Novel treatment options for acute hf a multidisciplinary approach (printer friendly)

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CME Information

CME Released: 12/23/2013 ; Valid for credit through 12/23/2014

Target Audience

This educational activity is intended for cardiologists, internists, primary care physicians, emergency medicinephysicians, nurse specialists, physician assistants, and pharmacists.

Goal

The goal of this activity is to discuss current and emerging therapies for acute heart failure with an emphasis on amultidisciplinary approach in order to improve patient outcomes.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Evaluate current and emerging therapeutic opportunities for patients with acute heart failure.2. Summarize collaborative strategies for multidisciplinary management of acute heart failure that starts in the

emergency department and continues following discharge.

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Author(s)

Mona Fiuzat, PharmD

Assistant Professor of Medicine, Duke University Medical Center, Durham, North Carolina

Disclosure: Mona Fiuzat, PharmD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Roche

Received grants for clinical research from: Astellas Pharma, Inc.; Gilead Sciences, Inc.; Otsuka Pharmaceutical Co.,

Ltd.; ResMed; Roche

Owns stock, stock options, or bonds from: ARCA Biopharma

Dr Fiuzat does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved

by the FDA for use in the United States.

Dr Fiuzat does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not

approved by the FDA for use in the United States.

Christopher M. O'Connor, MD

Director, Duke Heart Center; Professor of Medicine, Department of Medicine; Chief, Division of Cardiology and Clinical

Pharmacology, Duke University Medical Center, Durham, North Carolina

Disclosure: Christopher M. O'Connor, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Actelion Pharmaceuticals, Ltd; HeartWare International, Inc.; ResMed; Roche

Received grants for clinical research from: Amgen Inc.; Astellas Pharma, Inc.; GE Healthcare; Gilead Sciences, Inc.;

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Otsuka Pharmaceutical Co., Ltd.; Roche

Owns stock, stock options, or bonds from: NeuroTronik; Syncor

Owns patent with: Biscardia, LLC

Dr O’Connor does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics


Dr O’Connor does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not


John R. Teerlink, MD



Professor of Medicine, University of California, San Francisco; Director, Heart Failure and Clinical Echocardiography,

San Francisco Veterans Affairs Medical Center, San Francisco, California

Disclosure: John R. Teerlink, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Amgen Inc.; Corthera, Inc.; Cytokinetics; Merck & Co., Inc.; Novartis

Pharmaceuticals Corporation; Trevena, Inc.

Received grants for clinical research from: Amgen Inc.; Corthera, Inc.; Cytokinetics; Merck & Co., Inc.; Novartis

Pharmaceuticals Corporation; Trevena, Inc.

Dr Teerlink does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved


Dr Teerlink does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved


Robin J. Trupp, PhD, RN, ACNP-BC, CHFN

Clinical Associate, Duke University School of Nursing; Heart Failure Nurse Practitioner, Duke University Hospital

System, Durham, North Carolina

Disclosure: Robin J. Trupp, PhD, RN, ACNP-BC, CHFN, has disclosed no relevant financial relationships.

Dr Trupp does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved


Dr Trupp does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not


Editor(s)

Joy Marko, MS, APN-C, CCMEP

Scientific Director, Medscape, LLC

Disclosure: Joy Marko, MS, APN-C, CCMEP, has disclosed no relevant financial relationships.

Steering Committee

James L. Januzzi, MD



Associate Professor of Medicine, Harvard Medical School; Roman W. DeSanctis Endowed Clinical Scholar; Director,

Cardiac Intensive Care Unit, Massachusetts General Hospital, Boston, Massachusetts

Disclosure: James L. Januzzi, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Amgen Inc.; Critical Diagnostics; Novartis Pharmaceuticals Corporation;

Roche

Received grants for clinical research from: BG Medicine; Critical Diagnostics; Roche; Thermo Fisher Scientific Inc.

Ileana L. Piña, MD

Professor of Medicine & Epidemiology and Population Health, Albert Einstein College of Medicine; Associate Chief

for Academic Affairs, Montefiore Einstein Center, Bronx, New York

Disclosure: Ileana L. Piña, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: GE Healthcare; Novartis Pharmaceuticals Corporation

Served as a speaker or a member of a speakers bureau for: Otsuka Pharmaceutical Co., Ltd.

John R. Teerlink, MD

As listed above.

