Download Beta-blockers Versus ACE Inhibitors in Heart Failure

Beta-blockers Versus ACE Inhibitors in Heart Failure with Reduced Ejection
Fraction: Which Should be Utilized First?
By Genevieve Hale, Pharm.D., BCPS, PGY2 cardiology resident, VA Ann Arbor Healthcare System;
and Lindsey Greiner, Pharm.D., PGY1 pharmacy practice resident, VA Ann Arbor Healthcare
System
Target Audience
This continuing education activity was designed specifically for pharmacists.
Disclosure Statement
The authors do not have any conflicts of interest, or financial relationships with a commercial
interest, related to the activity.
Learning Objectives
At the end of this activity, participants should be able to:
 define heart failure and distinguish between the different types of heart failure.
 identify risk factors and causes of heart failure.
 explain the pathophysiology of heart failure and role of angiotensin-converting enzyme
(ACE) inhibitors and beta-blockers in heart failure physiology.
 explain the landmark trials involving ACE inhibitor and beta-blocker therapy in heart failure.
 recommend whether ACE inhibitors or beta blockers should be utilized first in heart failure
treatment.
Introduction
Heart failure (HF) is a progressive disease that creates a large burden within the health care
system. In Americans aged 40 years and older, the lifetime risk of developing HF is 20 percent.1
More than 650,000 new cases of HF are diagnosed each year.1 Heart failure is associated with
excessive hospital admissions, being the primary diagnosis in more than 1 million hospitalizations
annually.1 In addition, approximately 50 percent of patients will die within five years of HF
diagnosis.1
HF is defined as a complex clinical syndrome that results from any structural or functional
impairment of ventricular filing or ejection of blood.1,2 This general term is further classified into
types of dysfunction based on left ventricular ejection fraction (LVEF), including HF with reduced
ejection fraction (HFrEF), or HF with preserved ejection fraction (HFpEF). An LVEF of less than
40 percent signifies HFrEF, whereas an individual with an LVEF of greater than 50 percent has
HFpEF. These are usually accompanied by varying degrees of systolic and diastolic dysfunction.
Patients with HFrEF may exhibit systolic and diastolic dysfunction, but those with HFpEF are less
likely to have a reduction in systolic function.1-3 A unique aspect of this disease state is the absence
of definitive diagnostic testing; therefore, diagnosis is based on clinical judgment. 1-3 According to the
European Society of Cardiology, the criteria for a diagnosis of HFrEF requires symptoms and signs
of typical HF with a reduced LVEF. The diagnosis of HFpEF requires symptoms and signs of
typical HF, normal or only mildly reduced LVEF and LV that is not dilated, and relevant structural
heart disease (i.e., LV hypertrophy and/or left atrium enlargement), and/or diastolic dysfunction. 2
The most common symptoms and recognizable signs of HF are edema, dyspnea and fatigue with
elevated jugular venous pressure, pulmonary crackles, and displaced apex beats.2
Keeping these symptoms in mind, HF is further classified by functional class and
progression of structural disease (see Table 1).1,2 Unfortunately, there are a wide range of underlying
pathologies that play a role in the development of HF.
First-line agents in the management of HFrEF include angiotensin-converting enzyme
(ACE) inhibitors and beta-blockers (BB).1,2 These agents have demonstrated a reduction in mortality
and hospitalizations among HF patients. As ACE inhibitors and BB demonstrate clinical benefits in
multiple comorbid conditions, comorbidities and patient-specific factors should be considered when
determining initial therapy for the management of HF. This article aims to provide an overview of
HF and the utilization of ACE inhibitor and BB therapy.
Table 1. Stages and Functional Classifications of HF 1
ACCF/AHA Stages of HF
A
At high risk for HF but without structural heart disease of symptoms of HF
B
Structural heart disease but without signs or symptoms of HF
C
Structural heart disease with prior or current symptoms of HF
D
Refractory HF requiring specialized interventions
NYHA Functional Classifications
I
No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
II
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results
in symptoms of HF.
III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity
causes symptoms of HF.
IV
Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at
rest.
Etiology
The most common cause of HF is left ventricular dysfunction due to hypertension in
approximately 60 to 80 percent of the American population.1 However, impairments of the
pericardium, myocardium, endocardium, heart valves or metabolic abnormalities are other
underlying conditions that may lead to HF.1 The causes of HFrEF and HFpEF somewhat differ.
