Friday november 30, 2012
         
  09.00 12.30 MODIGLIANI Workshop 1
THE THROMBOSIS TRIALISTS WORKSHOP
DOSE AND TARGET PATIENT POPULATIONS ISSUES
         
    Chairpersons: Peter CLEMMENSEN, Copenhagen, DEN - George-Andrei DAN, Bucharest, ROM
    Webcast: Johanne SILVAIN, Paris, FRA
   

The development of new antithrombotic agents is a challenging area of cardiovascular medicine.
These agents generally have a narrow therapeutic margin, and it is often difficult to find the optimal balance between efficacy (reduction of ischemic events) and safety (no excess of bleeding events).

Phase II trials are designed to generate signals of safety and efficacy and to select the dose or doses for phase III pivotal trials. However, phase II data are limited by small numbers of events and short follow-up. Some recent phase III trials have produced results that were unanticipated from the phase II findings.

Adaptive designs to explore safety (bleeding) risks have been proposed to overcome the current limitations of dose selection for phase III. Several concerns with these designs remain unresolved, such as appropriate methods to control Type I error for both safety and efficacy. Also, adaptive designs will only be useful if they are accepted by the regulatory agencies. The agencies have not announced a final position yet. Implementation of adaptive designs requires early and in-depth interaction between the agencies and study sponsors.

With the newer anti-thrombotic agents progressively potentially replacing warfarin, we are moving from a target INR guided dosing to an indication/risk guided dosing. Different doses are being developed for different indications. There is an intense discussion on whether doses of anticoagulants should be similar or different for preventing DVT after orthopedic surgery, for treating DVT and pulmonary embolism, for AFib, for prevention after ACS and for prevention in artificial valves. Dose - effect relationships are difficult to establish. A balance should be found between the dose relationship with clinical benefit and the dose relationship with the risk of bleeding. An intense discussion is also ongoing on whether a range of doses rather than one single dose should be made available for the same disease.

Exploring new indications for the newer anti-thrombotic agents might be one target of interest in patients with heart failure. In patients with coronary artery disease and HF, a majority of deaths (including sudden death) appear to be related to ischemia and worsening of heart failure. The presence of pulmonary embolism as a cause of worsening HF is underestimated and certain underlying pathophysiological mechanisms are common to both arterial and venous thrombi. It has been recognized since long that HF is associated with hypercoagulable state, and, at the cellular level, it has been reported that thrombin exerts multiple actions on cardiomyocytes which can favor the genesis of arrhythmias and myocyte injury. Antithrombotic strategies to reduce the risk of death, myocardial infarction (MI), or stroke have been tested in several randomized trials. These studies were underpowered and the recently published WARCEF trial is inconclusive. With the newest ant-thrombotic agents being probably safer, heart failure might be one of the next diseases where to expand the indications of new antithrombotics. Designing an anti-thrombotic trial in HF might also yield meaningful data regarding the potential role of thrombosis in patients with heart failure.

    The aim of this session is to explore novel, scientifically rigorous methodologies through an open, cooperative dialogue among investigators,
regulators, and sponsors.
       
    Session program:
         
    Dosing issues
  • How to secure the optimal dose(s) for phase III? Can adaptive design help?
Prodcast présentation Speaker: Nancy GELLER, NHLBI, USA
Prodcast présentation Discussant: Michael GIBSON, Boston, USA
Prodcast   General discussion
 
  • Different doses, different indications? DVT and pulmonary embolism, Atrial fibrillation, ACS, artificial valves
Prodcast présentation Speaker: Freek VERHEUGT, Amsterdam, NED
Prodcast présentation Discussant: Maarten SIMOONS, Rotterdam, NED
       
Prodcast   Industry viewpoint: Scott BERKOWITZ, Bayer, USA - Christophe GAUDIN, Sanofi, FRA - Lloyd HASKEL, J&J, USA - Yasser KHDER, Boehringer Ingelheim, FRA - Joerg KOGLIN, Merck, USA - John LAWRENCE, BMS, USA
Prodcast présentation Speaker: Christophe GAUDIN, Sanofi, FRA
Prodcast présentation Speaker: Yasser KHDER, Boehringer Ingelheim, FRA
Prodcast présentation Speaker: Joerg KOGLIN, Merck, USA
     
    Regulatory viewpoint: Angeles ALONSO, EMEA, ESP - Pieter DE GRAEF, EMEA, NED - Kaori SHINAGAWA, PMDA, JAP
Prodcast présentation Speaker: Angeles ALONSO, EMEA, ESP
  présentation Speaker: Pieter DE GRAEF, EMEA, NE + Discussion
Prodcast présentation Speaker: Kaori SHINAGAWA, PMDA
     
    New indications: Is heart failure a viable new potential indication for anti-thrombosis therapy
Prodcast présentation Speaker: Faiez ZANNAD, Nancy, FRA
Prodcast présentation Discussant: Efthymios DELIARGYRIS, MedCv, USA - Lloyd HASKEL, J&J, USA
  présentation Discussant: Lloyd HASKEL, J&J, USA
Prodcast présentation Regulatory viewpoint: Krishna PRASAD, MHRA, GBR
     
  Panellists:

ALONSO Angeles, EMEA, ESP - ANDO Yuki, PMDA, JAP - ANKER Stephan, Berlin, GER - BERKOWITZ Scott, Bayer, USA - BEYGUI Farzin, Paris, FRA - CALVO Gonzalo, Barcelona, ESP - CLEMMENSEN Peter, Copenhagen, DEN - CODY Robert, J&J, USA - DAN George-Andrei, Bucharest, ROM - DE FERRARI Gaetano, Pavia, ITA - DE GRAEF Pieter, EMEA, NED - DELIARGYRIS Efthymios, MedCo, USA - GAMRA Habib, Monastir, TUN - GAUDIN Christophe, Sanofi, FRA - GELLER Nancy, NHLBI, USA - GIBSON Michael, Boston, USA - HASKEL Lloyd, J&J, USA - KHDER Yasser, Boehringer Ingelheim, FRA - KOGLIN Joerg, Merck, USA - KUPFER Stuart, Takeda, USA - LAWRENCE John, BMS, USA - LEWIS Basil, Haïfa, ISR - MEHRAN Roxana, New York, USA - PRASAD Krishna, MHRA, GBR - ROSENBERG Yves, NHLBI, USA - SHINAGAWA Kaori, PMDA, JAP - SILVAIN Johanne, Paris, FRA - SIMON Tabassome, Paris, FRA - SIMOONS Maarten, Rotterdam, NED - TAIEL-SARTRAL Magali, Lilly, FRA - VERHEUGT Freek, Amsterdam, NED - WAHL Denis, Nancy, FRA - WASSMANN Sven, Munich, GER - ZANNAD Faiez, Nancy, FRA

 
  08.00 12.30 SOUTINE / UTRILLO Workshop 3
THE DIABETES TRIALISTS FORUM
DIABETES CLINICAL TRIALS: HELPED OR HINDERED BY THE CURRENT SHIFT IN REGULATORY REQUIREMENTS?
         
    Chairpersons: Marc PFEFFER, Boston, USA - Kausik RAY, London, GBR
    Webcast: Daniela DOBRE, Nancy, FRA  
 

Preamble: Glycaemic control is an inadequate surrogate marker of cardiovascular event reduction in patients with type 2 diabetes. Clinical trials to date have been unsuccessful in identifying a therapeutic approach that addresses the underlying problem in diabetes (glycaemic control) and reduces cardiovascular risk. The potential for some agents to increase the risk of cardiovascular events has led to substantial changes in regulatory requirements for new anti-diabetic therapies. These requirements, while key to ensuring the cardiovascular safety of new agents, fail to emphasize the need to show clinical benefits, such as less visual impairment, less need for dialysis, or fewer cardiovascular events and deaths. Changes in test results such as glycaemic control, serum creatinine, micro-albuminuria, or retinopathy are inadequate surrogates. Regulators should consider the potential advantages of offering extended patent protection in order to encourage companies to conduct long-term trials in diabetes and many other chronic medical conditions. Cooperative efforts among physicians, clinical trialists, regulators, and sponsors are needed to address unresolved issues including re-defining therapeutic targets that are meaningful to patients with diabetes, determining the appropriate length of follow-up for future trials, and considering the ethical and operational challenges of non-inferiority designs.

