Heart Failure

By Adam Sieg, Pharm.D., BCPS

Reviewed by Orly Vardeny, Pharm.D., FCCP, FAHA, FHFSA, BCACP; Stephen B. Vickery, Pharm.D., BCPS;
and Kevin Ordons, Pharm.D., BCPS, BCCP

LEARNING OBJECTIVES

1. Apply treatment strategies to reduce the progression of heart failure (HF) through assessing functional class.
2. Evaluate and justify traditional and newer treatment strategies for patients with stage C HF, specifically as they relate to
the 2017 guideline updates.
3. Develop treatment strategies for patients with stage D HF.
4. Evaluate treatment strategies for potential benefit/harm for the patient with HF with preserved ejection fraction.

INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
Current Status of Heart Failure
ACC/AHA
American College of Cardiology/
American Heart Association Statistics
AF Atrial fibrillation The prevalence of heart failure (HF) continues to be a significant bur-
ARNI Angiotensin receptor-neprilysin den, not only for the families and individuals who take care of these
inhibitor
patients but also for the health care system as a whole. With a reported
BNP B-type natriuretic peptide
915,000 new cases of HF diagnosed annually, 6.5 million Americans
CRT Chronic resynchronization therapy
20 years and older had a diagnosis of HF in 2011–2014 (Benjamin
CV Cardiovascular
2018). Despite significant efforts to identify and treat the underlying
GDMT Guideline-directed management
risk factors that may prevent HF, projections suggest that by 2030,
and therapy
HF cases will increase by 46%, totaling 8 million people (Heidenreich
HF Heart failure
2013). About 1%–2% of the adult population (in developed countries)
HFpEF Heart failure with preserved ejec-
tion fraction has a diagnosis of HF, which increases with advanced age (Ponikow-
HFrEF Heart failure with reduced ejection ski 2016). Patients of African American heritage have the highest risk
fraction of developing HF, followed by those of Hispanic/Latino ethnicity and
ICD Internal cardiac defibrillator whites. African American patients are believed to be at high risk of
LV Left ventricular developing HF because of a lower socioeconomic status and higher
LVAD Left ventricular assist device prevalence of risk factors (Ponikowski 2016).
MRA Mineralocorticoid receptor The economic burden of HF is of vast concern, with a reported
antagonist cost of $30.2 billion in 2012 and an anticipated cost increase by
RAAS Renin-angiotensin-aldosterone almost 130%, reaching $69.7 billion by 2030 (Heidenreich 2013).
system Efforts are under way to further explain risk factors and implement
strategies to manage risk factors and associated disease preven-
Table of other common abbreviations.
tion. However, despite an improved understanding of HF pathophys-
iology, risk factors, and management strategies, data are conflicting
on overall survival after an HF diagnosis. Compared with other termi-
nal diseases, HF survival remains unacceptably low. According to an
Oxford report, cancer survival has doubled, whereas HF survival has
not changed over the same period (Taylor 2017).
Ideally, a risk stratification score could be applied to an individ-
ual patient to help guide clinicians in treatment as well as to provide

