial consequences is achievable by two different methods: the inhibition of its synthesis and the blockade of its action at the receptor level, as it has already successfully shown with renin inhibition and angiotensin II antagonism. New drugs derived from the initial structure

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of FAD286A are currently under development. When available for human use, aldosterone synthase inhibitors by specifi cally decreasing aldosterone exposure should contribute for neutralizing on the long term the genomic and non-genomic direct effects of aldosterone at the level of the heart, the blood vessels and the kidneys.

LIST OF SUGGESTED READINGS1 Connell JM, MacKenzie SM, Freel EM, Fraser R, Davies E. A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function. Endocr Rev 2008;29:133-54.2 Funder JW, Mihailidou AS. Aldosterone and mineralocorticoid receptors: Clinical studies and basic biology. Mol Cell Endocrinol 2009;301:2-6.3 Lamberts SW, Bruining HA, Marzouk H, et al. The new aromatase inhibitor CGS-16949A suppresses aldosterone and cortisol production by human adrenal cells in vitro. J Clin Endocrinol Metab 1989;69:896-901.4 Trunet PF, Mueller P, Girard F, et al. The effects of fadrozole hydrochloride on aldosterone secretion in healthy male subjects. J Clin Endocrinol Metab 1992;74:571-6.5 Fiebeler A, Nussberger J, Shagdarsuren E, et al. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation 2005;111:3087-94.6 Menard J, Gonzalez MF, Guyene TT, Bissery A. Investigation of aldosterone-synthase inhibition in rats. J Hypertens 2006;24:1147-55.7 Mulder P, Mellin V, Favre J, et al. Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone. Eur Heart J 2008;29:2171-9.8 Lea WB, Kwak ES, Luther JM, et al. Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt. Kidney Int 2009;75:936-44.9 Funder JW. Trilostane, FAD286, and the role of aldosterone in the central regulation of blood pressure: focus on “Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats”. Am J Physiol Regul Integr Comp Physiol 2009;296:R992-

Update on aldosterone trials


Practical use of agents acting on the aldosterone system. Where to fi t into the RAAS drug armamentarium?

Bertram PITT, Ann Arbor – USA


Cardiovascular Clinical TrialsGoing Global

Chairpersons: Felipe Martinez, Jean Morgan

Felipe MARTINEZ, Cordoba – ARGPOSITIONS-Professor of Medicine. Cordoba National University (since 1994)-Director. Instituto Damic and Fundacion Rusculleda. (since 1993)OUTSTANDING ACHIEVEMENTS-Former President. Argentinean Federation of Cardiology (2002-2003)-Co Chairman. Scientifi c Program. World Congress of Cardiology (2008)

-Governor for Argentina. International Society of Cardiovascular Pharmacology (since 2007)SCIENTIFIC SOCIETIES/ COMETEES-Board Member. World Heart Failure Society-Fellow. American College of Cardiology-Member of 16 Steering Com. Of International TrialsSCIENTIFIC ACTIVITIES-Publications 129-Invited Speaker in more than 200 International Meetings, in 21 Countries.

Jean MORGAN, QuintilesJean received her undergraduate degree (Health Information Management) from Cumberland College of Health Sciences in Sydney Australia and her post graduate diploma in marketing from the University of Technology, Sydney Australia. Her career started as a data manager, running clinical trials at the Royal North Shore Hospital Radiation Oncology Unit in Sydney prior to moving over to work in the pharmaceutical industry as a clinical research manager.After several years working in clinical research for

Pharmacia and Lederle, Jean joined Quintiles in 1993. Working in Australia as well as Asia, Jean has personally managed or had senior oversight of clinical trials across a diverse range of therapeutic areas including oncology, cardiovascular, infectious diseases, rheumatology and respiratory medicine. Currently Jean is Vice President in the Cardiovascular & Diabetes Unit where she is responsible for project oversight and delivery for projects.

Overview of International cardiovascular clinical Trials and Current regulatory requirements for clinical trials in Russia and Ukraine

Vladimir POPOV, Moscow – RUSVladimir Popov MD, Dr Sc Med Leading Researcher of Cardiology Department, Moscow Medical Academy named after I.M. Sechenov, Head of Clinical Pharmacology, Central Hospital No. 6 of Russian Railways JSC, Moscow. RussiaDr Popov was awarded an MD with an honorary degree, a Master of Internal Medicine and PhD in Cardiology by the Kharkiv State Medical University, Ukraine. In 2007 he was awarded an Dr Sc Med in Cardiology by the Moscow University of Medicine and Dentistry .

He completed postgraduate training in Clinical Pharmacology and Internal Medicine at the Russian Medical Academy in Moscow.


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Dr. Popov has over 15 years of experience in cardiovascular multinational clinical trials, in roles as a co-investigator, principal investigator and project leader . Dr. Popov is a recognized leader in cardiovascular drug research and development. He has coordinated national and international clinical trials in the following therapeutic areas: Hypertension, CHF, Angina , Pulmonary Arterial Hypertension. He is Active Member of the Cardiovascular Pharmacology and Drug Therapy working group of the European Society of Cardiology , the British Association of Research Quality Assurance (BARQA GCP), and of the Russian Society of Pharmacoeconomics and Outcome Research (RSPQR). Scientifi c Expert of Romualdo Del Bianco Foundation, Florence, Italy. He has published more than 140 articles and abstracts, directed numerous symposia, and co-authored 3 books .

ABSTRACTMore and more industry-sponsored cardiovascular clinical trials (CVCTs) are conducted in emerging regions, especially in Russia and Ukraine. At the moment cardiovascular diseases represent the widely spread pathology in the structure of common morbidity and mortality in Ukraine and Russia. According to the recent data (2008) the general mortality rate due to cardiovascular diseases is 63,1 % in Ukraine and 56,6 % in Russia.The aim of the presentation is to review the development of CVCTs and regulatory requirements for clinical trials in Russia and Ukraine over the last years. Data from the US clinical trials register (www.ClinicalTrials.gov on the 1st of November 2009) and Federal Service on Surveillance in Healthcare and Social Development trials register (www.roszdravnadzor.ru) analyzed to study the magnitude of contribution by Russia and Ukraine to the Global CVCTs arena, based on registered industry sponsored phase I-IV trials. Over the period from 2005 up to the 3rd quarter of 2009 342 industry-sponsored CVCTs conducted in Russia. The major contribution into the total number of CVCTs was made by international multi-center phase II-III clinical trials (MICT). Largest number of MICTs conducted in 2007-2008 years (48 and 43 trials, respectively). Within 5 years, pharmaceutical companies from 23 countries sponsored clinical trials in Russia. International multi-center phase II-III clinical trials in Russia sponsored mainly by the world’s top pharmaceutical or biotech companies. Trials came from the USA – 16 %, Germany – 8 %, France – 8 %, UK – 6 %, Switzerland – 5 % and Japan - 3%. Seven phase I trials were initiated over the period 2005-2009 , 5 of them in 2008. The number of the Phase II trials made 28% of the all CTs, the peak of the CVCTs was in 2007(22 CT). The situation with Phase III MICT trials was stable (in 2005 - 22 CVCTs, in 2006 – 31 CVCTs, in 2007 and 2008 – 32 and by the 3rd quarter of 2009 – 24 CVCTs).It is well known that Russia and Ukraine belong to the world leaders in patient enrolment. The average patients recruitment rate in 2006 exceeded 4.7 patients per site per month. For some indications the fi gures were 10 times higher than in Western Europe and in the USA. For example for hypertension, this ratio amounted to 10.2. In Phases II- IV CVCTs launched in 2009, 8752 patients have been planned to be enrolled.According to the analysis of the number of CVCTs sponsored by international companies over the period 2005 – 2009, the fi rst place took Novartis which had 24 approved studies. Astra Zeneca was the leading company in patients recruitment (6324 patients). Main cardiovascular trials areas were: Hypertension, Dyslipidemia, Acute coronary syndrome, CHF. By the 1st of November 2009 99 and 42 CVCTs were ongoing in Russia and Ukraine respectively. Clinical Centers of Excellence leading by the number of trials investigators sites were selected: the Russian Cardiology Scientifi c Complex (www.cardioweb.ru), the Moscow University of Medicine and Dentistry (www.msmsu.ru) and the State Research Center for Preventive Medicine (www.gnicpm.ru).Since 1995, the FDA has carried out 36 audits of the activities of Russian clinical study centers. In 50 % of cases no shortcomings has been discovered (no action indicated (NAI)). Seventeen audits resulted in a positive grade (VAI), and only in one case a negative grade was obtained (offi cial action indicated (OAI)). East Europe has developed into a strongly emerging clinical trial region, with Ukraine and Russia now ranking among the leading active trial countries. Russia and Ukraine has become more and more attractive for the industry because it offers large patient populations, with many treatment-naïve patients and fast requirement rates with high data quality. References: http://www.roszdravnadzor.ru, http://www.clinicaltrials.org, http://www.moz.gov.ua, http://www.fda.gov , http://www.ClinicalTrialMagnifi er.com

Middle East and the Arab world, emerging to CardioVacular trials. Cultural, organisational and regulatory aspects

Mohamed SOBHY, Alexandria – EGY

ABSTRACTThough Egyptian medicine dates from about 2900 B.C, the best-known and most important pharmaceutical record is the “Papyrus Ebers” (1500 B.C.), a collection of 800 Rx, mentioning 700 drugs. In the last 200 years medical research has been hindered in the Middle East yet the Middle East has great potential for clinical trials. The latest epidemiological data on the Middle East shows clearly the evident diversity in the populations type and characters. A number of 14 countries form the Middle East with a total population of 280 million with some of the richest & poorest countries in the world. Each country holds its diversifi ed political, economic and health care environment.The Middle East has a reasonable pharmaceutical market valued annually at 6 billion dollars in 2006 but this number will increase dramatically in the next 10 years. The reason for that is a dramatic change that is occurring in the epidemiological pattern of disease in most countries of the Middle East. Changing from the traditional infectious disease to the Non-Communicable Diseases (NCDs) including cardiovascular diseases, diabetes, obesity and cancer. By the year 2020, NCDs are expected to account for 7 out of every 10 deaths in the developing regions compared with less than half today. Egypt is the biggest country in the Middle East in terms of population (75 million) with 48 % of the population between 15 and 45 years. These current demographics with the increased life expectancy from around 50 in 1960 to around 70 in 2006 and the prevalence of hypertension (30%), diabetes mellitus (7.2%) and hypercholesterolemia (20%) can predict an epidemic of cardiovascular disease in Egypt.The infrastructure of research in the Middle East needs remedies and this is obvious from the low publication rate yet there is a good foundation to build on in some countries. This foundation is mainly based on well-educated Physicians (Academics, Consultants, etc.) with post graduate experience in Europe or USA, big & diverse patient population covering various disease areas, various ethnic groups (e.g. Expats in Gulf countries), Relatively low cost of medical and clinical investigations and university hospitals, institutions and private Hospitals, well equipped, partnering with International Organizations/Reputable Universities.The culture of the Middle East in terms of population and patient understanding and acceptance for the concept of clinical trials is not yet established. The patients still are hesitant about there enrollment and there acceptance is mainly based on their believe in there doctor. Patient compliance in follow up visits and adherence to study protocol is pretty good based on previous trials. Within the present culture and understandings the phase III trials will be most easily accepted.The regulatory aspect ranges in the Middle East from very well established in Jordan to well established in Lebanon and Egypt and a plan to implement new rules in Saudi Arabia. The average approval timelines is about 3-5 months in most countries. There is some regulatory problems as for example the clinical trials law still in evolving phase, and documentation system not well developed and not comprehensive enough.To some up the Middle East is a promising region for cardiovascular research trials and with proper engagement we can yield very good results. This notion of course will be supported by the performance of the clinical trials already taking place in the Middle East.

Regional Risk Factors and Cardiovascular trials: no infl uence or highimpact?

Felipe MARTINEZ (Cordoba, ARG)

ABSTRACTGlobal approach is expanding to Medicine, and the cardiovascular therapeutics are not the exception. Multicentric international trials with pharmacologic interventions are being performed in the fi ve continents. However, baseline characteristics and in many cases regional rrisk factors are not exactly the same all over the planet. This is the justifi ed interest on the

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regional analysis of these issues in most popular and recent cardiovascular pharmacologic interventions in South America, and the comparison of potential impact with other regions of the world.The observation of the largest and most important Phase III recent cardiovascular completed and on going clinical trials shows in general the following main data, compared with North America , Europe and/or Asia: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 some risk factors a) more cigarrette consumption b) salty diet c) high intake of saturated fat3) Warmer weather and more outdoor activities4) Longer hospitalization timelines5) Specifi c differences in diseases severity 6) Lower number of cardiovascular interventionsThe impact of the above characteristics may result not only in some variation of results, but obviously in drug use for the management of different disorders along the cardiovascular continuun. Despite the recomendations of international guidelines, for the treatment of hypertension, coronary artery disease and heart failure, some “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.Another “Risk factor” is the impact of some endemic diseases affecting the cardiovascular system like Chagas , or the still mild incidence of rheumatic fever in some areas.An accurate analysis of such observations may help Cardiologists, and also Trialists to prepare, design and better understand multinational clinical studies. It may also be useful for local local Public Health Authorities.

Friday December 4th, 2009, 12.15- 1.45 pm

MEET AND EAT WITH THE EXPERTS

Ventilatory therapy for sleep disordered breathing (SDB) in heart failure and CV disease.

From proof of concept to evidence based medicine

Chairpersons: Luc Hittinger, Guillaume Jondeau

Introduction and overview: Why does sleep disordered breathing deserve the cardiologist’s attention?

Christiane ANGERMANN, Würzburg – GER

ABSTRACTSleep provides regular periods of physical and mental rest and covers a large proportion of our life time. Heart rate, cardiac output and vascular resistance decrease during sleep. This physiologic cardiovascular relaxation is disrupted in sleep-disordered breathing (SDB), when frequency and/or depth of breathing are defi cient. With a prevalence of up to nine percent, obstructive sleep apnea/hypopnea (OSA) is the most common form of SDB; this condition results from complete or partial collapse of narrowed upper airways. Due to close and complex interrelations between the respiratory and the cardiovascular system sequelae of SDB include hypertension, arrhythmias, atrial enlargement and myocardial hypoxemia and hypertrophy. Postulated pathophysiological mechanisms comprise hemodynamic, neuro-vegetative, immuno-modulatory and metabolic aspects. Intermittent hypoxemia and increased respiratory work during hyperventilation induce a mismatch between oxygen supply and demand that may impair cardiac function and trigger myocardial remodelling. In this context, OSA is suspected to induce nocturnal symptom onset in acute coronary syndromes as well as nocturnal sudden death. Regarding breathing mechanics, ineffi cient inspiratory efforts against an occluded pharynx result in abrupt intrathoracic pressure changes which may reach values over 100 mmHg. This translates into substantial increases in transmural left atrial and ventricular pressure and leads to structural and functional cardiac alterations such as wall thickening, diastolic dysfunction and atrial enlargement. In severe SDB, cycles of apnoea and arousal may occur several hundred times per night. The resulting high-amplitude oscillations in central and peripheral sympathetic nerve traffi c impact may trigger loss of myocardial contractility, cardiomyocyte apoptosis and necrosis. SDB leads to elevated morning plasma norepinephrine concentrations which contributes to an increased mortality risk. Analogous to ischemia-reperfusion injury, hypoxemia-reoxygenation injury leads to signifi cant oxidative stress. In sleep-apnoeic cardiovascular patients, production of free radicals in neutrophils and monocytes was shown, which may cause endothelial damage. This in turn may accelerate atherosclerosis and coronary artery disease (CAD) in subjects with SDB.Extracardiac effects of high sympathetic drive include peripheral vasoconstriction, increased tubular sodium reabsorption, fl uid retention, and activation of the renin-angiotensin-aldosterone-system which results in progressive hypertension and abolishes the normal circadian blood pressure variation. As all these pathophysiological sequelae of SDB constitute cardiovascular risk factors predispose to heart failure development, SDB per se must which be considered a risk factor. Correspondingly, prevalence of SDB in heart failure populations is high, amounting to 50% or more. While OSA is 4 – 10 times more common in heart failure patients and is frequently diagnosed in earlier disease stages, central sleep apnea/hypopnea (CSA) occurs more


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often in advanced heart failure stages. CSA is caused by a reduced central respiratory drive; its prevalence amounts to 35-66% depending on disease severity. Prevalence in the community is unknown, but is supposed to be rare. Respiration is highly susceptible to PaCO2-changes during sleep, and patients with pulmonary congestion fail to decrease respiratory rate. Relative hyperventilation induces hypocapnia, which attenuates the central respiratory drive thus inducing hypoventilation. Rising PaCO2 levels precipitate another period of compensatory hyperventilation. Alternating periods of hypo- and hyperventilation induce the typical crescendo-decrescendo oscillation of tidal volumes in CSA while the cycle length depends on circulation time.The multifaceted relations between SDB and cardiovascular diseases seem part of a cardio-sleep- respiratory disease continuum: OSA contributes to cardiovascular disorders which result in cardiac dysfunction and heart failure. Vice versa, heart disease by itself predisposes to CSA. Heart failure as the fi nal common pathway of all cardiovascular diseases represents one of the greatest contemporary socioeconomic challenges. Today, we begin to understand the role of SDB in the cardiologist’s domain, but SDB has remained under-diagnosed in all heart failure stages. Symptom overlap of SDB and heart failure as well as lack of physicians’ awareness may be possible explanations. Although impaired survival rates have been reported for both types of SDB in heart failure, only for OSA evidence-based treatment options are available, and suffi cient knowledge about CSA is lacking.

LIST OF SUGGESTED READINGS1. Brenner S, Angermann C, Jany B, Ertl G, Stork S. Sleep-disordered breathing and heart failure a dangerous liaison. Trends Cardiovasc Med. 2008;18(7):240-247.2. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, Pickering TG, Russell R, Woo M, Young T. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientifi c Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol. 2008;52(8):686-717.3. Oldenburg O, Lamp B, Faber L, Teschler H, Horstkotte D, Topfer V. Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail. 2007;9(3):251-257.4. Wang H, Parker JD, Newton GE, Floras JS, Mak S, Chiu KL, Ruttanaumpawan P, Tomlinson G, Bradley TD. Infl uence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol. 2007;49(15):1625-1631.5. Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol. 2007;49(20):2028-2034.6. Bradley TD, Logan AG, Kimoff RJ, Series F, Morrison D, Ferguson K, Belenkie I, Pfeifer M, Fleetham J, Hanly P, Smilovitch M, Tomlinson G, Floras JS. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353(19):2025-2033.7. Oldenburg O, Schmidt A, Lamp B, Bitter T, Muntean BG, Langer C, Horstkotte D. Adaptive servoventilation improves cardiac function in patients with chronic heart failure and Cheyne-Stokes respiration. Eur J Heart Fail. 2008;10(6):581-586.

Future clinical evidence needs? Design of the SERVE-HF protocol

Luc HITTINGER, Paris – FRA

How to screen and manage patients with SDB in the clinical cardiology routine?

Olaf OLDENBURG, Bad Oeynhausen – GERPriv.-Doz. Dr. med. Olaf Oldenburg studied medicine at the Westfälische-Wilhelms University of Münster, Germany and University of Southern California, Los Angeles, USA. He fi nished his doctoral thesis with magna cum laude in 1997 in the Department of Cardiology and Angiology of Münster’s medical school. He started his cardiology rotation at the Center of Internal Medicine, Department of Cardiology at the University Hospital Essen, Germany. From 2001 to 2002 he spent 2 years as a post-doctoral fellow in

cardiovascular physiology at the University of South Alabama, Mobile, USA. In 2003 he took a position in the department of cardiology at the Heart and Diabetes Center North-Rhine Westphalia, University Hospital, Ruhr-University Bochum, Bad Oeynhausen, Germany. As a senior cardiologist he is the head of cardiorespiratory diseases and sleep-disordered breathing as well as for the heart failure programme at this institution.