Approximately two-thirds of HFrEF cases arise due to coronary artery disease (CAD), likely
complicated by hypertension and/or diabetes.4 Underlying causes of HFrEF can be divided into
ischemic and nonischemic cardiomyopathies. Myocardial infarction (MI) is a major cause of
ischemic cardiomyopathy. An exhaustive list of syndromes that have the potential to develop into
nonischemic cardiomyopathies include familial or idiopathic causes, obesity, diabetes, thyroid
disease, acromegaly and growth hormone deficiency, excessive alcohol consumption, cocaine use,
cancer therapy, myocardial toxins (e.g., ephedra, amphetamine, anabolic steroids), tachycardiainduced, myocarditis, HIV, Chagas disease, hypersensitivity myocarditis, rheumatological and
connective tissue disorders, peripartum, iron overload, amyloidosis, cardiac sarcoidosis and
Takotsubo syndrome.1 Conversely, older, obese women and individuals with atrial fibrillation and
hypertension are more likely to develop HFpEF.5,6
Risk Factors
Unfortunately, adults 40 years of age or older have a 20 percent lifetime risk of developing
HF.7 More than five million people suffer from this disease presently.8 The prevalence of each type
of HF is equally divided at 50 percent in the general population.9 Those having the highest risk of
developing HF are individuals who are 65 years of age or older.10 In particular, African American
males are at a higher risk of developing HF, compared to Caucasian women having the lowest risk.1114
Prevention is of utmost importance, as the mortality rate within five years of diagnosis is estimated
to be 50 percent, as aforementioned.12,13 Hypertension, diabetes, metabolic syndrome and
atherosclerosis are amongst the most important modifiable risk factors of HF. 16-20 Long-term
treatment of these comorbid conditions can significantly reduce this risk up to 50 percent.21-24
Pathophysiology
As earlier described, HF is best characterized as a progressive disease. Changes that occur to
the myocardial anatomy, specifically the left ventricle, are a result of myocyte death and
neurohormonal activation.25,26 Compensatory mechanisms following myocardium injury lead to
reconstruction of the heart’s anatomy in a phenomenon known as remodeling, causing dilation of
the ventricle, hypertrophy and reduced contractility, and decline in systolic function.25,26 The reninangiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are activated as the
heart attempts to restore hemodynamic stability.
In the RAAS, renin, located in the juxtaglomerular cells of the renal afferent arteriole, is
cleaved by prorenin.27 Baroreceptors in the afferent arteriole walls are augmented by reduced
perfusion pressure and systemic volume causing renin release. 28 Angiotensinogen forms into
angiotensin I via cleavage of renin, subsequently leading to the activation of angiotensin II via ACE.
Alternatively, angiotensin II can also be converted from angiotensin I by protease chymase in an
alternative pathway.29 Angiotensin II responds to systemic volume depletion and lowered blood
pressure while maintaining cardiovascular homeostasis. 30 Local production of angiotensin has been
located in numerous tissues, including the heart.31,32 Of note, a negative feedback mechanism is
present in response to increased angiotensin II levels. Angiotensin II activates several cardiovascular
and renal mechanisms through angiotensin I receptors, including systemic arterial vasoconstriction,
renal arteriolar vasoconstriction, stimulation of renal tubular reabsorption of sodium and water,
vascular smooth muscle contraction, cellular proliferation, oxidative stress and aldosterone release
from the adrenal glands.27 Stimulation of the angiotensin I receptor by angiotensin II produces
cellular and fibroblast hypertrophy and collagen deposition leading to myocardial fibrosis in the
myocardium.33,34 Hypertrophy and fibrosis promote ventricular remodeling, a hallmark sign of
HFrEF. Aldosterone stimulates collagen synthesis and increases the level of ACE in the heart,
further increasing angiotensin II production.35,36
The SNS is responsible for heart rate acceleration, cardiac contractility, reduced venous
capacitance and peripheral vasoconstriction via cardiac sympathetic nerve fibers in the coronary
arteries, mainly in the ventricles.37 Once the SNS is activated, norepinephrine and epinephrine is
released. Norepinephrine increases contractile strength and blood pressure in the left ventricle, and
increases heart rate and shortens atrioventricular conduction by traveling through the sinus and
atrioventricular nodes. Locally released epinephrine and norepinephrine exert effects on the
myocardium and peripheral vessels.37 In HFrEF, SNS is hyperactive as a result of cardiovascular
reflex abnormalities.38,39 The inhibitory SNS arterial baroreceptor reflex is significantly diminished;
however, the excitatory peripheral chemoreceptor reflex is amplified.40
The activation of the RAAS and SNS is initially beneficial, but prolonged activation leads to
cardiac and peripheral hemodynamic instability. 41 This leads to harmful effects on, but not limited
to, the heart, blood vessels, kidneys, muscles, bone marrow, lungs and liver. Further damage
continues in a positive feedback fashion leading to symptomatology and deficiency within the
framework of the myocardium, including electrical abnormalities. 25,26 As a result, a decreased quality
of life, decrease in the functional capacity of the heart, decompensation, increase in hospitalizations
and premature death from pump failure or ventricular arrhythmia occurs. 2 Pharmacological therapy,
such as ACE inhibitors and BB aim to halt the cycle created by this detrimental environment by
working on RAAS and SNS.