PSAP 2019 BOOK 1 • Cardiology 89 Heart Failure

clearer expectations for family members. However, the many
prognostic scores developed in the past decades have shown
only moderate accuracy in predicting mortality (Rahimi 2014).
Distinguishing Between the Differences in HF
ACC/AHA and NYHA Recommendations
Heart failure is commonly associated with a clinical syndrome
that is highlighted by signs (elevated jugular venous pressure,
crackles, edema) or symptoms (swelling, shortness of breath,
fatigue). Development of cardiac structural and/or functional
abnormalities typically leads to reduced cardiac output or ele-
vated intracardiac pressures at rest and during activity, with
subsequent HF symptoms (Ponikowski 2016). The American
College of Cardiology and the American Heart Association
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
• General knowledge of the pathophysiology that
leads to heart failure
• Understanding of the NYHA functional classifica-
tion and the ACC/AHA staging system
• Drug knowledge of traditional HF therapies, includ-
ing ACEIs, ARBs, MRAs, and β-blockers
• Treatment options for patients with HFrEF and HFpEF
Table of common laboratory reference values
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
• Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/
AHA/HFSA focused update of the 2013 ACCF/AHA
guideline for the management of heart failure: a
report of the American College of Cardiology/Amer-
ican Heart Association Task Force on Clinical Prac-
tice Guidelines and the Heart Failure Society of
America. Circulation 2017;136:e137-61.
• Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC
guidelines for the diagnosis and treatment of acute
and chronic heart failure: the task force for the
diagnosis and treatment of acute and chronic heart
failure of the European Society of Cardiology (ESC).
Developed with the special contribution of the
Heart Failure Association (HFA) of the ESC. Eur J
Heart Fail 2016;18:891-975.
• Thompson PL, Davis TME. Cardiovascular effects
of glucose-lowering therapies for type 2 diabetes.
Clin Ther 2017;39:1012-25.
• Anderson SL, Marrs JC. A review of the role of the
pharmacist in heart failure transition of care. Adv
Ther 2018;35:311-23.
PSAP 2019 BOOK 1 • Cardiology
(ACC/AHA) developed a staging system to help pharmacists
and other health care professionals focus on preventive strat-
egies in patients at high risk and implement pharmacother-
apy plans once structural damage has developed (Table 1).
The New York Heart Association (NYHA) functional clas-
sification provides a complimentary scale to the ACC/AHA
system by describing HF severity on the basis of activity lim-
itation (Yancy 2017). Unlike the ACC/AHA system, the NYHA
classification has shown a strong relationship between
functional class, mortality, and quality of life in this patient
population.
HF Updates According to the 2017 Guidelines
Biomarkers for Prevention, Diagnosis,
and Prognosis
Beyond HF pharmacotherapy, new recommendations focus
on preventing, using early evaluation, and delaying the devel-
opment of HF through assessing biomarkers and managing
comorbidities (Yancy 2017; Ponikowski 2016). The B-type
natriuretic peptide (BNP) and atrial natriuretic peptide are
produced in response to high ventricular filling pressures to
bring about diuretic, natriuretic, and hypotensive responses
in addition to inhibition of the systemic sympathetic ner-
vous system and the renin-angiotensin-aldosterone system
(RAAS). Ideally, clinicians could use biomarkers in “at-risk”
patients (stage A) to help prevent structural heart damage
from becoming overt stage C symptoms. The STOP-HF is the
largest study to date to evaluate BNP as a potential screening
tool for patients with stage A HF (Ledwidge 2013). The com-
posite end point of asymptomatic left ventricular (LV) dys-
function with or without newly diagnosed HF was reduced in
patients screened with BNP. Given the limited supporting evi-
dence for BNP monitoring as a preventive measure, the guide-
lines recommend incorporating this strategy into a treatment
plan that includes consultation with a cardiovascular (CV)
specialist through optimizing guideline-directed manage-
ment and therapy (GDMT) (Yancy 2017; Ponikowski 2016).
In healthy patients, BNP and N-terminal-proBNP
(NT-proBNP) concentrations are often similar but should not
be used interchangeably. When LV dysfunction develops, the
relative concentrations of both increase, with higher values
in NT-proBNP. Commercially available assays vary, and insti-
tution-derived thresholds should be used when implement-
ing them into practice. In the Breathing Not Properly study,
patients with clinically diagnosed HF had significantly higher
BNP concentrations than did those without HF (675 vs. 110 pg/
mL, respectively) (Maisel 2002). A BNP greater than 100 pg/
mL correlated with an HF diagnosis with 90% sensitivity, 76%
specificity, and 83% accuracy. Of note, elevated BNP concen-
trations should be used in the context of the complete clinical
scenario, not in isolation, especially given the other cardiac