ABSTRACTSleep-disordered breathing (SDB) is associated with various cardiac and cardiovascular diseases. By now, not only statistical association but pathophysiological concepts are linking obstructive (OSA) and central sleep apnoea (CSA) to hypertension, arrhythmias and heart failure. For heart failure the prognostic impact has been proven and specifi c treatment is recommended by current ESC guidelines. Besides an emerging interest, a routine screening of cardiology patients is not adequately established and cardiac patients suffering from SDB are not getting suffi cient therapy. Since 2003 we have developed an in hospital screening program using several screening devices. The best experiences we have are achieved by using 6-channel-cardiorespiratory polygraphy devices with software-based analyses and manually review of each recording. With these unattended recordings of our in-hospital patients, a defi nitive diagnosis and graduation of CSA and OSA is possible. However in ambulatory patients even simpler devices with fully automatically analysis might be used to exclude SDB in most cases. In some cases however, full cardiorespiratory polysomnography is needed to adequately diagnose, characterise and graduate SDB even in cardiology patients. Traditionally, treatment of SDB is initiated by respiratory physicians in most cases. With identifi cation of SDB in patients with severe cardiac diseases like advanced heart failure, a good cooperation of cardiologists and respiratory physicians in daily clinical routine is needed to adequately treat these patients in a reasonable time. However, if such cooperation can not be achieved, cardiologist themselves should take care of their cardiac patients and screen, diagnose and treat these patients themselves.

LIST OF SUGGESTED READINGS(1) Arzt M, Floras J, Logan A et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure. Circulation 115, 3173-3180. 2007. (2) Gami A, Howard D, Olson E, Somers V. Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 352, 1206-1214. 2005. (3) Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 49, 2028-2034. 2007. (4) Kasai T, Narui K, Dohi T et al. Prognosis of patients with heart failure and obstructive sleep apnea treated wtih continuous positive airway pressure. Chest 133, 690-696. 2008.

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(5) Oldenburg O, Lamp B, Faber L, Teschler H, Horstkotte D, Töpfer V. Sleep disordered breathing in patients with symptomatic heart failure. Eur J Heart Failure 9, 251-257. 2007. (6) Oldenburg O, Lamp B, Freivogel K, Bitter T, Langer C, Horstkotte D. Low night-to-night variability of sleep disordered breathing in patients with stable heart failure. Clin Res Cardiol 97, 836-842. 2008. (7) Oldenburg O, Schmidt A, Lamp B et al. Adaptive servoventilation improves cardiac function in patients with chronic heart failure and Cheyne-Stokes respiration. Eur J Heart Failure 10, 581-586. 2008. (8) Pepperell J, Maskell N, Jones D et al. A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med 168, 1109-1114. 2003. (9) Philippe C, Stoica-Herman M, Drouot X et al. Compliance with and effi cacy of adaptive servo-ventilation (ASV) versus continuous positive airway pressure (CPAP) in the treatment of Cheyne-Stokes respiration in heart failure over a six month period. Heart 92, 337-342. 2006. (10) Wang H, Parker J, Newton G et al. Infl uence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol 49, 1625-1631. 2007.


TRANSATLANTIC TRIALISTS Lunch Roundtable

Non industry sponsored trials and the role of NHLBI and EU public institutions

Chairpersons: Michael Lauer, Faiez Zannad

Michael LAUER, Bethesda – USAMichael Lauer, MD, FACC, FAHA, joined the National Heart, Lung, and Blood Institute (NHLBI) in July 2007 as Director of the Division of Prevention and Population Science; he now serves as the Director of the Division of Cardiovascular Sciences. A board certifi ed cardiologist, he received his MD from Albany Medical College in 1985 and underwent post-graduate training within the Harvard University system at Massachusetts General Hospital, Boston Beth Israel Hospital, the Harvard Graduate School of Education, and the Harvard School of Public Health. After

completing specialized research training in Cardiovascular Epidemiology at the Framingham Heart Study, he joined the cardiovascular medicine staff of the Cleveland Clinic in 1993. During 14 years at the Clinic, he established a world-renowned clinical epidemiology research program with primary focus on diagnostic testing and comparative effectiveness. His research led to over 200 publications in major medical journals (including New England Journal of Medicine, JAMA, Lancet, and Annals of Internal Medicine), grant support from the American Heart Association and the NIH, and election to the American Society of Clinical Investigation. Dr. Lauer has served as Contributing Editor for JAMA, co-Director of the Cleveland Clinic Coronary Care Unit, Director of Cardiac Clinical Research, and as fi rst Vice-Chair of the Cleveland Clinic IRB. He achieved distinction in medical education, leading the development of an award-winning clinical research curriculum at the newly founded Cleveland Clinic Lerner Medical College at Case Western Reserve University, where he was Professor of Medicine, Epidemiology, and Biostatistics. In November, 2008, he was awarded the prestigious Ancel Keys lectureship at the annual meeting of the American Heart Association. In his current position at NHLBI, Dr. Lauer is leading a $1.7 billion per year research division that oversees major programs in cardiovascular biology, translation, clinical research, comparative effectiveness, epidemiology and prevention.

Cardiovascular clinical trials under the EU Research Framework Programmes? A good start or a missed opportunity?


National Heart Lung and Blood Institute cardiovascular drug trials – future directions?

Michael DOMANSKI, Bethesda – USA


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MEET AND EAT WITH THE EXPERTS (2)

Management of atrial fi brillation:Trials that are rapidly changing

the landscape

Chairpersons: Dan Atar, Karl Swedberg

Dan ATAR, Oslo – NORProfessor and Head of Cardiology, Oslo University Hospital, Aker University of Oslo, Norway, Email: [email protected] Atar, MD, (50) is Head of Cardiology at Oslo University Hospital Aker, 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 certifi cation

in Internal Medicine and Cardiology in 1995. His research focuses on myocardial biomarkers, myocardial function, heart failure and cardiovascular pharmacology. He has written >100 articles and book chapters and holds the fellowship-titles FESC, FACC, and inaugural FAHA. Dan Atar is the past-Chairman of the ESC Working Group-3 (Cardiovascular Pharmacology and Drug Therapy), and Associate Editor of the international peer-reviewed journal “Cardiology” (Karger). He was on the writing committee for the 2007 ESC “Cardiovascular Disease Prevention Guideline” and the 2008 ESC “Guideline on acute and chronic Heart Failure”, and serves on the “2010 ESC Guideline on Atrial Fibrillation”, as well as the ESC/AHA/ACC guideline “New Defi nition of Myocardial Infarction”. He was chairing the FIRE.-trial, a multicenter study in patients with STEMI to reduce ischemia/reperfusion injury, published in 2009.

Will new drugs and new trials shift the rate vs. rhythm control paradigm (Dronedarone, Vernakalant)?

Gunter BREITHARDT, Münster – GER

New anti-thrombotic trials in atrial fi brillation (RE-LY) and possible consequence on anti-thrombotic strategies.

Greg LIP, Birmingham – GBRProfessor Lip is an academic clinical cardiologist based in a busy city centre teaching hospital, and leads a large multidisciplinary research group [including clinical and laboratory-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 fi brillation and hypertension specialist 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 sits on the cardiovascular research strategy committee of the university, and has taught/examined at undergraduate/postgraduate level

both nationally and internationally. More recently, he has been external examiner to the University of Hong Kong and University Putra Malaysia.Professor Lip is a member of the scientifi c documents committee of the European Heart Rhythm Association [EHRA], and serves on the board of the Working Group on Hypertension of the Heart of the European Society of Cardiology [ESC]. He is a member of the Working Groups of Thrombosis and Cardiovascular Pharmacology of the 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 fi brillation [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 defi ning endpoints for AF management, EHRA guidelines for antithrombotic therapy during ablation. He has acted as peer reviewer for recent ESC guidelines e.g. on cardiac resynchronisation therapy, hypertension, ST elevation myocardial infarction, etc. He is currently Chairing an ongoing ESC Task Force writing a Working Group of Thrombosis Position Statement on Antithrombotic therapy use in atrial fi brillation patients presenting with an acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting (due 2009). He is also on the writing committee of the next version of the ESC Guidelines on Atrial Fibrillation (due 2010) and will be Deputy Editor for the 9th ACCP guidelines on antithrombotic therapy for AF.He has acted as senior editor for major international textbooks [e.g. Lip GYH, Hall JE (eds) Comprehensive Hypertension. Mosby 2007] and section editor on hypertension [e.g. Crawford, DiMarco, Paulus Cardiology – now in 3rd edition], as well as contributed to major textbooks [e.g. the European Textbook of Cardiovascular Medicine (chapter on atrial fi brillation – this serves as the core curriculum for ESC cardiology trainees), Crawford’s Cardiology textbook chapter on atrial fi brillation, etc.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] designate), Thrombosis Research (Associate Editor), Europace (Associate Editor), Circulation (Guest Editor), etc.He has acted as grant peer reviewer for national/international grant giving bodies e.g. Medical Research Council (UK), Hong Kong Research Grants Council, Canadian Institutes of Health Research, etc.Professor Lip has acted as Chairman or served as member of steering committees of major international trials and has also acted as Chairman or member of trial Clinical Events Committees.

ABSTRACTAtrial fi brillation(AF) is the commonest sustained cardiac rhythm disorder, and is encountered in everyday clinical practice. Irrespective of a rate-control or rhythm-control strategy, stroke prevention with appropriate thromboprophylaxis still remains central to the management of this common arrhythmia. Indeed, AF is also a major contributor to stroke and thromboembolism, but stroke risk is not homogeneous. Thus, a crucial part of AF management requires the appropriate use of thromboprophylaxis. New data from trials such as RE-LY with the oral direct thrombin inhibitor, dabigatran, would overcome the limitations of warfarin and allow reexamination of thromboprophylaxis recommendations.High risk patients should have anticoagulation therapy, and are those with previous stroke or thromboembolism and those age ≥75, as well as those with 2 or more of the following risk factors: diabetes, hypertension, age 65-74, heart failure (or moderate-severe left ventricular dysfunction) – and probably, female gender and vascular disease. Low risk patients are those with no risk factors, and treatment with aspirin or no antithrombotic therapy is recommended, given the data for aspirin in this category of patients is poor, with little demonstrable effect on reducing thromboembolism but increasing the risk for bleeding. Unfortunately, many stroke risk assessment schema classify a large proportion of subjects into the ‘moderate risk’ category where treatment guidelines recommend either oral anticoagulation or aspirin, and only have modest predictive value for thromboembolism. Given the availability of new oral anticoagulant drugs, risk schema need to evolve to be better at identifying the ‘low risk’ category of patients where no antithrombotic therapy may be an option. A simple, novel risk factor based approach involving a simple scoring system [CHA2DS2-VASc, denoting Cardiac failure or dysfunction, Hypertension, Age over 75 years [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age 65-74 and Sex category [Female]), whereby 2 points are assigned for a history of stroke or transient ischaemic attack or age ≥75; and 1 point each for age 65-74 years, a history of hypertension, diabetes, recent cardiac failure, vascular disease (myocardial infarction, complex aortic plaque and peripheral

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arterial disease (PAD), including prior revascularization, amputation due to peripheral artery disease or angiographic evidence of peripheral artery disease, etc) and female gender], demonstrates improvement over previous schemes in identifying high-risk subjects, whist those designated ‘low risk’ rarely developed thromboembolism and only a small proportion are classifi ed as ‘intermediate risk’.

LIST OF SUGGESTED READINGSLip GY, Lim HS. Atrial fi brillation and stroke prevention. Lancet Neurol. 2007;6:981-93Lip GYH, Nieuwlaat R, Pisters R, Lane D, Crijns HJGM. Refi ning clinical risk stratifi cation for predicting stroke and thromboembolism in atrial fi brillation using a novel risk factor based approach: The Euro Heart Survey on Atrial Fibrillation. Chest 2009; DOI 10.1378/chest.09-1584

Ablation in atrial fi brillation: Reassessing the evidence.Etienne ALIOT, Nancy – FRA

Friday December 4th, 2009, 2 pm - 4 pm

CVCT EXPERT WORKSHOP Arterial stiffness and central blood pressure as

endpoints in hypertension trials

Chairpersons: Enrico Agabati-Rosei, Luc Van Bortel

Luc VAN BORTEL, Ghent – BELLuc Van Bortel studied medicine at Ghent University and specialized in internal medicine and clinical pharmacology. He graduated in tropical medicine at the Institute of Tropical Medicine (Antwerp). As a research fellow he was on mission in Zaire for 2 years. He obtained a Ph.D. in Medicine in 1993. He spent a 6-month intensive collaboration with Prof. dr. M. Safar and S. Laurent at Broussais Hospital Paris (Université Pierre et Marie Curie). For more than 20 years he is involved in research on arterial stiffness and in phase-1

clinical drug research. He was associate professor Clinical Pharmacology and Pharmacotherapy at Maastricht University (The Netherlands). From 2000 he is appointed full professor clinical pharmacology and pharmacotherapy at Ghent University (Belgium). He is currently head of Drug Research Unit Ghent, the phase-I drug research unit at Ghent University Hospital and is the leading professor of the hypertension excellence center at Ghent University Hospital. His unit is still involved in arterial stiffness research and has national and international collaboration.Professor Van Bortel is author/co-author of more than 300 publications in the fi eld of arterial stiffness, quality of life, clinical pharmacology and pharmacotherapy. He is chairman of the Working Group on arterial structure and function of the European Society of Hypertension. He is president of the Belgian Hypertension Committee and is treasurer of the Artery Society. His research team was awarded in 2007 as the best research team on hypertension in Belgium.

Clinical signifi cance of lowering central BP and arterial stiffness.

Athanas BENETOS, Nancy – FRA

Central BP and arterial stiffness as clinical endpoints in large scale trials. Metrological and methodological issues.

Stéphane LAURENT, Paris – FRA

Currently available drugs and new agents that decrease central BP and arterial stiffness. Insight from recent trials

Luc VAN BORTEL, Ghent – BEL

ABSTRACTObjective: To summarize the available evidence from clinical studies and trials for the effect of drugs on arterial stiffness and central blood pressure (cBP) beyond lowering peripheral (brachial) blood pressure (pBP). Methods: We searched for all-scale clinical trials and studies in humans, accessible through Medline (Pubmed) and hand-searching through cited references. No language restrictions were applied. Data are presented according drug classes in two parts: arterial stiffness and cBP.Results: Drug effects on cBP: None of the 4 retrieved studies supported a reduction in cBP beyond pBP with diuretics.


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Concerning beta-blockers (BB), 6 studies evaluated atenolol, 1 bisoprolol and 1 nebivolol. Atenolol and bisoprolol seems to decrease pBP more than cBP. This more pronounced effect on pBP with classical BBs was much less with nebivolol which may be related on its vasodilatator properties.In the group of calcium channel blockers (CCBs) 3 studies showed evidence for dihydropyridine CCBs to reduce cBP beyond pBP. These results were also supported by large clinical trials i.e. the CAFÉ-study. The majority of studies (8 out of 11) with angiotensin converting enzyme inhibitors (ACEIs) showed a reduction in cBP beyond pBP. Three studies showed a neutral effect. In these studies lisinopril, captopril and enalapril were used as ACEI, respectively. Both the CAFE and REASON trials confi rmed the effect of ACEIs on cBP.Two studies with angiotensin receptor blockers (ARBs) studying eprosartan and valsartan supported a reduction in cBP beyond pBP, while 2 other studies showed a neutral effect with the ARB eprosartan and telmisartan, respectively. Three studies showed a reduction in cBP beyond pBP with nitrates.Drug effects on arterial stiffness: A large number of studies have been reported on the effect of different classes of antihypertensive drugs on arterial stiffness. Results of studies with diuretics were heterogeneous. Some studies using spironolactone, indapamide or bendrofl umethiazide showed a decrease in arterial stiffness, while others with hydrochlorothiazide and amiloride did not. The combination diuretic hydrochlorothiazide/amiloride decreased arterial stiffness but less than the ACEI perindopril.Like diuretics, results on the effect of BBs on arterial stiffness are also quite heterogeneous. Nonselective BBs like propranolol did not improve arterial stiffness, selective beta-1 blockers were not conclusive, while selective beta-1 blockers with vasodilating properties like nebivolol improve arterial stiffness.The large majority of studies with ACEIs, ARBs, CCBs show that these agents improve arterial stiffness. Based on reports of older studies, the effect of nitrates on large artery stiffness is minimal or absent.As a decrease in blood pressure will decrease passively arterial stiffness, it is not always clear whether the improvement of arterial stiffness with an antihypertensive drug is only due to the decrease in blood pressure or whether also a direct effect of the drug on the arterial wall is present.Conclusions: Overall, it seems that the newer antihypertensive drugs (ACEIs, ARBs, dihydropyridine CCBs and BBs with vasodilating properties) as well as nitrates reduce cBP more than diuretics and classical BBs. Nonselective BBs do not improve arterial stiffness. The effect of beta-1 selective blockers, diuretics and nitrates on arterial stiffness appear to be small or absent. ACEIs, ARBs, CCBs and beta-1 selective BBs with vasodilating properties may improve arterial stiffness.

LIST OF SUGGESTED READINGS1. Agabiti-Rosei E, Mancia G, O’Rourke MF, Roman MJ, Safar ME, Smulyan H, Wang JG, Wilkinson IB, Williams B, Vlachopoulos C. Central blood pressure measurements and antihypertensive therapy: a consensus document. Hypertension. 2007;50:154-602. Van Bortel LM, Struijker-Boudier HA, Safar ME. Pulse pressure, arterial stiffness, and drug treatment of hypertension. Hypertension. 2001;38:914-21. 3. Asmar R. Effect of antihypertensive agents on arterial stiffness as evaluated by pulse wave velocity: clinical implications. Am J Cardiovasc Drugs. 2001;1:387-97. 4. Protogerou AD, Stergiou GS, Vlachopoulos C, Blacher J, Achimastos A. The effect of antihypertensive drugs on central blood pressure beyond peripheral blood pressure. Part II: Evidence for specifi c class-effects of antihypertensive drugs on pressure amplifi cation. Curr Pharm Des. 2009;15:272-89. 5. Mackenzie IS, McEniery CM, Dhakam Z, Brown MJ, Cockcroft JR, Wilkinson IB. Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension. 2009 54:409-13. 6. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O’Rourke M; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006 7;113:1213-25.7. Schneider MP, Delles C, Klingbeil AU, Ludwig M, Kolloch RE, Krekler M, Stumpe KO, Schmieder RE. Effect of angiotensin receptor blockade on central haemodynamics in essential hypertension: results of a randomised trial. J Renin Angiotensin Aldosterone Syst. 2008;9:49-56.8. Dhakam Z, McEniery CM, Yasmin, Cockcroft JR, Brown MJ, Wilkinson IB. Atenolol and eprosartan: differential effects on central blood pressure and aortic pulse wave velocity. Am J Hypertens. 2006;19:214-9.

Friday December 4th, 2009, 2 pm - 4 pm

MAIN PLENARY SESSIONCoronary artery disease management: Breaking new grounds with ivabradine

Chairpersons: Philippe G Steg, Ake Hjalmarson

Ake HJALMARSON, Göteborg – SWEÅke Hjalmarson, M.D., Ph.D, Professor of CardiologyBorn June 21, 1937 In Skövde, Sweden Swedish NationalityEducation at Göteborg University, M.D. 1968, Ph.D. 1968Specialist in: Cardiology 1975, Internal Medicine 1980Present Business Address: The Wallenberg Laboratory, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden

Phone: +46-31-3421981, +46-706290607, Fax: +46-31-817109E-mail: [email protected] Research Interests: Cardioprotection, Adrenergic regulation and signal transduction; Cardiomyopathy and CHF; Beta-blockers; Myocardial receptor autoantibodiesAcademic and Professional 1960-1964 Junior Res. Assistant of Physiology, Göteborg Univ.Positions:Senior Res. Assistant of Physiology, Göteborg Univ.Ass.Professor of Physiology, Göteborg UniversityAss.Professor of Medicine and Physiology, Penn. State University, Hershey, USAAss.Professor of Physiol. and Medicine, Göteborg Univ.1974-1987 Assoc. Professor of Internal Medicine, Göteborg Univ.Visiting Professor, Div. of Cardiology, Dept.of MedicineUniversity of California at San Diego, USA1989- 2003 Professor of Cardiology, Sahlgrenska University Hospital, Göteborg UniversityChairman and Head, Institute of Heart and LungDiseases, Göteborg University2004-present Professor of Cardiology, Wallenberg Laboratory, Sahlgrenska University Hospital, Göteborg UniversitySupervisor Ph.D. theses: 30 doctorsSteering Committees: Chairman: Göteborg Metoprolol Trial, MIAMI Trial, MDC Trial, MERIT, CORONA (EC)Member: RESOLVD, PICO, FRISC I, ACTIONBoard Member: Cardcon Ltd, Anatomica Ltd, A+ScienceNumber of Publications : 500

Heart rate reduction in clinical practice

Ake HJALMARSON, Göteborg – SWE

ABSTRACTThere is a strong evidence that heart rate has a central role in the patophysiology of angina pectoris. Elevated heart rate is an independent risk factor and one of the most important predictors of morbidity and mortality in healthy subjects at risk for coronary events and in patients with established coronary artery disease. Furthermore, reduction of elevated heart rate has been found to reduce mortality and morbidity in large placebo-controlled clinical trials of patients with coronary artery disease after myocardial infarction and in those with heart failure. Therefore, measurement of heart rate and reduction of elevated heart rate ought to be part of our daily clinical practice of the management of these patients. There is a consensus about this in our national and international guidelines.What about the methods of measuring heart rate? There is in fact no clear consensus about this.