    Trials (Interventions)
   
  • ADVANCE - VADT - ACCORD - PROACTIVE - TODAY (Gliclazide, metformin, acarbose, glimepiride, TZDs (rosiglitazone, pioglitazone)
    - FREEDOM
  • DPP4 Inhibitors: EXAMINE - TECOS - SAVOR (TIMI-53) - CAROLINA (Alogliptin, Sitagliptin, Saxagliptin, Linagliptin, Glimepiride)
  • GLP-1 Analogues: REWIND - ELIXA - EXSCEL - LEADER (Dulaglutide, Lixisenatide, Exenatide, Liraglutide)
  • SGLT2 Inhibitors: BI 10773 - CANVAS (BI 10773, Canagliflozin)
  • Glitazones/Glitazars: ALECARDIO (Aleglitazar, PPARa and ?)
  • IFG/IGT/Insulin Resistance: ORIGIN62 - ACE - IRIS - EASIE (Insulin glargine, Acarbose, Pioglitazone)
    Session program:
 
  • Target populations: How do we risk-stratify? Are additional biomarkers helpful?
Prodcast présentation Speaker: Wolfgang KOENIG, Ulm, GER
Prodcast   Discussion
Prodcast présentation Discussant: Adrian HERNANDEZ, Durham, USA
 
  • Globalization of Diabetes trials: Epidemiology of diabetes in the Middle East and Asian countries
Prodcast présentation Speaker: Prem PAIS, Bangalore, IND
Prodcast   Discussion
Prodcast présentation Speaker: Mohamed SOBHY, Alexandria, EGY
    Discussion
 
  • Globalization of Diabetes trials: Epidemiology of diabetes in the Middle East and Asian countries
  On top of or vs. Metformin? The issue of background therapy and comparator
Prodcast présentation Speaker: Michel MARRE, Paris, FRA
 
  • Insulin in type 2 diabetes: bad guy or good guy?
Prodcast présentation Speaker: Michel MARRE, Paris, FRA
Prodcast   Discussion
 
  • What else than glucose control? Lipids, BP, Weight, Kidney
Prodcast présentation Speaker: Denise BONDS, NHLBI, USA
 
  • Non-inferiority, superiority, or both? Operationalizing the FDA guidance
  Speaker: Marc PFEFFER, Boston, USA
Prodcast présentation Discussant: Stuart POCOCK, London, GBR
Prodcast présentation Regulatory viewpoint: Kristina DUNDER, EMEA, SWE
Prodcast   Discussant: After Pfeffer, Pocock and Dunder
     
    Panellists:
   

BONDS Denise, NHLBI, USA - DREXEL Heinz, Feldkirch, AUS - DUNDER Kristina, EMEA, SWE - GOLDSMITH David, London, GBR - GORDON David, NHLBI, USA - HERNANDEZ Adrian, Durham, USA - KOENIG Wolfgang, Ulm, GER - MARRE Michel, Paris, FRA - PAIS Prem, Bangalore, IND - PFEFFER Marc, Boston, USA - POCOCK Stuart, London, GBR - RAY Kausik, London, GBR - ROUSSEL Ronan, Paris, FRA - SOBHY Mohamed, Alexandria, EGY - SWYNGHEDAUW Bernard, Paris, FRA - TORP-PEDERSEN Christian, Copenhagen, DEN.

 
  12.45 15.15 MODIGLIANI Lunch Debate Session 1
THE DEVICE THERAPY TRIALISTS WORKSHOP
         
    Chairpersons: Gaetano DE FERRARI, Pavia, ITA - Ileana PIÑA, New York, USA
    Webcast: Tariq AHMAD, Durham, USA
    Device trial methodology, regulatory and implementation issues
   

Advances in interventional medical devices are increasingly affecting cardiovascular therapy, just as pharmacological innovation did the generation before. Yet, designing and conducting a device trial is challenging and drug trial designs may not necessarily be applied fully to device trials.

   
  • Although there is increasing recognition that this development process substantially differs from that for drugs, how much device trial methodology may deviate from drug trial methodology is a matter of discussion.
  • Regulation works differently for drugs, devices, and procedures, and there are wide international variations. Although progressively moving toward some alignment, currently, in Europe, industry needs only to fulfill the (light) criteria of “CE” mark before approval. General sale of devices may be permitted on the basis of proof of safety, rather than of efficacy or effectiveness. In any case, reimbursement claims may require collecting evidence in outcome cost-effectiveness trials. Regulators and commercial bodies should seek consensus.
  • Innovation is led by device industry which is facing the economic challenge of bringing innovation to the market in a very competitive environment. Multi sponsored trials and the cooperation with public funders may be instrumental in improving knowledge production for a better device therapy.
  • Interpretation of trial results, and consequently therapy adoption, is another challenge. The strength of evidence is not necessarily the main driver for adoption. Coronary angioplasty in stable CAD is widely adopted while, despite evidence for a beneficial effect of device therapy in heart failure, only a minority of eligible patients is currently offered these options.
  • Beyond trials aimed at evaluating safety, effectiveness and approval, trials that establish the value of a therapy and hence support utilization in clinical practice are most needed.
   

The aim of this session is to contribute to identifying and promoting innovative, cooperative and practical solutions that may help filling the gaps between device and drug trials, between CE mark and FDA regulations and between generating evidence and practical implementations..

    Session program:  
    How much one could deviate from “randomized - controlled” trials?  
   
  • Non randomized and/or non-blinded trials: When can they be trusted, what can help them to be “acceptable”?
 
  présentation Speaker: Stuart POCOCK, London, GBR  
   
  • Options of and alternatives to the “control group” in device trials
 
Prodcast présentation Speaker: William T. ABRAHAM, Columbus, USA  
   
  • Industry perspective
 
Prodcast présentation Speaker: Rob KIEVAL, CVRx, USA  
Prodcast présentation Speaker: Holger WOEHRLE, ResMed, GER  
    Discussion
    Approvability issues: Pathway to a more global device approval process  
Prodcast présentation Speaker: Ileana PIÑA, New York, USA  
    Post approval and registry studies. Advantages and limitations in complementing trial evidence base and improving therapy adoption  
Prodcast présentation Speaker: Ileana PIÑA, New York, USA  
Prodcast présentation Discussant: Roxana MEHRAN, Hew York, USA
    Comparative effectiveness studies. How they may help decision makers and support utilization in clinical practice?  
Prodcast présentation Speaker: Rita REDBERG, San Francisco, USA  
Prodcast présentation Discussant: Kenneth STEIN, Boston Scientific, US + Discussion
       
    Session program:  
   

ABRAHAM William T., Columbus, USA - ANKER Stephan, Berlin, GER - CARLSON Mark, St Jude Medical, USA - DE FERRARI Gaetano, Pavia, ITA - FARB Andrew, FDA, USA - GELLER Nancy, NHLBI, USA - JARCHO John, Boston, USA - KIEVAL Rob, CVRx, USA - LINDE Cecilia, Stockholm, SWE - MASCETTE Alice, NHLBI, USA - MEHRAN Roxana, New York, USA - PIÑA Ileana, New York, USA - POCOCK Stuart, London, GBR - REDBERG Rita, San Francisco, USA - STEIN Kenneth, Boston Scientific, USA - VINCENT Alphons, Medtronic, CHE - YADAV Jay, CardioMEMS, USA - WOEHRLE Holger, ResMed, GER

