Physiologic volume redistribution and acute heart failure management (printer friendly)

12/26/13 Physiologic Volume Redistribution and Acute Heart Failure Management (printer-friendly)

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CME Released: 09/23/2013; Valid for credit through 09/23/2014

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W. Frank Peacock, MD

Professor of Emergency Medicine; Associate Chair and Research Director, Baylor College of Medicine, Houston,

Texas, USA

Disclosure: W. Frank Peacock, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Singulex; The Medicines Company; Verathon Inc.

Served as a speaker or a member of a speakers bureau for: Abbott Laboratories; Alere; AstraZeneca

Pharmaceuticals LP; Daiichi Sankyo, Inc.; Verathon Inc.; Vital Sensors, Inc.

Received grants for clinical research from: Abbott Laboratories; Alere; BG Medicine; Brahms; Cardiorentis AG; GE

Healthcare; Janssen Pharmaceuticals Products, L.P.; Lilly USA, LLC; Novartis Pharmaceuticals Corporation; Roche;

The Medicines Company; Verathon Inc.

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

by the European Medicines Agency.

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

approved by the European Medicines Agency.

Panelists

Christian Mueller, MD

Department of Cardiology, University Hospital Basel, Basel, Switzerland

Disclosure: Christian Mueller, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Brahms; Novartis Pharmaceuticals Corporation; Roche

Served as a speaker or a member of a speakers bureau for: Abbott Laboratories; Alere; AstraZeneca

Pharmaceuticals LP; Brahms; Lilly USA, LLC; Novartis Pharmaceuticals Corporation; Roche; Siemens AG

Received grants for clinical research from: Abbott Laboratories; Alere; Brahms; Novartis Pharmaceuticals

Corporation; Roche; Siemens AG

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


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


Karl Swedberg, MD, PhD



Senior Professor, Section of Emergency and Cardiovascular Medicine, Department of Molecular and Clinical

Medicine, Sahlgrenska Academy, University of Göthenburg, Göthenburg, Sweden

Disclosure: Karl Swedberg, MD, PhD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Amgen Inc.; Novartis Pharmaceuticals Corporation; Roche; SERVIER

Served as a speaker or a member of a speakers bureau for: SERVIER

Received grants for clinical research from: Amgen Inc.; SERVIER

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


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


Piotr Ponikowski, MD, PhD

Professor and Head, Department of Heart Diseases, Medical University; Head, Department of Cardiology, Military

Hospital, Center for Heart Diseases, Wroclaw, Poland

Disclosure: Piotr Ponikowski, MD, PhD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Bayer HealthCare Pharmaceuticals; Corthera, Inc.; Johnson & Johnson

Pharmaceutical Research & Development, L.L.C.; Novartis Pharmaceuticals Corporation

Served as a speaker or a member of a speakers bureau for: Novartis Pharmaceuticals Corporation

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


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


Editor

Nancy Ashley, MSN, APRN-BC

Scientific Director, WebMD Global, LLC

Disclosure: Nancy Ashley, MSN, APRN-BC, has disclosed no relevant financial relationships.

Content Reviewer



Nafeez Zawahir, MD

CME Clinical Director

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

From Medscape Education

W. Frank Peacock, MD; Christian Mueller, MD; Karl Swedberg, MD, PhD; Piotr Ponikowski, MD, PhD

Slide 1.

W. Frank Peacock, MD: Hello. My name is Frank Peacock. I am Professor of Emergency Medicine, Associate

Chair and Research Director at Baylor College of Medicine in Houston, Texas in the United States. I will be your host

today as we discuss the future of acute heart failure management and volume redistribution. I am joined by several

colleagues. First is Christian Mueller from the Department of Cardiology at the University Hospital in Basel,

Switzerland. Second, we have Karl Swedberg, Professor of Medicine at the University of Göthenburg, in Göthenburg,

Sweden. In addition, we have Piotr Ponikowski, Professor and Head of the Department of Heart Disease at Medical

University, Wroclaw, Poland.