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In most larger clinical trials it is not stated in the methods how heart rate was recorded. In general it is recorded at rest in supine position from ECG, but the conditions are not strictly standardized (e.g. body position, length of rest, whether free of mental or physical stress, intake of coffee or tea or nicotine for a given time prior to the measurement). Defi nitions of how to measurer heart rate ought be given in guidelines, but for that purpose new studies have to be performed in the target population needing heart rate monitoring. One such study is the so-called REALITY in Sweden ( the cuRrent statE of Angina treatment in outpatient popuLation and heart rate monIToring survey). Despite the strong evidence of symptomatic and prognostic benefi ts of heart rate reduction suchtreatments are widely underutilized in clinical practice. In the European Heart Survey study (1) 3.779 patients with stable angina pectoris were enrolled in 35 countries. The average resting heart rate was 73 beats/min (similar to the BEAUTIFUL trial), 67% of the patients were on betablockers but the dose was only 45% of that used in the large clinical trials. Similar observations were made in the Danish National Registry study (2) of 55.315 patients who survived 30 days after myocardial infarction, 58% received a betablocker at discharge at a dose less than 50% of that in the clinical trials . These facts point to the need to investigate alternative strategies such as new combination therapies including selective sinus node inhibitors.The BEAUTIFUL trial (3) strongly supports the view that despite the present clinical use of betablockers at low dose (87% in BEAUTIFUL) a high proportion of the patients with stable angina pectoris have resting heart rate > 70 beats/min. These patients have a higher morbidity and mortality than those with lower heart rates. Benefi cial results on new coronary events were seen when adding Ivabradine to further reduce heart rate in these patients.In conclusion, heart rate should be carefully measured and monitored in patients with coronary artery disease to reduce angina symptoms and improve prognosis. Strong efforts should be made to lower resting heart rate to < 70 beats/min in all such patients by using betablockers and Ivabradine in combination.References:1. Daly C, Clemens F, Lopez-Sendon J et al. The clinical characteristics and investigations planned in patients with stable angina presenting to cardiologists in Europe: from the Euro Heart Survey of Stable Angina. Eur. Heart J. 2005; 26: 996 – 1010.2. Gislason G H, Rasmussen J N, Abildstrom S Z et al. Long-term compliance with betablockers, angiotensin-converting enzyme inhibitors, and statins after myocardial infarction. Eur. Heart J. 2006; 27: 1153 – 1158.3. Fox K, Ford I, Steg P G et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomized, double-blind, placebo-controlled trial. Lancet 2008; 372: 807 – 816.

New results with Ivabradine

Jeffrey BORER, New York – USAJeffrey S. Borer, M.D., is Professor and Chairman, Department of Medicine and Chief, Division of Cardiovascular Medicine, at the State University of New York Downstate Medical Center and College of Medicine in New York City. He is also Director of The Howard Gilman Institute for Heart Valve Disease and of the Cardiovascular Translational Research Institute at Downstate. Dr. Borer received his BA from Harvard, his M.D. from Cornell and trained at the Massachusetts General Hospital. He spent 7 years in the Cardiology Branch of the NHLBI at the NIH and a year at Guy’s Hospital in London as a Senior Fullbright Hays Scholar, where he completed the fi rst clinical demonstration of the utility of nitroglycerin in acute myocardial infarction, after previously performing the enabling animal studies at the NIH. Upon returning to the NIH, he developed stress radionuclide cineangiography, for the fi rst time allowing non-invasive assessment of cardiac function with exercise. He then returned to Cornell for 30 years, where he developed prognostic standards for regurgitant valve diseases and explored the cellular and molecular biology myocardial dysfunction in valve diseases, while also assessing the role of heart rate modifi cation in treating coronary disease and heart failure. This work now is being continued at SUNY Downstate. He has been an Advisor to the USFDA for 32 years, having Chaired the CardioRenal Advisory Committee for 3 terms; most recently, he Chaired the Cardiovascular Devices Advisory Committee. He is President of the Heart Valve Society of America and has served on the Boards of Governors/Trustees of multiple local and national professional societies. Dr. Borer has published 400 scientifi c papers and 4 books, edits the journal, Cardiology, and has received several awards and other recognitions, including the Public Service Medal of the U.S. National Aeronautics and Space Administration.

ABSTRACTSeveral descriptors (“risk markers”) can facilitate identifi cation of persons likely to develop coronary artery disease (CAD) or, if already affl icted, to suffer cardiovascular death or other coronary events. Among these is heart rate, for which a large body of epidemiological evidence has demonstrated an association with cardiovascular and total mortality in the general population as well as in patients with CAD.The pathophysiological importance of heart rate in CAD is well known. When CAD is present, heart rate is a critical factor in the generation of ischemia. Experimental data and clinical observations suggest that heart rate also is involved in the pathogenesis of atherosclerosis and plaque rupture. Indeed, a growing body of evidence supports resting heart rate not only as a risk marker but as a risk factor, i.e., a characteristic that, if modulated, is likely to be associated with modulation of the disease manifestations. This may be true for populations with several different types of cardiac disease. However, the evidence is strongest for patients with CAD in that alteration in heart rate now seems to benefi cially alter some outcomes in such patients. The relationship between resting heart rate and cardiovascular mortality in this patient group is strong, graded and independent of other factors such as blood pressure and physical activity. The results of the recent randomized, controlled BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study underline the importance of heart rate reduction in managing stable coronary disease. Prospective analysis of data from the placebo arm indicate that resting heart rate >70 bpm is a strong independent predictor of adverse clinical outcome; ivabradine, a selective If current blocker and, hence, heart rate slowing agents, signifi cantly improved coronary outcomes in patients with heart rate ≥70 bpm. Recently presented data in patients with stable CAD enrolled in the TNT trial (Treating to New Targets) have confi rmed that heart rate >70 bpm predicts major cardiovascular events. These data, taken together, support consideration of heart rate in defi ning risk and guiding therapy in patients with CAD.

LIST OF SUGGESTED READINGSBorer JS, Fox K, Jaillon P, Lerebours G, for the European Ivabradine Investigators. Anti-anginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blinded, multicentered, placebo-controlled trial. Circulation 2003;107:817-823.Borer JS. If inhibitors as specifi c heart rate reducing agents. Nature (Clinical Practice Cardiovascular) 2004,1:1-7.Borer JS. Therapeutic effects of If blockade: evidence and perspective. Pharmacological Research 2006; 53:440-446.Fox K, Borer JS, Camm J, Danchin N, Ferrari R, Lopez Sendon JL, Steg PG, Tardif JC, Tavazzi L, Tendera M, for the Heart Rate Working Group. Resting Heart Rate in Cardiovascular Disease. Journal of the American College of Cardiology 2007;50:823-830.DiFrancesco D, Borer JS. The funny current: cellular basis for the control of heart rate. Drugs 2007;67 (Suppl 2):15-24.Borer JS, LeHeuzey Y. Characterization of the heart rate lowering action of ivabradine, a selective If current inhibitor. American Journal of Therapeutics, 2008;15:461-473.Tendera M, Borer JS, Tardif J-C. Effi cacy of If inhibition with ivabradine in different subpopulations with stable angina pectoris. Cardiology, 2009;114:116-125.Borer JS, Tardif J-C. Effi cacy of ivabradine, a selective If inhibitor, in diabetic patients with chronic stable angina, American Journal of Cardiology, 2009, in press.

Coronary artery disease management: A step further with ivabradine

Philippe G STEG, Paris – FRA


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Friday December 4th, 2009, 4.30 pm – 7 pm

MAIN PLENARY SESSIONThe future of antithrombotic therapy

in coronary syndromes at the acute and post-acute phases

Chairpersons: Nicolas Danchin, Dan Atar

Nicolas DANCHIN, Paris – FRANicolas DANCHIN, M.D, F.E.S.C., F.A.C.C., is a Professor of Medicine, Consultant Cardiologist and Head of the Department of coronary artery disease and intensive cardiac care at Hôpital Européen Georges Pompidou in Paris, France. He has a special interest in coronary artery disease, its treatment modalities including interventional cardiology and its prevention, and has written extensively on these and related topics. He is currently President of the French Society of Cardiology, consultant for the French Drug Agency, and a former

member of the Scientifi c Committee of the French National Health Insurance Authority (CNAM). He also co-chairs Task Force 1 of the Cardiovascular Round Table of the European Society of Cardiology. He edits the Annales de Cardiologie et Angéiologie and Consensus Cardio and is on the Editorial board of Heart and ACCEL. To date, he has published more than 300 papers in peer-reviewed journals.

The pharmacology of modern anti-thrombotic drugs: how to maximise the benefi t-to-bleed risk ratio?

Tabassome SIMON, Paris – FRA

Resistance to antiplatelet agents: biological fantasy or clinical reality?

Gilles MONTALESCOT, Paris – FRAGilles Montalescot is Professor of Cardiology at Pitié-Salpétrière Hospital in Paris, France where he heads the Cardiac Care Unit. He is a practicing Interventionnal Cardiologist and has extensive experience in basic and clinical research. He is the director of the INSERM research Unit U856 on Thrombosis.Dr Montalescot has been an investigator for many of the new drugs developed in the past fi fteen years as well as for many of the new interventional technologies. Dr. Montalescot is a senior scientist and has been the

national coordinator of many international trials and the chairman of several national or international randomized trials including ADMIRAL, ARMADA, ALBION, STEEPLE, ARCHIPELAGO, ABOARD, ACAPULCO and the ongoing AMERICA, ATOLL, ARCTIC and ALBATROSS trials. Dr Montalescot is an active member of several organizations with a major interest in education and research in thromboembolic diseases. He has been the chairman of the working group on Thrombosis of the French Society of Cardiology and a nucleus member of the Working Group on Thrombosis and Platelets of the European Society of Cardiology. He has served on several task force committees on antithrombotic drugs and acute coronary syndromes. Dr Montalescot has received several awards in his country including the J. Valade Prize from the Fondation de France and the J. Escalle award from the National Academy of Medicine. He is a member of the editorial board of the European Heart Journal and has published over 250 peer-reviewed articles in journals such as The NEJM, JAMA, Lancet, Circulation, ATVB and Circulation Research. He has also numerous international invited lectures to his credit.

How the results of the most recent trials will change the anti-thrombotic strategy in acute coronary syndromes?

Nicolas DANCHIN, Paris – FRA

Post acute coronary syndromes. Risk and management of anti-thrombotic therapy in the ambulatory patient.

Philippe Gabriel STEG, Paris – FRA

38


Friday December 4th, 2009, 4.30 pm – 7 pm

JOINT SESSIONThe CardioRenal Forum – European Society of

Cardiology (ESC) Working-Group on Pharmacology and Drug Therapy

Optimising Care at the Cardio-Renal Interface

Chairpersons: Alexandre Mebazaa, Bengt Fellstrom

Cardiovascular outcomes in chronic kidney disease, Rationale for future clinical trials.


Cardiovascular protection trials in end stage renal disease.

Bengt FELLSTROM (Uppsala – SWE)

Clinical trials targeting renal protection in heart failure and cardiovascular disease:

Marco METRA, Brescia – ITAMarco Metra, MD, Associate Professor of Cardiology, Section on Cardiovascular Diseases, Department of Experimental and Applied Medicine University of Brescia, Brescia, ItalyProf. Metra is associate professor of cardiology in the Section of Cardiovascular Diseases of the Department of Experimental and Applied Medicine at the University of Brescia, Italy. He received his medical degree from the University of Parma in 1981 and subsequently served as fellow in cardiology and in internal medicine

at the Universities of Parma and Brescia. He was a research associate at the Committee on Clinical Pharmacology of the University of Chicago, Illinois, (Director, Prof. Leon I. Goldberg) United States, in 1985, returning to the University of Brescia the following year as research associate. His research is focused on heart failure, in particular on the functional evaluation of the patient with heart failure, on the role of sympathetic activity and ß-blocker therapy, and on the assessment and treatment of acute heart failure. Prof. Metra was principal investigator in the Studies of Oral Enoximone Therapy in Advanced Heart Chronic Heart Failure (ESSENTIAL) trial and is principal investigator and member of the Executive Committee in the ongoing trials PROTECT and REACH-UP, assessing the effects of the selective adenosine A1 receptor antagonist rolofylline on congestion and renal function in hospitalized patients with acute heart failure, volume overload and reduced renal function (PROTECT) or with worsening renal function (REACH-UP) and he is co-chairman and member of the executive committee of the RELAX-HF trial, assessing the vasodilator relaxin in patients with acute heart failure. He was also a member of the steering committees of the COMET (carvedilol or metoprolol European Trial) and VERITAS (Tezosentan in acute heart failure) trials and is a member of the steering committee of the SHIFT and ASCEND–HF trials concerning medical treatment of chronic and acute heart failure, respectively.A board member of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) from 2001 to 2008, Prof. Metra served as secretary of the executive board from 2004 to 2006. He has also been a member of the ESC’s Committee for Practice Guidelines (years 2004 to 2006), and has been cochair with Prof. Dickstein of the 2008 meeting of the HFA of ESC, held in Milan in June 14-17, 2008. Prof. Metra is author of 175 articles in peer-reviewed journals (total impact factor, 475) as well as of numerous other publications and book chapters.

ABSTRACTAcute heart failure (HF) is the leading cause of hospitalisation for patients aged >65 years. Despite a relatively satisfactory response in the acute phase, patients have a poor outcome with mortality and rehospitalisation rates of 10-15% and 30-40%, respectively, at 6-12 months from discharge. Persistent fl uid retention and worsening renal function during the initial hospitalisation have been consistently shown as major independent predictors of outcomes. Thus, interventions aimed at congestion relief and renal preservation may have a favourable impact on both early relief of symptoms and post-discharge outcomes.Renal adenosine release seems one of the most important mechanisms causing renal deterioration in patients with acute heart failure, In the kidney, type I adenosine receptors mediate increased proximal tubule sodium uptake and glomerular afferent arteriole vasoconstriction in response to increased sodium delivery to the distal nephron (so called tubule-glomerular feedback). The administration of type IA adenosine receptor antagonists may therefore be associated with benefi cial effects on symptoms (relief of congestion), renal function and prognosis in the patients with acute HF.Preliminary studies conducted in relatively small groups of patients (i.e. 50 to 300 patients) have shown benefi cial effects of type IA adenosine receptor antagonists on diuresis, symptoms and renal function of patients with acute HF, fl uid overload and mild to moderate impairment of renal function.1,2 In the PROTECT pilot trial, 301 patients hospitalized for acute HF with an eGFR 20-80 mL/min, and elevated natriuretic peptide levels were randomised to placebo or rolofylline 10, 20, or 30 mg/day, administered as 4-hour infusions for 3 days in addition to iv loop diuretics. Compared with placebo, rolofylline resulted in trends towards greater proportions of patients with marked or moderately improved dyspnoea and fewer patients with worsening HF and/or renal function.3 This trial is the foundation of the PROTECT trial. The PROTECT trial was aimed at the assessment of the effects of rolofylline, compared to placebo, on symptoms and 60-days outcomes in 2033 patients admitted for acute HF with mild to moderate renal dysfunction and elevated natriuretic peptides plasma levels. Patients were randomised 2:1 to rolofylline or placebo at <24 hours from admission. The primary endpoint was a 3 category ordered outcome of treatment success, lack of change, or treatment failure. Treatment success was defi ned as moderate to marked improvement in dyspnea at both 24 and 48 hours after randomisation in the absence of treatment failure. Treatment failure included any of the following: death or readmission for HF through Day 7, worsening symptoms and/or signs of HF after Day 2 through 7 or discharge with the need for rescue therapy, persistent renal impairment (SCr increase ≥0.3 mg/dL through Day 7 confi rmed at Day 14, or initiation of hemofi ltration or dialysis through Day 7). No signifi cant difference was found between rolofylline and placebo with regards of the primary end point. Rolofylline was associated with more successes than placebo, but also more failure (odds ratio versus placebo 0.92, 95%CI 0.78, 1.09, p=0.348). The secondary composite endpoint of death or cardiovascular or renal hospitalization occurred in 30.7% of rolofylline patients ( 25.7% were hospitalized and 8.9% died) and 31.9% of placebo patients (25.6% were hospitalized and 9.5% died), yielding a time to fi rst event hazard ratio of 0.98, 95% CI 0.83-1.17, p=0.86). Rolofylline did not reduce the incidence of renal impairment compared to placebo (15.0% vs 13.7%, respectively, odds ratio versus placebo 1.11, 95% CI 0.85, 1.46; p = 0.44). More patients on rolofylline experienced nervous system disorders, with 11 patients (0.8%) experiencing seizure and 16 patients (1.2%) experiencing stroke on rolofylline, with no patients experiencing seizure and 3 patients (0.5%) experiencing stroke on placebo.1 Thus, we still lack of studies showing a favorable effect of a pharmacologic agent on renal function as well as that this may be translated into a betetr outcome. References1 Dittrich HC, Gupta DK, Hack TC, Dowling T, Callahan J, Thomson S. The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma fl ow in ambulatory patients with heart failure and renal impairment. J Card Fail. 2007;13:609-17.2 Givertz MM, Massie BM, Fields TK, Pearson LL, Dittrich HC; CKI-201 and CKI-202 Investigators. The effects of KW-3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. J Am Coll Cardiol. 2007;50:1551-60. 3 Cotter G, Dittrich HC, Davison Weatherley B, Bloomfi eld DM, O’Connor CM, Metra M, Massie BM, for the PROTECT Steering Committee, Investigators, and CoordinatorsThe PROTECT Pilot Study. (2008) A Randomized, Placebo-Controlled, Dose-Finding Study of the Adenosine A1 Receptor Antagonist Rolofylline in Patients with Acute Heart Failure and Renal Impairment. J Card Fail;14:631-404 Metra M. Hot Line session III presentation. ESC meeting 2009.


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Saturday December 5th, 2009 8 am – 1 pm

CVCT EXPERT WORKSHOPAntithrombotic Acute Coronary Syndromes trials.

Methodological and interpretation issues

Chairpersons: Gregory Yh Lip, Stuart Pocock

Stuart POCOCK, London – GBRStuart Pocock is Professor of Medical Statistics at the London School of Hygiene and Tropical Medicine. His primary research interest concerns clinical trials, both as regards methodological developments and applied collaboration in major trials. His particular methodologic interests include: standards for the statistical reporting of trials and epidemiological studies, the statistical ethical and organisational principles for data monitoring including early stopping guidelines, the presentation of time-to-event (survival) data, the pros and cons of equivalence trials, and problems of multiplicity in trial reporting eg subgroup analyses, multiple outcomes and covariate adjustment.Professor Pocock runs a statistical centre for the design, conduct, analysis and reporting of major clinical trials, especially in cardiovascular diseases. He is also a consultant statistician for a wider range of clinical trials in which expert statistical advice is needed, and serves as a statistical member of many trial data monitoring and steering committees. He collaborates internationally especially with the Cardiovascular Research Foundation in New York and the New England Research Institutes in Boston. He is a frequent lecturer on a variety of clinical trial issues.

Selecting the appropriate design

Positive control, placebo-controlled trials vs. non inferiority head-to-head comparative trials.Which way to go?