 
  12.45 15.15 SOUTINE / UTRILLO Lunch Debate Session 2
SATELLITE SYMPOSIUM
NEW EVIDENCE, NEW GUIDELINES AND FUTURE DEVELOPMENTS WITH IVABRADINE
         
    Chairpersons: Gaetano DE FERRARI, Pavia, ITA - Ileana PIÑA, New York, USA
    Webcast: Nicolas GIRERD, Nancy, FRA
   
  • The new set of guidelines of the ESC Heart Failure Association and of other major international societies has recently been published. They have integrated the newest evidence with the main pharmacological innovation Ivabradine.
  • Beyond the main results of the BEAUTIfUL and SHIfT trials, a number of pre-specified analyses have yielded results that will help optimizing the implementation of the use of this new agent in ischemic heart diseases as well as in heart failure with LV systolic dysfunction.
  • Ivabradine is a specific inhibitor of the If current in the sinoatrial node providing a pure HR reduction without modification of other cardiovascular parameters. Treatment with ivabradine therefore provides an opportunity to assess the effects of lowering HR without directly altering other aspects of cardiac function. Beta-blockers and digoxin are other heart rate slowing agents, but with additional pharmacological effects, some of which are beneficial and others are deleterious, thus limiting the safety and adherence to these agents.
  • It is likely that the newest heart failure guidelines will extend the recommendation of using mineralocorticoid receptor antagonists (MRAs) to Class I, level of evidence A. While, ivabradine benefits were observed in SHIfT on top of betablockers, of digoxin and also of MRAs, the question of the right timing of initiating ivabradine, relative to the optimization of beta-blocker and digoxin therapy and the timing of initiating an MRA is to be debated.
  • BEAUTIfUL and SHIfT have also led to a series of stimulating hypotheses that constitute the rationale for the currently SIGNIfY trial, which is enrolling patients with coronary artery disease and normal left ventricular systolic function with a resting HR of =70 bpm. The primary endpoint will take into consideration only coronary artery disease outcomes.
  • Is heart failure with preserved ejection fraction the next frontier?
       
    Session program:  
    CLARIfYing the CAD patient in our practice  
  Speaker: Jean-Claude TARDIF, Montréal, CAN  
    SHIfTing evidence in heart failure management  
Prodcast présentation Speaker: Jeffry BORER, New York, USA  
    Save life and save cost with ivabradine  
  présentation Speaker: Martin COWIE, London, GBR  
    Debate: When to initiate ivabradine therapy in clinical practice?  
       
    Panellists:  
Prodcast  

BORER Jeffrey, New York, USA - COHEN-SOLAL Alain, Paris, FRA - COWIE Martin, London, GBR - DAN George-Andrei, Bucharest, ROM - GHEORGHIADE Mihai, Chicago, USA - MAGGIONI Aldo, Florence, ITA - METRA Marco, Brescia, ITA - ROSANO Giuseppe, EMEA, ITA - TARDIF Jean-Claude, Montréal, CAN - TAVAZZI Luigi, Cotignola, ITA - TSOUDEROS Yannis, Servier, FRA - ZANNAD Faiez, Nancy, FRA

 
       
  15.30 19.30 MODIGLIANI Workshop 2
ATHEROSCLEROSIS IMAGING IN CLINICAL
TRIALS Facilitating the discovery of effective therapies
         
    Chairpersons: Jagat NARULA, New York, USA - Ahmed TAWAKOL, Boston, USA
    Webcast: Bart STAELS, Lille, FRA
   

Phase III clinical endpoint trials evaluating treatments for atherosclerosis typically require very large sample sizes, cost hundreds of millions of dollars and historically have had very low success rates. As a result, few new therapies that attenuate the progression of atherosclerosis have been identified in over 30 years (since the discovery of statins). Nearly a decade ago, in recognition of the low success of Phase III trials, regulatory agencies called for the adoption of new biomarkers or surrogate endpoints to enhance the rate of clinical development. To that end, several cardiovascular imaging technologies have gone through evolutionary cycles of validation over the past decade and several have demonstrated promise as clinical tools and as clinical trial biomarkers.
With the rapid development and implementation of these imaging approaches, it is important to delineate the opportunities and limitations associated with these tools. In particular, it is essential to identify imaging biomarkers that might accurately predict eventual clinical success based on the observed changes in the atherosclerotic imaging measurements. With such tools as gatekeepers, only those treatments with proven efficacy during Phase II trials would be promoted to Phase III with the expectation of high likelihood of success in the clinical endpoint trials. By enhancing the success rate of Phase III clinical trials, use of these imaging tools have the potential to accelerate the discovery of treatments for atherosclerosis.

    Session program:  
    Overview: Why are imaging endpoints needed in CV clinical trials  
    Speaker: Speaker: Jagat NARULA, New York, USA  
    Well established methods for imaging opproaches: IVUS and IMT  
  présentation Speaker: Jean-Claude TARDIF, Montréal, CAN  
Prodcast présentation Discussant: Wolfgang KOENIG, Ulm, GER
    Coronary CTA in clinical trials  
  Speaker: Udo HOFFMANN, Boston, USA  
    MRI imaging in clinical trials  
  Discussant: Robin CHOUDHURY, Oxford, GBR
    PET-CT imaging in clinical trials  
  Speaker: Ahmed TAWAKOL, Boston, USA  
Prodcast présentation Discussant: James RUDD, Cambridge, GB + General discussion
         
    Panellists:  
 

AGEWALL Stefan, Oslo, NOR - BONDS Denise, NHLBI, USA - CHOUDHURY Robin, Oxford, GBR - FAYAD Zahi, New York, USA - GAMRA Habib, Monastir, TUN - GAUDIN Christophe, Sanofi, FRA - HOFFMANN Udo, Boston, USA - KOENIG Wolfgang, Ulm, GER - MENDELSOHN Michael, Merck, USA - NARULA Jagat, New York, USA - REDBERG Rita, San Francisco, USA - ROSANO Giuseppe, EMEA, ITA - ROSENBERG Yves, NHLBI, USA - RUDD James, Cambridge, GBR - SCOTT Robert, Amgen, USA - STAELS Bart, Lille, FRA - TARDIF Jean-Claude, Montréal, CAN - TAWAKOL Ahmed, Boston, USA - WASSERMAN Scott, Amgen, USA

         
  15.30 19.30 SOUTINE / UTRILLO Workshop 4
CARDIOVASCULAR PREVENTION IN CHRONIC KIDNEY DISEASE
NEW THERAPEUTIC OPTIONS AND FUTURE OPPORTUNITIES
         
    Chairpersons: David GOLDSMITH, London, GBR - Luis RUILOPE, Madrid, ESP
    Webcast: Nicolas GIRERD, Nancy, FRA
   
  • Cardiovascular events are 10 to 20 fold higher in CKD patients. Heart failure is the main cardiovascular complication that occurs in renal patients. Nearly all CV prevention and heart failure trials excluded patients with moderate to severe CKD. Therefore, the general approach and recommendations for CV prevention in the general population may not be equally effective and completely safe in renal patients.
  • Renal failure is associated with increased vascular inflammation and oxidative stress linked to development of cardiovascular disease. Nrf-2 (NF-E2-related factor 2) is a regulator of anti-oxidant, anti-inflammatory and detoxification pathways. Intervention trials of the synthetic nrf2/nf?b modulator, bardoloxone methyl, in patients with advanced kidney disease associated with type 2 diabetes, demonstrated improvement of renal function (BEAM trial), suggesting that such agents may have therapeutic benefit in chronic renal failure.
  • The ongoing BEACON trial assesses the efficacy of bardoxolone methyl relative to placebo in delaying progression to end-stage renal disease and cardiovascular deaths in patients with Stage 4 CKD and type 2 diabetes.
  • More specifically in chronic hemodialysis patients, results from the very few clinical trials undertaken thus far, including trials on lipid reduction, normalization of hematocrit, and increased dialysis dosage, have been unsuccessful.
  • New CV prevention opportunities are being investigated in specific trials in CKD and hemodialysis patients.
   