Given the fact that there is heterogeneity among patients with heart failure, we are going to discuss the different

clinical profiles of patients presenting with acute decompensation. Christian, can you start us off and make some

comments?

Christian Mueller, MD: Sure, Frank. I think one of the most important advances of recent years was to highlight that

Physiologic Volume Redistribution and Acute Heart FailureManagement CME

CME Released: 09/23/2013; Valid for credit through 09/23/2014

http://www.medscape.org/



acute heart failure is not a uniform disease. I think it is fair to say it is even not a uniform syndrome.

Slide 2.

Acute heart failure patients differ enormously, both in their vital signs and in the cardiac disease that underlies acute

heart failure, triggering the acute episode. Just to highlight some examples, I think it is accepted that patients differ in

pulmonary edema, with some having hypoxemia, whereas many other patients have normal oxygen saturation. There

are patients who have really profound hypertension, who, we have learned, have a very good prognosis; and, of

course, there are patients who are in cardiogenic shock and are on the other extreme of the syndrome.

Just to start with, I think cardiac disorders are very different based on whether left ventricular systolic dysfunction,

diastolic dysfunction, or right ventricular dysfunction is the key problem. I think we are just beginning to understand

how to best characterize the phenotype of acute heart failure patients.

Dr Peacock: Yes, there is no doubt that the spectrum of presentations is broad. Nevertheless, when they present

acutely, we do establish some generic goals based on the basic management of that population. We should say a

little bit about what those goals of therapy may possibly be. Karl, can you comment on what your feelings are on

goals and the rationale for treatment of these different patient populations?

Slide 3.

Karl Swedberg, MD, PhD: Yes. One of the most important goals with treatment of these patients is, of course, to

relieve symptoms because they are very symptomatic. They seek help for something that is being developed, not in

an hour, but usually in most cases over several days. The problem, which supports Christian’s statement, is that we

have a poor understanding of how the pathophysiology translates into symptoms. We think we know why patients are

dyspneic, and in many situations our explanation fits.

Slide 4.



We have a hemodynamic imbalance that we think is the trigger, but it turns out that symptoms—in particular,

dyspnea—are much more complex than just a simple pathophysiologic change. It is obviously difficult to correct the

dyspnea rapidly because we have various contributing factors to address when handling the imbalance in

pathophysiology. I think this disconnection between symptoms and pathophysiology is one of the most important

challenges in managing acute heart failure.

Dr Peacock: There is a clear challenge for the clinician when faced with these patients. I think the good news is that

most of them come in with a stable blood pressure, and some are hypertensive. Therefore, we can approach them

differently from the small minority of patients who are hypotensive.

Slide 5.

For the sake of discussion, historically, we have used diuretics to relieve symptoms in the patients who have a stable

blood pressure. I think there is real value in clarifying the distribution piece of that pathophysiologic question, which is

that it is not just volume of fluid but also distribution of fluid. Piotr, can you talk a little bit about whether we should

unload the patient or redistribute their fluid?

Piotr Ponikowski, MD, PhD: That is a very good question, Frank; thank you. I am very glad that Christian already

initiated this discussion that acute heart failure is not just one entity. There are many patient profiles.

Slide 6.

You are correct in pointing out that most of the patients we are seeing are actually congested due to fluid overload,

no doubt, and we try to decongest them. We try to unload them, but we clearly need to understand that some of

them are well-characterized by a so-called kind of cardiac failure where they also accumulate fluid, but they gain the

fluid over days and sometimes even weeks and then deteriorate.

However, the other group you mentioned, those with high blood pressure or normal blood pressure, which is the

majority of patients, can be characterized by fluid redistribution, so indeed we do need to decongest them. We need



to unload them with diuretics, but we also need to clearly understand that diuretics are not the only group of drugs in

our armamentarium to use. But I believe we will be discussing this later. We are now moving forward with the concept

of redistribution. There are several elegant papers over the last 2, 3, 4 years showing, actually, redistribution in this

certain group of patients who are coming to us with pretty normal ejection fraction with very, very rapid symptoms and

very severe congestion over the lungs. These are the best candidates for the sort of treatment that actually

redistributes the fluid rather than simply diuresing them.