Peter S. Pang, MD

Associate Professor, Northwestern University Feinberg School of Medicine; Associate Chief, Department of

Emergency Medicine, Northwestern Memorial Hospital, Chicago, Illinois

Disclosure: Peter S. Pang, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Janssen Pharmaceuticals Products, L.P.; Medtronic, Inc.; Novartis

Pharmaceuticals Corporation; Otsuka Pharmaceutical Co., Ltd.; SpringLeaf Therapeutics; Trevena, Inc.

Received grants for clinical research from: Abbott Laboratories; Alere

William T. Abraham, MD

Professor of Internal Medicine, Physiology, and Cell Biology; Director, Division of Cardiovascular Medicine, Ohio

State University Wexner Medical Center, Columbus, Ohio

Disclosure: William T. Abraham, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Abbott Laboratories; BIOTRONIK; CardioKinetix Inc.; CardioMEMS, Inc.;

CVRx, Inc.; Medtronic, Inc.; Novartis Pharmaceuticals Corporation; St. Jude Medical; Sunshine Heart, Inc.; Zoll

Medical Corporation

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

From Medscape Education Cardiology

John R. Teerlink, MD; Christopher O’Connor, MD, FACC, FESC; Mona Fiuzat, PharmD, FACC; Robin J. Trupp, PhD,

Novel Treatment Options for Acute HF: A MultidisciplinaryApproach CME

http://www.medscape.org/cardiology



RN, ACNP-BC

Slide 1.

John R. Teerlink, MD: Hello. I am John Teerlink, Professor of Medicine at University of California San Francisco and

Director of the Heart Failure and Clinical Echocardiography Department at the San Francisco VA Medical Center in

San Francisco, California. I would like to welcome you to this program titled, “Novel Treatment Options for Acute

Heart Failure: A Multidisciplinary Approach”.

This program may include discussion of investigational drugs, biologics, or diagnostics not approved by the FDA for

use in the United States. The goals of this program are to evaluate current and emerging therapeutic opportunities for

patients with acute heart failure and to summarize the collaborative strategies for multidisciplinary management of

acute heart failure that starts in the emergency department and continues through the patient’s care at home.

CME Released: 12/23/2013 ; Valid for credit through 12/23/2014



Slide 2.

Joining me today is Dr Mona Fiuzat, who is an Assistant Professor of Medicine at the Duke University Medical

Center, as well as Dr Christopher O’Connor, Professor of Medicine and Chief of Cardiology, as well as Director of the

Duke Heart Center at Duke University Medical Center, as well as Dr Robin Trupp, who is a Nurse Practitioner in the

Division of Cardiology and Clinical Associate of the School of Nursing at the Duke University Medical Center.

Welcoming them makes me wonder who is actually taking care of patients back at Duke with basically all of you

here with us today. Anyway, welcome.

Christopher O’Connor, MD, FACC, FESC: Thank you, John.

Mona Fiuzat, PharmaD, FACC: Thank you, John.

Robin J. Trupp, PhD, RN, ACNP-BC: Thank you, John.



Slide 3.

Dr Teerlink: We are here to talk about the acute heart failure epidemic. I think all of us recognize that over six million

persons are currently diagnosed with heart failure now and over 670,000 new diagnoses this year. This has resulted in

over 1 million hospitalizations for heart failure, over 3.6 million diagnoses of heart failure in the hospitalized patients,

and an annual cost over 23 billion dollars. It is the most common cause of admission in the elderly in the United

States, and it is clearly a major problem. You all confront these patients. Do you have a sense of who these patients

are and who are you seeing in the clinic? What are the kind of characteristics of these folks that you are seeing and

taking care of? Hunt et.al. Roger VL Jencks



Slide 4.

Dr O’Connor: John, from a heart center standpoint, this is a huge problem, these admissions, these 1 million

admissions. As the Director of the Heart Center, we are very concerned about how can we prevent these admissions,

but more importantly, once they are admitted, how do we get them through the hospital course safely, without

complications, without increasing the length of stay, treated well, so they are not readmitted in 30 days. We are

penalized as a heart center if they are readmitted, and we want the best course for these patients.

Dr Teerlink: Certainly, with the change in these CMS rules now, that is kind of a real pressure on us, and I think one

of the things that you are working at a very specialized heart center. I think one of the things that we have had to

transition a bit from is the view of the heart failure patient at these highly specialized transplant centers to getting an

understanding of who the general patients are with acute heart failure. http://www.cms.gov/

Dr O’Connor: Yes.