The aim of this workshop is to discuss innovative designs and execution plans of CV prevention trials in CKD as well as the interpretation and implementation of the results of such trials and the approvability - regitrsbaility of potentially new CV prevention in CKD indications.

    Standard of care and novel opportunities for CV prevention and the treatment of heart failure in patients with moderate to severe CKD?  
  présentation Speaker: Hermann HALLER, Hannover, GER  
    Lipid lowering agents. Now, we have an option! (SHARP, 4D, AURORA)  
Prodcast présentation Speaker: Colin BAIGENT, Oxford, GBR  
    Erythropoiesis stimulating agents and iron treatment optimization in CKD patients (CREATE, CHOIR, TREAT)  
  présentation Speaker: Marc PFEFFER, Boston, USA  
    EVOLVE: A major cardiovascular outcomes trial in hemodialysis patients  
Prodcast présentation Speaker: Chris MIX, Amgen, USA  
Prodcast présentation Speaker: David WHEELER, London, GBR  
Prodcast présentation Discussant: Ziad MASSY, Boulogne-Billancourt, FRA
Prodcast   Discussion
    Antioxidant inflammation modulation with bardoxolone? (BEACON)  
  présentation Speaker: David WARNOCK, Birmingham, USA  
    RAAS inhibitors and Mineralocorticoid receptor antagonists (FOSIDIAL, ALCHEMIST)  
Prodcast présentation Speaker: Patrick ROSSIGNOL, Nancy, FRA  
    Heart failure and other CV endpoints in CKD trials. Definition and adjudication issues.  
  Speaker: Stefan ANKER, Berlin, GER  
    Interpretation and approvability issues  
    Speaker: Paul AUDHYA, Reata, USA  
Prodcast présentation Discussant: Pieter DE GRAEF, EMEA, NED
       
    Panellists:  
   

ANKER Stefan, Berlin, GER - AUDHYA Paul, Reata, USA - BAIGENT Colin, Oxford, GBR - BUYSSE Jerry, Relypsa, USA - CALVO Gonzalo, Barcelona, ESP - DE FERRARI Gaetano, Pavia, ITA - DE GRAEF Pieter, EMEA, NED - GOLDSMITH David, London, GBR - GORDON David, NHLBI, USA - HALLER Hermann, Hannover, GER - KJELDSEN Keld, Copenhagen, DEN - MASSY Ziad, Boulogne-Billancourt, FRA - MIX Chris, Amgen, USA - PFEFFER Marc, Boston, USA - ROSANO Giuseppe, EMEA, ITA - ROSSIGNOL Patrick, Nancy, FRA - RUILOPE Luis, Madrid, ESP - WACHTER Rolf, Göttingen, GER - WARNOCK David, Birmingham, USA - WHEELER David, London, GBR

 
         
         
SATURday DECember 1st, 2012
         
  08.00 12.30 MODIGLIANI Workshop 5
THE ATHEROSCLEROSIS TRIALISTS FORUM
         
    Chairpersons: Wolfgang KOENIG, Ulm, GER - Anthony WIERZBICKI, London, GBR
    Webcast: Tabassome SIMON, Paris, FRA
    Will new compounds be able to reduce the residual risk in high risk patients when treatment targets based on new ESC guidelines have
been achieved (e.g. LDL-C < 70mg/dl)?

Despite widespread early intervention in acute coronary syndromes and complete revascularization of stenotic lesions complemented by aggressive polypharmacotherapy, still a high percentage of patients develop a secondary event. This has been shown in various registries and recent data from the GRACE registry have suggested that we grossly underestimate long-term risk in these patients. Thus, despite all our current efforts there is room for improvement.
   
  • A very active clinical research programme is delivering an important number of new potential therapeutic targets that may be ready for trial testing.
    • Can OMICS technology help us out here in terms of new specific biomarkers taking advantage of the proteome, metabolome or the transcriptome?
    • What is the relevance of Mendelian Randomisation studies to investigate the potential causal role of biomarkers in the pathophysiology of disease and to identify and select new drug biotargets.
  • One major question relates to the value of biomarker-guided and/or risk guided therapy and how to design appropriate trials to test these therapeutic strategies. Should therapy be targeted to patients with specific biomarkers profiles? e.g. low HDL, high inflammatory burden (elevated CRP), high Lp-PLA2 activity etc.?
  • A fairly large number of lipid-associated new targets or targets reflecting other pathways of the complex atherosclerotic process are being evaluated in mechanistic imaging studies but also in large randomised controlled clinical trials looking for important cardiovascular endpoints. In all of these trials the standard of care is much better than seen in the real world situation. Thus, the question arises, whether these additional compounds will lead to a clinically significant reduction in cardiovascular events on top of optimal standard care.
     
    Trials (Interventions)
   
  • CETP inhibitors: dalcetrapib, anacetrapib, evacetrapib (DAL-Outcomes I, DAL-Outcomes II, DEFINE, REVEAL, evacetrapib, ApoA1 mimetics, ApoA1 Milano, AIM-HIGH, HPS-Thrive)
  • Directly augmenting apo A-I: Intravenous apo A-I therapy, Recombinant apo A-I Milano/phospholipids (ETC-216), Purified native apo A-I/phospholipids (CSL-111/112)
  • Oral upregulators of endogenous apo A-I production RVX-208: ASSURE, SUSTAIN
  • Phospholipase inhibitors: VISTA-16, SOLID, STABILITY
  • Anti-inflammatory therapy: CANTOS (IL-1ß antibody), CIRT (MTX), Anakinra (IL1 RA), IL-6 RA (Taxilicumab)
  • New LDL-lowering compounds: PCSK9 inhibitors, apoB antisense, ISIS
         
    Session program:
    Will we be able to answer the question of HDL as a therapeutic target after the CETP inhibitor trials?  
Prodcast présentation Speaker: Eric STROES, Amsterdam, NED  
Prodcast présentation Discussant: Robert ROSENSON, New York, USA + Discussion
    Identifying new targets: The value of omics and mendelian randomization studies  
  présentation Speaker: Daniel SWERDLOW, London, GBR  
Prodcast   Discussion  
    Identifying new targets: Monoclonal Antibody Inhibitor of PCSK9  
Prodcast présentation Speaker: Wolfgang KOENIG, Ulm, GER  
  Speaker: Robert SCOTT, Amgen, USA  
 
    Panellists:
    AGEWALL Stefan, Oslo, NOR - BONDS Denise, NHLBI, USA - CASAS Juan Pablo, London, GBR - CHOUDHURY Robin, Oxford, GBR - DAN George-Andrei, Bucharest, ROM - DREXEL Heinz, Feldkirch, AUS - FAYAD Zahi, New York, USA - GAUDIN Christophe, Sanofi, FRA - GORDON David, NHLBI, USA - HOFFMANN Udo, Boston, USA - KOENIG Wolfgang, Ulm, GER - MENDELSOHN Michael, Merck, USA - POCOCK Stuart, London, GBR - RAY Kausik, London, GBR - REDBERG Rita, San Francisco, USA - ROSENBERG Yves, NHLBI, USA - ROSENSON Robert, New York, USA - RUDD James, Cambridge, GBR - SCOTT Robert, Amgen, USA - SIMON Tabassome, Paris, FRA - STAELS Bart, Lille, FRA - STROES Eric, Amsterdam, NED - TARDIF Jean- Claude, Montréal, CAN - TAWAKOL Ahmed, Boston, USA - TORP-PEDERSEN Christian, Copenhagen, DEN - WASSERMAN Scott, Amgen, USA - WIERZBICKI Anthony, London, GBR
         