ACE Inhibitors and Landmark HFrEF Trials
As the name implies, ACE inhibitors block the transformation of angiotensin I into
angiotensin II by decreasing the production of the ACE enzyme. These agents also increase nitric
oxide stimulation, causing positive outcomes on endothelial function by halting the breakdown of
bradykinin.42 Additionally, cardiac hemodynamics and exercise capacity are improved by decreasing
systemic vascular resistance.43,44 However, it is important to keep in mind that not all patients will
tolerate these agents. Common side effects include hypotension, dizziness and dry cough.
Monitoring for severe adverse events, including angioedema and anaphylactic reactions, must also be
taken into consideration.45
There are several landmark trials that have demonstrated the impact of ACE inhibitors in
HF patients starting with CONSENSUS.46 This study looked at patients with New York Heart
Association (NYHA) class IV symptoms with a heart size greater than 550 mL/m2 (women) and 600
mL/m2 (men) receiving enalapril compared to placebo for a mean of 6.2 months. Patients were
randomized to enalapril 5 mg twice daily and, as tolerated, were then increased to 10 mg twice daily
after one week up to a goal (target) dose of 20 mg twice daily. Patients had to be on a diuretic and
digoxin for at least two weeks. Other medications such as spironolactone, BB and vasodilators were
allowed to help control symptoms. Of note, only 3 percent of patients were on concomitant BB
treatment, yet 52 percent were also taking spironolactone. The primary endpoint was six-month
mortality. The secondary endpoint was 12-month and overall mortality. Originally planned to
continue for several years, the Ethical Review Committee observed a consistent mortality difference
in favor of enalapril after a year and a half, which ended the trial early. The mortality benefits
observed were significantly different compared to placebo, showing a 40 percent relative risk
reduction at six months (p = 0.002), 31 percent at one year (p = 0.001) and 27 percent reduction in
total mortality over the entire study period (p = 0.003). Furthermore, cardiac death (including death
from renal-artery thrombosis, endocarditis, pulmonary emboli after leg amputation, bronchitis and
concomitant HF, occlusion of femoral arterial graft and HF in relation to melena) was significantly
reduced compared to placebo (p = 0.001) as well as progression of congestive HF (p = 0.001).
Additionally, heart size was significantly reduced in the enalapril group (p = 0.02). This investigation
showed that enalapril in patients with severe HF can reduce mortality and improve symptoms. This
was the first trial to demonstrate a mortality benefit of ACE inhibition in HF.
CONSENSUS proved that ACE inhibitors were useful in severe HF patients; however,
effectiveness in patients with NYHA class I, II and III symptoms was still unknown. Subsequently,
the SOLVD trial aimed to answer this question. This trial was separated into the SOLVD treatment
trial for patients with overt HF, and the SOLVD prevention trial for patients without HF
symptoms.47,48 For both trials, patients diagnosed with congestive HF with an LVEF less than 35
percent were included. Patients received either enalapril 2.5 to 5 mg twice daily that was then
titrated, if tolerated, to a target dose of 10 mg twice daily or placebo for a mean of 41 months. The
primary endpoint was all-cause mortality. Secondary endpoints included hospitalization for
congestive HF, incidence of MI, mortality due to specific causes, and a combined analysis of
morbidity and mortality. In the SOLVD treatment trial, 57 percent of patients had class II
symptoms, 30 percent had class III symptoms and 11 percent had class I symptoms. Patients were
allowed to receive other HF agents, including digoxin, diuretics, vasodilators and calcium channel
blockers. Only 8 percent of patients were also receiving a BB. No patients received spironolactone.
A significant difference in all-cause mortality was found in favor of enalapril, observed to be most
marked in the first 24 months with a risk reduction (RR) of 16 percent (RR 0.16; 95 percent CI, 0.05
to 0.26; p < 0.0036). A significant difference in favor of enalapril also appeared when comparing
deaths or hospitalization for CHF (RR 0.26; 95 percent CI, 0.18 to 0.34; p < 0.0001), cardiovascular
death (RR 0.18; 95 percent CI, 0.06 to 0.28; p < 0.002), cardiac events (RR 0.19; 95 percent CI, 0.07
to 0.29; p < 0.0015), and HF or arrhythmia with CHF (RR 0.22; 95 percent CI, 0.06 to 0.35; p <
0.0045). A nonsignificant positive trend for reduction in MI with enalapril use was also observed
(RR 0.28; 95 percent CI, -0.08 to 0.52; p < 0.07). A significant reduction in mortality and
hospitalizations for CHF in patients treated with an ACE inhibitor and conventional therapy was
further established. This added to the results provided by CONSENSUS by demonstrating a 16
percent reduction in the risk of death with an ACE inhibitor in patients with an LVEF less than 35
percent with symptoms associated with any NYHA class.