Slide 5.

Dr Teerlink: In general, these are patients who are in their mid-70s, half of these patients are women, and they have

multiple multiple comorbidities with an increasing incidence of diabetes in these patients. In your center, where would

you say the mean blood pressure is for your kind of transplant patients coming into the hospital would be? Adams,

Cleland, Fonarow

Dr O’Connor: John, you make a good point. Everybody thinks, well they used to think that advanced heart failure in

these transplant centers was for patients who had these low blood pressures, but as you point out, the most

common type of heart failure has an elevated blood pressure, is congested, and has lots of comorbidities, is elderly,

and it is a real different challenge than we used to think about.

Dr Teerlink: Right. Right. Which makes it sort of an exciting, new area because we have not had the chance to

actually look at it as a specific disease entity. What we are also seeing, I think, is that we are dividing these patients

up into three main groups. You have the patients who have known heart failure, who are coming in with a worsening of

their chronic heart failure episodes. This represents most of the patients or so. The rest of the patients are split

between the patients who are coming in with new-onset heart failure, and then these very advanced heart failure

patients, who places at advanced cardiac centers you specialize in taking care of those types of patients.

As you point out, you talked about the issue with readmission is an issue. Robin, from your experience with these

patients, I mean, clearly they are very sick patients. Do you have a sense of what their kind of post-discharge event

rate is in terms of mortality?



Slide 6.

Dr Trupp: Why I think nationally, we know that it is about 15%, but it is even higher in those that have advanced

heart failure, so it is a big challenge because as you are admitted already, they have a lot of comorbidities and the

whole transition of care form inpatient to outpatient is a huge endeavor that we really never appreciated until now.

Cotter, G.

Dr Teerlink: Right. I think one of the things that has always been interesting to me to discover is if you had a choice,

and this would be a strange choice to be given, of being admitted to the hospital with an acute myocardial infarction,

or an acute heart failure episode that your mortality and chance of being rehospitalized for heart failure are actually

higher if you are admitted with an acute heart failure episode.



Slide 7.

This kind of circles around where we are with, I think, the current goals of heart failure therapy, and Chris, you did a

great job of summarizing them. I think we want to first make people feel better, help them get rapid improvement in

their symptoms, and clinical stabilization, but also try to find ways to improve those longer term outcomes. We

currently are trying to meet those goals and - - Mona, currently, we have current therapies. Can you tell us a bit about

how those therapies are established, and do they help with these kind of current goals?



Slide 8.

Dr Fuizat: Sure. I think that really the cornerstone for acute heart failure right now is the diuretics. We know that here

is a strong story. We know that they work very well when the patients are in the hospital, but really, this therapy has

not changed much in the last, really 15, 20 years from where we started. Really just he symptomatic relief and we do

not have long-term outcome benefits that we can really tie to those types of therapies.



Slide 9.

We also know that from data from registries has shown us that patients are still leaving the hospital congested.

About half of the patients are still having some congestion. About a third of the patients are still having some

significant congestion, and I think that is really leading us back to this high readmission rate. I think with the

challenges, especially in the US, of having shorter hospital stays, we are getting those patients out without really fully

being able to treat them, and so here we are with the 30-day readmission rates post-event rates. (ADHERE)

Dr Trupp: I was just going to add, I think one of the challenges is that with diuretics, the impact on the kidney is so

pronounced that once they start to see a shift in renal function, we kind of back off on the diuretics, which is one

reason they go home probably not fully unloaded, or with normal volume states.

Dr Teerlink: Yes, I think that is something I definitely want to get to a little later, to the pathophysiology of this

congestion and other issues. We have the diuretic therapies. What about other agents that we have to potentially

help patients who are admitted with acute heart failure?

Dr Fiuzat: Right. Again, vasodilators, really not been shown to have long-term benefits, some symptomatic relief in

some patients, not all patients, inotropes, perhaps even dangerous in some patients. We are really left with an unmet

need for treating these patients in the hospital when they come in, and sending them back out where they are going

to end up back in the hospital, so this is really where the needs are, I think, in the pharmacotherapy.

Dr Teerlink: We have these sort of unmet needs. We have a patient population that is growing. Do we have an

understanding of what is the underlying pathophysiology of these acute heart failure patients? Chris, what do you

think?



Slide 10.