Stuart POCOCK, London – GBRYasser KHDER, Boehringer Ingelheim – ParisYasser KHDER obtained his medical degree and his speciality in internal medicine from Damascus University, Syria in 1987; subsequently he was graduated as specialist in cardiovascular pathology from Nancy Medical School, France in 1992. Between 1992 and 1996 YK had part time activity as a clinical cardiologist. Meanwhile, he also had a part time academic research assignment in the National Institute of Health and Medical Research (INSERM). During this period YK was successfully graduated as a BSc in clinical pharmacology, a MSc in clinical epidemiology, methods in clinical research and a DSc in human biology from the Nancy University, France.Currently YK is a Scientifi c Director Cardiology in Boehringer-Ingelheim, leading Dabigatran clinical development program in ACS. Beforehand YK worked 7 years in Novartis Pharma AG, Basel, Switzerland as a Diovan® Global Phase IV Leader, Aliskerin European Clinical Team Leader, Protocol Review Committee Cardiovascular Scientifi c Director and Global Program Leader for a NCE in phase 2B.Before Novartis, YK 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 to prevent reperfusion injury at the acute phase of myocardial infarction.

ABSTRACTPlacebo-controlled, superiority trials are the standard approach to evaluate treatment effi cacy. They allow controlling for the placebo effect and require the smallest sample size to detect a treatment effect. Wherever possible and justifi ed, they should be considered as the fi rst choice for medical treatment evaluation as, for instance, when there is no proven reference therapy (ISIS 2) and when the tested drug is developped as an add-on to the reference therapy (CURE). However, if a standard treatment exists; placebo-controlled trials are ethically unjustifi able, especially in severe disease conditions such

as Acute Coronary Syndromes (ACS) where effi cacious treatments exist. Active controlled superiority trials comparing the new medical therapy to the reference therapy are ideal when the tested medical therapy is hypothesised to be superior to reference therapy (TRITON, PLATO). Nevertheless, assay sensitivity is so far required for the validity of these active controlled superiority trials. In several situations the new medical therapy is hypothesised to be equally effi cacious to a proven existing therapy but could eventually offer some advantages in term of safety, fewer side effects, ease of use or price. In these situations active-controlled trials must be used. An active control arm can therefore be used in the phase 2, dose-ranging studies to help for the dose adaptation during the study course, as well as, the dose selection and the decision-making to move to phase 3 (SEPIA-ACS1). In these situations phase 3 studies are designed as non-inferiority trials. No-inferiority trials are not easy to design, diffi cult to conduct and often subject to critics. Good historical placebo-controlled trials documenting the effi cacy of the reference therapy must exist; the non-inferiority margin has to be carefully justifi ed by robust data from historical placebo-controlled trials. Moreover non-inferiority margin determination should not be only based on statistical criteria; both feasibility and clinical relevance should also be taken into consideration. Non-inferiority trials have to ensure that the studied population, the backgrounds therapy, the dosing of the reference therapy and the evaluation criteria are consistent with the historical studies used for the determination of the non-inferiority margin (SYNERGY, OASIS 5). Adherence to treatment and data quality are particularly important in non-inferiority trials. It is generally accepted that both the intention-to-treat and the per-protocol populations should be used to conclude of non-inferiority. These trials require larger sample size than placebo or active controlled superiority studies especially if the treatment effect size is neutral, however the sample size could be smaller if the tested drug has some effi cacy advantage over reference therapy.

Adaptive design. Strengths and limitation

Sidney GOLDSTEIN, Detroit – USAMickael DOMANSKI, Bethesda – USA

Defi ning the appropriate patient population: ACS, AMI, STEMI/NSTEIM: terminology and defi nition matters.

David MORROW, Boston – USAMarteen SIMOONS, Rotterdam – NEDProfessor and Chief of Cardiology, Thoraxcenter,Erasmus University Rotterdam, The NetherlandsPresident European Society of Cardiology 2000-2002Education1968 doctoral exam. University of Utrecht1970 artsexamen (qualifi ed physician) M.D.1976 Doctor of Medicine (Ph.D thesis) University of Utrecht1978 Registration as cardiologist (after training in internal medicine and cardiology at the University Hospital Rotterdam “Dijkzigt” in Rotterdam.)Appointments1968 Assistant Professor, Department Physiology Utrecht1978 Cardiologist Thoraxcenter, Erasmus University, Rotterdam1989 Professor of intensive cardiac care Erasmus University and University Hospital Rotterdam “Dijkzigt” in Rotterdam.)1996 Professor of cardiology, Erasmus University and University Hospital Rotterdam “Dijkzigt” in Rotterdam.)2003 Chief of Cardiology, Chairman Thoraxcenter and Chairman COEUR (cardiovascular research school Erasmus University Rotterdam)Field of ScholarshipIntensive care and coronary care: in particular treatment of patients with Acute Coronary Syndromes (myocardial infarction), and management of chronic coronary artery disease.Exercise physiology, exercise testing, and nuclear cardiology.Computer analysis of electrocardiograms, and ischemia monitoring.Since more than 20 years Chairman or member of the Steering Committee of national and international clinical trials, particularly related to acute coronary syndromes.

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Including:• Interuniversity Cardiology Institute of the Netherlands, trial of intracoronary streptokinase• European Cooperative Study Group trials with rtPA in acute myocardial infarction• MAAS (lipid lowering therapy, quantitative angiographic analysis)• CAPTURE (abciximab in PTCA)• GUSTO trials I-IV (acute myocardial infarction and acute coronary syndromes)• PURSUIT (acute coronary syndromes)• FROST (acute coronary syndromes)• PENTUA (acute coronary syndromes)• EUROPA (secondary prevention in coronary artery disease)Mentor and supervisor of 25 young scientists completing their PhD-thesis.Author and co-author of 615 publications in peer reviewed journals (PubMed) as well as several book chapters up to January 1, 2007.Editorial responsibilitiesEuropean Heart Journal (Editorial Board)Circulation (Editorial Board 1996-2004)Netherlands Journal of Cardiology (Editorial Board)Cardiology in Review (Editorial Board)Reviewer for different Journals including:The Lancet, The New England Journal of Medicine, Journal American College of Cardiology, Cardiovascular Research, Thrombosis and Hemostasis, Nederlands Tijdschrift voor GeneeskundeMembership and function in scientifi c organisations:President of European Society of Cardiology 2000-2002Board of the European Society of Cardiology 1991-2004Secretary and Chairman of the Working Group on Exercise Physiology: Pathophysiology and Electrocardiography of the European Society of Cardiology.Chairman Scientifi c Advisory Board Netherlands Heart FoundationFollow European Society of CardiologyFellow Royal College of Physicians (London)Fellow American College of CardiologyFellow American Heart Association (Clinical Cardiology)Fellow Royal Netherlands Academy of Science and ArtsActive Member of the European Academy of Sciences and Arts

Study drug and comparator drug related issues:, Clinical and Regulatory challenges.

What is the optimal “reference” comparator? Gregory Yh LIP, Birmingham – GBR Timing of randomisation/dosing

Gabriel STEG, Paris – FRANicolas DANCHIN, Paris – FRANicolas DANCHIN, M.D, F.E.S.C., F.A.C.C., is a Professor of Medicine, Consultant Cardiologist and Head of the Department of coronary artery disease and intensive cardiac care at Hôpital Européen Georges Pompidou in Paris, France. He has a special interest in coronary artery disease, its treatment modalities including interventional cardiology and its prevention, and has written extensively on these and related topics. He is currently President of the French Society of Cardiology, consultant for the French Drug Agency, and a former member of the Scientifi c Committee of the French National Health Insurance Authority (CNAM). He also co-chairs Task Force 1 of the Cardiovascular Round Table of the European Society of Cardiology. He edits the Annales de Cardiologie et Angéiologie and Consensus Cardio and is on the Editorial board of Heart and ACCEL. To date, he has published more than 300 papers in peer-reviewed journals.

Endpoint defi nition:Time to fi rst event vs. cumulative events

Torp PEDERSEN, Copenhagen – DENChristian Torp-Pedersen, MD, PhD, FACC, FESCProfessor of Internal Medicine, University of Copenhagen. Senior consultant in cardiology, Gentofte Hospital, Copenhagen. Fellow of the American College of Cardiology and Fellow of the European Society of Cardiology. Research has been mainly biochemistry, cardiovascular epidemiology and controlled clinical trials. Principal investigator of the TRACE study, steering committee member and co-designer of the DIAMOND studies. Steering Committee member of more than 10 international sltudies, currenly most notably ATHENA and SCOUT.

Aldo MAGGIONI, Florence – ITA

Composite events

John WARREN, London – GBRJohn Warren is a clinical scientist who works for the UK Medicines Healthcare products Regulatory Agency. He is a member of the European Scientifi c Advice Working Party since 2003. Previous appointments include Clinical Pharmacology at the Royal Postgraduate Medical School and Senior Lecturer at the National Heart and Lung Institute, with Honorary Consultant status at the Brompton, Charing Cross and Chelsea & Westminster Hospitals. He is the author of over 100 publications in international

journals on the physiology and pharmacology of the autonomic system and a book on the Endothelium. See: FASEB Journals 1993;7:1394-1400; 1994;8:247-251; 1995:9:411-418; Am J Physiol 1992;263:H1963-1966; 1993;265:H176-182; 1994;266:H1846-1853;1998;275:H1388-1394;Clinical Science 1983; 64:475-479; 1984; 66:79-85; 1984; 66:47-51.Previously on Editorial Board of Microvascular Research and Clinical Pharmacology & Therapeutics.

ABSTRACTSeparate pieces of evidence that are inadequately convincing on their own may become convincing when combined as a composite. Three questions arise from such an approach. How should the contribution of each component be weighted?If the composite is positive, how should the components be interpreted in terms of patient risk benefi t?If such an approach is used to assess effi cacy, how can a similar approach be used as a balance for safety?The holy grail of risk benefi t assessment is mortality. This is a composite endpoint of deaths from all causes. There is no diffi culty in interpretation as convincing evidence that an intervention prolongs life is persuasive for the patient and the prescriber. Death is accurate; there is no need to convene experts to diagnose borderline cases. It is cheap to collect. With investigator persistence, survival data can be obtained for over 99% of trial participants. It can usually b e measured at short time intervals, the time of most deaths being recorded within an accuracy of an hour. The merits of all deaths as an endpoint is that is captures the magnitude of effi cacy on the target organ as well as the fatal adverse events from any organ malfunction.Cardiovascular mortality is useful for identifying benefi t from therapy where a signal may be detected that is otherwise not signifi cant in terms of all cause mortality. The defi nition is not simple. Only a minority of deaths undergo post mortem, even then there is no pathology visible to confi rm a fatal arrhythmia. Common cardiovascular composite endpoints are mostly driven by the rate of non-fatal myocardial infarction. This useful endpoint may be strengthened by the addition of stroke and all cause mortality. Ischaemic or haemorrhagic components of stroke are important to mechanisms of action, but total stroke incidence is what matters to the patient.Cardiovascular disease is the cause of death in 75% of diabetics and this had led to discussions on the role of MACE (Major Adverse Cardiac Events), or other


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composites, to evaluate new signals from diabetes therapy. This is an issue particularly suited to discussion at the present meeting.We are used to explaining the life threatening importance of cardiovascular disease, but usually in the absence of convincing all cause mortality benefi t. Perhaps it is time to consider specifying this degree of uncertainty in the label. Should all drug labels include a point estimate and 95% CI to answer the question: “It is likely to affect my life expectancy?”

LIST OF SUGGESTED READINGS1. Montori VM et al, BMJ 2005;330:594-6.2. www.fda.gov/ohrms/DOCKETS/ac/08/.../2008-4368s1-06-Guest-Nissen.ppt.3. FDA opinions on muraglitazar, rosiglitazone and ACCORD.4. www.fda.gov/downloads/Drugs GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf

Balancing benefi t vs. risk

Edmond ROLAND, Paris – FRAEdmond ROLAND MD, FAHADr Roland is graduated from the University of Paris, France and board certifi ed in cardiology. After several years of clinical appointment in academic institutions, he joined the pharmaceutical industry and spent several years in the US. As Head of worldwide cardiovascular clinical research, he gained extensive experience in global drug development and international regulatory processes. Since 2001, he has

resumed clinical activities. Currently, Dr Roland is an attending cardiologist at the teaching hospital “Hôpital Européen Georges Pompidou” in Paris. He is also a Clinical Expert for the French Agency for Safety of Health Products (afssaps). In addition, he is a member of the EMEA Effi cacy Working Party sub-group on cardiovascular issues. The mission of this therapeutic working group is to develop European guidance documents for the clinical development of cardiovascular products. The cardiovascular working group is also providing technical expertise for the EMEA scientifi c advices.

ABSTRACTThe benefi t/risk assessment is a key step in the drug review and approval process. EMEA has developed a structured list of benefi t and risk criteria for reviewers to improve transparency and consistency of regulatory decisions. The presentation will discuss the regulatory approach to benefi t/risk assessment of antithrombotic drugs in acute coronary syndromes (ACS). Bleeding is the major adverse outcome of antithrombotic drugs and is closely associated with an increase in fatal and non-fatal adverse events. Assessing causality, is however extremely challenging given the complex relationship that exits between bleeding, antithrombotic therapies, ischaemia and invasive procedures. The issues of composite end-points and sub-group analysis will be discuss through the results of several recent clinical trials in ACS (ACUITY, TRITON-TIMI 38 and PLATO studies). Composite end-points are often used as primary end-points in the evaluation of benefi t/risk. Although composite end-points may increase the event rate and thus the statistical power of the study, they may mislead if component end-points are of widely differing clinical importance to patients, the number of events in the more important components is small and the size of effect differs across components. For example, a claim that a therapeutic intervention reduces a composite of cardiovascular death, myocardial infarction, and revascularisation procedures is problematic if most events were revascularisation procedures and treatment had a large effect on revascularisation but not on death or infarction. The use of composite primary end-points for effi cacy and safety is frequently complicated by gradients in importance to patients and in magnitude of the effect of treatment across component end-points. Higher event rates and larger treatment effects associated with less important components may result in misleading impression of the impact of treatment.Analyses of sub-groups of study patients to evaluate the heterogeneity of treatment effect may provide useful information to select the patient

population which would benefi t most of the drug. However, sub-group analyses also introduce analytical challenges and can lead to overstated and misleading results.References(EC) Points to consider on multiplicity issues in clinical trials (CPMP/EWP/908/99)(ICH Topic E9) NfG on statistical principles for clinical trials (CPMP/ICH/363/96)(EC) Guideline on the evaluation of medicinal products for cardiovascular prevention (EMEA/CHMP/EWP/311890/2007)Freemantle N., et al. Composite Outcomes in Randomized Trials, Greater Precision but with Greater Uncertainty? JAMA 2003; 289: 2554-2559Wang R, et al. Statistics in Medicine-Reporting of Subgroup Analyses in Clinical Trials.N Engl J Med, 2007; 357: 2189-2194Wiviott SD, et al. Prasugrel versus Clopidogrel in Patients with Acute Coronary SyndromesN Engl J Med, 2007; 357: 2001-2015Wallentin L., et al. Ticagrelor versus Clopidogrel in patients with Acute Coronary SyndromesN Engl J Med, 2009; 361: 1045-1057

Gregory Yh LIP, Birmingham – GBR

Interpretation issues:

Statistically signifi cant vs. clinically meaningful results? “A Statistical Interpretation of Recent Trials”

Stuart POCOCK, London – GBR

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Saturday December 5th, 2009 –2 pm – 5 pm

CVCT EXPERT WORKSHOP:

Data Safety and Monitoring Committees (DSMC) in CV trials

Chairpersons: Stuart Pocock, Bertram Pitt

Data accessData cleaning issues

Jorgen SELDRUP, QuintilesJorgen was born and bred in Denmark and obtained his postgraduate degree in Statistics from Aarhus University, Denmark, in 1971. His career started in January 1970 as the fi rst statistician at Geigy UK Ltd. Jorgen’s CRO experience includes fi ve years with a Paris-based CRO prior to joining Quintiles in 1994.From 2000 to 2003 he worked in ‘public health’ in Singapore as Director of the Clinical Trials & Epidemiology Research Unit (CTERU), the Ministry of Health. He was also responsible for creating disease

registries for cancer, stroke, cardiovascular disease, renal disease and eye disease. While in Singapore he was a member of the National Medical Research Council, visiting scientist at the Centre for Drug Evaluation, and was Associate Professor at the National University of Singapore. He returned to Quintiles in 2003 and joined the Centre for Statistics in Drug Development in 2006. As a statistical consultant, he advises on drug development plans, all aspects of clinical trial methodology and on building regulatory defense cases. He has extensive experience of Data Monitoring Committees and has been the Biostatistical voice on several R&D Due Diligence teams. He is an honorary member of PSI (Statisticians in the Pharmaceutical Industry which he founded in 1977 and became its fi rst chairman) and ISCB (International Society for Clinical Biostatistics of which he was President 1992-94).

ABSTRACTOne of the biggest (regulatory) concerns regarding a study with interim analysis is the potential for compromising the integrity of the investigation. If unblinding a study for the purpose of a DSMC review is needed, which may not always be the case, the concern is that such unblinding may lead to bias: that knowing the treatment key and/or details of the interim result will infl uence study personnel in a broad sense in the way they continue to conduct the study. Hence, it is of utmost importance to protect the blindness as far as possible as regards any other scientifi c and/or operational study personnel.However, in this environment data need to be prepared for review. Databases need to be prepared, potentially amalgamated and/or reconciled, analysed and reported upon.Cardiovascular trials are typically event driven trials. This introduction to the availability of data for DSMC review will use this design to discuss a series of issues related to such data preparations including 1. Preparing the DSMC Charter2. What does the DSMC want to see?3. Who prepares the data for the DSMC?4. How does the DSMC interact with Study sponsors 5. How clean does clean data need to be?6. Timing of database preparation relevant to DSMC meetings7. DSMC outputs – number of outputs, type of outputs (hard copies, electronic)8. Event and safety monitoring needs

Robert CODY, MerckRobert J. Cody MBA, MD is the Global Director for Scientifi c Affairs, for the cardiovascular therapeutic area, of Merck Research Laboratories, Merck & Co. Prior to joining MRL, and while on leave of absence from the University of Michigan, he was Vice-President for Medical Affairs and Chief Medical Offi cer of CVRx, Inc., a medical device company in Minneapolis, MN. At the University of Michigan Health System, Dr. Cody was Professor of Internal Medicine and served as Associate Chief in the Division of Cardiology, and Director of the Heart Failure & Transplant Management Program. He was a member of numerous Health System committees, and chaired the Medical School Institutional Review Board for several years . Dr. Cody received his bachelors degree from St. Joseph’s University in Philadelphia, Pennsylvania, his MD degree from Penn State University, and his MBA from the University of Michigan Business School. Dr. Cody completed a residency in Internal Medicine at the Cleveland Clinic Foundation in Cleveland, Ohio, and his cardiovascular training at Massachusetts General Hospital and Harvard Medical School. Prior to the University of Michigan, Dr Cody held faculty positions at the Ohio State University Medical Center and Weill Cornell Medical School, New York-Presbyterian Hospitals. For over twenty-fi ve years, his research focused on neurohormonal control factors in heart failure and hypertension, as well as the pathophysiology of heart failure. This included translational research in the renin-angiotensin-aldosterone system, autonomic control of the circulation, natriuretic peptides, and endothelin. Dr. Cody has led the design and monitoring of numerous international clinical trials in heart failure, and has served as chair of numerous DMC’s for international trials. Dr. Cody has authored or co-authored over 250 original research reports, review articles and book chapters. His honors include an Established Investigator Award of the New York Heart Association, and the James H. and Ruth J. Wilson Professor of Cardiology of Ohio State University. He is currently an editorial board member of the American Journal of Cardiology. He is a Fellow of the American College of Physicians, American College of Cardiology, American Heart Association, and the American College of Physician Executives. He serves as a member of the University of Michigan Health System Advisory Group, and the Board of Trustees of the Hunterdon Health System.