The SOVLD prevention trial looked at asymptomatic patients who were not receiving HF
treatment. All-cause mortality was not significantly different between treatment and placebo groups
(RR 0.08; 95 percent CI, -0.08 to 0.21; p = 0.30). There was a larger but nonsignificant reduction in
mortality from cardiovascular causes in those receiving enalapril (RR 0.12; 95 percent CI, -0.03 to
0.26; p = 0.12). When patients in whom HF developed and those who died were combined, the total
number of deaths and cases of HF was significantly less in the enalapril group (RR 0.29; 95 percent
CI 0.21 to 0.36; p < 0.001). In addition, fewer patients given enalapril died or were hospitalized for
HF (RR 0.20; 95 percent CI, 0.09 to 0.30; p < 0.001). This trial showed that ACE inhibitors can
significantly reduce the incidence of HF and rate of related hospitalizations in asymptomatic
individuals with left ventricular dysfunction. There was also a trend toward fewer cardiovascular
deaths in patients who received enalapril.
Before ACE inhibitors and BB, vasodilators were the mainstay of HF treatment. The VHeFT II trial compared the then standard therapy to the emerging ACE inhibitor therapy. 49 Men
with a LVEF of less than 45 percent and reduced exercise tolerance were followed for a mean of 2.3
years. Patients received enalapril 20 mg daily or hydralazine 300 mg plus isosorbide dinitrate 160 mg
daily. Mortality by any cause was the primary endpoint. Secondary endpoints were not specified, but
factors such as mortality for each year studied, change in LVEF and exercise capacity by looking at
oxygen consumption were reviewed. No patients were on concomitant BB or spironolactone
therapy. Results showed a nonsignificant favorable trend in patients receiving enalapril regarding allcause mortality over the entire study course (p = 0.08). However, mortality after two years was
significantly less in the enalapril arm (p = 0.016). After the first year of treatment, enalapril reduced
mortality by 13 percent and hydralazine/isosorbide dinitrate by 9 percent. This increased over time,
as enalapril reduced mortality by 54 percent and hydralazine/isosorbide dinitrate by 48 percent over
five years. Sudden cardiac death occurred significantly less in the enalapril group whether with (p =
0.032) or without warning (p = 0.015) of an event. Left ventricular ejection fraction after 13 weeks
and annually after randomization were significantly increased in both treatment groups for three
years (p = 0.0001) with the increased LVEF after 13 weeks being significantly greater in the
hydralazine/isosorbide dinitrate group (p = 0.026). Oxygen consumption was shown to be increased
significantly by hydralazine/isosorbide dinitrate after 13 weeks (p < 0.0001) and after six months (p
< 0.0001), but not enalapril. The transverse diameter of the heart was also found to be significantly
reduced in both treatment arms after 13 weeks and one year (p < 0.0001). There was no significant
difference amongst patients in either group. Based on these results, the investigators suggested using
the hydralazine/isosorbide dinitrate combination agent with ACE inhibitor therapy for further
mortality benefit and symptom relief in HF. Overall, this trial revealed ACE inhibitor superiority
over hydralazine plus nitrate combination therapy in HF patients.
STOP AND REFLECT
A 60-year-old Caucasian male presents to your clinic with a new HF diagnosis. His
LVEF is 20 percent and he is exhibiting dyspnea on exertion and +1 pitting edema. His
current HF failure regimen includes furosemide 20 mg daily and hydralazine 300
mg/isosorbide dinitrate 160 mg, one tablet daily. What medication changes should you
consider in this patient?
Beta-blockers and Landmark HFrEF Trials
BB inhibit the binding of norepinephrine and epinephrine to beta receptors located in the
heart, bronchial and vascular musculature. Properties of BB that are beneficial in HF include
decreased sympathetic outflow from the vasomotor centers of the brain, and the inhibition of renin
release by the kidneys.50 In total, three BB have proven to be effective in mortality reduction among
patients with HFrEF – bisoprolol, carvedilol and metoprolol succinate. Both bisoprolol and
metoprolol succinate are selective for beta-1 receptors, although this selectivity may be lost at higher
doses. Metoprolol succinate maintains its beta-1 selectivity until a maintenance dose of 200 mg is
reached, and bisoprolol maintains its beta-1 selectivity until a maintenance dose of 20 mg daily is
reached, which exceeds the target dose in HFrEF.50,51 Carvedilol blocks alpha-1, beta-1 and beta-2
receptors.52
An important concept to remember when initiating BB in HF is the potential for fluid
retention and worsening symptoms of HF. For this reason, BB should be initiated at low doses, and
increased gradually to their target doses. If fluid retention does occur, a patient’s diuretic dose
should be increased, and up-titration of the BB dose should be postponed until the patient is
clinically stable.52 In some cases such as when patients are unresponsive to diuretic therapy or
patients require the use of inotropes, it may be useful to temporarily lower the dose or discontinue
the BB.53 Of note, worsening HF symptoms with a BB should not be a reason to avoid BB
permanently. Additional adverse effects with BB include fatigue, bradycardia, heart block and
hypotension.