Dr O’Connor: It is multifactorial, as you can imagine. We have not really been very good at totally characterizing

these patients. That is maybe part of the challenge of why the therapies, we try to apply them to everyone, and we

have not seen the benefit, but we know they come in congested, we know that there is myocardial injury, we know

there is intense activation of the renin-angiotensin system, inflammatory markers. We know there is significant

endothelial dysfunction. All these things are happening in this state, so we need therapies that can attack at multiple

levels.

We know that there is a hemodynamic compromise of renal function, and that can play a big role. We know there is

congestion of the liver and congestion of the gastrointestinal tract that can play a role in adversely affecting the

outcome of these patients. A lot of organs are involved, and a lot of pathways that are activated when the patient

comes in decompensated.

Dr Teerlink: Certainly, one of the challenges that Mona referred to is the issues of diuretics, and Robin mentioned

also how we back off on diuretics when the patient’s creatinine goes up, we back off on diuretics. We stop their ACE

inhibitors. You are describing a neurohormonal storm in acute heart failure.

Dr O’Connor: That is right. Yes.

Dr Teerlink: We are yet withdrawing these therapies in many patients. I think one of the things that we are learning

from the trials that all of us have been involved in is that this congested state, if anything, requires more active

decongestion. Rather than backing off, many times, we actually need to intensify therapies, but it requires an

understanding of hat underlying pathophysiology.



Slide 11.

Dr O’Connor: Well in the fluid, we are learning. We have seen recent paper come to jacc heart failure, where the fluid

is, perhaps more interstitial than it is intravascular, and so pulling the fluid out is much more complicated than just

being able to use loop diuretics. I think when we have renal compromise, you start going up on the dose of the

diuretics, you start to get more renal compromise, you cannot pull the fluid off. These patients leave, physicians get

frustrated, and then they leave partially congested, and then when the com back in the hospital, they are even sicker

in that readmission. That is where you get that high mortality.

Dr Teerlink: Each of these episodes during these congested states, are there other adverse sequelae to these other

organs? I mean, do you think there is suggestion of end organ damage in these episodes?



Slide 12.

Dr O’Connor: I think there is, as you and I know, we have published on this, this troponin, I think is really very

important whether that is due to myocardial stretch or myocyte loss from other mechanisms. I think there is an

association with perhaps mortality or morbidity down the road with troponin release. A marker of something bad going

on, and we certainly, as you know, the regulatory industry, very concerned about the development of inotropes and

even using troponin as a potential safety marker.

Dr Teerlink: Exactly. Exactly. We are kind of in this situation where we have a big problem. We are learning more

about the pathophysiology, and I think that has opened some real options for defining these areas of unmet need. If I

may, I guess I will take a little prerogative and outline kind of three areas that I am seeing as real unmet needs.

First, I think we need agents that improve that volume removal while maintaining or improving renal function. Chris,

you were one of the co-PIs for one of the most important trials in this arena. Can you tell us a little bit about rolofylline

and how that worked out?



Slide 13.

Dr O’Connor: Sure. Yes. We had high hopes. We had high hopes for many of the drugs that we worked with.

rolofylline was one of them and it was a drug that looked like it helped renal function. Looked like there was also

benefit indirectly on decongestion. It looked like there was also benefit indirectly on decongestion. When we did the

large trial, we really did not see either of those benefits and a big disappointment. (O’connor)

As you know, ultrafiltration as a device therapy we thought would be very effect acute decompensated heart failure.

We did not see any improved outcomes in that study we did in the network.

Dr Teerlink: The ROSE-AHF study. (Chen)

Dr O’Connor: Yes. The ROSE-AHF study. Low-dose nesiritide, dopamine, not showing any benefits in this space,

so a) there is opportunity, b) we have had a lot of failures.

Dr Teerlink: Yes. There remains an unmet need.

Dr O’Connor: Yes.

Dr Teerlink: Then the second area that I think we have seen is drugs that improve cardiac performance without these

adverse effects, so Mona, you did a nice job outlining some of these adverse effects including hypotension,

arrhythmias, and death. A number of agents have come down the pipe along those lines, stresscopin, and the

nitroxyl donors, both of which were in early phase development kind of gone back for pharmacologic reformulation.



Slide 14.

