Transcript Beta Blockers in Acute Decompensated Heart Failure

Management of Acute
Decompensated Heart Failure
Washington Metropolitan Society of Health-System
Pharmacists
September 28, 2013
Rockville Maryland
David S. Roffman, PharmD, BCPS/AQ Cardiology
Professor
Pharmacy Practice and Science
School of Pharmacy
University of Maryland
Financial Disclosures for David S.
Roffman, PharmD
Nothing to disclose
Learning Objectives
At the completion of the lecture, the participants will be able to:
1. Describe the typical presentation of acute decompensated
heart failure (ADHF)
2. List the therapeutic objectives associated with
pharmacologic therapy for ADHF
3. State the indications, adverse effects, and monitoring
parameters for the use of inotropes, vasodilators, pressors,
and loop diuretics in the treatment of ADHF
4. Describe emerging pharmacotherapeutic options for ADHF
Heart Failure Guidelines
2013 ACCF/AHA Guideline for the Management of Heart Failure
A Report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines
http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation
Applying Classification of Recommendations
and Level of Evidence
Class I
Class IIa
Class IIb
Class III
Benefit >>> Risk
Benefit >> Risk
Additional studies with
focused objectives
needed
Benefit ≥ Risk
Additional studies with
broad objectives
needed; Additional
registry data would be
helpful
Risk ≥ Benefit
No additional studies
needed
Procedure/ Treatment
SHOULD be
performed/
administered
IT IS REASONABLE
to perform
procedure/administer
treatment
Procedure/Treatment
MAY BE CONSIDERED
Level of Evidence:
Level A:
Data derived from multiple randomized clinical trials or meta-analyses
Multiple populations evaluated
Level B:
Data derived from a single randomized trial or nonrandomized studies
Limited populations evaluated
Level C:
Only consensus of experts opinion, case studies, or standard of care
Very limited populations evaluated
Procedure/Treatment
should NOT be
performed/administered
SINCE IT IS NOT
HELPFUL AND MAY
BE HARMFUL
Definitions of HFrEF and HFpEF
http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation
Clinical Profiles of Hospitalized HF
Patients

Volume overload
– pulmonary/systemic vascular congestion
– precipitated by acute BP increase

Profound depression of CO
– hypotension
– renal insufficiency
– shock syndrome

Signs/symptoms of both
The Hospitalized Patient
Diagnosis of HF
I IIa IIb III
The diagnosis of heart failure is primarily based on signs and
symptoms derived from a thorough history and physical exam.
Clinicians should determine the following:
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a. adequacy of systemic perfusion;
b. volume status;
c. the contribution of precipitating factors and/or comorbidities
d. if the heart failure is new onset or an exacerbation
of chronic disease; and
e. whether it is associated with preserved, normal, or reduced
I IIa IIb III
ejection fraction.
Chest radiographs, echocardiogram, and echocardiography are key
tests in this assessment.
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The Hospitalized Patient
I IIa IIb III
Precipitating Factors for Acute HF
It is recommended that the following common
potential precipitating factors for acute HF be
identified as recognition of these comorbidities,
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is critical to guide therapy:
• acute coronary syndromes/coronary
ischemia
• severe hypertension
• atrial and ventricular arrhythmias
• infections
• pulmonary emboli
• renal failure
• medical or dietary noncompliance
The Hospitalized Patient
I IIa IIb III
I IIa IIb III
Patients Being Evaluated for Dyspnea
Concentrations of BNP or NT-proBNP should be
measured in patients being evaluated for dyspnea in
which the contribution of HF is not known. Final
diagnosis requires interpreting these results in the
context of all available clinical data and ought not to
be considered a stand-alone test.
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Acute coronary syndrome precipitating HF
hospitalization should be promptly identified by
electrocardiogram and cardiac troponin testing,
and treated, as appropriate to the overall
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condition and prognosis of the patient.
Therapeutic Objectives for Acute
Decompensated Heart Failure