Multiple trials have demonstrated the utility of BB in HFrEF. The U.S. Carvedilol Heart
Failure Study Group trial was the first trial to demonstrate a mortality benefit with BB in the
treatment of HF.54 This trial included patients with symptoms of HF for at least three months, a
LVEF ≤ 35 percent, and two or more months of treatment with diuretics and an ACE inhibitor.
Patients were randomized to carvedilol 6.25 mg twice daily or placebo, with a gradual dose increase
to 25 to 50 mg twice daily over two to 10 weeks, as tolerated. The mean total daily dose of carvedilol
was 45 mg. The primary outcome was all-cause mortality. Treatment with carvedilol led to a 65
percent relative risk reduction for death as compared to placebo (p < 0.001). In addition, carvedilol
led to fewer hospitalizations due to cardiovascular causes (RR 0.73; 95 percent CI, 0.55-0.97; p =
0.036) and a decrease in the combined risk of death or hospitalization due to cardiovascular reasons
(HR 0.62; 95 percent CI, 0.47-0.82; p < 0.001). In this trial, 95 percent of patients also received an
ACE inhibitor at baseline. This was the first trial to demonstrate the utility and benefit of BB
therapy in HF patients.
Next, the COPERNICUS trial enrolled patients with severe symptomatic chronic HF,
defined as dyspnea or fatigue at rest or on minimal exertion for two months, a LVEF < 25 percent
despite optimal medical therapy and clinical euvolemia.55 Patients were randomized to carvedilol
3.125 mg twice daily or placebo. Doses were doubled every two weeks to achieve a target dose of 25
mg twice daily, as tolerated. The mean daily dose of carvedilol achieved in COPERNICUS was 37
mg. Patients were evaluated for a primary outcome of all-cause mortality, in which carvedilol
demonstrated a 35 percent relative risk reduction compared to placebo (p = 0.00013). A secondary
outcome in COPERNICUS was the combined risk of death or all-cause hospitalization. For this
outcome, carvedilol demonstrated a 35 percent relative risk reduction compared to placebo (p <
0.001). In addition to carvedilol or placebo, 97 percent of patients received an ACE inhibitor or
angiotensin II receptor blocker (ARB), and 20 percent of patients received spironolactone at
baseline. COPERNICUS further highlighted the mortality benefits as well as decrease in
hospitalization that BB therapy offered to the HF population.
CIBIS-II included patients with NYHA class III-IV symptoms of HF, and a LVEF ≤ 35
percent.56 Heart failure was diagnosed at least three months prior to enrollment. Additionally,
patients needed to be clinically stable for at least six weeks for HF symptoms, and three months for
unstable angina or MI. Study participants were randomized to bisoprolol 1.25 mg daily or placebo,
with dose titrations to a goal dose of 10 mg daily. This dose was achieved in 43 percent of patients
during the study. Ninety six percent of patients were also taking an ACE inhibitor during this trial.
The primary outcome was all-cause mortality. Secondary outcomes included all-cause hospital
admissions, cardiovascular mortality, the composite of cardiovascular mortality and cardiovascular
hospital admissions, and permanent premature treatment withdrawal. Patients were followed for a
mean of 1.3 years, and the trial was stopped early due to a 32 percent risk reduction in all-cause
mortality with bisoprolol as compared to placebo (p < 0.0001). In addition, bisoprolol decreased allcause hospitalizations (HR 0.80; p = 0.0006), cardiovascular mortality (HR 0.71; p = 0.0049), and
cardiovascular mortality and cardiovascular hospital admissions (HR 0.79; p = 0.0004). CIBIS II
revealed that bisoprolol was another option for BB therapy in HF patients, which also reduced
morbidity and mortality as well as hospitalizations.
The MERIT-HF trial compared metoprolol succinate 12.5 mg or 25 mg daily to placebo in
the reduction of all-cause mortality among HF patients for a mean follow-up of one year.57 The
metoprolol dose was doubled every two weeks to a target of 200 mg daily, as tolerated. Inclusion
criteria for this trial was patients with NYHA class II-IV HF for at least three months with an LVEF
≤ 40 percent within three months. Patients needed to be on optimum therapy with an ACE
inhibitor and diuretic. This trial demonstrated a 34 percent relative risk reduction in all-cause
mortality with metoprolol succinate (p = 0.00009), and led to its FDA approval in HF management.