Dr Peacock: Yes, and it appears that, at least from the acute presentation, redistribution of fluid seems to be

clinically somewhat underplayed. In my perspective, as a practitioner, the dominant intervention I can do is to change

things around or promote movement of the fluid, rapidly. The other piece you mentioned is the diuretic piece, where

we have very few data and hardly any data prospectively.

Slide 7.

I think the largest trial we have is the DOSE trial. How much do we really know about diuretic use? Christian, can you

comment a little bit on our strategies with diuretics and what we are supposed to be doing?

Dr Mueller: Frank, I think that is one of the additional unfortunate aspects of heart failure management. Acute heart

failure is common, and we have predominantly 2 treatments. We have IV diuretics, and we have nitrates. Despite the

fact that these medications have been around for decades, we have extremely poor clinical data that guide our clinical

use of both IV diuretics and nitrates. For the nitrates, there are some very small randomized studies that have been

performed in patients with pulmonary edema. For the diuretics, the largest piece of evidence that we have is in

studies of about 300 patients, which is an incredible small number of patients to define clinical practice worldwide. I

think part of the poor outcome of acute heart failure patients, at least in my point of view, is related to poor evidence

that guides us on how to best use currently available treatments.

Dr Peacock: Yes, we have the DOSE trial, and we did some work a few years ago in the ADHERE Registry looking

at time dependency of diuretics.



Slide 8.

There actually was a mortality reduction with early diuretics, but only in the sickest ones, only the patients. We risk

stratified with BNPs greater than approximately 800 pg/mL. For the patients who were not that sick (lower BNP

levels), the diuretic time did not even matter. When you are trying to make those decisions emergently and you do

not have your objective measures yet, at that point you are not really even certain who is going to benefit from acute

diuretics. I think clinically the vasodilators do seem to have some important impact, but a lot of that is anecdotal, as

you said. There are so few data with very few randomized trial data on vasodilators. Piotr, can you comment on the

impact of nitrates and other vasodilators and the unloading and redistribution controversy?

Dr Ponikowski: YesI can,with pleasure. Indeed, I very much like to use nitrates in combination with diuretics. But in

several cases, nitrate therapy is a first-line treatment. Obviously as previously stated, there are only a few studies.



Slide 9.

The first trial was a small trial, published 15 years ago in The Lancet. Gad Cotter, as primary author, showed that in

several cases with those patients who are coming to us with this vascular type of acute heart failure, nitrates would

be the best option. To be honest, in my clinical practice, I very much like the combination of diuretics with nitrates. In

most cases, I feel strongly that this combination would redistribute fluid, and the majority of patients would actually

be candidates for that sort of a combination.

You pointed out very, very nicely that time matters as well, and I do not know whether now is the best time to raise

this, but perhaps we need to mention that the sooner we initiate this therapy, the better. In other words, the sooner

we see our patient in the emergency department and the sooner we start thinking of the acute failure syndrome as a

deadly condition, the sooner we try to relieve the symptoms. I am sure we are also going to discuss that treating

sooner may have some impact on improving the outcome, which is also very important.

Slide 10.

Indeed, I like nitrates and the combination of nitrates and diuretics, but only for the patients who can tolerate this

strategy. We are not talking about patients with cardiogenic shock or hypotensive patients but those with preserved

blood pressure and obviously those patients with high blood pressure. For those patients, I really love the

combination therapy.

Dr Peacock: It sounds like we have really boiled down the entire world of heart failure management to blood

pressure, diuretics, and nitrates. It is a little bigger than that entity. We have looked at some other options

historically; and looking toward the future, we have studies with other drugs in the pipeline as well. Karl, do you want

to comment on any other options we currently have or drugs that have been explored?