A program that we have been involved with very actively is the Omecamtiv Mecarbil program. It is a selective cardiac

myosin activator. It avoids the intracellular increases in calcium, cyclic AMP, which is directly related to those

adverse effects that you outlined for us. We recently reported the Atomic AHS study. It is a 600-patient study in a

kind of complicated ascending cohort dose design, but I think the main message from that was it seemed like the

highest dose from that group. Cleland JGF

DNA proved dyspnea provided trends to reducing worsening heart failure. It seemed to be well tolerated, however, vis

à vis that earlier discussion, there were these very small troponin leaks that were detected, but really unclear

clinically significance this time. We are proceeding with that in terms of the oral program, the COSMIC-HF trial. That

is an area that remains an unmet need, but I think there may be a glimmer of hope there.

Finally, the third area is these vasodilators with demonstrated clinical benefits that health care providers will actually

use. Mona, what are some of the problems with the currently available vasodilators in terms of their use?

Dr Fuizat: Yes. I think one of the advantages that some of these newer therapies do offer is the fact that they do not

have to be titrated up. Really, you just start the medication and you can continue it through the hospitalization

without a lot of monitoring, without a lot of concern over some of the adverse effects that might happen, the

hypotension of course is a problem. We are not seeing that perhaps with some of the newer agents, so I think those

really offer an advantage.

Dr Teerlink: Thank you. One of the questions will be, is that because we are getting smarter in how we design our

trials?

Dr O’Connor: No.

Dr Teerlink: Is it because the agents are really that much better, and we will have to see?



Dr O’Connor: I think it is probably both. I think it is both.

Slide 15.

Dr Teerlink: I think it is probably a combination of both. We have at least three really interesting agents in this

arena. We have the TRV027, and the BLAST-AHF study that is coming up, and TRV027 is in Phase II, it is an

angiotensin type 1 receptor-biased ligand agonist, and this is the only drug that I am aware of recently that has been

endorsed with a Nobel Prize in Chemistry. A colleague from Duke, Dr Lefkowitz, shared the Nobel Prize for this

discovery of this mechanism. Drs Felker and Dr Pang are going to be the co-PIs for the Phase II international dose

finding study with this really interesting new approach in patients for acute heart failure. Additionally, Chris, you are

also co-PI on a very interesting new program with ularitide. Can you tell us a little bit about that quickly?

Dr O’Connor: Yes. This true AHF study, ularitide is an important study. I think it is a study looking at this agent that

pharmacologically vasodilator has very favorable effects on the renin angiotensin activation, renal hemodynamics. It is

what we think is one of those kind of safe vasodilators. We are conducting a clinical outcomes study looking at in

hospital assessment of worsening heart failure and assessment of the patient in the short-term, but also mortality.

This is a study that is planned at the onset of 2,000 patients, but could be sized up to a larger sample size. Really

looking at the acute decompensated heart failure patient, and getting treatment in early. That is something we have

not emphasized. I know you will, but we think one of the lessons we learned from ASCEND is probably early is going

to be very important in getting good outcomes.



Slide 16.

Dr Teerlink: I think it is an excellent point and carrying on in that, so we now have a completed Phase III study in the

acute heart failure arena with serelaxin, and serelaxin is a recombinant form of the hormone of pregnancy, relaxin.

Relaxin is currently in everybody sitting here right now. It is, in pregnancy, believed to contribute to the adaptations,

both cardiovascularly and renally, to the stresses of pregnancy.

We had preliminary studies that also suggested this is an agent that improves signs and symptoms of heart failure.

Clinical outcomes, and had this tantalizing suggestion of an improvement in mortality based on very small numbers,

but also this kind of global improvement in different types of organ protection.

We performed the RELAX-AHF study. 1,161 patients admitted for heart failure, who came in with normal to elevated

blood pressure, so we are targeting a specific patient population having mild to moderate renal impairment, and were

randomized to 48 hours of the placebo versus serelaxin. What we saw in this was we saw improved symptom relief

as measured by this visual analog scale over a five-day period, with a 19% treatment effect. Very highly significant P-

value, meeting the primary endpoint, showing that it was a positive trial.



Slide 17.

Did not show any improvement in the short-term dyspnea benefit, but in addition, along with this improvement in

dyspnea, we also saw significantly greater improvements in the signs and symptoms of heart failure, the worsening

heart failure episodes itself in hospital, the length of ICU and CCU stays were improved, as well as the overall length

of hospitalization, but there was no impact on the 60-day rehospitalizaion rate. In the context of all these kind of

improvements in clinical signs and symptoms, we showed a 37% reduction in the cardiovascular and all-cause

mortality, associated with improvement in those biomarkers. Teerlink

Getting back to that issue about end-organ protection, and showing that maybe there is some relationship between

calming this initial hormonal storm and providing longer term benefits. We are testing this hypothesis again in

RELAX-AHF2, and this is going to be a 6,000 patient study. We are going on and carrying on with this concept.