  08.00 12.30 SOUTINE / UTRILLO Workshop 6
MULTIDISCIPLINARY EXPERT WORKSHOP: ACHIEVEMENTS, CHALLENGES AND BARRIERS
TO IMPLEMENTATIONS OF THE ESC 2012 CHRONIC HEART FAILURE GUIDELINES
         
    Chairpersons: Alain COHEN-SOLAL, Paris, FRA - Adrian VOORS, Groningen, NED
    Webcast: Nicolas GIRERD, Nancy, FRA
   

Background: The ESC-HFA chronic and acute heart failure guidelines have recently been published. However, the challenge for guidelines does not cease with a consensus document. Practical implementation is the critical step in establishing higher standards of care for individual patients. Improved guideline uptake is not only an index of better standards but a validation of the process of guideline production.

Improving consensus between guidelines is also important, differences in recommendations may act as a barrier to guideline. The NICE CHF guidance was updated in 2010, and it is not likely to be revised in short term.

Practice differs from the guideline recommendations. Registries suggest differences in guideline interpretation and treatment/management of CHF between different stakeholders. Similarities and differences exist between GPs and hospital physicians’ approaches to management of CHF.

One important issue that is not covered by the current guidelines is the class effect issue. Canadian and Australian CHF guideline and 2010 NICE guideline name eplerenone as preferred drug in heart failure, ESC mentions only mineralocorticoid receptor antagonists (MRAs.) as a class.

How to interpret compound vs. class effects while following guideline recommendations is an important issue.

Cost-effectiveness is a key not only to the content of guidelines but also in the assessment of implementation. Limits on healthcare resources mandate that resource-allocation decisions be guided by considerations of cost in relation to expected benefits. In cost-effectiveness analysis, the ratio of net healthcare costs to net health benefits provides an index by which priorities may be set.

Aims: This multidisciplinary consensus workshop aims at discussing CHF guideline implementation issues and the consequences on defining the place of MRA/eplerenone in management of CHF.

    Session program:  
    Impact of major clinical trials on ESC Chronic Heart Failure 2012 guidelines. Game changer trials: EMPHASIS-HF, SHIFT, Devices…  
Prodcast présentation Speaker: Faiez ZANNAD, Nancy, FR  
    Discussant: John CLELAND, Hull, GBR
    Expected implications on heart failure epidemiology  
Prodcast présentation Speaker: Justin EZEKOWITZ, Edmonton, CAN  
    Expected implications on heart failure epidemiology  
   
  • NICE
Speaker: Suzanna HARDMAN, London, GBR  
   
  • German CHF registry: REFLECT –HF
Prodcast présentation Speaker: Carsten TSCHOEPE, Berlin, GER  
   
  • Eurobservational, the ESC Heart failure Registry
Prodcast présentation Speaker: Aldo MAGGIONI, Florence, ITA  
    Compound vs. class effect. Drug class recommendations in guidelines  
   
  • ESC-HFA guidelines
  présentation Speaker: Luigi TAVAZZI, Cotignola, ITA  
   
  • Canadian, Australian CHF guideline and 2010 NICE guideline
Prodcast présentation Speaker: Justin EZEKOWITZ, Edmonton, CAN  
    Is it always safe to believe in class effect: Spironolactone vs. eplerenone differences and clinical relevance?  
Prodcast   Speaker: Bertram PITT, Ann Arbor, USA  
    EMPHASIS-HF Cost effectiveness Model and Guideline implementation from the payer’s perspectives  
  Speaker: Ron AKEHURST, Sheffield, GBR  
         
    Panellists:
    AKEHURST Ron, Sheffield, GBR - ANKER Stephan, Berlin, GER - AZIZI Michel, Paris, FRA - BRUTSAERT Dirk L, Antwerp, BEL - BUYSSE Jerry, Relypsa, USA - CLELAND John, Hull, GBR - CODY Robert, J&J, USA - COHEN-SOLAL Alain, Paris, FRA - EZEKOWITZ Justin, Edmonton, CAN - FIUZAT Mona, Durham, USA - HARDMAN Suzanna, London, GBR - KJELDSEN Keld, Copenhagen, DEN - MAGGIONI Aldo, Florence, ITA - METRA Marco, Brescia, ITA - PFEFFER Marc, Boston, USA - PIÑA Ileana, New York, USA - PITT Bertram, Ann Arbor, USA - ROSANO Giuseppe, EMEA, ITA - SWYNGHEDAUW Bernard, Paris, FRA - TAVAZZI Luigi, Cotignola, ITA - TSCHOEPE Carsten, Berlin, GER - VOORS Adrian, Groningen, NED - WACHTER Rolf, Göttingen, GER - ZANNAD Faiez, Nancy, FRA
         
  12.45 15.15 MODIGLIANI Lunch Debate Session 3
HEART FAILURE TRIALISTS WORKSHOP
LEARNING FROM RECENT TRIALS AND SHAPING THE FUTURE OF HEART FAILURE TRIALS
         
    Chairpersons: Alexandre MEBAZAA, Paris, FRA - Christopher O’CONNOR, Durham, USA
    Webcast: Daniela DOBRE, Nancy, FRA
   

Decreasing the very high mortality and rate of re-hospitalization associated with acute worsening HF is one of the most important unmet needs in cardiovascular medicine. Despite positive signals in Phase II studies, no drug has proven to reduce the appallingly high mortality or readmission rates. The reasons for these ‘failed’ trials are multiple, including the adequacy of candidate drugs, dosing, patient selection and disease characterization, and trial conduct. The phenotypes and pathophysiology of the syndrome are poorly understood. The syndrome is heterogeneous and the taxonomy is complex and remains without a consensus. Hospitalization for acute worsening HF is understood by some as the result of progressive worsening of chronic HF and by others as an entity which acuteness has been compared to what is acute coronary syndrome to chronic coronary artery disease. Some believe that hospitalizations for HF do not represent a distinct pathophysiology than chronic HF and could be better managed by the optimization of chronic HF neurohumoral therapy. On the other hand although there are no data to support that short-term in-patient therapeutic approach improves post-discharge clinical outcomes, some speculate that protecting the injured heart during the acute process might have long term benefit. Alleviating dyspnea is still considered by regulatory agents as an endpoint valid in itself, as far as there is no excess of deaths. However most patients improve with standard therapy and the magnitude of additional dyspnea relief by the investigational drug might be marginal and therefore hardly statistically detectable. Alternative ways to test for and/or quantify dyspnea have been investigated with the aim to define a dyspnea measure that is more sensitive to change.

RELAX-HF and ASTRONAUT are two trials whose results have just been announced. Both exemplify the issues highlighted here above. RELAX-HF is a phase II/III trial design trial of 48 hour IV infusion of relaxin for the treatment of signs and symptoms in patients hospitalized for acute decompensated HF (no EF criteria). ASTRONAUT evaluates the 6 months efficacy and safety of aliskiren therapy on top of standard therapy, on morbidity and mortality when initiated early after hospitalization for acute decompensated HF and low EF. Results of PRONTO are now available. PRONTO is a randomized trial comparing the potent and rapid acting calcium channel blocker Clevidipine vs. SOC for the ability to rapidly control blood pressure and provide dyspnea relief in acute heart failure patients. PRONTO examplifies yet another trial model: intervening within the first 2 hours after admission. Lessons learnt from RELAX-HF and PRONTO within the context of other recent trials in acute heart failure will be the main topic of brainstorming at this workshop, examining the potential change in paradigm in this area. The aim of this workshop is to learn

The aim of this workshop is to learn from the PRONTO, RELAX-HF and ASTRONAUT experiences within the context of the other acute HF trials, understand the consequences of the results on the design of future trials, revision of regulatory guidlenes and on possible regulatory labeling on clinical practice.