Dr Swedberg: Yes, Frank, one important aspect is, of course, that we try to control neurohormonal activation. This

has been such a successful story in chronic heart failure where angiotensin-converting enzyme inhibitors and beta-



blockers have been very successful in reducing clinical events and improving prognosis. When we have applied this

therapy in the emergency department and in the acute setting, we have not been successful. There have been several

studies in this area around various options, and the results have been fairly neutral at best.

Slide 11.

There are other options—using, for example, tolvaptan—with which I was very involved. With tolvaptan (vasopressin

V2 receptor blocker), we tried to initiate it in the type of patients we just discussed as a combination of antagonizing

vasopressin and standard therapy compared with placebo with standard therapy, and it was completely neutral. We

translated the therapy into a chronic phase. Let me correct that statement and say it was not completely neutral

because there was a little more fluid loss in the tolvaptan-treated patients, but it was marginal and it did not translate

into an effect on outcomes.

Using the experience from the chronic situation or stable patients has not so far been successful in the acute

situation. As it was pointed out by Christian and Piotr, managing these patients in the acute setting is very different

from the stable phase. There is a limited understanding about what is occurring in these patients, and that is why we

need to explore something that could handle what has happened over the last few days or weeks, as was pointed

out. There is obviously still much to learn and to do.

Dr Peacock: This difference between the acute and chronic phases, I think, is really critical. We have seen a long

list of drugs that have been studied. You talked about tolvaptan. But the list of studies with drugs that did not seem to

have any positive effect on patient outcomes is very long.

Slide 12.

For example, a drug may have an effect on early symptom relief but no long-term benefit. What comes to mind for me

is ASCEND-HF. I was so disappointed in those results. They enrolled people at 24 hours. In my personal experience,

we have used nesiritide in the first couple of hours and it had a profound dyspneic effect, and so that timing becomes

really critical. Piotr, you were a big player in the RELAX-AHF trial, which was just recently completed and

demonstrated some very provocative results. Part of the success, I think, is related to the early enrollment, which you

had a huge role in. Do you want to comment?

Dr Ponikowski: Thanks, indeed. I would rather use promising results more than provocative results. I am glad that

Karl mentioned that there are neutral trials; I fully concur with Karl’s statement that actually 3 or 4 years ago our

armamentarium was very limited as we all agreed with only nitrates, diuretics, inotropes for some cases, in addition

to oxygen and morphine. So we were very limited. Now, we have what I would prefer to call promising results from

RELAX-AHF. If I recall from your paper, Karl, some years ago, for the first time ever, it was pointed out that time

really matters in heart failure. In other words, the sooner you get these patients to the emergency department, the

sooner you initiate the treatment, the better.

Now we actually followed your advice and we designed the RELAX-AHF trial in this way. We tried to enter our

patients very quickly into the trial, with only 16 hours time between the presentation and the initiation of the therapy.

Slide 13.

We wanted serelaxin to be given early in the RELAX-AHF trial. It is a DNA-recombinant form of a pregnancy hormone,

relaxin, which actually is responsible for all the hemodynamic changes and adrenal adjustments in pregnancy. There

are very positive effects with this drug on the hemodynamic profile. The drug also has antifibrotic vasodilatory effects.

Slide 14.



These patients were given either placebo or serelaxin intravenously for 48 hours, and we observed them until day 180.

We improved dyspnea.

Slide 15.

We were not able to improve hospitalization at day 60. We have a lot of information related to these trial results that

we are going to share with the cardiology community. The results are really promising and need to be confirmed and

re-evaluated in another trial.

Slide 16.

For the first time ever, we had a positive impact on the long-term, 180-day mortality. Short-term therapy, for the first

time ever, affects 180 days out, which is great because we only were somehow trying to make the comparison

between acute heart failure and acute coronary syndromes. With acute coronary syndromes, the sooner we treat

patients, the better. We give the IV thrombolysis or provide the percutaneous coronary intervention so you can

improve mortality. Here with heart failure, we also imposed the treatment very early, and we hope we can replicate

these results showing that this serelaxin really works positively in a group of patients with acute heart failure. But

keep in mind that we selected patients with normal or elevated blood pressure, so again, we treated patients with a

vascular type of heart failure.

