Download Beta-blocker Use in Decompensated Heart Failure

Beta-blocker Use in Decompensated
Heart Failure
Rami Alharethi, MD, and Ray E. Hershberger, MD
Corresponding author
Ray E. Hershberger, MD
Division of Cardiology, UHN-62, Oregon Health & Science
University, 3181 SW Sam Jackson Park Road,
Portland, OR 97239, USA.
E-mail: [email protected]
Current Heart Failure Reports 2006, 3:75 – 80
Current Science Inc. ISSN 1546-9530
Copyright © 2006 by Current Science Inc.
Despite the current advances in treatment, acute decompensated heart failure accounts for more than 1 million
hospital admissions annually. Many of the patients hospitalized are already receiving long-term treatment with
β -blockers. For patients who receive full dose β -blocker
therapy and suffer acute decompensated heart failure,
clinicians face two key questions: what to do, if anything,
with the dosage of β -blocker and what is the best way to
integrate inotropic and β -blocker therapies for patients
who require inotropes. This article discusses these issues
and reviews the available literature. Because these topics
have received little systematic evaluation, we also present
our clinical approaches to these problems.
Introduction
The use of neurohormonal antagonists such as angiotensin-converting enzyme inhibitors, aldosterone inhibitors,
and β-adrenergic receptor blockers for the treatment of
heart failure (HF) has led to decreased mortality and
rehospitalization rates [1–4]. Despite these advances in
treatment, more than 1 million patients are hospitalized
annually in the United States with decompensated HF
[5]. In-hospital mortality rates are reported at 4.7% to
13.9% [6,7] and mortality rates 60 days after discharge
are reported at 8.5% [7].
Acute Decompensated HF
The increase in left ventricular filling pressure activates
the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the release of nonosmotic
vasopressin, which in turn affects renal hemodynamics and decreases sodium and water excretion [8]. This
results in a wide range of clinical presentations for decompensated HF [9,10]. Although most patients present with
progressive volume overload without acute pulmonary
edema, some present with acute pulmonary edema and/
or low cardiac output [7,9]. Most patients are treated with
intravenous diuretics and a few may require inotropic
support or other vasoactive therapy [6,7,9].
With our current guidelines for the treatment of
chronic HF [11••], many patients with worsening heart
failure are taking β-blockers. In the ADHERE [6] and the
IMPACT-HF registry [7] 48% and 50%, respectively, of
the patients admitted with decompensated HF were taking β-blockers. This presents a dilemma regarding the
adjustment of β-blocker dosages, especially in view of
the wide range of clinical presentations of worsening HF
and the absence of guidelines for the treatment of acute
decompensated HF.
Insights into Beta-blocker Use in Acute
Decompensated HF from Beta-blocker and
Other Clinical Trials
Long-term treatment with β-blockers in patients with HF
decreases the circulating levels of vasoconstrictors such
as norepinephrine, renin, endothelin, and proinflammatory cytokines [2,12–18] and may upregulate myocardial
β-1-receptor density [19], which in turn may help restore
the inotropic and chronotropic responsiveness of the
myocardium. β-Blocker use also decreases mortality and
rehospitalization rates [1–4]. Despite these encouraging
effects, approximately 10% of patients who were treated
with metoprolol succinate (TOPROL-XL; AstraZeneca
Pharmaceuticals LP, Wilmington, DE)in the MERIT-HF
study [2] and 17% of patients who were treated with
carvedilol in the COPERNICUS study [1] were hospitalized for worsening HF. Most of these patients were treated
by an increase in the diuretic dose and adjustment of
other vasoactive therapy.
Few reports are available regarding possible benefits
of β-blockers in acute decompensated HF. Aronson and
Burger [20] reported from the PRECEDENT study that
patients who were admitted with worsening HF and had
been on β-blocker therapy had significantly fewer ventricular tachycardia episodes, substantially higher time
76 Treatment: Beta-blockers
domain indices of the heart rate variability [21], better
cardiac autonomic regulation, and lower plasma levels
of norepinephrine and interleukin-6 (although the latter
finding did not reach statistical significance) [22].
Beta-blocker Use in Patients with Acutely
Decompensated HF not Requiring
Inotropic Therapy
We are unaware of studies that have systematically evaluated approaches to the adjustment of β-blocker dosages
with acutely decompensated HF. We cite one expert
opinion [23]. This is a concern because of the possibility
that ongoing β-blocker administration might aggravate
the acutely decompensated state. Although abundant
evidence is available that the acute administration of a
β-blocker in a patient with cardiomyopathy and compensated HF can cause an initial drop in left ventricular
ejection fraction due to its acute negative inotropic effect
[24], we have no published accounts of the hemodynamic
effects of acute β-blocker withdrawal after long term use
in decompensated HF. One might surmise that with the
acute withdrawal of β-blockade cardiac function would
improve, but it is also possible that other salutary effects
(eg, heart rate control, anti-arrhythmic effects, beneficial
metabolic and/or neurohormonal effects in the myocardium), perhaps especially important in an acutely
decompensated patient, would be lost. This issue begs for
critical, focused investigation.