Adjudicating issues

Aldo MAGGIONI, Florence – ITAGilles DAGENAIS, Quebec – CAN

ABSTRACTThe Data Safety Monitoring Board (DSMB) monitors progress in patient recruitment, protocol compliance and data quality, and provides advice to the principal investigator about the conduct of the trial and integrity of the data to protect the validity and credibility of the trial. In addition, one of its main responsibilities concerns safety of the participants. Indeed, the DSMB should help to ensure the overall safety of participants in the trial by protecting them from avoidable harm.1, 2For its meetings, the DSMB receives the data to monitor recruitment, compliance, data quality, adverse events and the outcomes of the study. Some of the outcomes are adjudicated and others are not. Which data should the DSMB see? What are the issues regarding adjudicating cardiovascular outcomes? The presentation will attempt to answer these two questions and will be highlighted with some examples To fulfi l its responsibilities, the DSMB should see the adjudicated and non-adjudicated outcomes. For example, in a trial evaluating warfarin with and without antiplatelet agents, the risk of hemorrhagic and non-hemorrhagic strokes in an old population is high. In such a trial, the DSMB needs most of the strokes adjudicated based on imaging for the safety of the participants and effi cacy of the intervention. The DSMB may recommend priority in adjudicating strokes if there is some delay in adjudicating such outcomes. An example showing some issues in adjudicating is a trial in high-risk patients with hospitalization for congestive heart failure as one of the main outcomes. Adjudication of such an outcome is not always easy.3 First, nowadays more patients are not hospitalized for such an event; they are treated in outpatient clinics or physicians’ offi ces. Before the trial begins, the DSMB should highlight this point to the principal investigator because it may have an impact on the estimated number of events. During the trial, several aged participants will be


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hospitalized with heart failure and pneumonia or other major infections, or with heart failure and atrial fi brillation with rapid ventricular response. What is the preponderant outcome causing the hospitalization the pneumonia or the heart failure? The adjudicators will make the call. However, the adjudicators may refute one out of four cases considered by the local investigator to be heart failure. The DSMB members should know this information when they are reviewing the adjudicated and the non-adjudicated data of heart failure. Such information is important for assessing the immediate and estimated effi cacy of the intervention on heart failure. Adjudication of other outcomes such a death and myocardial infarction may also have their issues.4-6References1 DeMets D, Califf R, Dixon D, et al. Issues in regulatory guidelines for data monitoring committees. Clin Trials 2004; 1: 162-9.2 Damocles Study Group A proposed charter for clinical data monitoring committees: helping them to do their job well Lancet 2005; 365: 711-22.3 Zannad F, Stough WG, Pitt B, et al. Heart failure as an endpoint in heart failure and non-heart failure clinical trials: the need for a consensus defi nition. Eur Heart J 2008; 29: 413-21. 4 Petersen JL, Haque G, Hellkamp AS, et al. Comparing classifi cations of death in the Mode Selection Trial: Agreement and disagreement among site investigators and clinical events committee. Contemp Clin Trials 2006; 27: 260-8.5 Mahafey KW, Roe MT, Dyke CK, et al. Misreporting of myocardial infarction endpoints: Results of adjudication by a central clinical events committee in the PARAGON-B trial. Am Heart J 2002; 143: 242-8.6 Näslund U, Grip L, Fischer-Hansen J, et al. The impact of an endpoint committee in a large mulicentre, randomized, placebo-controlled clinical trial. Results with and without the end-point committee’s fi nal decision on endpoints. Eur Heart J 1999; 20: 771-7.

Unblinding issues

Nancy GELLER, Bethesda – USANancy L. Geller has been the Director of the Offi ce of Biostatistics Research at the National Heart, Lung and Blood Institute of the National Institutes of Health since 1990. She directs a group of 12 statisticians who collaborate in the design, implementation, monitoring and analysis of multicenter clinical trials in heart, lung and blood diseases and sleep disorders. She has been or is involved in a number of cardiovascular trials, including Post-CABG, PEACE, AFFIRM, the Women’s Health Initiative, FREEDOM, ACCORD and COAG, a

trial testing genetic dosing of Warfarin. She has research interests in clinical trial methodology, especially in issues of clinical trial design, monitoring and multiplicity, i.e, multiple endpoints and multiple treatment comparisons. She is an Associate Editor of Biometrics and a member of the Editorial Board of Clinical Trials. She is a Fellow of the American Statistical Association and recently was elected 2011 President of the American Statistical Association. She is the winner of the 2009 Janet L. Norwood Award for outstanding achievement by a woman in the statistical sciences.

ABSTRACTWe examine some aspects of blinding of outcome data during the course of a clinical trial, considering trial investigators, the steering/executive committees, the data and safety monitoring committee (DSMC), the trial statistician and the trial sponsor. Views on these topics are strong and diverse and we will give opposing views to the following questions.1. Should the DSMC be blinded to treatment identifi cation or should they be completely unblinded?2. Might the trial Executive or Steering Committee see data (such as event rates) that all investigators should not see? Should aggregate biomarker data or process data be revealed to some investigators? 3. Should the sponsor ever see outcome data during the course of a trial? With respect to unblinding outcome data, are government sponsors different from industry sponsors? Can the sponsor separate itself from its fi duciary responsibilities? 4. Is the trial statistician bound by the same rules as other investigators? Should the trial statistician be unblinded to treatment assignment? Should the trial statistician work for the sponsor?

LIST OF SUGGESTED READINGS1 Fleming, TR, Sharples, K, McCall, J, Moore, A, Rodgers, A and Stewart, R (2008). Maintaining confi dentiality of interim data to enhance trial integrity and credibility. Clinical Trials 5:157-167.2 Ellenberg, S, Fleming TR, DeMets, DL (2002). Data monitoring committees in clinical trials: a practical perspective. Wiley, Chichester, West Sussex, England.3 Pocock, SJ and Furberg, C (2001). Procedures of Data and Safety Monitoring Committees. American Heart Journal 141:289-294.4 DeAngeles, CD and Fontanarosa, PB. (2008). Impugning the integrity of medical science: the adverse effects of industry infl uence. Journal of the American Medical Association 299:1833-1835.5 Lachenbruch, PA and Wasserstein, R. Guest authorship, mortality reporting and integrity in Rofecoxib studies reply. Journal of the American Medical Association 300:904.6 Borer, J, Gordon, DJ and Geller, NL (2008). When should data and safety monitoring committees share interim results in cardiovascular trials? Journal of the American Medical Association 299:1710-1712.

Stopping rules in adaptive design trials

Methodological issues

Stuart POCOCK, London – GBRMickael DOMANSKI, Bethesda – USA

Ethical issues

Sidney GOLDSTEIN, Detroit – USADavid GORDON, Bethesda – USASpecial Assistant for Clinical Studies, DCVS, NHLBI, NIHEducation: 1971 Ph.D., Department of Chemistry, University of Chicago (Thesis: Optical Activity as a Structural Probe in Biological Membranes and Other Particulate Systems -- Information and Artifact.)1973 M.D., University of Chicago Pritzker Medical School1981 M.P.H., Department of Epidemiology, University of North Carolina, Chapel Hill (Thesis: Dietary Determinants of Plasma Cholesterol Change in the Recruitment Phase of the Lipid Research Clinics Coronary Primary Prevention Trial.)Major Projects: Lipid Research Clinics (LRC) Coronary Primary Prevention Trial (CPPT) Cholesterol Reduction in Seniors Program (CRISP) Pilot Study NHLBI Conference on Cost and Health Implications of Cholesterol LoweringWorkshop on Analysis of Cholesterol-Lowering TrialsAntihypertensive and Lipid Lowering to prevent Heart Attack Trial (ALLHAT)Women’s Angiographic Vitamin and Estrogen (WAVE) TrialBypass Angioplasty Revascularization Investigations II Diabetes (BARI 2D) TrialCell Therapy NetworkAdvisory PanelsNational Cholesterol Education Program Adult Treatment Panel I-II (ex offi cio)National Cholesterol Education Program Adult Treatment Panel III Research Interests/Publications Dr. Gordon has authored or co-authored more than 70 publications in the fi eld of cardiovascular epidemiology and clinical trials. Topics include: The LRC-CPPT, ALLHAT-LLT, and other cholesterol lowering trials. Lead author of LRC collaborative study design and 2nd results paper.Role of circulating HDL and triglycerides in coronary artery disease.Seasonal variation in cholesterol.Exercise ECG testing as a correlate of cardiovascular risk factors and predictor of cardiovascular events.Meta-analysis of cholesterol trials.Impact of diet, exercise, and weight on circulating lipids.Cholesterol in the elderly.Handling of interim clinical outcome data by DSMCs.

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As a graduate student, Dr. Gordon was the primary author of four peer-reviewed publications on optical activity as a structural probe of particulate systems. As an NHLBI post-doctoral fellow, Dr. Gordon was the primary author of four peer-reviewed publications on the isolation and characterization of cytoplasmic actins.

ABSTRACTThe ethical foundation of any clinical trial rests upon a contract between the sponsor and investigators with the patients who volunteer to participate. Patients agree to accept treatment under a protocol that may be more or less effi cacious than what they may receive in conventional medical practice and to be subjected to the burden and risk of undergoing research procedures that may not be of direct benefi t to them. In return, they may gain access to a new potentially effi cacious treatment that may not be available outside the trial and may receive ancillary medical care that might otherwise be unaffordable. But in addition to these direct tangible benefi ts, many research volunteers have altruistic motives, such as the desire to contribute to scientifi c knowledge that may lead to treatments that will improve the lives of future patients who will suffer from the same condition, including perhaps the patient’s children or grandchildren. This contract is embodied by the informed consent process, which among other things, guarantees that the trial asks an important scientifi c question for which there is equipoise, that the trial will be conducted with integrity and rigor, that the patients’ risks will be minimized, and that the trial will be terminated if and when the original state of equipoise no longer exists. Adoptive designs were introduced with the intent of making clinical trials more fl exible and more effi cient, by allowing certain design parameters to be reset during the trial based on the results to that point. For example, one might begin with a small sample size (which could detect only a large effect) and then enlarge the trial if the initial effect estimate falls below that threshold. Or similarly, one might extend the follow-up time or increase recruitment into specifi c subgroups or even change the treatment allocation ratio of treatments based on interim results at pre-specifi ed times. Statistical methods have been developed to preserve type 1 and type 2 error rates when this is done, usually at the cost of adding more patients, but fewer than would be required for a separate pilot trial. From an ethical standpoint adaptive designs have some obvious advantages. By enabling investigators to skip over pilot studies and combine two or more conventional trials into a single adaptive trial:• Fewer patients are exposed to risk.• Effective treatments become available to the public sooner.• Resources saved by earlier elimination of ineffective treatments may be redirected to more promising treatments.However, adaptive designs also pose signifi cant issues that may compromise the contract with research participants:• They are diffi cult to explain to patients – how “informed” is the consent?• If IRBs, DSMBs do not understand the methodology, how can they monitor the study effectively?• Adaptive modifi cations may be contaminated by knowledge of results – decisions may need to be taken away from the DSMB.• Complexity may lead to poor public understanding, acceptance, and application of results.While adaptive designs may be useful in certain situations, conventional designs are preferable at least in settings when the major design parameters are adequately known.

LIST OF SUGGESTED READINGS1 Mehta CR, Patel NR. Adaptive, group sequential and decision theoretic approaches to sample size determination. Stat Med 2006; 25:3250-3269.2 Fleming TR. Standard versus adaptive monitoring procedures: a commentary. Stat Med 2006; 25:3305-3312.3 Harrington RA, Stone GW, McNulty S, et al. Platelet Inhibition with Cangrelor in Patients Undergoing PCI. NEJM 367: nejm.org – November 15, 2009.4 Bhatt DL, Lincoff AM, Gibson M, et al. Intravenous platelet blockade with cangrelor during PCI. NEJM 367: nejm.org – November 15, 2009.5 Kastrati A. Cangrelor – a champion lost in translation. NEJM 367: nejm.org – November 15, 2009

Regulatory issue

Amin KADI, MFF – ParisProfessional ExperiencesFrom Oct 2003, President Founder and Managing Director of:• Monitoring Force France • Monitoring Force Maghreb • BiodataForce• Monitoring Force Tunisia • Monitoring Force Morocco • Med force Consult AlgeriaIn charge of regulatory submission fi les and Medical advisor specifi cally for the Maghrebin’s projectsMay 2002 – Sept 2003, Euraxi Pharma – Development Director• Business Development • Development portfolio• Development process system • Development Maghreb activitiesMay 00 – Mars 2002, Pharmacia-Head of therapeutic area Cardiology & • Management of 4 Project manager• Development of strategic medico-marketing plan to develop sales for two major products in France (190 & 240 MF)• Development and follow up of a medical studies plan in the glaucoma• Pricing fi elds concerning Xalatan• Launch of phase IV program concerning Celbrex (3000 GPs & 6000 patients) in arthritis• Medical manager for EPHESUS study in France (heart failure and hypertension with eplerenone)• Registry of d’ALDACTONE on heart failure (RALES)• Medical manager in France and Tunisia for a morbid-mortality study on the thrombogenis prophylaxis with patient hospitalized for a medical reasonAugust 96 – Mars 99, Roche – Project Manager therapeutic area Cardiology• Medical Manager – phase IV programs: 9 studies concerning m i b e f r a d i l and 22000 patients, 4500 GPs et 1000 Cardiologists• Medical Manager of phase III programs on hypertension and heart failure concerning mibefradilMars 99 – May 00, Roche – Head of therapeutic area Cardiology• Management of 1 Project manager and 3 ‘medecins regionaux’• Responsible of medical development• Registry of a new indication of carvedilol in heart failure treatment in FranceNov 95 – Dec 95, Lipha Sante – Medical responsible for Bretaqne• Follow of medico-marketing local plan: phase IV concerning fosinopril in hypertension and coronary syndrome• Formation responsibility of fi elds forceDec 95 – July 96, Synthelabo – Medical responsible for Ile de France (Region of Paris)• Follow of medico-marketing local plan: phase IV concerning Inipomp on gastric refl ux• Formation responsibility of fi elds forceNov 92 – Nov 94, Cardiologists on Intensive care at le Mans hospital• Coronarography • Echocardiography • Rhythmic Holter• ETTMaghreb Experience, 10 studies:•Heart failure •Thrombogenis prophylaxis•Oncology •Parkinson disease •2 studies in Hypertension•2 studies with Cox 2 in surgery •1 study in dyslipidemia•1 study in acute coronary syndromeEducation and Training 1982 - Baccalaureat D1988 - Medical Doctor diploma1992 - Cardiology diploma – Universite de medicine d’Angers (49)1993 - Interventional Cardiology diploma – University Paris V1994 - Echocardiography diploma – University Paris V1995 - Paediatric cardiology diploma – University Paris V2000 - HEC Certifi cate (management)2001 - HEC Certifi cate (hard negotiation)


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PUBLICATION COMMITTEE MEMBERS

Laurent BONELLO Age 32 (born March, the 8th, 1977)email: [email protected] POSITION :2008 - Present: Head of the research, head of the catheterization laboratory and of the intensive care unit, Cardiology department, Hopital universitaire nord, Marseille.Research activityLate breaking trial presentation

1-ACC 2008 : Adjusted Clopidogrel loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance. Chicago 2008.2-AHA 2008 : Tailored Clopidogrel Loading Dose According to Platelet ReactivityMonitoring to Prevent Acute and Subacute Stent Thrombosis. Nouvelle Orléans2008.Young investigator award- L Bonello, F Paganelli, M Arpin-Bornet, P Auquier, F Dignat-George, P Barragan,L Camoin-Jau. VASP phosphorylation analysis predicts ischemic recurrence in patients undergoing coronary angioplasty. Congress of the American college of cardiology. New Orleans 2007, fi nalist of the Young investigator award. - L. Bonello et al. Cardiac Troponin Ic Elevation Following Successful Percutaneous Coronary Intervention: Effects of an Acute Oral Loading Dose of Trimetazidine. Congrès mondial commun de la société européenne de cardiologie et de la fédération internationale de cardiologie (Barcelone 2006): International meeting oral presentation and lectures1) Individualized anti platelet therapy to optimise outcome. Snowmass Colorado. 2009.2) Platelet reactivity monitoring to prevent stent thrombosis. ESC Munich 2008.3) Stent thrombosis: early and long term anti platelet agent. ESC Barcelona 2009.4) Body Mass Index is the Main Determinant of High On-treatment Platelet Reactivity and of Failed Dose Adjustment According to Platelet Reactivity Monitoring. AHA Orlando 2009.5) Platelet reactivity monitoring. Transcatheter Cardiovascular Therapeutics: Washington DC 2008.Selected publications Waksman R, Bonello L. The 5 Ts of bifurcation intervention: type, technique, two stents, T-stenting, trials. JACC Cardiovasc Interv. 2008 Aug;1(4):366-8. Bonello L, De Labriolle A, Steinberg D, Waksman R. Thrombus aspiration during percutaneous coronary intervention. Lancet. 2008 Sep 20;372(9643):1034. Bonello L, Camoin-Jau L, Dignat-George F, Paganelli F. A threshold of platelet reactivity for ischaemic events? Eur Heart J. 2008 Jul 9. Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O, Simeoni MC, Barragan P, Dignat-George F, Paganelli F. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol. 2008 Apr 8;51(14):1404-11.Widemann A, Sabatier F, Arnaud L, Bonello L, Al-Massarani G, Paganelli F, Poncelet P, Dignat-George F. CD146-based immunomagnetic enrichment followed by multiparameter fl ow cytometry: a new approach to counting circulating endothelial cells. J Thromb Haemost. 2008 May;6(5):869-76. Amabile N, Susini G, Pettenati-Soubayroux I, Bonello L, Gil JM, Arques S, Bonfi l JJ, Paganelli F. Severity of periodontal disease correlates to infl ammatory systemic status and independently predicts the presence and angiographic extent of stable coronary artery disease. J Intern Med. 2008 Jun;263(6):644-52. Bonello L, Paganelli F, Arpin-Bornet M, Auquier P, Sampol J, Dignat-George F, Barragan P, Camoin-Jau L. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost. 2007 Aug;5(8):1630-6. Bonello L, Basire A, Sabatier F, Paganelli F, Dignat-George F. Endothelial injury induced by coronary angioplasty triggers mobilization of endothelial progenitor

cells in patients with stable coronary artery disease. J Thromb Haemost. 2006 May;4(5):979-81. In press publications (accepted)- Bonello et al. Consensus on the defi nition of high on treatment platelet reactivity. J Am Coll Cardiol. - Bonello et al. Impact of loading dose adjustment on platelet reactivity in homozygotes of the 2C19 2* loss of function polymorphism. Int J Cardiol. - Bonello N, Armero S, Paganelli F, Mancini J, Burignat-Bonello C, Delabriolle A, Maillard L, Barragan P, Lévy N, Dignat-George F,Camoin-Jau, Bonello L. Relation of Body Mass Index to High On-Treatment Platelet Reactivity and of Failed Clopidogrel Dose Adjustment According to Platelet Reactivity Monitoring in Patients Undergoing Percutaneous Coronary Intervention. Am J Cardiol. - Bonello L et al. Platelet reactivity monitoring of clopidogrel loading dose in Unprotected Left Main Coronary Artery Stenting. Arch Cardiovasc Dis. - Is the future personalized anti-platelet therapy for coronary artery disease patients ? Expert Review of Cardiovascular Therapy. Other activitiesReviewer for : the Lancet, Circulation JACC, international journal of cardiology, American journal of cardiology, CRM.