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Improve survival?
Resolve pulmonary vascular congestion
Preserve end organ performance
Achieve previous baseline heart failure
status (NYHA Classification)
Reduce the risk of rehospitalization
Recommended Therapies for
Hospitalized HF Patients
http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation
Recommended Therapies for
Hospitalized HF Patients
http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation
The Hospitalized Patient
Treatment With Intravenous Loop Diuretics
I IIa IIb III
Patients admitted with HF and with evidence of significant
fluid overload should be treated with intravenous loop
diuretics. Therapy should begin in the emergency department
or outpatient clinic without delay, as early intervention may be
associated with better outcomes for patients hospitalized with
decompensated HF (Level of Evidence: B).
If patients are already receiving loop diuretic therapy, the
I IIa IIb III initial intravenous dose should equal or exceed their chronic
oral daily dose. Urine output and signs and symptoms of
congestion should be serially assessed, and diuretic dose
should be titrated accordingly to relieve symptoms and to
reduce extracellular fluid volume excess. (Level of Evidence:
C).
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Diuretic Therapy in ADHF
Hunt et.al. 2009. J Am Coll Cardiol 53;15:1-90
The Hospitalized Patient
I IIa IIb III
Intensifying the Diuretic Regimen
When diuresis is inadequate to relieve congestion, as
evidence by clinical evaluation, the diuretic regimen
should be intensified using either:
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a. higher doses of loop diuretics;
b. addition of a second diuretic (such as
metolazone, spironolactone or intravenous
chlorthiazide) or
c. Continuous infusion of a loop diuretic.
The Hospitalized Patient
I IIa IIb III
Ultrafiltration and Intravenous Inoptropic Drugs
Ultrafiltration is reasonable for patients with
refractory congestion not responding to medical
therapy.
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I IIa IIb III
Intravenous inotropic drugs such as dopamine,
dobutamine or milrinone might be reasonable for
those patients presenting with documented severe
systolic dysfunction, low blood pressure and
evidence of low cardiac output, with or without
congestion, to maintain systemic perfusion and
preserve end-organ performance.
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The Hospitalized Patient
Monitoring and Measuring Fluid Intake and Output
I IIa IIb III
Effect of HF treatment should be monitored
with careful measurement of fluid intake and
output; vital signs; body weight, determined at
the same time each day; clinical signs (supine
and standing) and symptoms of systemic
perfusion and congestion. Daily serum
electrolytes, urea nitrogen, and creatinine
concentrations should be measured during the
use of intravenous diuretics or active titration
of HF medications.
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Diuretic Strategies in Patients with Acute
Decompensated
Heart Failure
A. Bolus dosing more effective
B. Continuous infusion more effective
C. Higher dose more effective than lower dose
D. Both B and C are correct
Diuretic Strategies in Patients with
Acute Decompensated Heart Failure
In a prospective, double-blind, randomized trial, we assigned 308
patients with acute decompensated heart failure to receive
furosemide administered intravenously by means of either a
bolus every 12 hours or continuous infusion and at either a low
dose (equivalent to the patient’s previous oral dose) or a high
dose (2.5 times the previous oral dose). The protocol allowed
specified dose adjustments after 48 hours. The co-primary end
points were patients’ global assessment of symptoms, quantified
as the area under the curve (AUC) of the score on a visualanalogue scale over the course of 72 hours, and the change in
the serum creatinine level from baseline to 72 hours.
Felker GM, Lee KL, Bull DA, et.al., N Engl J Med 2011;364:797-805
Diuretic Strategies in Patients with Acute Decompensated Heart Failure
Felker GM, Lee KL, Bull DA, et.al., N Engl J Med 2011;364:797-805
Diuretic Strategies in Patients with Acute Decompensated Heart Failure
Felker GM, Lee KL, Bull DA, et.al., N Engl J Med 2011;364:797-805
Diuretic Strategies in Patients with Acute Decompensated Heart Failure
Felker GM, Lee KL, Bull DA, et.al., N Engl J Med 2011;364:797-805
Diuretic Strategies in Patients with Acute Decompensated Heart Failure
Felker GM, Lee KL, Bull DA, et.al., N Engl J Med 2011;364:797-805
Diuretic Strategies in Patients with Acute Decompensated Heart Failure
Felker GM, Lee KL, Bull DA, et.al., N Engl J Med 2011;364:797-805
Fluid and Sodium Restriction in
Acute Decompensated Heart Failure
Fluid and sodium restriction in ADHF
patients improves weight loss and
clinicaal stability in hospitalized ADHF
patients
– A. True
– B. False
Aggressive Fluid and Sodium Restriction
in Acute Decompensated Heart Failure
A Randomized Clinical Trial
To compare the effects of a fluid-restricted (maximum
fluid intake, 800 mL/d) and sodium restricted
(maximum dietary intake, 800 mg/d) diet
(intervention group [IG]) vs. a diet with no such
restrictions (control group [CG]) on weight loss and
clinical stability during a 3-day period in patients
hospitalized with ADHF
JAMA Intern Med. 2013;173(12):1058-1064
Aggressive Fluid and Sodium Restriction
in Acute Decompensated Heart Failure
A Randomized Clinical Trial
JAMA Intern Med. 2013;173(12):1058-1064
Aggressive Fluid and Sodium Restriction
in Acute Decompensated Heart Failure
A Randomized Clinical Trial
JAMA Intern Med. 2013;173(12):1058-1064
Aggressive Fluid and Sodium Restriction
in Acute Decompensated Heart Failure
A Randomized Clinical Trial
JAMA Intern Med. 2013;173(12):1058-1064
The Hospitalized Patient
I IIa IIb III
In all patients hospitalized with HF, both with
preserved and low ejection fraction, transition
should be made from intravenous to oral
diuretic therapy with careful attention to oral
diuretic dosing and monitoring of electrolytes.
With all medication changes, the patient
should be monitored for supine and upright
hypotension and worsening renal function and
HF signs/symptoms.
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The Hospitalized Patient
Preserving End-Organ Performance
I IIa IIb III
In patients with clinical evidence of hypotension associated with
hypoperfusion and obvious evidence of elevated cardiac filling
pressures (e.g., elevated jugular venous pressure; elevated
pulmonary artery wedge pressure), intravenous inotropic or
vasopressor drugs should be administered to maintain systemic
perfusion and preserve end-organ performance while more
definitive therapy is considered.
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I IIa IIb III Invasive hemodynamic monitoring should be performed to guide
therapy in patients who are in respiratory distress or with clinical
evidence of impaired perfusion in whom the adequacy or excess of
intracardiac filling pressures cannot be determined from clinical
assessment.
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Intravenous Inotropic Agents Used
in ADHF
http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation
Inotropic Support in Acute Heart
Failure