We do not adjust β-blocker dosages for the acutely
volume overloaded outpatient with preserved blood pressure, good perfusion, and adequate renal function (the
so-called “warm and wet” patient) [25••] but attempt
to quickly reestablish euvolemia over 24 to 72 hours. In
otherwise stable outpatients this can be achieved with
increased oral doses of loop diuretics, at times augmented
by oral thiazide diuretics, or with outpatient doses of an
intravenous loop diuretic. For patients who need to be
hospitalized we use intravenous loop diuretics, either
intermittently or with continuous infusion.
Less stable outpatients or hospitalized patients on
full dose β-blockade who are hypotensive with marginal
perfusion or azotemia require more careful evaluation.
If these patients demonstrate an initial response to intravenous diuretics and we anticipate a brief time period
(eg, 1–3 days) to regain clinical stability, we usually will
not consider a reduction in β-blocker dosage unless the
patient’s clinical response is not satisfactory.
We typically reduce the β-blocker dose by 50% in
patients on full dose β-blockade who are teetering toward
full decompensation, that is, those who require hospitalization after failing intensive ambulatory HF management
[26], those who are resistant to intravenous diuretics
and/or demonstrate progressive renal dysfunction, or
those who appear likely to require inotropic support. For
continued deterioration we consider a further reduction
to 25% of the original dose. We do not acutely stop βblockers except for pharmacologic emergencies (eg, acute,
severe, reversible airways disease) or for those committed
to prolonged inotropic therapy.
Patients who are hospitalized for acute noncardiac
illness with decompensated HF (either before hospitalization or consequent to the medical complication) present
additional complexities and need to be approached carefully. Again, we have not found any systematic studies that
guide β-blocker dosing for these patients; we only provide
our own clinical approach, which has not been formally
evaluated. For these patients we try to avoid reducing the
β-blocker dose except for an obvious indication (eg, acute
reversible airways disease or status asmaticus that calls
for corticosteroids or a symptomatic, new complete heart
block requiring β-agonist infusion pending pacemaker
implantation). We also avoid reducing the β-blocker for
patients who are hemodynamically unstable as described
in the previous paragraph. For patients who have decompensated HF as well as a major medical illness (such as
pneumonia, urosepsis, acute cholecystitis, or gastrointestinal bleeding) complicating their HF management, we
suggest that invasive hemodynamic monitoring with a
pulmonary artery catheter should be strongly considered.
This is particularly relevant for patients who require fluid
resuscitation, multiple blood transfusions, pressors, or
inotrope support. We suggest that β-blocker dose adjustments should be considered as outlined earlier.
Continued Beta-blocker Use in Patients on
Full Dose Beta-blockade who Require
Inotropic Therapy
Indications for inotropic therapy
This issue is immensely complicated. Unfortunately, lack
of systematic investigation provides almost no published
reports upon which to base treatment recommendations. Of several thorny issues embedded within this
topic, the most fundamental unresolved issue is the role
and indication for the use of inotropes in patients with
decompensated HF. Recent studies [6,27,28] have shown
that inotropes should not be used in patients who do not
require their use for the purpose of shortening the hospital stay or improving other outcomes.
Based upon these and other studies, a great deal of
concern has been expressed regarding inotropic therapy
use under any circumstances [6,29]. Yet most clinicians know that some patients, especially those with
advanced, decompensated life-threatening HF (who
were not part of the aforementioned studies because
of ethical concerns), are likely to die within minutes to hours without inotropic therapy to reestablish
adequate blood pressure and perfusion to vital organs.
These patients present a continuum of disease—from
advanced decompensated HF to those who are truly
dependent upon inotropic therapy—that is, those in
Beta-blocker Use in Decompensated Heart Failure
whom inotrope withdrawal will lead to imminent
demise [30,31••,32••]. We advise the use of inotropes
only for patients who require their use. Short of systematic and standardized measures to define such a patient
population, clinicians will need to continue to rely on
their clinical judgment to define this population. In our
experience the number of patients in this group are few,
and we hospitalize these patients only after they have
failed multiple stages of outpatient disease management tactics in our HF treatment program [26].
Choice of an inotropic drug
In contrast to the indications for inotrope use, the choice
of an inotropic drug for patients receiving metoprolol or
carvedilol has received greater attention [33–35,36•,37•].
In patients not receiving β-blockers, the most commonly
used inotropes are dobutamine, a β-1- and β-2-adrenergic
receptor agonist that increases the production of intracellular cyclic adenosine monophosphate, and milrinone, a
phosphodiesterase III (PDE III) inhibitor that decreases
the degradation of cyclic adenosine monophosphate [38].
The use of these inotropes in patients receiving long
term β-blockade was evaluated in several small studies.