         
    The various drug intervention options
    RELAX-HF, Omecamtiv mecarbil and other drug still on trial  
Prodcast présentation Speaker: Michael FELKER, Durham, USA  
    ASTRONAUT  
Prodcast présentation Speaker: Aldo MAGGIONI, Florence, ITA  
    Execution issues. Where best to screen and enroll patients? Overcoming variations in health care systems and globalization issues  
Prodcast présentation Speaker: Mihai GHEORGHIADE, Chicago, USA  
    PRONTO: The merit and consequences of a very early intervention with an arterial vasodilator  
Prodcast présentation Speaker: Frank PEACOCK, Cleveland, USA  
    Endpoint related issues. The value of dyspnea as an endpoint in acute HF, upon admission trials  
Prodcast présentation Speaker: Alexandre MEBAZAA, Paris, FRA  
    The value of repeat events in post discharge hospitalized HF trials  
Prodcast présentation Speaker: Stuart POCOCK, London, GBR  
Prodcast présentation Regulatory viewpoint: Yuki ANDO, PMDA, JAP - Robert HEMMINGS, MHRA, GBR  
         
    Panellists:
    ANDO Yuki, PMDA, JAP - ANKER Stephan, Berlin, GER - BAKRIS George, Chicago, USA - BRUTSAERT Dirk L, Antwerp, BEL - BUYSSE Jerry, Relypsa, USA - CLELAND John, Hull, GBR - CODY Robert, J&J, USA - COHEN-SOLAL Alain, Paris, FRA - DUNDER Kristina, EMEA, SWE - DUNLAP Stephanie, Chicago, USA - FELKER Michael, Durham, USA - FIUZAT Mona, Durham, USA - GHEORGHIADE Mihai, Chicago, USA - GORDON David, NHLBI, USA - HEMMINGS Robert, MHRA, GBR - KIM Jae, Amgen, USA - MAGGIONI Aldo, Florence, ITA - MARTINEZ Felipe, Cordoba, ARG - MEBAZAA Alexandre, Paris, FRA - METRA Marco, Brescia, ITA - O’CONNOR Christopher, Durham, USA - PEACOCK Frank, Cleveland, USA - PFEFFER Marc, Boston, USA - PIÑA Ileana, New York, USA - POCOCK Stuart, London, GBR - ROESSIG Lothar, Bayer, GER - ROSANO Giuseppe, EMEA, ITA - SHINAGAWA Kaori, PMDA, JAP - SWYNGHEDAUW Bernard, Paris, FRA - VOORS Adrian, Groningen NED - ZANNAD Faiez, Nancy, FRAER Rolf, Göttingen, GER - ZANNAD Faiez, Nancy, FRA
         
  12.45 15.15 SOUTINE / UTRILLO Lunch Debate Session 6
   

ESC Working group on cardiovascular pharmacology and drug therapy
International Society of Cardiovascular Pharmacotherapy (ISCP)
CardioVascular Clinical Trialists (CVCT)
Joint session

HEART FAILURE TRIALISTS WORKSHOP
LEARNING FROM RECENT TRIALS AND SHAPING THE FUTURE OF HEART FAILURE TRIALS
     
    Chairpersons: Juan Carlos KASKI, London, GBR - Bertram PITT, Ann Arbor, USA - Luis RUILOPE, Madrid, ESP
    Webcast: Patrick ROSSIGNOL, Nancy, FRA
   
  • “Drugs, in general, act not on single targets operating in a vacuum, but perturb a complex network of interacting proteins or metabolites to modify the dynamic output of a system that can extend well beyond the pathway in which the original target is operative. Therefore, to develop drugs in this century, one needs to move beyond the reductionist biomedical science of Occam, Descartes, Osler, and Ehrlich, and consider the complex biological system within which a drug acts holistically, in its tractable entirety. One needs to apply the principles of systems biology to pharmacology, and thereby establish the new discipline of systems pharmacology.” Dr Joseph Loscalzo, Lewis A. Conner Lecture, Circulation 2012.
  • “We need to develop a robust, viable business model through which the pharmaceutical industry can move from drug development strategies that are population-based to strategies that focus on increasingly individualized therapies. There needs to be an alignment of incentives that move the industry from conventional blockbuster drugs developed in large populations with single drug targets within which one size fits all toward smaller, better defined systems pharmacologybased molecular pathophenotypes that benefit from these well conceived therapies with minimal risk.” Dr Joseph Loscalzo, Lewis A. Conner Lecture, Circulation 2012.
  • “Regulatory bodies like the FDA and the EMA will most likely require new trials to scrutinize events (i.e. AMI) very strictly. Well conducted registries will be important in this context so clinicians can report their findings in real life patients. Academic institutions and independent pharmacological and pharmacotherapy associations such as ISCP should provide mechanistic data as to the possible reasons for the detected increased prevalence of MI in some patient groups receiving treatment with direct thrombin inhibitors. Lessons learned with other new pharmacological agents in the past will necessarily require that the medical and pharmacological communities together with industry and regulatory agencies take up the challenge and work synergistically and in synchrony to clarify the side effects and excess MI risk – albeit minimal according to current studies - associated with the newer anticoagulants.
    We are all now at the start of a long and winding road that should hopefully take us to better understand the mechanism of action, the therapeutic efficacy and the adverse effects associated with the use of the new anticoagulants. Together we should prevent unnecessary complications that might derive from the use of these important agents in the wrong patient groups.”
    Juan Carlos Kaski, Cardiovasc Drugs Ther, 2012
       
    Omics research and system biology. Keys for future personalized medicine  
   

How future trials may help optimizing benefit-to-risk ratio. The role of specialist scientific organizations.
ISCP:

  présentation Speaker: Felipe MARTINEZ, Cordoba, ARG  
   

CVCT:

Prodcast présentation Speaker: Faiez ZANNAD, Nancy, FRA  
   

ESC Working group in Pharmacology and Drug Therapy

Prodcast présentation Speaker: Christian TORP-PEDERSEN, Copenhagen, DEN  
    The role of biomarkers  
Prodcast présentation Speaker: Stefan BLANKENBERG, Hamburg, GER  
    Industry viewpoints  
    Speaker: Michael MENDELSOHN, Merck, USA  
    Journal editor’s viewpoints  
Prodcast   Discussion: John JANDRO, Boston, USA, NEJM  
Prodcast présentation Discussant: Rita REDBERG, San Francisco, USA, Arch Intern Med
         
    Panellists:
    ADAMS Kirkwood, Chapel Hill, USA - ADOURIAN Aram, BG Medicine, USA - BLANKENBERG Stefan, Hamburg, GER - CALVO Gonzalo, Barcelona, ESP - CLEMMENSEN Peter, Copenhagen, DEN - COOK Nakela, NHLBI, USA - GELLER Nancy, NHLBI, USA - GOLDSMITH David, London, GBR – HOUDIJK Wim, Biomérieux, FRA - JANUZZI Jim, Boston, USA - JARCHO John, Boston, USA - KASKI Juan Carlos, London, GBR - LOSCALZO Joseph, Boston, USA - MARTINEZ Felipe, Cordoba, ARG - MENDELSOHN Michael, Merck, USA - PITT Bertram, Ann Arbor, USA - REDBERG Rita, San Francisco, USA - ROSENBERG Yves, NHLBI, USA - RUILOPE Luis, Madrid, ESP - SNIDER James, Critical Diagnostics, USA - TORP-PEDERSEN Christian, Copenhagen, DEN
         
  15.30 17.00 MODIGLIANI Debate Session 4
HEART FAILURE REMOTE MONITORING TRIALS
         
    Chairpersons: Stefan ANKER, Berlin, GER - Ileana PIÑA, New York, USA
    Webcast: Daniela DOBRE, Nancy, FRA
       
    Case studies and ultimate methodology for future trials  
   

Remote monitoring remains an appealing option for following patients after a heart-failure hospitalization. Trials employing common strategies (simple phone calls with a nurse and Telemonitoring of vital signs) have in general not demonstrated improvement in survival and or reduction in risk of readmission; meta-analysis of telemonitoring trials using these common strategies, however, have shown improvements in survival and hospitalization rates. Recently, trials of more complex implanted remote monitoring devices that provide physiologic information have reported mixed results.