In the presence of significant hypotension,
dopamine may enhance both blood pressure
and peripheral organ perfusion.
Dopamine, in pressor doses (greater than 5
mcg/kg/min), increases myocardial oxygen
demand and potentially limits augmentation
of peripheral perfusion via peripheral
vasoconstriction
Issues with Intravenous
Inotropes
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Initial choice of therapy
Weaning
Patient related variables
Differences in efficacy
Adverse effect profile
Survival data
“Long-term” infusions
The Hospitalized Patient
I IIa IIb III
Invasive Hemodynamic Monitoring
Invasive hemodynamic monitoring can be useful for
carefully selected patients with acute HF who have
persistent symptoms despite empiric adjustment of
standard therapies, and
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a. whose fluid status, perfusion, or systemic or
pulmonary vascular resistances are uncertain;
b. whose systolic pressure remains low, pr is
associated with symptoms, despite initial
therapy;
c. whose renal function is worsening with therapy;
d. who require parenteral vasoactive agents; or
e. who may need consideration for advanced device
therapy or transplantation.
The Hospitalized Patient
Parenteral Inotropes
I IIa IIb III
Use of parenteral inotropes in normotensive
patients with acute decompensated HF without
evidence of decreased organ perfusion is not
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recommended.
I IIa IIb III
Routine use of invasive hemodynamic
monitoring in normotensive patients with
acute decompensated HF and congestion
with symptomatic response to diuretics and
vasodilators is not recommended.
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Vasodilator Support in Acute
Heart Failure
Nitroglycerin, nitroprusside, and
nesiritide, have been demonstrated to
improve symptoms and hemodynamics in
acute heart failure.
Vasodilator Support in Acute
Heart Failure


Nitroprusside infusions (initial dose 0.1
mcg/kg/min) improve symptoms of
pulmonary congestion, and signs of
peripheral perfusion.
Titration of infusion rate is initailly
based on invasive hemodynamic
monitoring.
Vasodilator Support in Acute
Heart Failure

Nitroprusside patient variables:
– Chronic liver disease
– Renal insufficiency
– Blood pressure
– Malnourished patients
Vasodilator Support in Acute
Heart Failure

Nitroprusside toxicities:
– Cyanide intoxication: metabolic acidosis
– Thiocyanate toxicity: Hyper-reflexia,
seizures, altered mental status. Serum
concentration assay available
Vasodilator Support in Acute
Heart Failure