Dr Peacock: You mentioned that the earlier the treatment, the better. I have been pushing this for years that heart

failure is similar to myocardial infarction (MI). But people for some reason do not anticipate that heart failure is such a

critical event. The idea that an MI treatment would have an impact a year later is easy to comprehend. Everybody just

says, "Of course, that makes sense." For heart failure, it has been a much harder thing to move forward. I think it is

clear. I believe the RELAX-HF investigators enrolled patients on average at 7 hours.

Dr Ponikowski: Yes, the average time to enrollment from presentation with symptoms in the ED was 7 hours

Dr Peacock: That is the earliest enrolling large randomized trial that has ever been done, and, as you said, it yielded

promising results. It was outstanding.

Slide 17.

We did another trial (PRONTO trial) with the same strategy in mind using clevidipine, which is an arterial vasodilator.

We enrolled in 2 hours. We essentially made dyspnea go away in 3 hours from the time of aggressive blood pressure

lowering to something in the normal range, as specified by the investigator. The dyspnea scores decreased from 65

or 70 mm on a 100-mm scale to 10. But once again it is the early enrollment and early treatment that are so critical

to the heart failure patient. I think we are finally coming to an era where the time of treatment matters. It is not just

myocardium or minutes; it is minute or dyspnea and minutes or death for heart failure as well. I hope we will continue

this trend.

Slide 18.

The TRUE-AHF acute heart failure trial, which I know you are working on as well, has some of that same strategy. Do

you want to say anything about that trial?

Dr Ponikowski: Yes, we are doing this together, so indeed we can even make the whole story more sharpened,

cutting the enrollment from 16 hours to 12 hours. Again, it is more or less the same kind of strategy with ularitide.

However, I am glad that you mentioned that this early phase is extremely important, not only for symptomatic relief

but also for end organ protection. We have learned this from many papers. I remember your first paper published in

The New England Journal of Medicine, showing very clearly that the troponin leak or deterioration may be damaging



to the myocardium for critical importance. We learned this also from the RELAX-HF trial. We can only prospectively

validate this in another trial called TRUE-AHF with ularitide. We are looking forward to verifying this premise that

sooner is better, now in acute heart failure settings.

Dr Peacock: I think we have left what I would call the desert of acute heart failure for the last 20 years and are now

entering a period that is exciting. I think we really have opportunities to change the way we deliver care. Karl,

Christian, do you want to add any additional comments?

Dr Mueller: I think there is an opportunity for the doctor to bring together the initial observation with the initial

troponin level, which is such a powerful prognosticator, and the impact of agents that act by unloading the heart in

relation to follow up troponin levels.

Slide 19.

I think this is a very convincing additional piece of information that provides a pathophysiological, plausible

explanation for some of the outcome difference observed with serelaxin. There was a difference on the course of

troponin levels between active treatment and placebo and I think that brings together the observational data and the

specific benefits of this therapy. I think the pathophysiological clues help us to understand why the difference in

mortality might have been observed.

Dr Swedberg: Frank, I have seen so many disappointments over the years in acute heart failure, and we are left

with, as was pointed out, the treatments that we have had available for decades.

Slide 20.

These treatments seem to be simple in their mechanism of action, and we have a situation that is very serious in that

the acute heart failure situation translates into high morbidity and mortality. Viewing acute heart failure in a different

way and the potential impact of different approaches—like we heard with ularitide and serelaxin, for example—in

addition to considering this concept that time matters; I think it gives us at least promising opportunities for improving

outcomes.

Slide 21.

Dr Peacock: In summary, I think we need to use diuretics and vasodilators early. We also have future trials to finish

and to determine if there are new opportunities for heart failure treatments. I would like to thank the members of our

faculty for participating and you for attending our conference.


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Physiologic volume redistribution and acute heart failure management (printer friendly)

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Transcript of Physiologic volume redistribution and acute heart failure management (printer friendly)