The 2 most recently published device remote monitoring trials are excellent case-studies that may serve for methodologically refining future trials:

         
   
  • The CHAMPION trial was the first trial of a technology based (pulmonary artery pressure) telemonitoring (CardioMEMS), published in a major scientific journal (The Lancet) without standing positive results. The FDA advisory panel found the device to be safe (9-1 vote) but did not vote in favor of efficacy (4-6 vote) because of inability to distinguish the effect of the device from the support provided by the Sponsor to the investigators during the trial. The panel and the FDA were also concerned that this level of Sponsor support may not be practical in the commercial setting. The PIs and the Sponsor, however, pointed out that the device provides information only and to adequately test the trial hypothesis (management of pulmonary artery pressure in addition to routine HF care would reduce HF hospitalizations), there had to be a protocol compliance mechanism to ensure that physicians reviewed and responded to pulmonary artery pressures per the protocol mandated guidelines. This trial poses interesting methodological questions regarding the evaluation of diagnostic devices; how do we design trials with therapeutic endpoints for purely diagnostic devices?
  • The DOT-HF trial reported that Telemonitoring based on thoracic impedance was unexpectedly associated with more frequent hospital admissions in the Telemonitoring group. Then the question arises whether this trial failed because the technology - i.e. impedance - failed to deliver the right alerts at the right time or whether the strategy of care using the technology (beep alerts to the patient, no decision support to the health care providers who managed patients according to a standardized intervention algorithm, on the basis of the available data and the clinical evaluation) was inadequate/ insufficient.
     
   

The aim of this workshop is by analyzing lessons from these 2 case-studies, to hopefully reach agreement on the ultimate methodology of future trials of remote monitoring.
ISCP:

       
    Session program:  
    How to minimize bias? Trial design, control group, blinding and other methodological issues  
  Speaker: Stefan ANKER, Berlin, GER  
    Treatment optimization: Letting investigators decide vs. applying protocol defined algorithms (predefined, monitored, decision support
systems)
 
Prodcast présentation Speaker: William T. ABRAHAM, Columbus, USA  
    What endpoint for securing approval (FDA, and in EU, beyond CE mark) and reimbursement  
Prodcast présentation Debate led by regulatory agencies: Andrew FARB, FDA, USA - Ileana PIÑA, New York, USA  
         
    Panellists:
    ABRAHAM William T., Columbus, USA - ANKER Stefan, Berlin, GER - BORER Jeffrey, New York, USA - BRUTSAERT Dirk L, Antwerp, BEL - CODY Robert, J&J, USA - DE FERRARI Gaetano, Pavia, ITA - FARB Andrew, FDA, USA - LINDE Cecilia, Stockholm, SWE - MEHRAN Roxana, New York, USA - SHIPMAN Tami, St Jude Medical, USA - STEIN Kenneth, Boston Scientific, USA - SWYNGHEDAUW Bernard, Paris, FRA - VINCENT Alphons, Medtronic, CHE - YADAV Jay, CardioMEMS, USA
         
  15.30 17.00 SOUTINE / UTRILLO Debate Session 7
WHAT IS THE OPTIMAL DESIGN FOR BIOMARKER STUDIES?
         
    Chairpersons: Jim JANUZZI, Boston, USA - Faiez ZANNAD, Nancy, FRA
    Webcast: Alain COHEN-SOLAL, Paris, FRA
         
    How should diagnostic/prognostic markers be studied?  
Prodcast présentation Speaker: Jim JANUZZI, Boston, USA  
Prodcast présentation Discussant: James SNIDER, Critical Diagnostics, USA
    Best statistical methods for evaluating the merits of a novel marker  
Prodcast présentation Speaker: Stefan BLANKENBERG, Hamburg, GER  
Prodcast présentation Discussant: Nancy GELLER, Bethesda, USA
Prodcast   Discussion:
    Biomarker guided-therapy: Are there other endpoints besides mortality that matter? Selecting the best outcome measures  
Prodcast présentation Speaker: Michael FELKER, Durham, USA  
    Targeting biomarker defined mechanistic phenotypes. Challenges and opportunities of a new paradigm  
  présentation Speaker: Faiez ZANNAD, Nancy, FRA  
  Discussant: Kirkwood ADAMS, Chapel Hill, USA
    Debate led by Journal Editors: There are too many studies and the quality is variable.
Should there be a position statement establishing rules for biomarker studies?
 
Prodcast   John JARCHO, Boston, USA, NEJM  
Prodcast   Rita REDBERG, San Francisco, USA, Arch Intern Med  
Prodcast   Mona FIUZAT, Durham, USA, JACC-HF  
    John CLELAND, Hull, GBR, Former Eur J Heart Failure  
         
    Panellists:
    ADAMS Kirkwood, Chapel Hill, USA - BLANKENBERG Stefan, Hamburg, GER - CLELAND John, Hull, GBR - COHEN-SOLAL Alain, Paris, FRA - COOK Nakela, NHLBI, USA - DUNLAP Stephanie, Chicago, USA - FELKER Michael, Durham, USA - FIUZAT Mona, Durham, USA - GELLER Nancy, NHLBI, USA - HOUDIJK Wim, Biomérieux, FRA - JANUZZI Jim, Boston, USA - JARCHO John, Boston, USA - KIM Jae, Amgen, USA - LASALVIA Luis, Siemens, USA - LOSCALZO Joseph, Boston, USA - MASCETTE Alice, NHLBI, USA - MEBAZAA Alexandre, Paris, FRA - NARULA Jagat, New York, USA - O’CONNOR Christopher, Durham, USA - PATHAK Atul, Toulouse, FRA - POCOCK Stuart, London, GBR - REDBERG Rita, San Francisco, USA - SEMJONOW Véronique, Philips, NED - SNIDER James, Critical Diagnostics, USA - VOORS Adrian, Groningen, NED - ZANNAD Faiez, Nancy, FRA
         
  15.20 19.30 MODIGLIANI Debate Session 5
NOVEL DIURETIC STRATEGIES IN HEART FAILURE
         
    Chairpersons: Keld KJELDSEN, Copenhagen, DEN - Gian Paolo ROSSI, Padua, ITA
    Webcast: Patrick ROSSIGNOL, Nancy, FRA
         
   
  • Clinical congestion due to volume overload is the main cause of hospitalization for patients with HF and is an important therapeutic target. Failure to achieve effective and rapid correction of this condition in many patients hospitalized for HF results in prolongation of hospital stay and unfavorable after-discharge outcome.
  • Loop diuretics, though often effective for treating congestion, have significant limitations. Discovering ways to optimize exposure to loop diuretics, achieving effective decongestion while protecting renal function, is an important goal of current clinical research in HF.
  • Vasopressin antagonists are effective in removing large amounts of water, but not salt, in HF. The EVEREST trial in unselected acute systolic heart failure did not show benefit on CV outcomes and only a modest benefit on dyspnea. Whether vaptans in HF are still a viable option is an important question. Better targeting specific vasopressin receptors with highly selective agents, better profiling of patients more likely to benefit, combination with mineralocorticoid receptor antagonists are options that are worth exploring.
  • Aquapharesis (Ultrafiltration: UF) has been shown to be a safe and effective therapeutic modality for correction of volume overload in hospitalized patients with HF, not responding to intravenous diuretics and vasoactive medications. Should UF replace intravenous diuretics as a first-line therapy for patients with hypervolemia admitted for HF? The validity of such a concept is being examined in the NHLBI larger CARRESS study.
         