Nitroglycerin infusion may be
preferred in patients an active or
recent history of ischemia.
Nitroglycerin is a less potent arteriolar
dilator than nitroprusside
Vasodilator Support in Acute
Heart Failure
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Nesiritide is a brain naturetic peptide (BNP) which
has significant vasodilator effects.
Dosing regimen, 0.2 mcg/kg bolus followed by 0.01
mcg/kg/min continuous infusion
Reduces LV filling pressure, variable effect on CO,
urine output, sodium excretion
Better than diuretics for dyspnea
Longer t ½ than nitroglycerin or nitroprusside
Adverse renal outcomes
History of New Treatments in
ADHF
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1988: Milrinone approved based on
small hemodynamic studies
2000: Levosimendan approved in
Sweden then 40 countries
2001: Nesiritide based on 489 patient
VMAC trial
Research on Drugs for Acute
Heart Failure
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
PubMed search for “heart failure”
(19,154)/”randomized controlled
trials”(2176)/”acute disease”(61) for novel,
intravenous treatments for acute heart
failure
Search results: Levosimendan, nesiritide,
rolofylline, tezosentan
Levosimendan
(REVIVE I and II)
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700 patients, placebo controlled
Primary endpoint: Clinical composite
based on patient global assessment
during first 5 days of treatment
(positive)
Increased ventricular/atrial
arrhythmias, symptomatic
hypotension, early mortality
JCHF. 2013;1(2):103-111. doi:10.1016/j.jchf.2012.12.004
Levosimendan vs.
Dobutamine (SURVIVE)

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1327 patients
Primary endpoint: All cause mortality
at 180 days not achieved
No secondary endpoints achieved
Decreased BNP
JAMA. 2007 May 2;297(17):1883-91
Nesiritide (ASCEND-HF)
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Placebo controlled post approval trial
Prespecified primary endpoint
(dyspnea relief) not met
No beneficial effect on hospital
readmisiion, all-cause mortality,
worsening renal function
N Engl J Med 2011;365:32-43
Rolofylline (Protect)
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2033 patients
Failed to meet primary clinical
composite endpoint
No reduction in hospital readmissions
Complicated by seizures and stroke
N Engl J Med 2010; 363:1419-28
Tezosentan (VERITAS)
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1448 patients
No improvement in dyspnea
No improvement in worsening heart
failure or death at 7 days
No improvement in renal function,
hospital readmission or mortality
JAMA 2007;298:2009-19
The Hospitalized Patient
Reconciling and Adjusting Medications
I IIa IIb III
I IIa IIb III
Medications should be reconciled in every patient
and adjusted as appropriate on admission to and
discharge from the hospital.
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In patients with reduced ejection fraction experiencing
a symptomatic exacerbation of HF requiring
hospitalization during chronic maintenance treatment
with oral therapies known to improve outcomes,
particularly ACE inhibitors or ARBs and beta-blocker
therapy, it is recommended that these therapies be
continued in most patients in the absence of
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hemodynamic instability or contraindications.
Serelaxin
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Recombinant human relaxin-2 (peptide that
regulates maternal adaptations to
pregnancy)
Increased arterial compliance, cardiac
output, renal blood flow.
Suggested benefit on dyspnea and postdischarge clinical outcomes in patients
admitted with evidence of congestion,
normal to elevated blood pressure, mild to
moderate renal dysfunction.
Serelaxin (RELAX-AHF)


Prospective, randomized, double-blind,
placebo-controlled, parallel group trial 1161
patients comparing serelaxin to placebo.
The RELAX-AHF trial tested the hypothesis
that serelaxin-treated patients would have
greater dyspnea relief compared with
patients treated with standard care and
placebo
Lancet 2013; 381: 29–39
Serelaxin (RELAX-AHF)
Inclusion Criteria
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Acute heart failure within past 16 hours,
Dyspnea at rest or minimal exertion
Pulmonary congestion on CXR
BNP > 350 ng/L, NT-proBNP > 1400 ng/L
GFR 30 – 75 ml/min/1.73 m2
Systolic BP > 125 mm Hg
Treated with > 40 mg iv furosemide
Lancet 2013; 381: 29–39
RELAX-AHF Trial
RELAX-AHF Trial
Lancet 2013; 381: 29–39
RELAX-AHF Trial
Lancet 2013; 381: 29–39
Serelaxin
June 2013: FDA grants serelaxin “breakthroughtherapy” designation based on RELAX-HF Trial
Breakthrough designation therapy reserved for the
development or review of drugs seen as poteentiaal
game changers for serious and life-threatening
conditions that have preliminary evidence in at least
one clinically significant endpoint over other available
therapies
Other Investigational Drugs for
AHF

TRV027
– Β-arrestin-biased AT1R ligand, competitively inhibits G-protein
signaling
– Reduces MAP, increases cardiac contractility, maintains stroke
volume, preserves GFR
– Anti-apoptotic effect