This study also demonstrated a significant reduction in all-cause mortality plus all-cause
hospitalization (RR 0.19; 95 percent CI, 0.10-0.27; p < 0.001), all-cause mortality or HF
hospitalization (RR 0.31; 95 percent CI 0.20-0.40; p < 0.001), death or heart transplant (RR 0.32; 95
percent CI, 0.16-0.45; p < 0.001), cardiac death or nonfatal MI (RR 0.39; 95 percent CI, 0.25-0.51; p
< 0.001), and all-cause mortality or all-cause hospitalization or ED visit for HF (RR 0.32; 95 percent
CI, 0.21-0.41; p < 0.001) with metoprolol as compared to placebo. At baseline, 89 percent of
patients enrolled in the trial received an ACE inhibitor, and 7 percent received an ARB. With the
positive results of MERIT-HF, metoprolol succinate joined carvedilol and bisoprolol in effective BB
agents to prevent morbidity and mortality in HF.
Table 2. Landmark Trials of ACE inhibitors and Beta-blockers
Trial
Agents
Primary
Results
Outcomes
CONSENSUS 1. Enalapril 5-20 mg
Six-month
Six-month mortality: 26 percent vs.
twice daily
mortality
44 percent (RR 0.60; p = 0.002)
(as tolerated)
SOLVD-T
SOLVD-P
V-HeFT
CIBIS II
2. Placebo
1. Enalapril 2.5-10 mg
twice daily
(as tolerated)
2. Placebo
1. Enalapril 20 mg
daily
2. Hydralazine 300
mg/Isosorbide
dinitrate 160mg daily
1. Bisoprolol 1.2510mg daily (as
tolerated)
2. Placebo
COPERNICUS 1. Carvedilol 3.125-25
mg twice daily (as
tolerated)
MERIT-HF
All-cause
mortality
Two-year
mortality and
overall
mortality
35 percent vs. 40 percent (RR 0.84;
95 percent CI 0.74-0.95; p = 0.0036)
14.8 percent vs. 15.8 percent (RR
0.08; 95 percent CI, -0.08 to 0.21; p
= 0.30)
Two-year mortality: 18 percent vs.
25 percent (p=0.016)
Overall mortality: 132 events vs. 153
events (p = 0.08)
All-cause
mortality
All-cause mortality: 11.8 percent vs.
17.3 percent p<0.0001)
All-cause
mortality
All-cause mortality: 11.2 percent vs.
16.8 percent (p = 0.00013)
2. Placebo
1. Metoprolol succinate All-cause
12.5-200 mg daily
mortality and
all-cause
2. Placebo
mortality plus
all-cause
hospitalization
All-cause mortality: 7.2 percent vs.
11 percent (p = 0.00009)
All-cause mortality plus all-cause
hospitalization: 32 percent vs. 38
percent (p < 0.001)
Table 3. Pharmacology and Target Doses of ACE Inhibitors
Drug
Half-life
Onset of
Dose Range and
(Hours)
Action
Frequency
(Hours)
Captopril
2
0.25-0.5
6.25-150 mg thrice daily
Enalapril
11
1-2
2.5-10 mg twice daily
Lisinopril
12
1-2
5-20 mg daily
Ramipril
16
1-2
2.5-10 mg daily or in
divided doses
Quinapril
25
1-2
5-40 mg daily or in
divided doses
Fosinapril
12
1-2
5-20 mg daily
Table 4. Pharmacology and Target Doses of Beta-blockers
Drug
Half-life
Onset of
(Hours)
Action
(Hours)
Bisoprolol
9-12
1-2
Carvedilol
7-10
1-2
Metoprolol
Succinate
3-4
1-2
12.5-200 mg
daily
Target Dose for
Survival Benefit
50 mg thrice daily
10 mg twice daily
10-20 mg daily
5 mg daily
20 mg twice daily
20 mg daily
Dose Range
and Frequency
1.25-10 mg daily
3.125-50 mg
twice daily
Target Dose
for Survival
Benefit
10 mg daily
25 mg twice
daily (< 85 kg)
50 mg twice
daily (> 85 kg)
200 mg daily
STOP AND REFLECT
Three months later, the same 60-year-old Caucasian male returns to your clinic for
optimization of HF management. His current HF regimen includes furosemide 20 mg
daily, lisinopril 20 mg daily and hydralazine 300 mg/isosorbide dinitrate 160 mg, one
tablet daily. He is euvolemic on examination. What medication changes should you
consider in this patient?