It looks like we have some interesting things coming down the pike, but all of these therapies do not do anybody any

good if we do not find a good way to take care of the patients in hospital, so Robin, this is something that you have

done extensive research on and really helped. It is why you are doing the great work you are at Duke right now.

Dr Trupp: Thank you.

Dr Teerlink: Can you tell us a bit about how we can approach multidisciplinary care in acute heart failure?



Slide 18.

Dr Trupp: I think these new therapies give us the chance to redesign both the care of acute heart failure, but how

that care is delivered in the inpatient setting. Our guidelines recommend outpatient multidisciplinary teams, but the

guidelines say little about inpatient care and the use of multidisciplinary teams or even interdisciplinary. I actually

prefer that term because I think it is more about the disciplines working together with each other.

I think it is quite exciting and I guess we need to think about forming these teams, who would be on the teams, and

more importantly, everyone can form the team, and the hospitals, we have teams, we have stroke teams, we have

code teams, we have rapid response teams, they all know their roles, they all work together, but how do you suggest

or think it would be good to get these different disciplines together to begin to look at acute heart failure. I think that

this will have an impact on the patient as they transition to the outpatient. Those are just some ideas.

Dr Teerlink: Who do you think are the providers that we - - who do we need to invite to the discussion, I guess is the

question?

Dr Trupp: Obviously, medicine and nursing, but I think pharmacy is a huge player that is typically under-recognized,

dietary plays a role as well, social services is a big one, case management, some places cardiac rehab. I think really

the sky is the limit. It gives us a chance, as long as these people play a role in assisting and facilitating inpatient and

transitioning to outpatient care.

Dr Fiuzat: It think too, it is important to recognize the emergency room as part of this because we are talking about

really early care as soon as the patient hits the door starting their heart failure therapies. I think that they really

should be incorporated more as part of our teams for heart failure care.

Dr Trupp: It think we need to recognize that because that is the portal of entry for most patients, so we need to work

with them so even maybe consulting in the ED when patients appear, to see who should be admitted and who should

not be.



Dr O’Connor: Exactly.

Dr Trupp: It should be a joint decision and not one person.

Dr Teerlink: This sort of goes to what Chris was saying earlier, that one of the things we have learned is there is a

reason it is called acute heart failure. Right? I mean, we have all these teams set up for myocardial infarctions where

time is myocardium. Do you think we have gotten to the stage now where we can actually consider time is

myocardium in acute heart failure as well?

Dr O’Connor: I think that is exciting. I mean, if these new agents really do what we think they might do, and we can

show by early intervention you reduce troponin release, you reduce injury, you reduce mortality, I mean, that is so

exciting. We have been waiting for this for 30 years.

Dr Teerlink: Shh. We are not supposed to talk about that.

Dr O’Connor: Only 20 for you. Ten for my colleagues over here.

Dr Trupp: Thank you, so much.

Dr Teerlink: It is clear that we need to bring into the conversation the emergency room. This is really a very broad

consensus. What do you think are the factors that contribute to developing that kind of good team and that good

teamwork?

Dr Trupp: I think it is everyone coming together and understanding the purpose. You can put people together, but

that does not form a team, so whoever is on the team has to have a common goal and believe in it. Creativity should

be valued because, obviously, what we have been doing is not working, given our readmission rates. Getting them to

feel valued. There has to be trust and mutual respect. It is no longer hierarchical. It is even playing grounds for

everyone.

Dr O’Connor: No. that does not work.

Dr Trupp: To me, it is just really exciting to think that we are going to have something new to offer as well as a new

way to deliver it.

Dr Teerlink: This does offer, as you point out, and exciting opportunity to kind of start again, and to reaffirm that this

is a very important target that really requires an approach across multiple disciplines, what more interdisciplinary

approaches.

Dr Trupp: Correct.

Dr O’Connor: What I think is interesting about that point, Robin, is that it is bringing together the health systems,

the third party payers, the government because we are getting all on the same page now. We all realize that we can

do better, and there is now incentive from all of these leadership positions to encourage these teams to be built.

Dr Teerlink: Not to get political here, but are you saying 30-day readmission rate may actually have some beneficial

effects in terms of instigating this?