Ularitide
– Synthetic foem of urodilatin (naturetic peptide produced by
kidneys)
– Binds to specific naturetic peptide receptors, imcreasing
intracellular cyclic GMP
– Relaxes smooth muscle cells, vasodilation and increased renal
blood flow
– Ongoing TRUE-AHF study: Symptoms, HF improvement, and
death
Other Investigational Drugs
for AHF

Omecamtiv mecarbil
– Selective cardiac myosin activator
– ATOMIC-AHF was a randomized, double-blind, placebo-controlled Phase
II clinical trial that enrolled 613 patients hospitalized with acute heart
failure (AHF) treated for 48 hours with an intravenous formulation of
omecamtiv mecarbil or placebo and designed to evaluate the safety,
pharmacokinetics, pharmacodynamics, and potential efficacy of
omecamtiv mecarbil in patients with AHF
– The primary efficacy endpoint of dyspnea symptom response was not
met; favorable trends between the dose and plasma concentration of
omecamtiv mecarbil and dyspnea response. The incidence of worsening
heart failure within seven days of initiating treatment appeared lower in
each of the cohorts on omecamtiv mecarbil. Rates of adverse events
(AEs), serious AEs, adjudicated deaths and hospitalizations were similar
between omecamtiv mecarbil and placebo groups. Omecamtiv mecarbil
was not associated with an increased incidence of tachyarrhythmias nor
were heart rate or blood pressure adversely affected.
Continuation of Outpatient ACE/ARB
Therapy
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Blood pressure
Renal function
Volume dependency
Substitution of hydralazine/nitrates
Beta Blocker Use in ADHF
Foranow GC. J Am Coll Cardiol 2008;52:190-9
Beta Blockers in Acute Decompensated
Heart Failure
Foranow GC. J Am Coll Cardiol 2008;52:190-9
The Hospitalized Patient
I IIa IIb III
I IIa IIb III
In patients hospitalized with HF with reduced ejection
fraction not treated with oral therapies known to improve
outcomes, particularly ACE inhibitors or ARBs and betablocker therapy, initiation of these therapies is
recommended in stable patients prior to hospital
discharge.
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Initiation of beta-blocker therapy is recommended after
optimization of volume status and successful
discontinuation of intravenous diuretics, vasodilators, and
inotropic agents. Beta-blocker therapy should be initiated
at a low dose and only in stable patients. Particular
caution should be used when initiating beta-blockers in
patients who have required inotropes during their hospital
course.
New
The Hospitalized Patient
Severe Symptomatic Fluid Overload
I IIa IIb III
In patients with evidence of severely
symptomatic fluid overload in the absence of
systemic hypotension, vasodilators such as
intravenous nitroglycerin, nitroprusside or
neseritide can be beneficial when added to
diuretics and/or in those who do not respond
to diuretics alone.
New
The Hospitalized Patient
Reconciling and Adjusting Medications
I IIa IIb III
Comprehensive written discharge instructions for all
patients with a hospitalization for HF and their
caregivers is strongly recommended, with special
emphasis on the following 6 aspects of care: diet,
discharge medications, with a special focus on
adherence, persistence, and uptitration to
recommended doses of ACE inhibitor/ARB and betablocker medication, activity level, follow-up
appointments, weight monitoring, and what to do if
HF symptoms worsen.
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Recommendations for Hospital
Discharge
http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation
Improvement of Guideline Beta-Blocker Prescribing in
Heart Failure: A Cluster-Randomized Pragmatic Trial
of a Pharmacy Intervention
We conducted a pragmatic cluster-randomized trial, where facilities (n 5
12) with patients (n 5 220) were the clusters. Eligible patients had a
beta-blocker prescription that was not guideline concordant. Level 1
intervention included information to a pharmacist on facility guideline
concordance. Level 2 also provided a list of patients not meeting
guideline goals. Intervention and follow-up periods were each 6 months.
Achievement of full concordance with recommendations was low
(4%e5%) in both groups, primarily due to lack of tolerability. However,
compared with level 1, the level 2 intervention was associated with 1.9fold greater odds of improvement in prescribing (95% confidence
interval [CI] 1.1e3.2). Level 2 patients also had greater odds of a higher
dose (1.9, 95% CI 1.1e3.3). The intervention was aided by the patient
lists provided, the electronic medical record system, and staff support.
Journal of Cardiac Failure Vol. 19 No. 8 2013
Acute Decompensated Heart Failure


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Few well controlled trials
Little data to demonstrate improved
morbidity/mortality
Need for newer, more effective, lower
ADR-inducing agents