Guideline Recommendations
As a result of the described landmark trials, the 2013 ACCF/AHA guidelines recommend
the use of ACE inhibitors (Level of Evidence A) and BB (Level of Evidence B) in all individuals with a
history of MI or acute coronary syndrome (ACS) and reduced LVEF with evidence of structural
heart abnormalities.1 In patients without a history of MI, ACE inhibitors (Level of Evidence A) and BB
(Level of Evidence C) are still recommended to prevent symptomatic HF and reduce mortality.1 The
ESC 2012 guidelines also recommend the use of ACE inhibitors and BB and suggest that both be
started as soon as possible after diagnosis due to their mortality benefits as well as ACE inhibitors
effects on remodeling and improvement in LVEF by BB.2 Of note, in the suggested treatment
algorithm of the ESC guideline, ACE inhibitors are initiated with diuretics first, then BB are
subsequently added to therapy.
Special Considerations
Both ACE inhibitors and BB have demonstrated mortality benefit in HFrEF. It is
recommended that both classes of medications be initiated in HFrEF. When determining which
agent to initiate first, it is important to consider patient-specific factors and comorbidities.
Pregnancy/Lactation/Women
One factor to consider when choosing a HF strategy is pregnancy. A boxed warning exists
for ACE inhibitors, stating that they should be discontinued as soon as possible when pregnancy is
detected.45 This is because drugs acting on the RAAS can cause injury or death to a developing fetus.
As a result, women, especially those of child-bearing age, are less inclined to receive ACE inhibitor
therapy. In cases of HF and pregnancy, a BB would be the safest option for management. ACE
inhibitors are also excreted in breast milk; breast-feeding while on ACE inhibitor therapy is not
recommended by the manufacturer.45 Caution in breast-feeding is also recommended with BB use.5052
Symptomatic Heart Failure
As previously mentioned, BB have the potential to increase fluid retention and worsen the
symptoms of HF.50,52 While this effect does not exclude a patient from the initiation of a BB, it may
temporarily limit the ability to titrate a BB to a target dose. This effect is not seen with ACE
inhibitors, so an ACE inhibitor may be a preferable initial agent for a patient hospitalized with
symptoms of HF.
Myocardial Infarction/Angina
Both ACE inhibitors and BB are recommended to be initiated post MI for secondary
prevention.58 Additionally, BB have utility for the management of angina. In a patient with HF and
complaints of chest pain, increasing the BB dose may be the best first option.
Atrial Fibrillation
Atrial fibrillation (AF) is an irregular heart beat characterized by uncoordinated atrial
activation and ineffective atrial contraction.59 Patients may experience symptoms, including fatigue,
palpitations, dyspnea, syncope, and development or worsening of HF. A BB can be utilized for rate
control and may alleviate such symptoms. Some data suggests that bucindolol may be beneficial in
patients with AF and HF; additional research is warranted.60 Currently, carvedilol, metoprolol
succinate and bisoprolol remain the only BBs indicated for HFrEF.
Ventricular Arrhythmias
Ventricular arrhythmias range in severity from being asymptomatic, to causing sudden death,
and include conditions such as premature ventricular complexes, ventricular tachycardia, and
ventricular flutter and fibrillation.61 BB are recommended for the suppression of ventricular ectopic
beats and arrhythmias and have shown efficacy in the reduction of sudden cardiac death among
patients with and without HF. Additionally, carvedilol may be superior to metoprolol in the
prevention of ventricular arrhythmias.62 Among patients prescribed BB therapy in the Multicenter
Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADITCRT), ventricular arrhythmias occurred in 26 percent of patients prescribed metoprolol, and 22
percent of patients prescribed carvedilol (HR 0.80; 95 percent CI: 0.63 to 1; p = 0.05).62
Diabetes/Chronic Kidney Disease
ACE inhibitors demonstrate protective effects on the kidneys and may be especially helpful
in patients with diabetes or chronic kidney disease. These protective effects partially are a result of
antihypertensive mechanisms. Additionally, intrarenal efferent vasodilation leads to a fall in filtration
pressure contributing to beneficial effects.63 Of note, use of an ACE inhibitor can cause acute kidney
injury, and should be used with caution in patients with a history of fluctuating renal function. In
terms of BB therapy, carvedilol may be a better option for HF patients with concomitant diabetes.
Compared to metoprolol, carvedilol does not blunt insulin sensitivity and has not been shown to
worsen diabetes control as measured by HbA1C.64,65
Restrictive Lung Disease
Beta-receptors are located throughout the body, including beta-2 receptors found in the
lungs. In patients with restrictive lung disease, utilization of a BB may exacerbate breathing
problems. Although metoprolol and bisoprolol are selective to beta-1 receptors in the heart, keep in
mind they may lose their selectivity at higher doses as mentioned previously.50,51 On the other hand,
bisoprolol is the most beta-1 selective agent, and retains beta-1 selectivity at its target dose for HF,
10 mg daily.1,51 ACE inhibitors have no effect on the beta receptors, and may be a better option in
such patients. However, keep in mind the potential of ACE-induced coughing.45
Asian/African Americans and ACE-induced Cough
A common side effect of ACE inhibitors is a dry cough, which may lead to a discontinuation
of the medication. Studies have shown that an ACE inhibitor-induced cough is more common
among black and Asian patients.66,67 Thus, ethnicity is an important factor to consider when initiating
medications for the management of HF. In black and Asian patients, it may be reasonable to initiate
an ARB as an alternative to an ACE inhibitor if a history of dry cough exists.