Doctor Thibaud DAMY, 27/06/71Doctor Thibaud Damy qualifi ed in medicine at the University of Paris XI in 1996. After a period of postgraduate cardiology training in several Parisian hospitals and a PhD on the effect of nitric oxide on heart failure at the University Paris VII, he was appointed fi rst as a senior registrar at Paris V University (2004), then at Paris XII (2005-2006) and subsequently in 2007 as a senior lecturer in cardiology and honorary consultant cardiologist at Henri Mondor Hospital, Creteil, France. In August 2008, he obtained a secondment for 16

months as a senior research fellow at the Academic Cardiology Department of Professor John G Cleland at the University of Hull (UK).Doctor Damy’s main fi eld of interest is heart failure, extending from its epidemiology and physiopathology through to its diagnosis and treatment. Particular current interests include the role of the nitric oxide pathway, neurohumoral systems, sleep apnoea syndrome, right ventricule function, and pulmonary artery pressure in heart failure.Main publicationsDamy T, d’Ortho M, Estrugo B, Margarit L, Mouillet G, Mahfoud M, Roudot-thoraval F, Vermes E, Hittinger L, Roche F, Macquin-Mavier M. Heart Rate Increment Analysis Is Not Effective for Sleep-Disordered-Breathing Screening in Patients with Chronic Heart Failure. J Sleep Res 2009, August 31.Damy T, Viallet C, Lairez O, Deswarte G, Paulino A, Maison P, Vermes E, Gueret P, Adnot S, Dubois-Rande JL, Hittinger L, Comparison of four right ventricular systolic echocardiographic parameters to predict adverse outcomes in chronic heart failure. Eur J Heart Fail. 2009 Sep ; 11(9) :818-24.Damy T, Kirsch M, Khouzami L, Caramelle P, Le Corvoisier L, Roudot-Thoraval F, Dubois-Randé JL, Hittinger L, Pavoine C, Pecker F. Glutathione defi ciency in cardiac patients is related to the functional status and structural cardiac abnormalities PloS ONE 2009; 4(3):e4871.Mar 25.Paulino A *, Damy T*, Margarit L, Stoïca M, Deswarte G, Khouria L, Vermes E, Meizels A, Hittinger L, d’Ortho MP.Prevalence of Sleep Apnoea Syndromes in a 316 patient-French cohort of stable Congestive Heart Failure. Arch Cardiovasc Dis. 2009 Mar; 102(6-7): 509-18. *: fi rst co-authorsJK.Bendall*, T.Damy*, P.Ratajczak, P.Milliez, E.Robidel, F.Marotte, J.L.Samuel, C.Heymes. Role of myocardial neuronal nitric oxide synthase-derived NO in -adrenergic hyporesponsiveness in rats with experimental heart failure. Circulation 2004 Oct 19; 110 (16): 2368-75. *: premiers co-auteurs T.Damy, P.Ratajczak, A.Shah, G.Hasenfuss, J.L.Samuel, C.Heymes. Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet 2004 Apr 24;363; 1365-7T.Damy, P.Ratajczak, F.Marotte, E.Robidel, P.Oliviéro, L.Rappaport, J.L.Samuel, C.Heymes. Upregulation of Cardiac Nitric Oxide Synthase 1-Derived Nitric Oxide in Heart Failure in Senescent Rats. Physiological Response to NOS1 Inhibition on Myocardial Contractility. FASEB J .2003 oct;17(13):1934-6

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Finn GUSTAFSSONFinn Gustafsson, MD, PhD (born 1968) is a consultant cardiologist at Rigshospitalet in Copenhagen, Denmark. After graduation from Faculty of Medicine, University of Copenhagen in 1994, he subsequently completed his training in cardiology and internal medicine in various hospitals in Copenhagen. In 2000 he defended a PhD thesis in microvascular physiology at University of Copenhagen. Following a clinical fellowship at Toronto General Hospital, Ontario, Canada, he now is a staff cardiologist in the heart

failure and transplantation program at Rigshospitalet. Major scientifi c areas of interest include epidemiology and intervention in heart failure, as well as medical aspects of cardiac transplantation and left ventricular assist device therapy. He has served as an investigator and on steering committees of several clinical trials in the fi elds of heart failure and transplantation. He has authored or co-authored more than 90 papers in international, peer-reviewed medical journals as well as co-authored books and monographs on heart failure. He has been a member of the nucleus of the Working Group for Cardiovascular Drug Therapy of the European Society of Cardiology since 2006.Selected publications from 2009:Rosenberg J, Schou M, Gustafsson, Badskjær J, Hildebrandt P: Prognostic threshold of NT-proBNP in primary care.Eur Heart J 2009; 30: 66-73.Gustafsson F, Schou M, Videbæk L, Dridi N, Ryde H, Handberg J, Hildebrandt P on behalf on the Danish Heart Failure Clinics Network: Incidence and predictors of hospitalization or death in patients managed in multidisciplinary heart failure clinics. Eur J Heart Fail 2009; 11:413-419.Klovaite J, Gustafsson F, Sander K, Mortensen SA, Nielsen LB: Severely impaired von Willebrand factor-dependent platelet aggregation in patients with continuous-fl ow left ventricular assist device (HeartMate II). J Am Coll Cardiol 2009; 53:2162-2167.Gustafsson F, Barth D, Delgado DH, Nsouli M, Sheedy J, Ross HJ: The impact of everolimus versus mycophenolate on blood- and lymphocyte cyclosporine exposure in heart transplant recipients. Eur J Clin Pharmacol 2009; 65:659-65Andersen, M, Videbæk R, Boesgaard S, Sander K, Hansen PB, Gustafsson F: Incidence of ventricular arrhythmias in patients on long-term support with a continuous-fl ow assist device (Heartmate II). J Heart Lung Transplant 2009; 28: 733-735.Møller DV, Pham TT, Gustafsson F, Hedley P, Ersbøll MK, Bundgaard H, Andersen CB, Torp-Pedersen C, Køber L, Christiansen M: The role of lamin A/C mutations in Danish patients with idiopathic dilated cardiomyopathy. Eur J Heart Fail 2009; 11:1031-1035.Sheshgiri R, Gustafsson F, Sheedy J, Xiao R, Librach CL, Rao V, Ross HR , Delgado DH: Everolimus but not Mycophenolate Mofetil Therapy is Associated with Soluble HLA-G Expression in Heart Transplant Patients. J Heart Lung Transplant 2009: 28:1193-7 Gustafsson F, Ross HJ: Pathophysiology of exercise intolerance in heart failure. In Kirklin J, Branner N, and Jessup M (eds.) Advanced Heart Failure. ISHLT monograph, Vol. 3 (1), Elsevier 2009.

Professor Atul PATHAKDepartment of Clinical PharmacologyDepartment of CardiologyUniversity Hospital and Faculty of MedicineToulouse, FRANCE.Mail: [email protected] : +33621516352Hospital :+33561323017University +33561145961Professor Atul PATHAK, is a Pharmacologist and

Cardiologist. He is leading a clinical research team focusing on cardiovascular pathophysiology and clinical pharmacology and is affi liated to INSERM (National Institute of Medical Research). Professor Pathak is consultant in Clinical Cardiology focusing on patient’s care with cardiovascular risk factors (metabolic and cardiovascular) and their consequences such as Heart Failure in the Cardiometabolic department of Toulouse University Hospital. Professor Pathak was resident in Cardiology from 1996 to 2001 and trained in Toulouse (France), Aachen (Germany) and Cleveland (Cleveland Clinic, USA). After that period, he obtained his MD (highest distinction) at the Faculty of Medicine in Toulouse and obtained a tenure position as a research scientist at INSERM up to 2002. He obtained his European Phd (highest distinction) in Clincal and Experimental Pharmacology in 2005. He also worked as a post doctoral research fellow in the Department of Cardiology at Hospital Erasme and Free University of Bruxelles from 2004 to 2005. He joined the Faculty of Medicine at the University Paul Sabatier in Toulouse as an Associate Professor in 2002 and has been Assistant Professor since 2005. He has been nominated full tenure Professor in Clinical Pharmacology in 2009 and is currently leading the Clinical Unit of Cardiovascular Pharmacology in the University Hospital of Toulouse.Doctor Pathak is the author of more than 80 international publications. His research interests are: (i) new diagnostic tools and treatment of cardiometabolic risk factors and heart failure, (ii) the human sympathetic nervous system, (iii) neurotransmitters of the neuro cardiac synapse and more generally Clinical Pharmacology of Cardiovascular diseases. He is currently leading both a clinical and an experimental team working on the nervous regulation of cardiovascular function and, more particularly, the role of the autonomic nervous system in the control of arterial pressure, cardiac rhythm and contraction, and associated diseases (i.e. obesity, diabetes). Professor Pathak has been awarded by the ESC (Young Investigator Award), by the British Pharmacological Society and the French Society of Cardiology. He is also member of the French Association of Pharmacologists, the French Society of Hypertension and Cardiology, the American Society for Heart Failure. He is elected President of the Cardiovascular Pharmacology Working Group of the French Society of Cardiology. He has both academic and institutional commitments, among them participation at advisory board at AFSSAPS (French FDA) and HAS for the review of clinical trials protocol, assessment of benefi t /risk ratio of drugs (marketed or under development) and medico-economic issues (regarding lipid or blood pressure lowering drugs).

Yasser KHDER obtained his medical degree and his speciality in internalmedicine from Damascus University, Syria in 1987; subsequently he wasgraduated as specialist in cardiovascular pathology from Nancy MedicalSchool, France in 1992. Between 1992 and 1996 YK had part time activityas a clinical cardiologist. Meanwhile, he also had a part time academicresearch assignment in the National Institute of Health and Medical Research(INSERM). During this period YK was successfully graduated as a BSc in clinicalpharmacology, a MSc in clinical epidemiology, methods in clinical researchand a DSc in human biology from the Nancy University, France.Currently YK is a Scientifi c Director Cardiology in Boehringer-Ingelheim, leadingDabigatran clinical development program in ACS. Beforehand YK worked 7years in Novartis Pharma AG, Basel, Switzerland as a Diovan® Global Phase IVLeader, Aliskerin European Clinical Team Leader, Protocol Review CommitteeCardiovascular Scientifi c Director and Global Program Leader for a NCE inphase 2B.Before Novartis, YK worked 5 years in Merck KGaA, where he led severaldevelopment programs such as bisoprolol in silent myocardial ischemia,nicorandil in cardiac surgery and PCI as well as Na+/H+ exchanger inhibitor toprevent reperfusion injury at the acute phase of myocardial infarction.

Dr Yasser KHDERYasser KHDER obtained his medical degree and his speciality in internal medi-cine from Damascus University, Syria in 1987; subsequently he was graduated as specialist in cardiovascular pathology from Nancy Medical School, France in 1992. Between 1992 and 1996 YK had part time activity as a clinical cardio-logist. Meanwhile, he also had a part time academic research assignment in the National Institute of Health and Medical Research (INSERM). During this period YK was successfully graduated as a BSc in clinical pharmacology, a MSc in clinical epidemiology, methods in clinical research and a DSc in hu-man biology from the Nancy University, France.Currently YK is a Scientifi c Director Cardiology in Boehringer-Ingelheim, lea-ding Dabigatran clinical development program in ACS. Beforehand YK wor-ked 7 years in Novartis Pharma AG, Basel, Switzerland as a Diovan® Global Phase IV Leader, Aliskerin European Clinical Team Leader, Protocol Review Committee Cardiovascular Scientifi c Director and Global Program Leader for a NCE in phase 2B.Before Novartis, YK worked 5 years in Merck KGaA, where he led several de-velopment programs such as bisoprolol in silent myocardial ischemia, nico-randil in cardiac surgery and PCI as well as Na+/H+ exchanger inhibitor to prevent reperfusion injury at the acute phase of myocardial infarction.

Professor Atul PATHAKDepartment of Clinical PharmacologyDepartment of CardiologyUniversity Hospital and Faculty of MedicineToulouse, FRANCE.Mail: [email protected] : +33621516352Hospital :+33561323017University +33561145961Professor Atul PATHAK, is a Pharmacologist and

Cardiologist. He is leading a clinical research team focusing on cardiovascular pathophysiology and clinical pharmacology and is affi liated to INSERM (National Institute of Medical Research). Professor Pathak is consultant in Clinical Cardiology focusing on patient’s care with cardiovascular risk factors (metabolic and cardiovascular) and their consequences such as Heart Failure in the Cardiometabolic department of Toulouse University Hospital. Professor Pathak was resident in Cardiology from 1996 to 2001 and trained in Toulouse (France), Aachen (Germany) and Cleveland (Cleveland Clinic, USA). After that period, he obtained his MD (highest distinction) at the Faculty of Medicine in Toulouse and obtained a tenure position as a research scientist at INSERM up to 2002. He obtained his European Phd (highest distinction) in Clincal and Experimental Pharmacology in 2005. He also worked as a post doctoral research fellow in the Department of Cardiology at Hospital Erasme and Free University of Bruxelles from 2004 to 2005. He joined the Faculty of Medicine at the University Paul Sabatier in Toulouse as an Associate Professor in 2002 and has been Assistant Professor since 2005. He has been nominated full tenure Professor in Clinical Pharmacology in 2009 and is currently leading the Clinical Unit of Cardiovascular Pharmacology in the University Hospital of Toulouse.Doctor Pathak is the author of more than 80 international publications. His research interests are: (i) new diagnostic tools and treatment of cardiometabolic risk factors and heart failure, (ii) the human sympathetic nervous system, (iii) neurotransmitters of the neuro cardiac synapse and more generally Clinical Pharmacology of Cardiovascular diseases. He is currently leading both a clinical and an experimental team working on the nervous regulation of cardiovascular function and, more particularly, the role of the autonomic nervous system in the control of arterial pressure, cardiac rhythm and contraction, and associated diseases (i.e. obesity, diabetes). Professor Pathak has been awarded by the ESC (Young Investigator Award), by the British Pharmacological Society and the French Society of Cardiology. He is also member of the French Association of Pharmacologists, the French Society of Hypertension and Cardiology, the American Society for Heart Failure. He is elected President of the Cardiovascular Pharmacology Working Group of the French Society of Cardiology. He has both academic and institutional commitments, among them participation at advisory board at AFSSAPS (French FDA) and HAS for the review of clinical trials protocol, assessment of benefi t /risk ratio of drugs (marketed or under development) and medico-economic issues (regarding lipid or blood pressure lowering drugs).

Yasser KHDER obtained his medical degree and his speciality in internalmedicine from Damascus University, Syria in 1987; subsequently he wasgraduated as specialist in cardiovascular pathology from Nancy MedicalSchool, France in 1992. Between 1992 and 1996 YK had part time activityas a clinical cardiologist. Meanwhile, he also had a part time academicresearch assignment in the National Institute of Health and Medical Research(INSERM). During this period YK was successfully graduated as a BSc in clinicalpharmacology, a MSc in clinical epidemiology, methods in clinical researchand a DSc in human biology from the Nancy University, France.Currently YK is a Scientifi c Director Cardiology in Boehringer-Ingelheim, leadingDabigatran clinical development program in ACS. Beforehand YK worked 7years in Novartis Pharma AG, Basel, Switzerland as a Diovan® Global Phase IVLeader, Aliskerin European Clinical Team Leader, Protocol Review CommitteeCardiovascular Scientifi c Director and Global Program Leader for a NCE inphase 2B.Before Novartis, YK worked 5 years in Merck KGaA, where he led severaldevelopment programs such as bisoprolol in silent myocardial ischemia,nicorandil in cardiac surgery and PCI as well as Na+/H+ exchanger inhibitor toprevent reperfusion injury at the acute phase of myocardial infarction.

47

6th Global CardioVascular

Clinical Trialists Forum


QIMT BY RADIO FREQUENCY (EXAMINATION OF TRACKING) METHOD OF EVALUATION THICKNESS OF THE INTIMA MEDIA AMONG PATIENTS HAVING CARDIO VASCULAR RISK FACTORS Clinical implication: about 150 cases: (study realised between October 2007 and March 2009)Dr. Xavier Castellon ¹, Dr. Vera Bogdanova²¹Department of Cardiology, Private Hospital Athis Mons 38, Jules Valles 91200 Athis Mons - ²Paris, France

Subjects: Biomarkers and Bio imaging, Outcome research, Prognostication The main aim of this study is to reveal an early diagnosis of a pre clinical evolution atheroma plaque, in the patients with cardiovascular risk factors. The intima media thickness is an independent cardiovascular risk factor. The measurement of the intima media is increasingly part of clinical evaluation of patients with risk factors. Mass or individual screening of this marker has high cardiovascular risk should be done at present in all patients with Cardio Vascular risk factors. QIMT is a promising method that allows us to calculate the intima media radio in real time on a reliable and reproducible. Method: QIMT by Radio Frequency, Method of the examination used is in conformity with the IMT protocol of Mannheim standarts of normal values according to age, measurements of IMT based on the radio frequency. This study has been done with 150 patients (100 men and 50 women), aged between 45 and 60 years, having cardiovascular risk factors (Dyslipidemy, standard diabetes II no complicated, hypertension and tobacco). All patients having atheroma plaque located in the carotids have been excluded from the study. Results: 3% of the group of men and 2% women had resulted pathological (≥ 900 micrometers). Conclusion: The QIMT technics of exploration of an early detection pre clinic evolution of atheroma plaque is easy, specici c, chip, and reproducible to use a routine of preventive cardiology. It enables us to calculate in real time the thickness intima media in a few minutes, making the results reliable with a sensitivity of 95% and a speci city of 94%. Comments: The QIMT can be used as a method of exploration complementary to the Endothelial Function, associates to others high-risk markers (biological: Homocysteine, Willebrand, Micro Albuminuria and Markers of Oxidative Stress: plasmatic rates of the vitamins C, α- Tocopherol, γ- Tocopherol, â- carotene, Lipidic peroxides, oxidized LDL, oxidized Antibodies LDL, OLIGO- ELEMENTS: Selenium, Copper, Zinc, Cu/Zn report/ratio) rate of plasmatic proteins: Proteins thiol) and with VIF (vasodilatation by intermediary of ow) on located in the brachial artery.

EFFECTS OF THREE FISH BASED MEALS/WEEK ON CARDIOVASCULAR RISK FACTORESLucio MOS, Valeria Dialti, Giancarla Marcuzzi, Stefano martina, Manola Bettio, Olga Vriz, Schiaulini Gemma

Aim of this study was to evaluate the effects of three sh meals/week on blood pressure and lipid pro le in hypertensive patients. The patients guaranteed to eat sh almost in three meals of the week. To improve the compliance they could buy salmon trout (fresh, smoked or pre cooked) at a 1/3 of market price in af liated stores in San Daniele del Friuli area. One trout based meal corresponds to 1000 mg omega-3 fatty acids. 78 patients were enrolled in the study, after the rst visit 16 were excluded for exclusion criteria The 62 patient underwent to blood pressure measurement, ambulatory blood pressure monitoring and blood samples for lipid pro le three times, before the study, after three months and after 6 months of diet. All 76 patients were on stable antihypertensive therapy for almost 4 months and 22 patients were stable therapy with statin. No signi cative variations of therapy during the study were noted. Every patient answered a questionnaire about their alimentary habits and about their physical activity, there was no change on their physical activity or variations in the alimentary habits except the three sh-based meals.Systolic ( SBP), diastolic (DBP) blood pressure, Heart rate ( HR), total cholesterol (TC), triglycerides (TG), HDL cholesterol at baseline (1), three months (2) and 6 months (3) are reported in the table.

Weight (Kg)

SBP (mmHg)

DBP (mmHg)

HR b/min)

TC (mg%)

TG (mg%)

HDL (mg%)

1 80.7±13 146.4±12 88.8±6 65±8 221±38 125±64 51±12

2 80.4±13 141.8±11 86.2±7 65±7 228±39 125±57 54±13

3 81.4±13 141,3±12 84.7±7 63±7 232±44 133±85 56±15

N. S 1vs3 ** 1vs 3 * N. S N. S N. S 1 vs 3 **

The absence of body weight changes con rmed the non-variation of the physical activities and of the alimentary habits, The lowered pressure is in line with the scienti c literature regard the omega-3 fatty acids supplements. The increase of the HDL cholesterol without change in LDL cholesterol is another positive fact.In conclusion, considering the limits given by the limited studied population and a lack of a control group, the results con rmed that even a small increase of sh-based meals have a positive effect on cardiovascular risk factors.

EPLERENONE ADD-ON ANTIARRHYTHMIC PHARMACOTHERAPY REDUCES THE OCCURRENCE OF ATRIAL FIBRILLATION EPISODES IN A 18 MONTHS STUDY Tase Adrian, Marius Mihaila, MD; Gabriela Stanciulescu, MD; Cristina Trache, MD; Daniel Blajan, MD; Ovidiu Tetiu, MD

Background. Repetitive atrial brillation (AF) alters atrial structure, including RAAS overexpression which could have a decisive role, aldosterone being involved in in ammation, brosis, remodeling.The aim of this study was to compare two therapeutic regimens (each one including three subregimens), in order to assess the bene t of eplerenone in our patients (p).Method. The study considered 60 p with reversible AF, starting with 1st Nov. 2007, 31 paroxysmal/29 persistent, structured in two comparative groups, demographically balanced (slight male, and 6th decade predominence, respectively), the rst treated with antiarrhythmic drugs {Amiodarone (A) 72% p or Propafenone (P) 20% p or Sotalol (S) 8% p} + exogenous potassium supplement (K+), the second with the same antiarrhythmics in quite similar proportions {A 70% p or P 24% p or S 6% p} + eplerenone (E). We also compared the occurrence of AF episodes 18 months before the initiation of treatment with E versus 18 months after the initiation of treatment with E. The p treated previously with BB’s (indirect antirenin effect), ACEI’s, ARB’s, spironolactone were not included in the study.Results are structured in the adjacent table:

Therapeutic armAF Episodes (18 mo. before)

AF Episodes(18 mo. after) p value

A + K+ 8,7+/-1,7 10,6+/-2,5 <0,01

P + K+ 9,0+/-2,4 10,3+/-1,7 <0,01

S + K+ 8,9+/-0,9 10,2+/-1,1 <0,05

Antiarrhythmic + K+ 8,9+/-2,7 10,5+/-2,8 <0,005

A + E 9,2+/-2,1 3,6+/-2,0 <0,01

P + E 9,0+/-2,5 3,9+/-2,3 <0,01

S + E 8,9+/-2,4 3,9+/-2,5 <0,05

Antiarrhythmic + E 9,1+/-2,3 3.7+/-1,9 <0,005 Conclusions. The speci c blocker of mineralocorticoid receptor E is a valuable additional therapeutic option in prevention of AF episodes occurrence. E brings an endogenous potassium, more friendly than K+ exogenic uptake. Beyond, it reduces RAAS activity and could reduce the brosis involved in structural remodeling. These bene cial effects were independent of BP lowering and are probably due to the antiin ammatory efects of E. This study is going on, in order to improve the statistical signi cance and clinical relevance.