However, these patients did not have acute decompensated HF. Lowes et al. [34] showed that patients who
are treated with carvedilol long term respond less favorably to dobutamine than to milrinone, requiring higher
doses of dobutamine (15–20 µg/kg/min) to increase the
cardiac index. Metra et al. [35] noted different responses
to dobutamine in patients treated long term with the
β-1-selective antagonist metoprolol versus the nonselective β-blocker carvedilol, which blocks both β-1- and
β-2-adrenergic receptors. Patients receiving metoprolol
showed no difference between baseline (before initiation
of β-blockade) and after 9 to 12 months of metoprolol
therapy for cardiac index (Fig. 1), heart rate, and systemic vascular resistance, and only a modest change in
responsiveness in the decrease in the pulmonary artery
and systemic arterial pressures. In contrast, substantial differences were observed in the dobutamine dose
response curve after long-term carvedilol therapy. The
improvement of cardiac index, the increase in systemic
pressure, the decrease in systemic vascular resistance, and
the decrease in pulmonary artery pressure were markedly
blunted, and the heart rate responsiveness was blunted to
a lesser degree. In particular, with carvedilol the pulmonary artery pressure actually increased with dobutamine,
an effect that was suggested to result from the blockade of
vascular β-2-receptors and other pharmacological properties of the drug. Notably, the use of either β-blocker did
not affect the response to intravenous enoximone, an
investigational PDE III inhibitor with properties similar
to those of milrinone, and metoprolol even augmented
the response to enoximone. The study by Bollano et al.
[33] also showed differential responses to dobutamine
for metoprolol or carvedilol.
Alharethi and Hershberger
77
These results suggest that the choice of inotropic
therapy in a patient receiving long-term β-blocker
therapy may be important. Dobutamine appears to be
nearly as effective in the presence of the β-1-antagonist metoprolol, but this is not the case with full dose
carvedilol. However, the use of a PDE III inhibitor in
patients treated long term with β-blockers appears to
be as efficacious as it is in patients not receiving βblockers [36•,37•].
Beta-blocker dosing for patients receiving
inotropic therapy
A third issue is the best approach to β-blocker dosing for
a patient who has been treated long term with β-blockers once inotropic therapy has been initiated. Again, we
have been unable to find a systematic evaluation in the
literature examining β-blocker dosage once a patient has
been started on inotropic therapy. (However, the use of
PDE III inhibitors to facilitate the initiation and uptitration of β-blockers in patients with advanced HF has
been examined [39–41]). We again offer only our own
clinical experience: for patients treated with carvedilol
we decrease the dose by 50% and decrease it by another
50% (to 25% of the original dose) within 2 or 3 days if
the patient continues to require intravenous inotropic
therapy. For patients treated with metoprolol, we take a
less aggressive position on the urgency, frequency, and
degree of dose reductions, particularly if the patient has
responded clinically to inotropic therapy (eg, effective
diuresis, improved perfusion, blood pressure, and renal
function). We have not formally evaluated these aspects
of our clinical experience. Well designed studies are
needed to evaluate these issues.
Conclusions
β-Blockers are currently standard therapy for HF, and
the number of patients already on long-term β-blocker
therapy who are admitted with decompensated HF
will increase. These patients present a challenging
dilemma to clinicians regarding the most appropriate
strategy for β-blocker use, with the concern that some
patients may further deteriorate after the withdrawal
of β-blockers [42,43].
In the absence of guidelines for the treatment of acute
decompensated HF and recognizing a wide range of the
clinical presentations and causes of these decompensations,
we recommend the following for adjusting β-blockers.
For outpatients, we emphasize increased doses of
diuretics to reestablish euvolemia as quickly as possible
without a change in β-blocker dosing.
For patients requiring hospitalization (having
failed intensive ambulatory outpatient management),
we propose considering the reduction of β-blocker
doses if the patient is unresponsive to diuretic and/or
vasodilator therapy.
78 Treatment: Beta-blockers
Figure 1. Absolute changes (mean ± SEM) from baseline in cardiac index after dobutamine (A,C) or enoximone (B,D) administration, before
(open symbols) and after (closed symbols) long-term β-blocker treatment with metoprolol (A,B) or carvedilol (C,D). Asterisks immediately
above or below the standard error bars indicate significance of dose-specific differences from baseline. Asterisks between the dose-response
curves indicate significance of dose-specific differences from baseline between, before, and after β-blocker therapy. P values at the bottom of
each graph indicate differences between the slopes of the dose-response curves before and after metoprolol or carvedilol treatment.
*P < 0.05; **P < 0.01; ***P < 0.001. (Adapted from Metra et al. [35]; with permission.)
For patients requiring inotropic therapy, we suggest
considering the reduction of β-blocker doses as outlined
earlier, particularly for patients receiving carvedilol.
Although dobutamine appears nearly as efficacious in patients receiving metoprolol, the use of a
PDE III inhibitor should be considered in patients
on high dose carvedilol, particularly for those with
significant cardiogenic shock and other signs of
advanced decompensation.
Clinical Trial Acronyms
ADHERE—Acute Decompensated Heart Failure National
Registry; COPERNICUS—Carvedilol Prospective Randomized Cumulative Survival; IMPACT-HF—Initiation
Management Pre-discharge Assessment of Carvedilol
Heart Failure; MERIT-HF—Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure;
PRECEDENT—Prospective Randomized Evaluation of
Cardiac Ectopy with Dobutamine or Nesiritide Therapy.
Beta-blocker Use in Decompensated Heart Failure
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