    Session program:  
    Insights from DOSE and gaps in evidence with diuretic therapy  
Prodcast présentation Speaker: Alice MASCETTE, NHLBI, USA  
    The Vaptans story post-EVEREST.
What is next? ACTIVATE, TACTICS and BALANCE trials
 
Prodcast présentation Speaker: Michael FELKER, Durham, USA  
Prodcast présentation Discussant: William T. ABRAHAM, Colombus, USA
    Ultrafiltration for acute cardiorenal syndrome in heart failure. UNLOAD and AVOID-HF and CARRESS trial  
Prodcast présentation Speaker: Gian Paolo ROSSI, Padua, ITA + Discussion  
    Ultrafiltration for acute cardiorenal syndrome in heart failure. UNLOAD and AVOID-HF and CARRESS trial  
         
    Panellists:
    ABRAHAM William T., Colombus, USA - ANKER Stefan, Berlin, GER - CLELAND John, Hull, GBR - CODY Robert, J&J, USA - FELKER Michael, Durham, USA - FIUZAT Mona, Durham, USA - GHEORGHIADE Mihai, Chicago, USA - GOLDSMITH David, London, GBR - HEMMINGS Robert, MHRA, GBR - KIM Jae, Amgen, USA - KJELDSEN Keld, Copenhagen, DEN - MASCETTE Alice, NHLBI, USA - MEBAZAA Alexandre, Paris, FRA - PITT Bertram, Ann Arbor, USA - ROSSI Gian Paolo, Padua, ITA - VOORS Adrian, Groningen, NED
         
  17.20 19.30 SOUTINE / UTRILLO Debate Session 8
HYPERTENSION TRIALIST WORKSHOP: AUTONOMIC MODULATION THERAPY
         
    Chairpersons: George BAKRIS, Chicago, USA - Sverre E. KJELDSEN, Oslo, NOR
    Webcast: Michel AZIZI, Paris, FRA
         
   
    Resistant hypertension is usually defined as uncontrolled hypertension despite the intake of at least 3 antihypertensive drugs in full doses including a diuretic. Most investigators would also claim that this also implies 24-hours systolic blood pressure remaining above 135 (or 140) mmHg. Over the years some evidence has accumulated that raised sympathetic nervous system activity is involved in the pathogenesis of hypertension and particularly so in more severe hypertension.
  • Ablation of the renal nerves located in the adventitia of renal arteries has emerged as a novel treatment modality and a catheter manufactured by Adrian/Medtronic has been CE approved in Europe based on one RCT (SYMPLICITY -2). A much larger trial is ongoing (SIMPICITY 3). Several other producers have applied for approval.
  • CVRx have developed Barostim based on carotid baroreceptors stimulation and have gathered some early experience with encouraging results that led to CE mark.
  • These techniques have rapidly been taken up in several countries including in a large number of centers in Germany.
  • Beyond resistant hypertension, various devices providing autonomic modulation therapy are entering the clinical development stages also in heart failure, CKD and diabetes.
  • Vagal stimulation developed by Medtronic (Biocontrol) and Boston Scientific are being tested in the INOVATE-HF and NECTAR-HF respectively in systolic heart failure.
  • Spinal Cord stimulation is considered by many in small proof of concept trials (St Jude SCS HEART) (Medtronic DEFEAT-HF)
  • Understanding the differences in the clinical and regulatory environments in the United States and Europe helps explain why much early device testing takes place outside of the United States, and why the introduction of new devices into clinical practice is usually significantly delayed in the United States when compared with Europe.
  • Both phenomena are direct results of inherent differences in the criteria for approval and the process required to obtain approval. In particular, the European CE Mark process requires demonstration of safety only (and not efficacy) and relies heavily on non-governmental notified bodies to regulate the approval and post-approval process. In contrast, the approval of a new high-risk device in the United States requires demonstration of both safety and efficacy and is more highly regulated by a central governmental agency (CDRH/FDA).
   

The aim of this workshop is to assemble primary investigators of a number of important ongoing trials and discuss preliminary results, strengths and limitations of the current trials, efficacy and safety endpoint related issues, as well as issues related to optimal trial design, approvability and implementation into daily clinical practice.

   

Device companies: CVRx, Medtronic, St. Jude, Marquette, Boston Scientific, Vessix Vascular, ReCor Medical, Adrian, Biosense, Maya Medical.

   

Trials: ARSENAL – DERENEDIAB - DENERV-HTN – DEPART – DREAMS – DIASTOLE - the Dutch trial – ENCOReD – INSPiRED - Oslo RDN Trial - PRAGUE-15 - REDUCE-HTN – ReSET – REVISE - Symplicity HTN 1-2-3 - the GBR trial - INNOVATE-HF - NECTAR-HF - SCS HEART - DEFEAT-HF - SCS Heart

    Session program:  
    Resistant hypertension trials: Can renal denervation therapy lower blood pressure?  
Prodcast présentation Speaker: Felix MAHFOUD, Homburg, GER  
Prodcast présentation Discussant: Michel AZIZI, Paris, FRA
    Barostim: Experience so far and future developments  
  présentation Speaker: Hermann HALLER, Hannover, GER  
Prodcast présentation Discussant: Nadim YARED, CVRx, USA
    Autonomic modulation therapy for heart failure: Preclinical data and ongoing trials  
Prodcast présentation Speaker: Faiez ZANNAD, Nancy, FRA  
  Discussant: Gaetano DE FERRARI, Pavia, ITA
    Debate : What relevant endpoints in autonomic nerve modulation therapy trials?
What kind/level of evidence? Targets to meet for approval (FDA, and in EU, beyond CE mark) and reimbursement
 
Prodcast   Investigator viewpoint: George BAKRIS, Chicago, USA - Ileana PIÑA, New York, USA  
Prodcast   Regulatory viewpoint: Andrew FARB, FDA, USA
Prodcast   Industry viewpoint: Rob KIEVAL, CVRx, USA
Prodcast   Industry viewpoint: Kenneth STEIN, Boston Scientific, USA
         
Prodcast   Panellists:
    AZIZI Michel, Paris, FRA - BAKRIS George, Chicago, USA - DE FERRARI Gaetano, Pavia, ITA - FARB Andrew, FDA, USA - GOBBI Giorgio, Medtronic, CHE - HALLER Hermann, Hannover, GER - KIEVAL Rob, CVRx, USA - KJELDSEN Sverre E., Oslo, NOR - LINDE Cecilia, Stockholm, SWE - MAHFOUD Felix, Homburg, GER - PATHAK Atul, Toulouse, FRA - PIÑA Ileana, New York, USA - SLEIGHT Peter, Oxford, GBR - STEIN Kenneth, Boston Scientific, USA - WACHTER Rolf, Göttingen, GER - YARED Nadim, CVRx, USA - ZANNAD Faiez, Nancy, FRA