FROM “HOLIDAY HEART SYNDROME” TO ATRIAL FIBRILLATION. ELECTROPHYSIOLOGICAL CHARACTERISTICSOswald Londono Sanchez, S. Pacreu Terradas, M. Pujol

Aim. Atrial brillation (AF) and supraventricular tachycardia are common arrhythmias in smoker patients and in those who developed cardiomegaly for several factors, including ethanol consumption for more than ten years. We decide to follow up patients with ethanol problems and controlled by the Emergency Department at the Hospital to determine the possibility to develop AF and alcohol effects in cardiac arrhythmias. Materials and Methods. We studied a group of 100 patients with history of ethanol consume for many years with atrial brillation and without it (Table 1). We performed echocardiography control studies to determine the left auricular sizes, classi ed the patients for cardiovascular risk factors and including patients with atrial brillation history, control thyroidal hormones. We excluded those patients with hormonal alterations. Results. Alcohol-related atrial arrhythmias might be attributed to intra-myocardial catecholamine release or to toxic direct effect of the metabolite acetaldehyde, affecting the refractory periods and dispersion, as well as conduction velocity and triggering factors. The increased heart rate changes re ected at the ECG were P wave duration signi cantly prolonged by ethanol – a predisposing factor for atrial brillation, because reduces corrected sinus node recovery time. 65% of patients presented rst atrial dilatation secondary to alcohol cardiomegaly, but we can not consider that recovering the normal heart size is possible to restablish left atrial size.

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CARDIAC AND BRAIN DAMAGE AFTER VERY HIGH TROPONINES-I LEVEL AFTER CARDIAC SURGERYO.Londono, S.Pacreu, L.Paredes, M.Pujol

Introduction. Cardiac-speci c biomarkers such as troponin-I, troponin-T and CK-MB have been used extensively to predict myocardial injury and ischaemia.High levels of troponines –I leads to an important cerebral hypoperfusion and brain damage associated with cardiac surgery has been extensively studied many times.Cerebral hypoperfusion during cardiopulmonary bypass surgery has long been thought to be a factor in the aetiology of brain damage with evidence of post-operative neurological de cits. Cerebral injury may also occur in the early post-operative period, or alternatively, any intraoperative damage may be exacerbated by hypoperfusion at this stage.Aim. We have investigated the level of troponin-I release in both off-pump and CPB-technique CABG surgery, as well as postulated a relationship of troponin release and post-operative neurological outcome. Materials and Results. A total of 50 adult patients undergoing coronary artery bypass graft (CABG) were enrolled into either an off-pump or on-pump groups, with 22 and 28 patients participating in each. Group A (on-pump) underwent myocardial revascularisation with CPB and cardioplegic arrest, while Group B (off pump) underwent beating heart surgery. The measurement of troponin-I is a 1-step enzyme immunoassay method, with speci city and sensitivity set at 0.4 ug/mL.We used the NIH Stroke Scale, and neuropsychologic assessment was assessed on cognitive function using modi ed Weschler Memory Scale, for which scores were standardized to achieve a composite measure of concentration. A set of statistical analysis was done to correlate troponin-I release with different surgical techniques of CPB and OPCAB. Although each independent technique showed a marked rise of troponin-I from baseline to 6 hours post-operatively, the difference in troponin release was not signi cant between the 2 groups at speci ed time intervals (p=0.124). There was however a signi cant correlation of troponin-I release with the number of grafts used in the surgery, irrespective of the type of grafts or surgical technique. None of the patients in either group showed any neurological or cognitive de cits presenting at day 3 and day 7 post-operatively. The ndings of this study demonstrate that there is no signi cant short-term cognitive or neurological dysfunctions post-operatively, as indicated by troponin-I release in assessing the severity of myocardial injury, but we need to justify the time spent for surgeons as a important factor for the recovering time and clinical consequences.

HYPOADIPONECTINEMIA AS A RISK FACTOR OF CARDIOMETABOLIC ABNORMALITIES IN HYPERTENSIVE PATIENTSTetiana Ascheulova, Tatiana Ambrosova, Olga Kovalyova, Victoria Smirnova

Clusters of cardiometabolic abnormalities such as abdominal obesity, insulin resistance, hypertension and dyslipidemia are resulted in development and progression of cardiovascular diseases. Adiponectin is the fat-speci c hormone which expressed and secreted from adipose tissue, among others biologically active adipokines: tumor necrosis factor (TNF-α), interleukin (IL-6). Adiponectin exhibits pleiotropic effects on vascular cells, modifying endothelial cell function – stimulates the production of nitric oxide, proliferation of smooth muscle cells and lipid accumulation of macrophages that play important role in the pathogenesis of arterial hypertension and coronary heart diseases. The aim of our clinical study was to assess plasma adiponectin levels in relation to clinical and metabolic parameters, TNF-α, IL-6 activity in patients with arterial hypertension. Design and methods: Anthropometric parameters (height, body mass, body mass index (BMI), waist circumference (WC)); plasma adiponectin, TNF-α, IL-6, insulin levels by ELISA, glucose – by biochemical method were measured, HOMA-IR index was calculated in 85 hypertensive patients. Results: Patients were divided into 3 tertiles depend on adiponectin levels: 1st tertile (1,92±0,18 mcg/mL (min-max - 0,68 - 3,68)) include 28 patients (7 males, 21 females), 2nd tertile (5,46±0,22 mcg/mL (min-max - 3,78 - 7,45) include 28 patients (7 males, 21 females), 3rd tertile (9,50±0,24 mcg/mL (min-max - 7,55 - 12,73) include 29 patients (10 males, 19 females). In the 1st tertile with lowest adiponectin levels WC was 101,5±3,43 cm, BMI - 32,30±1,31 kg/m2, insulin - 20,56±2,37 μU/ml, HOMA-IR - 6,02±0,91, TNF-α - 19,82±4,23 pg/ml, IL-6 - 12,59±0,63 pg/ml.2nd tertile with middle adiponectin levels characterized by following means of WC 94,21±2,77 cm, BMI - 30,18±1,07 kg/m2, insulin - 17,15±2,91 μU/ml, HOMA-IR - 5,28±1,57, TNF-α - 17,38±5,06 pg/ml, IL-6 - 11,60±0,43 pg/ml.In the 3rd tertile with highest adiponectin levels all examined parameters were minimal: WC - 90,2±1,99 cm, BMI - 27,88±0,9 kg/m2, insulin - 14,61±2,25 μU/ml, HOMA-IR - 4,75±0,97, TNF-α - 15,86±3,95pg/ml, IL-6 - 9,78±0,34 pg/ml. Our results suggest that the lowest adiponectin means was in hypertensive patients the highest were anthropometric parameters that re ects overweight and abdominal obesity presents: WC, BMI, and also carbohydrates metabolism parameters: insulin plasma, HOMA-IR that accompanied by increased activity of others adipokines - TNF-α, IL-6.Conclusion: Results of our study revealed hypoadiponectinemia which was associated with development and progression insulin resistance, hyperinsulinemia, obesity and in ammatory reaction in hypertensives patients.

NITRIC OXIDE METABOLISM OF THE COMBINED THERAPY OF BISOPROLOLE AND INDAPAMIDE AT OVERWIGHT HYPERTENSIVE PATIENSSvetlana Potabenko, Gerasimchuk Nina

Purpose: Obesity is one of the leading risk factor hypertension. Such pathogenic combination relevant for the development endothelial dysfunction.The aim of the study was to investigate the level of nitrite/nitrate anion and S-nitrosotiole at overweight patients with arterial hypertension therapy on the dynamics combined bisoprolole and indapamide.Method: 48overweight hypertensive patients (Ï – stage, 2-3 degree of arterial hypertension, mean age – 51,3±9.8 years) and 16 practically healthy persons were examined.Blood serum content of nitrite/nitrate anion had been determined by spectrophotometric method with Griss reagent, S-nitrosotiole by uorometric method. The received data were expressed in mcmol/l, mmol/l.Results: Overweight patients with arterial hypertension manifested the increase of S-nitrosotiole blood serum content (0.46±0.15 mmol/l versus 0.22±0.03 mmol/l in controls, p<0.05), the decrease of nitrite anion (NO2¯) blood serum content (13.04±5.86 mcmol/l versus 14.19±1.8 mcmol/l in controls, p<0.05), the decrease of nitrate anion (NO3¯) blood serum content (18.83±7.83 mcmol/l versus 24.06±2.46 mcmol/l in controls, p<0.05). After 14 days of treatment of the bisoprolole in a combination with indapamide we observed the decrease of S-nitrosotiole blood serum content by 21.31% (0.362±0.12 mmol/l), the increase of nitrite anion (NO2¯) blood serum content by 21.1% (15.8±5.34 mcmol/l), the increase of nitrate anion (NO3¯) blood serum content by 21.8% (22.94±6.69 mcmol/l), p< 0,05 in comparison with the baseline level.After 2 month of treatment (n=10) we observed the decrease of S-nitrosotiole blood serum content by 32.2% (0.339±0.13 mmol/l), the increase of nitrite anion (NO2¯) blood serum content by 34.6% (19.0±7.05 mcmol/l), the increase of nitrate anion (NO3¯) blood serum content by 31.2% (27.2±7.6 mcmol/l), p< 0,05 in comparison with the baseline level.Conclusions: 2 months of treatment on the bisoprolole in a combination with indapamide is accompanied decrease of a level S-nitrosotiole and by signi cant increase of a level stable metabolites NO.

IMPACT OF EDUCATION IN “LIPID - SCHOOL” ON THE QUALITY OF TREATMENT PATIENTS WITH CARDIOVASCULAR RISK FACTORSNataliia Pertseva, Turlyun Tamara

Actuality: Atherosclerosis is one of the most common cardiovascular disease. The presence of hyperlipidemia results in accumulation of atherosclerotic plates in damaged endotelium of vessels, its narrowing and worsening of heart’s oxygenation. Acute coronary syndrome, cardial arrest and stroke (events associated with atherosclerosis) are the most common reasons of death as in Ukraine so in the world. According to results of the long-term project EUROASPIRE (Eropean Action on Secondary Prevention through Intervention to Reduce Events) the lipidloweringtherapy directed on the prevention of cardiovascularevents and death in patients of high risk is used not so widely. In Ukraine, there are only 1 to 7% patients receiving statins from of people needing this therapy. It is necessary to organize “Lipid – schools” for patients with lipid disorders in order to increase their level of understanding the health condition and to improve the complaince between patient and medical team.The aim of the study was to analyze the level of cholesterol and its fractions in patient with cardiovascular risk factors and how statins in uence on it.We made a retrospective analysis of medical case histories of patients with cardiovascular risk factors.Results: 300 medical case histories were analyzed: 149 (49%) women and a 151 (51%) man by age from 19 to 86 years (middle ages of 56,6±0,82 year). The body mass index (BMI) was from 19,19 to 49,88 (middle BMI 28,16±0,81). Type 1 diabetes mellitus (DM) was found in 49 cases (16%), type 2 DM – in 204 cases (68%). The level of total cholesterol in type 1 DM was determined in 9 (3%) patients (5,26±0,17 mmol/l), in type 2 DM - in 41 (13,6%) patient (4,7±0,1 mmol/l). Statins were assigned in two cases of type 1 DM patients and in 38 (12,6%) cases of type 2 DM patients. Arterial hypertension was found in 205 (68,3%) cases. The level of total cholesterol was measured in 78 (25,9%) patients with arterial hypertension (4,7±0,15 mmol/l). Statins were prescribed for 94 (31,3%) patients with arterial hypertension.The presence of the carried myocardial infarction was found in 123 (41%) patients, total cholesterol was measured in 51 (17%) cases (4,7±0,12 mmol/l). Statins were prescribed for 80 (26,6%) patients with carried myocardial infarction.Conclusions: there are a lot of cardiovascular risk factors in examined patients - BMI is over normal range (28,16±0,81), middle ages – 56,6±0,82 years.Patients have concomitant diseases, development of cardiovascular diseases is more frequent in men, than in women. However, in spite of presence of cardiovascular risk factors the inspection of total cholesterol and its fractions is not fully conducted and it hampers the purpose of adequate lipidlowering therapy. Evaluation of the complete level of laboratory tests to determine cholesterol and its fractions, constant clinical monitoring and education in the “Lipid – school” for patients with lipid disorders will increase the patients adherence to lipidlowering therapy, changing their life style, and will signi cantly reduce the risk of development of cardiovascular events.

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A GOOD CONTROL OF CARDIOVASCULAR RISK FACTORS – THE KEY FOR A GOOD PROGNOSIS AND REDUCTION OF MORTALITY.Dr. O. Londono, Dra. S.Pacreu, Dr. L. Muntaner, Hospital Universitari Bellvitge, Barcelona, Spain

Aim. We selected a group of 500 patients controlled for us ambulatory during three years with cardiovasculars risk factors: hypercholesterolemia, hypertension, lung disease, smoking and diabetes mellitus. Other diseases like hepatic, kidney and oncologic were discharged from the observational study.Materials and Methods As a group with a high risk for ischeamic events we decide a control every three months with blood analyses for triglicerids, cholesterol and glucose. A tread mile and echo-cardiography doppler were performed twice a year. No diet control was assumed. During a median follow-up duration of 3.6 years, there were 35 discharged patients: 3 sudden death (reasons no studied for us); oncology pathology, 4 vascular cerebral accidents, refused in keeping on control, and others. Results Even the rigorous control 6% of patients suffered an ischemic event: infarct of myocardium Killip 1, different localization. The clinical symptomatology was typical for angina instable with positive myocardial injury enzymes.The coronariography results showed lesions damage in one coronary artery with small atherosclerotic plaques. Conclusions In patients with cardiovascular risk factors a consciously follow-up and control of these factors can reduce mortality and give good prognosis if an ischeamic event occurs. We must understand that cardiovascular events are inevitable even if take the reasonable measures, but the proportion on consequences are lower than in control groups.

Women MenControl Group

Age 59 (43-75) 58 (45-70)58,5 (39-78)

Diabetes insulin-requiring 25% 18% 1,8%

Diabetes non-insulin requiring 14% 10% 2,9%

Hypertension 23% 37% 4,5%

Glucose control 152-225 138-176 1,03%

Hyperlipidemia 37% 42% 0,7%

Smoking 21% 39% 35%

Tread mile 2% (+) 2,6% (+) 0,6%

Echo cardiography Doppler 0,3%

EF 48-63% 47-74%

Contractility alterations

23% hipokinesia inferior;12% hipokinesia antero-lateral

35% hipokinesia inferior;21,5% hipokinesia apical- lateral

Vessel disease 2,5% 7,5% 0,4% Control group: the value indicates patients never required for cardiologic control. Table1. Baseline characteristics

RIGHT HEART FAILURE IN A SIMPLE ECHO VASCULAR DOPPLER IMAGEO. Londono Sanchez1, S. Pacreu2 1 Hospital Vall d’Hebron, Barcelona, Spain; 2 Hospital del Mar, Barcelona, Spain

The very important diagnostic roll for our Doppler ultrasound examination was demonstrated in a very especial case of arterial-venous stulae. This patient has being operated without later complication. A 50 years old patient with a history of treated hypertension was referred to our Hospital because of chest pain with elevated for ischeamic markers. Was performed percutaneous coronary intervention including implantation of a bare-metal stent. Arterial puncture was realized without any complication, apparently. After the intervention the patient was transferred to the recovery room.Two hours later the patient called to the nurse because of increasing shortness of breath and appearance of facial, legs and hands edemes. Cardiologist responsible of recovering hall was called and check the patient not nding any special clinical alteration. One hour later the nurse call the interventionist for increasing symptoms. The chest auscultation showed an increasing of pulmonars crepitation, the physical examination note the increased edemes facials and inferior extremities. The puncture femoral right zone was free of hematomes, but auscultation evidenced a systolic murmur. Was performed echo Doppler examination, founding the images showed below.

It was diagnosed an arterio-venous stula. Was decided to transfer the patient to the surgery room and was operated without later complication. We check once more the lm recorded during intervention and found the blood escape at the time when catheters were out.Three months later control Conclusions: Our study was conducted to objectively assess baseline rates of vascular complications after any intervention using transfemoral route, and determine the important place that have taken the new perclose system for obtaining arterial hemostasis and the echo-Doppler analyses to provide the maximum information of the arterial status. Three important ndings in our study.

TABLE I Vascular access site complications identifi ed by blinded physical examination (n=200)

Perclose suture device (n=100) Hand (n=100)

Oozing Ecchymosis Hematoma Ecchymosis or hematoma Ecchymosis and hematoma Pulsatile mass Distal extremity pain Distal extremity discoloration New bruit Any of above*

2 (2%) 3 (3%) 2 (2%) 5 (5%) 2 (2%) 1 (1%) 1 (1%) 0

25(25%)

7 (7%)19 (19%) 8 (8%)4 (4%)2 (2%) 4 (4%)1 (1%) 012 (12%)

*p = 0.0041 Data are presented as number (%) of patients.

TABLE II Vascular accsess site pathology diagnosed by ultrasound (n=200)

Perclose suture device (n=100) Hand (n=100)

Hematoma Pseudoaneurysm Arteriovenous fi stula Femoral artery thrombosis

4 (4%) 001

10 (10%)000

*p = 0.0041 Data are presented as number (%) of patients.

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ECONOMIC EFFICIENCY OF TREATMENT BY ACENOCOUMAROL IN PATIENTS WITH PERMANENT FORM OF ATRIAL FIBRILLATION, WITH USING PHARMACOGENETICS TESTINGBasil N. Shan2, Dmitriy A. Sychev1 1 Institute of Clinical Pharmacology of Science Center of examination of medical applications Roszdravnadzor , Moscow, Russia; 2 Moscow State Uni-versity, Moscow School of Economics, Chair of Financial strategy.

Introduction. Acenocoumarol is the global standard of anticoagulant therapy, but often treatment with acenocoumarol accompanied by adverse drug reactions. Model of personalized medicine, actively developing now, can reduce the number of side effects during therapy of Acenocoumarol, mainly due to individual genetic characteristics (polymorphisms of genes CYP2C9 and VKORC1). Materials and Methods. In the work we included 84 patients with permanent form of atrial brillation, aged 44 to 73 years, of whom 44 men and 40 women, treated at two hospitals in Moscow. These patients were randomized into two equal groups with usual way of selecting dosage of acenocoumarol only, and usual way of selecting dosage with pharmacogenetics testing.To assess the ef cacy and safety of treatment by acenocoumarol, used the results of a retrospective study on the in uence of polymorphisms of genes CYP2C9 and VKORC1, the clinical status of the patient, and laboratory ndings, the results of research on blood clotting. Also we analyzed the costs of treating both groups by economic standards of the Russian Ministry of Health Care, data and costs of all things for pharmacogenetics testing.Results. In the rst group, in terms of 100 patients were nearly 25% of light side effects (nasal bleeding) and nearly 5% of serious side effects (bleeding in the digestive tract). In the second group, also in terms of 100 patients, light side effects were observed only in nearly 5% of patients, and serious side effects were not observed at all. Financial expenses in the rst group, in terms of 100 patients, were 157785,53 €, and in the second group, in terms of 100 patients, were 146367,52 €.Conclusions. Selection of the dose of acenocoumarol, with using models of personalized medicine, reduces the risk of side effects in 5 times, and also reduces the costs of treating of 100 patients at 11418,01 €.