Dr O’Connor: Instigating some. Instigating some good behavior.

Dr Trupp: We have to find some good benefits from it [crosstalk].

Dr Teerlink: How have you implemented this in your hospital? Do you have any pointers for people who are saying, I

believe, but how do I do it?



Dr Fiuzat: Well, I think you are seeing three member of the team here, but I think, really, incorporating someone to

represent each of the disciplines and coming together. Doing research together, working together on patient care, and

extending that to the outpatient care as well, I think, has really worked for us.

Dr Trupp: Yes. I think we have to get rid of silos. I know that is an old euphemism, but it is important. You cannot

have home care doing this, and primary care doing. We all have to begin to talk together because what we have in

common is the patient, and I think Chris’s comment is about systematic system wide approaches are very important.

It can no longer just be my facility, it has to be the patient’s community that is looking at them from that perspective

so we have to look beyond our walls to those providers out in the community.

Dr Teerlink: I will say that I have had the pleasure of working with Mona back in San Francisco. I will point out that I

think another very important aspect is just as you were for us, you really end to have some single strong advocate

who will push this through because as much as people are kind of giving lip service to being for this, it really takes an

individual to kind of spur on the process and gather the people together and coordinate the systems.

One of the things that we have been recommending at the VA health network has been having these specific

champions, and this is also H2H, the Hospital-to-Home initiative, where they are trying to find champions at the

individual hospital who will really lead this process forward.

Dr Trupp: You can have a champion, but it has to be the right champion, who believes in what you are doing, who

has the teamwork skills, the leadership communication, et cetera. Not everyone that is willing or wants to do it

should be the selected individual.

Dr Teerlink: Great. Great. This has been a great conversation and I guess I would like to go through and give

everybody a chance to maybe give their last point and summarize, if you will, something that you think is important or

takeaway message. Robin, let us start with you, and anything - - specific summary you would like to share.

Dr Trupp: Just I think it is an exciting time, and yes, no one likes the 30 day readmission penalties, but if some

good comes out of a necessary evil, which may be a political undertone, but it is what it is. I think that it is going to

be good.

Dr Teerlink: This is supposed to be controversial in discussing.

Dr Trupp: Thank you.

Dr Teerlink: Chris, what would you say?

Dr O’Connor: It is an exciting time because of the therapies, and the opportunities to have therapies that actually

work in acute decompensated heart failure. I think the community of healthcare providers are so excited about these

recent developments.

Dr Teerlink: Mona?

Dr Fiuzat: It is hard to add much to what my colleagues have said, but I agree. I think as a pharmacist it is very

exciting to have new therapeutic opportunities in the hospital and really make sure the patients are getting well

treated before they are leaving and making sure they are not going to be coming back, and of course, reducing side

effects as always. A really exciting thing to have in the armamentarium.

Dr Teerlink: Very good. I think you have used one of the required words for all discussions. We have used the word

armamentarium. I think I will add to that and use the other word that you have to use in these kinds of discussions

and say, this can perhaps represent a paradigm shift. We do actually now have an opportunity to look at acute heart

failure from a new and interesting ways, both in terms of understanding its pathophysiology better, having understood

where we have been in terms of current therapies, and how to bring people together to use these old therapies and



perhaps the new therapies to help our patients with acute heart failure.

Slide 19.

I really thank all of you for a really fantastic discussion. I would like to thank you for participating in this activity. You

may now take the CME post-test by clicking on the Earn CME Credit link. Please also take a moment to complete

the program evaluation that follows. Thank you very much.

This transcript has been edited for style and clarity.


Abbreviations

AE = adverse effect

AHF = acute heart failure

ASCEND HF = A Study Testing the Effectiveness of Nesiritide in Patients With Acute Decompensated Heart Failure

ATOMIC-AHF = Study to Evaluate the Safety and Efficacy of IV Infusion Treatment With Omecamtiv Mecarbil in

Subjects With Left Ventricular Systolic Dysfunction Hospitalized for Acute Heart Failure

BLAST-AHF = A Study to Explore the Efficacy of TRV027 in Patients Hospitalized for Acute Decompensated Heart

Failure

CMS = Centers for Medicare & Medicaid Services

IPPS = inpatient prospective payment system

PROTECT = Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline

fr Patients Hospitalized With Acute Heart Failure and Volume Overload to Assess Treatment Effect on Congestion