Conclusion
Heart failure is a progressive disease marked by any structural or functional impairment of
ventricular filing or ejection of blood. First-line agents for this condition include ACE inhibitors and
BB, as several landmark trials have demonstrated a benefit in morbidity and mortality as well as a
reduction in hospitalizations. To our knowledge, only one large, randomized, controlled trial aimed
to find whether ACE inhibitors or BB should be initiated first in HFrEF by comparing bisoprololfirst to enalapril-first treatment. The primary endpoint, all-cause mortality or hospitalization, was
found to be similar between both drug classes (absolute difference -1.6 percent; 95 percent CI, 0.076 to 0.044; HR 0.94; 95 percent CI, 0.77-1.16), indicating that ACE inhibitors and BB are equally
safe and efficacious to initiate first.68 European guidelines favor the use of ACE inhibitors first when
utilizing a step-wise approach for initiating first-line therapy. In comparison, the United States
guidelines do not specify the use of one agent over another. With this said, clinicians should use
their clinical judgment and take into account patient-specific characteristics when deciding whether
to utilize an ACE inhibitor or BB first when starting HF therapy. Beta-blockers may be preferable in
HF patients who are pregnant, or have a history of angina or arrhythmias. ACE inhibitor therapy
may be preferable in symptomatic HF patients, patients with diabetes or chronic kidney disease, or
in lung disease. Despite which agent is utilized first, the goal is to include both agents in the
medication regimen in order to maximize morbidity and mortality benefits among HF patients.
Continuing Education Self-assessment Questions
1. Which of the following distinguishes HFrEF from HFpEF?
a. Evidence of left ventricular diastolic dysfunction
b. A left ventricular ejection fraction of less than 40 percent
c. A left ventricular ejection fraction of greater than 50 percent
d. Evidence of a left ventricular thrombus
2. What is the most common cause/risk factor in developing heart failure?
a. Hypertension
b. Arrhythmia
c. Sleep apnea
d. Myocardial infarction
3. Which compensatory mechanisms are harmful to the myocardium resulting in HF if stimulated
over a prolonged period of time?
a. Sympathetic nervous system (SNS)
b. Parasympathetic nervous system (PNS)
c. Renin-angiotensin-aldosterone system (RAAS)
d. Both A and C
4. Which landmark trial demonstrated a 31 percent risk reduction in mortality over one year when
using ACE inhibitor treatment in patients with NYHA class IV symptoms?
a. SOLVD treatment
b. SOLVD prevention
c. CONSENSUS
d. V-HeFT II
5. Which landmark trial demonstrated a 16 percent risk reduction in mortality when using ACE
inhibitor treatment in patients with any type of NYHA symptoms?
a. SOLVD treatment
b. SOLVD prevention
c. CONSENSUS
d. V-HeFT II
6. Which landmark trial demonstrated a 35 percent risk reduction in mortality when using BB
treatment in patients with a LVEF less than 25 percent?
a. MERIT HF
b. COPERNICUS
c. CIBIS-II
d. US Carvedilol Trial
7. Which trial demonstrated mortality benefit with patients randomized to bisoprolol?
a. MERIT HF
b. COPERNICUS
c. CIBIS-II
d. US Carvedilol Trial
8. A 48-year-old female with HF and a LVEF of 25 percent presents to clinic two weeks after the
initiation of metoprolol succinate 25 mg daily. Today, she complains of dyspnea on exertion, and
a 7-pound weight gain within the past five days. Additional medications include lisinopril 10 mg
daily and furosemide 20 mg daily. What medication change would you recommend at this time?
a. Discontinue lisinopril
b. Switch patient to metoprolol tartrate 25 mg twice daily
c. Increase furosemide to 40 mg daily
d. Increase metoprolol succinate to 50 mg daily
9. In which patient would you consider initial HF management with an ACE inhibitor?
a. 25-year-old pregnant female with LVEF 35 percent
b. 56-year-old male with a history of diabetes and gout
c. 62-year-old female with complaints of chest pain on exertion
d. 70-year-old male with ICD placement for supraventricular tachycardia
10. In which patient would you consider initial HF management with a BB?
a. 48-year-old male with diabetes and proteinuria
b. 36-year-old female presenting with pitting edema and shortness of breath
c. 58-year-old male with atrial fibrillation with rapid ventricular rate
d. 64-year-old male with severe COPD
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