LEVELS OF ENDOTHELIN-1 AND RENIN DEPENDING ON THE DAILY STRUCTURE OF ARTERIAL BLOOD PRESSURE IN PATIENTS WITH RHEUMATOID ARTHRITISElina Mikhaylova Cardiology Department, Yaroslavl Regional Clinical Hospital, Yaroslavl, Russia. [email protected]

Background: Cardiovascular death is considered the leading cause of mortality in patients with RA. Cardiovascular disease has a tendency to remain silent in the rheumatoid patient. Traditional cardiovascular risk factors do not seem to be responsible for the increased cardiovascular risk. Objective: To study daily structure of arterial blood pressure in patients with RA, depending on plasma endothelin-1 (ET-1), levels of renin and aldosterone. Methods: 92 (65%) patients with rheumatoid arthritis (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 arterial blood pressure (ABP); the level of endothelin-1 (ET-1) in the blood plasma in all participants; the level of renin and aldosterone in the blood plasma. Results: Level of ET-1 in patients with RA and AH correlated positively with index of time of Systolic Blood Pressure (SBP) at the day R=0,69; p=0,005, minimal SBP night R=0,5; p <0,03 and maximal Diastolic BP (DBP) night R=0,57; p <0,03, also with the index of time DBP night R=0,66; p=0,009. There were found out positive correlations between level ET-1 and minimal SBP day r=0,64, average DBP day r=0,70, index of time DBP day r=0,80, average DBP night r=0,77 at p <0,05. At patients with AH such correlations were not established. At comparison of hormones in plasma, level of renin in patients with RA+AH was 5,6 times less, than in group of patients with AH and in 3 times lower, than in control group (0,16 (0,06; 0,58) ng/ml/hour against 0,47 (0,2; 0,65) ng/ml/hour, p <0,05). In group of patients with RA without AH level of renin was not different then in the control group (0,64 (0,08; 0,4) ng/ml/hour against 0,47 (0,2; 0,65) ng/ml/hour, p <0,05). The level of renin, negatively correlated in patients with RA and AH, with maximal the BP in the day (R =-0,3; p <0,05), unlike this data in patients with AH. The average systolic BP in patients with RA + АГ correlated negatively with level of renin (R =-0,41; p=0,01), time index of SBP day (R =-0,37; p=0,03), maximal systolic BP night (R =-0,43; p=0,01). Conclusion: For patient with RA+AH it is typical the tendency for suppression of renin. The reasons are still not clear. It can be connected with production of serum antibodies to renin (Samorjadova at al. 1991) and it may be that ET-1 inhibit basic secretion of renin in isolated glomerule and cortical cells of kidneys of rats (Prasad A. et al., 1998.). However the reasons are not clear and the answer may lead to open the new perspectives in treatment of AH at patients with RA.

PROSPECTS OF RESEARCH OF DRUGS WITH METABOLIC ACTION IN THE TREATMENT OF THE PATIENTS WITH HEART’S DISEASESSapatyi Andriy, Kupnovytska I.G., Dzvinyatska O.F., Belegai R.I., Kutynska I.P.

Drugs with metabolic action are all wider with the traditional facilities of pharmacotherapy of ischemic heart disease. Their advantages are practically complete absence of side effects, good bearableness, orientation of operating on the deep metabolic mechanisms of ischemia, cardioprotective action.Purposes of research. To rotin ef ciency and unconcern of action of corvitine - the «Best domestic commodity of 2006» in a nomination «Development and making of pharmaceutical products» - for patients with the acute myocardium infarction on a background an arterial hypertension and chronic heart failure.Research methods. Clinical inspection of patients with the estimation of psychical and emotional spheres, immunological methods, instrumental methods - electrocardiography, Holter’s monitoring, echocardiography, day’s monitoring of blood pressure, determination of function of endothelia of artery and thickness of layer of its intima-media with the using of test with reactive hyperemia.Research results. The action of corvitine is rst represented at the united cardiologic pathology during research on 138 patients and 20 practically healthy people. It is well-proven that in the conditions of acute medicinal test corvitine shows in uence on expansion of vessels, changing diameter of humeral artery on 31,7%for patients on ischemic heart disease and on 24,4% - in healthy (р<0,05) and thickness of its layer of intima-media – 4,2% and 8,5% accordingly (р<0,05). Corvitine in the standard chart of pharmacotherapy of patients with the acute myocardium infarction on a background an arterial hypertension and chronic heart failure improves clinical motion of disease regardless of degree of clinical expressed of cardiac insuf ciency, normalizes the psychical and emotional states of patients, that in same queue it is possible to consider as displays of increase of index of quality of life, shows an antiarhythmical and easy antihypertensive action, carries out a cardioprotective effect, improving structurally functional changes of myocardium. Plugging of corvitine in the complex chart of treatment results in substantial regress of displays of local in ammation, limits the area of necrosis of myocardium, stabilizes interleukine’s status, repressing activity of cytokine’s link of pathogeny of this pathology.Conclusions. Corvitine is an effective and safe drugfor correction of chronic heart failure for patients with the acute myocardium infarction, that arose up on a background an arterial hypertension. However for today his subsequent study is perspective with plugging in research as possible of greater amount nosology excellent cardiologic patients different age, sex and races on the basis of construction of charts of international randomized multicentral clinical tests, that would allow adequately to represent all moments of metabolization of standard principles of pharmacotherapy.

RELATIONSHIPS BETWEEN LEPTIN, TUMOR NECROSIS FACTOR- AND INSULIN LEVELS IN OBESE HYPERTENSIVE PATIENTSTetiana Ambrosova, Goptsii Olena Kovalyova Olga

Association of obesity, hypertension and metabolic abnormalities is complex and incompletely understood. It was proposed that adipose tissue can release such adipocytokines as leptin, tumor necrosis factor-α (TNF-α) which can involved in the development of obesity and insulin resistance in the patients with arterial hypertension (AH). Theaimofourstudywas investigate relationships between leptin, TNF-α and insulin blood levels in hypertensive patients with obesity. Design and methods: 123 patients with AH (53.82±0.91 years old) have been studied. All patients were examined by detailed clinical, anthropometric (height, body mass, body mass index (BMI), waist circumference) and laboratory methods. Blood leptin levels by “Leptin (Sandwich) ELISA (DRGInstrumentsGmbH, Germany), TNF-α by ELISA “alpha-TNF (IFA-BEST, Russia), insulin levels by “Insulin ELISA (DRG Instruments GmbH, Germany)were measured. Patients were divided into two groups depend on BMI means: 1 group (n=20) with normal BMI < 25 kg/m2; 2 group (n=103) overweight and obese subjects with BMI > 25 kg/m2. Control group includes 21 healthy persons. Results: Comparison of average means of leptin, TNF-α and insulin in hypertensives accordingly to BMI showed signi cant and statistically higher leptin (11.66±0.74 ng/ml) levels, TNF-α (8.24±0.38 pg/ml) levels and insulin (17.48±1.57 mkgU/ml) in 2nd group patients as compared with 1st group patients in which leptin levels was (7.34±0.77 ng/ml), TNF-α levels – (3.70±0.30 pg/ml), and insulin levels (7.78±1.01 mkgU/ml) (р<0.05 in all cases of comparison) and control group of normotensive persons: leptin levels in which characterized by minimal means (6.21±0.27 ng/ml), TNF-α levels (1.88±0.23 pg/ml), and insulin (5.97±2.71 mkgU/ml) (р<0.05 in all cases of comparison). In patients with arterial hypertension and obesity it was found positive correlation between leptin and TNF-α levels (R=0.55; р=0.001), between leptin and insulin levels (R=0.37; р=0.0001); and between TNF-α and insulin levels (R=0.50; р=0.001).Conclusion: Results of our clinical study indicate statistically signi cant elevation of leptin, TNF-α and insulin levels in patients with arterial hypertension related to overweight and obesity presence and positive statistically signi cant correlations between these parameters.

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LONG-TERM EFFICACY OF NEBIVOLOL MONOTHERAPY IN PATIENTS WITH MASKED HYPERTENSIONVladimir Popov, Osipova I.V1., Antropova O.N. 1 , Zaltsman A.G. 2 , Kurbatova I.I. 2 , Aksenova O.G. 3, Atkova E.O 4, Bulanova N.A. 5., Popov V.V 5

1Altai State Medical University, Barnaul; 2 Clinical Hospital at Barnaul Station of JSC Russian Railways; 3 Berlin-Chemie, Moscow; 4 Department of Railway Medicine, Russian Academy of Railways, Moscow; 5Moscow Medical Academy named after I.M. Sechenov, Moscow, Russia. Email: [email protected]

Background: Elevated blood pressure is a major risk factor for cardiovascular disease morbidity and mortality in speci c occupational group - train’s operators and locomotive crews. Objective: The purpose of this study was to investigate the antihypertensive activity of nebivolol monotherapy over a twelve -month period in patients with profession related stress factors and masked hypertension (MH). Methods: This was an open labeled, prospective, controlled, twelve -month study of the ef cacy of nebivolol (NebiletÒ, Berlin-Chemie, Germany) in 30 males with MH. Nebivolol was administered at the initial dose of 2,5 – 5 mg once a day. If the target blood pressure (BP) level was not reached, the dose was titrated up every two weeks by 2,5 mg/day. “Of ce” systolic and diastolic blood pressure (SBP and DBP), BP before the beginning of work and daily monitoring of BP (DMBP) were performed . .Results: Treatment with nebivolol resulted in statistically signi cant reduction in DBP and SBP from baseline within rst week of study period . During the long-term treatment, the effects increased; the maximal reduction of SBP by 19,3% (p<0,001) was observed after 12 weeks of therapy and stayed at the same level after 12 months . 88 % patients had a good response to monotherapy, in 12% of cases the combined therapy was required.The positive in uence of nebivolol on the main DMBP parameters was con rmed. Based on the DMBP data, the average SBP level during the nebivolol treatment decreased: daytime SBP by 10,0% (p<0,001), nighttime SBP by 7,0% (p<0,001) and daily SBP by 6,8% (p<0,001). The variability of daytime SBP decreased by 15,7% (p<0,01) and nighttime SBP by 15,6% (p<0,05); and as well the variability of daytime DBP decreased by 14,7% (p<0,05) and nighttime DBP by 12,8% (p<0,05). Treatment with nebivolol resulted normalization of the SBP and DBP diurnal rhythm, i.e., decrease of “non-dippers” rate (up to 40% and 43,3%) and increase of “dippers” rate (up to 60% and 56,7%). However, signi cant difference between “non-dippers” and “dippers” rate was not found (p>0,05). During the nebivolol therapy, heart rate ef ciently decreased in 7 days to 66,8 ± 0,8 (13,4%; p<0,001). Conclusions: The study demonstrated that nebivolol was effective and well tolerated in the long term, and its antihypertensive activity continued to increase during the 12 months of monotherapy in locomotive drivers with masked hypertension. These results support the use of nebivolol monotherapy in patients with masked hypertension that allows ef ciently control BP: “of ce” BP; BP before a shift and DMBP.

SUCCESSFULNESS OF TWO PHARMACOLOGICAL STRATEGIES FOR CONVERSIONS OF RECENT-ONSET ATRIAL FIBRILLATION AND PERSPECTIVES OF LOCAL DRUGS DELIVERYGoran MILICEVIC, Strinic D, Gavranovic Z, Udiljak N, Bakula M

Introduction. Pharmacological conversion of recent-onset atrial brillation is important practical issue. Related to question of the ESC WG on Cardiovascular Pharmacology and Drug Therapy ‘how to best achieve cardioversion’, we analyzed successfulness of a single drug and sequential drug administration strategies. Furthermore, we tried to enhance the review with an idea on increasing the ef cacy of conversion by local delivery of drugs.Methods. A systematic review of controlled trials, published in indexed journals, with antiarrhythmic drugs (of a class III, IC and IA, and atrial-selective) was performed. Eligible studies had to be randomized, controlled, parallel-designed, human trials that prove ef cacy of pharmacological cardioversion of recent-onset atrial brillation. Results. High diversity in conversion rate of a single antiarrhythmic drug administration is shown, depending on drug dosage and time of its application. Sequential drug administration showed high success rate, but higher time consumption (Table 1).

Table1. Pharmacological conversion of recent-onset atrial fi brillation

DRUG SUCCESS rate

Single antiarrhythmic agent strategy Class

Conclusion. Atrial-selective drugs have rapid onset of action, but sequential administration of older antiarrhythmic drugs shows excellent success rate. To enhance short-term success rate, local delivery of atrial-selective drugs may be needed. Possible models are proposed.

MOXONIDIN AND LUNG FUNCTION IN PATIENTS WITH ARTERIAL HYPERTENSION AND MODERATE CHRONIC OBSTRUCTIVE PULMONARY DISEASENataliya Slepchenko, Sidorov A.A., Mostovoy Y.M.

This work is devoted whether moxonidine has an in uence on lung function in patients with arterial hypertension (AH) and concomitant moderate chronic obstructive pulmonary disease (COPD). Methods. The 34 patients with arterial hypertension (AH) and concomitant moderate chronic obstructive pulmonary disease (COPD) were included to study. Blood pressure was measured and the spirometry was performed before and after 3 month of therapy. After two weeks without antihypertensive medications (washout period) moxonidin was prescribed to all these patients. 10 patients take moxonidin in total daily dose of 0,2 mg, another patients were treated with moxonidin 0,4 mg. The therapy of COPD was stable during this period and it consists of long-acting β2-agonist salmeterol in total daily dose 100 mcg and short-acting β2-agonist salbutamol pro renata.Results. Before treatment BP was 154,5±2,7/96,8±1,3 mm Hg and it was 128,3±3,1/79,3±2,5 mm Hg after taking moxonidin. The data of spirometry before taking moxonidin are FVC =81,4±3,4%, FEV1 69,5±3,4%, PEF=72,3±3,1%. These data are changed after treatment. FVC = 92,2±4,2%*, FEV1= 83,2±2,3%*, PEF=86,3±3,6%*(* p<0,05 with the data before treatment).Conclusion. Moxonidin is effective antihypertensive drug. Treatment with moxonidin also improves lung function in patients with concomitant COPD. It has no direct in uence on data of spirometry. Perhaps, these positive effects connected with diminished pressure in pulmonary artery and with improvement of mechanics of breath.

FIBRINOGEN AS A RISK FACTOR OF THE DEVELOPMENT OF CARDIOVASCULAR DISEASES IN PATIENTS INFECTED BY HELICOBACTER PYLORI.M. Sechenov, MVladimir Popov, Grechushnikov V.B., Nelyubin V.N., Popov V.V. Non State Healthcare Institution Central Clinical Hospital No.6, “Russian Rail-way joint-stock company”, Moscow , Moscow Medical Academy named after I.M. Sechenov, Moscow, Russia. email: [email protected]

Background: As is well known, Helicobacter pylori (Н.P.) infection is the main reason of the development of chronic gastritis, gastric or duodenal ulcer disease and stomach cancer. However, recent numerous studies prove the wide enough range of extragastral manifestations of the H. P infection. In a number of articles the role of the infectious process caused by H.P. as a risk factor of the development of cardiovascular diseases is discussed. However, a number of studies have reported con icting results.Objective: The aim of the study was to examine a possible relationship between H.P infection and cardiovascular disease in patients with gastrointestinal tract disorders.Methods: One hundred twenty six (126) patients with gastrointestinal tract disorders were investigated. 54 (42,8%) males and 72 (57,1%) females aged 19 to 81 were involved. Esophagogastroduodenoscopy (EGD), abdominal ultrasonography (USG), blood biochemistry (cholesterol, HDL, LDL, VLDL, brinogen, C-reactive protein were performed. Diagnostics of the infection H. pylori was performed by histological and cytological methods (by the quick urease test and PCR method). Results: The EGD revealed 65 (51,5%) cases of gastritis, 32 (25,3%) cases of acute and chronic gastric and duodenal erosion, 2 (1,58%) cases of duodenal ulcer, 14 (11,1%) cases of cicatrical and ulcerous gastrointestinal alterations, 13 (10,3%) cases of esophagitis. The following concomitant diseases were revealed: - 38 (30,1%) patients had coronary heart disease, 31 patients had 31 Н.P. (+) (81,5%);- 77 (61,1%) patients had essential hypertension, 66 patients had Н.P. (+) (85,7%);- 11 (8,7%) patients had different types of heart rhythm disturbance.Н.P. DNA fragments persistence in peripheral blood mononuclear cells was revealed in 37 patients (29,4%). Our results con rmed statistically signi cant direct correlation of increased level of brinogen (р < 0,001) in patients infected with Н.P. The in uence of the Н.P. infection on other biochemical parameters was not found. Conclusions: Apparently, the H.P infection in patients with chronic gastrointestinal tract disorders can in uence on the development of concomitant cardiovascular diseases by means of the increase of blood brinogen. Н.P. infection and plasma brinogen concentration are important risk factor for cardiovascular disease. Approach focusing on the ef cacy of the eradication of Н.P. infection on the prevention and treatment of cardiovascular diseases should be a potential target for new cardiovascular clinical trials.

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STATINS AND SERIOUS MUSCULOSKELETAL ADVERSE REACTIONS: OVERVIEW OF POST-MARKETING SURVEILLANCES AND RANDOMIZED CLINICAL TRIALSKateryna Zakharchenko, Popov V. Moscow Medical Academy named after I.M. Sechenov, Moscow, Russia.

Objectives: The aim of the study was to analyzed safety data from key randomized clinical trials (CT), post-marketing surveillances and other medical databases about a possible relationship between musculoskeletal Serious Adverse Reactions (SAR) of statin therapy.Methods and Results: Major reports of statin therapy safety from the following database: WHO (Pharmaceuticals newsletter), FDA safety alerts, Canadian Adverse Reaction Newsletters (CARN), Australian Adverse Drug Reaction Advisory Committee (ADRAC) Bulletins, MEDLINE, PubMED, Medscape and available reports from randomized clinical trial were identi ed for analyzed. We reviewed alerts and reports that contain information about frequency of serious and uncommon musculoskeletal reactions rhabdomyolysis during statin therapy (Cerivastatin wasn’t included). Key randomized CTs demonstrated the following rates of rhabdomyolysis during statin therapy: 1.6 incidences above placebo per 100 000. According to the data from ASCOT, GREACE, AVERT, MIRACL, PROVE-IT for Atorvastatin - cases of rhabdomyolysis is 0.03% , Simvastatin (4S , HPS, A to Z Studies ) – total cases 0.06%, Rosuvastatin (JUPITER, AURORA, CORONA) -0.007% cases, Pravastatin and Fluvastatin - 0 %.We also analyzed post marketing databases. In US in 2006: the following numbers of spontaneous SARs of rhabdomyolysis were registered: for Atorvastatin – 348 cases, Simvastatin – 760 cases, Rosuvastatin – 103 cases, Pravastatin – 75 cases, Fluvastatin - 56 cases. However, the FDA has continued to receive reports of statin-associated dose-related rhabdomyolysis in 2008 related to combinations of Simvastatin/Amiodarone. There are 35 cases of all rhabdomyolysis reports received from marketing authorisation of statins in Canada according to CARN in 2001; and there are 8 new cases of rhabdomyolysis associated with statins registered in 2004. CARN in 2007 reported that 46 deaths were statin-associated, 24 from them related to atorvastain, the percentage of rhabdomyolysis was not provided. In ADRAC total numbers rhabdomyolysis reports up 2004 for Simvastatin - 91; Atorvastatin - 26, Pravastatin - 5, Fluvastatin - 2, by late 2007 in Australia received 5846 adverse reactions reports, that implicated a statin, almost 1/3 were of muscle disorders, the percentage of rhabdomyolysis was not indicated.Conclusions: The study demonstrated on the basis of data, available from published reports of CTs and post-marketing reports of musculoskeletal SAR, such as rhabdomyolysis, that it is necessary to take into account the possible risk while using dangerous combinations and doses of statins during the statin-therapy. Thus cardiologists and GP appear to become a very important informative source for registrations of such SARs during the post registration phase of the pharmacovigilance.And also the ndings must be a motive for the development of the new statins` generation and tracking and prevention of the possible SAR.

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