And Renal Function

RELAX-AHF = Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure




ROSE-AHF = Renal Optimization Strategies Evaluation in Acute Heart Failure

SBP = systolic blood pressure

TRUE-AHF = Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure

USD = US dollars

References

1. Hunt SA, Abraham WT, Chin MH, et al.; American College of Cardiology Foundation; American Heart

Association. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and

Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American

Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International

Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90. Abstract

2. Roger VL, Go AS, Lloyd-Jones DM; on behalf of the American Heart Association Statistics Committee and

Stroke Statistics Subcommittee. Heart disease and stroke statistics -- 2011 update: a report from the

American Heart Association. Circulation. 2011;123:e18-e209. Abstract

3. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service

program. N Engl J Med. 2009; 360:1418-1428. Abstract

4. Centers for Medicare & Medicaid Services. Readmissions Reduction Program.

http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/Readmissions-

Reduction-Program.html. Accessed December 17, 2014.

5. Adams KF Jr, Fonarow GC, Emerman CL, et al; ADHERE Scientific Advisory Committee and Investigators.

Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design,

and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National

Registry (ADHERE). Am Heart J. 2005;149:209-216. Abstract

6. Cleland JG, Swedberg K, Follath F, et al. The EuroHeart Failure survey programme: a survey on the quality of

care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J.

2003;24:442-463. Abstract

7. Cotter G, Milo O, Davison B. The pathophysiology of AHF: new insights from recent studies of novel diuretics

and vascular modulating therapies. World J Cardiovasc Dis. 2013;3:133-145.

8. Nieminen M, Bohm M, Cowie MR, et al . Executive summary of the guidelines on the diagnosis and treatment

of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart

J. 2005;26:384-416. Abstract

9. Gammage M. Treatment of acute pulmonary edema: diuresis or vasodilatation? Lancet. 1998;351:382-383.

Abstract

10. O'Connor CM, Fiuzat M. Impact of serial troponin release on outcomes in patients with acute heart failure:

analysis from the PROTECT pilot study. Circ Heart Fail. 2011;4:724-732. Abstract

11. Chen HH, AbouEzzeddine OF, Anstrom KJ, et al; for the Heart Failure Clinical Research Network. Circ Heart

Fail. 2013;6:1087-1094. Abstract

12. Cleland JGF, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on

cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2

trial. Lancet. 2011;378:676-683. Abstract

13. Marti C, Cole R, Kalogeropoulos A, Georgiopoulou, Butler J. Medical therapy for acute decompensated heart

failure: what recent clinical trials have taught us about diuretics and vasodilators. Curr Heart Fail Rep.

2012;9:1-7. Abstract

14. National Institutes of Health. Efficacy and safety of relaxin for the treatment of acute heart failure (RELAX-AHF)

. http://clinicaltrials.gov/ct2/show/NCT00520806?term=RELAX-AHF&rank=1. Accessed December 17, 2013.

15. National Institutes of Health. Efficacy and safety of ularitide for the treatment of acute decompensated heart

failure (TRUE-AHF). http://clinicaltrials.gov/ct2/show/NCT01661634?term=true-ahf&rank=1. Accessed

http://www.medscape.com/medline/abstract/19358937













December 17, 2013.

16. National Institutes of Health. Study to evaluate the safety and efficacy of IV infusion treatment with omecamtiv

mecarbil in subjects with left ventricular systolic dysfunction hospitalized for acute heart failure (ATOMIC-

AHF). http://clinicaltrials.gov/ct2/show/NCT01300013?term=atomic+ahf&rank=1 . Accessed December 17,

2013.

17. National Institutes of Health. A study to explore the efficacy of TRV027 in patients hospitalized for acute

decompensated heart failure (BLAST-AHF). http://clinicaltrials.gov/ct2/show/NCT01966601?term=blast-

ahf&rank=1 . Accessed December 12, 2013.

18. Teerlink JR, Cotter G, Davison BA, et al; RELAXin in Acute Heart Failure (RELAX-AHF) Investigators.

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomized,

placebo-controlled trial. Lancet. 2013;381:29-39. Abstract

Disclaimer

The educational activity presented above may involve simulated case-based scenarios. The patients depicted in thesescenarios are fictitious and no association with any actual patient is intended or should be inferred.

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that supporteducational programming on medscape.org. These materials may discuss therapeutic products that have not beenapproved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcareprofessional should be consulted before using any therapeutic product discussed. Readers should verify allinformation and data before treating patients or employing any therapies described in this educational activity.

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