and non-cardiac causes of BNP elevation. The current guide-
lines state that BNP and NT-proBNP biomarkers can help sup-
port a diagnosis but may be more useful to rule out HF.
90 Heart Failure
 Table 1. ACC/AHA Staging System and NYHA Functional Classification
ACC/AHA HF Staging System
Stage Description
A Patients at high risk of developing HF but
without structural heart disease
• HTN, DM, CAD, metabolic syndrome
B Patients with structural heart disease but no
signs or symptoms of HF
• Previous MI, low EF, no symptoms
C Patients with structural heart disease and
current or previous symptoms
• Low EF, HF signs/symptoms
D Patients with symptoms despite maximal
medical therapy
• End-stage HF
CAD = coronary artery disease; DM = diabetes mellitus; EF = ejection fraction; HF = heart failure; HTN = hypertension; N/A = not
applicable.
Information from: Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for
the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137-61.
Beyond its potential diagnostic capabilities, BNP can serve
as a prognostic marker in both patients with chronic HF and
patients with acute decompensated HF. A systematic review
using BNP as a prognostic marker showed that for every
100-pg/mL increase in BNP, the relative risk of mortality was
increased by 35% (Doust 2005). However, even GDMT may not
offset the risk of mortality in patients with persistently ele-
vated BNP concentrations.
A new recommendation from the ACC/AHA 2017 guideline
pertains to the use of pre-discharge BNP concentrations as
a prognostic marker for rehospitalizations or risk of death.
Studies have shown a strong correlation between patients
with higher BNP concentrations at discharge and those who
did not have a reduction in BNP concentrations with respect
to subsequent mortality or readmission (Logeart 2004).
Despite the potential usefulness of BNP concentrations as a
prognostic marker, the current guidelines posit that targeting
certain concentrations or a relative change may be unpracti-
cal and potentially harmful to patients.
Comorbidity Management in HF
Anemia
Beyond optimizing GDMT, comorbidity management can
help improve quality of life and avoid complications. Certain
PSAP 2019 BOOK 1 • Cardiology
NYHA Functional Classification
Functional Class Description
No associated N/A
functional class
I No limitation of physical activity
II Slight limitation of physical activity
III Marked limitation of physical activity
IV Unable to carry on any physical activity
without discomfort
medications for diabetes (e.g., sulfonylureas, thiazolidinedi-
ones) or arthritis (e.g., NSAIDs) can exacerbate HF symptoms.
Pharmacists treating patients with HF must actively review
patients’ medications to avoid unwarranted complications.
Anemia is common in patients with HF, but its overall
prevalence varies within the literature. Symptoms associ-
ated with anemia commonly parallel those associated with
HF (dyspnea and fatigue) and occur because of reduced oxy-
gen delivery to tissues. Although the cause of anemia is likely
multifactorial, it may include decreased intake and/or absorp-
tion of iron, creating iron-deficiency anemia. Alterations in GI
absorption can result from intestinal edema, use of medica-
tions altering gastric pH (e.g., proton pump inhibitors or his-
tamine-2 antagonists), or ingestion of foods that may reduce
absorption (e.g., calcium, tannins, phosphates, antacids).
Controversy continues to surround the role of inflammation
in chronic diseases because of conflicting data. Of particular
importance are the negative clinical consequences that stem
from iron deficiency in patients with HF. Most notably, stud-
ies have shown an increase in all-cause mortality in patients
with a concomitant iron deficiency and HF independently of
anemia (Okonko 2011). In a meta-analysis of five prospective
studies, intravenous iron therapy was evaluated for its effect
on death and hospitalizations in patients with heart failure
91 Heart Failure
with reduced ejection fraction (HFrEF) (Jankowska 2016).
The study showed that intravenous iron in patients with iron
deficiency (regardless of concomitant anemia) improves out-
comes (all-cause death or CV hospitalizations), alleviates HF
symptoms, and improves overall quality of life. However, this
analysis showed no discernible differences regarding all-
cause mortality or CV deaths. Although previous studies have
been underpowered to detect a survival benefit with iron ther-
apy, the currently enrolling AFFIRM-AHF (left ventricular ejec-
tion fraction [LVEF] less than 50%) and IRONMEN (LVEF less
than 45%) trials should provide information on the potential
benefits of iron therapy for CV death and hospitalizations in
patients with HF (clinicaltrials.gov).
Erythropoiesis-stimulating agents (ESAs) have also been
evaluated in patients with HF and anemia. Evidence support-
ing ESA use has been mixed, with limited sample sizes among
clinical trials. The largest study to date was a randomized dou-
ble-blind study evaluating darbepoetin alfa (n=2278) in symp-
tomatic HF (EF of 40% or less with Hgb 9–12.5 g/dL) (Ghali
2008). After 27 weeks, darbepoetin was not associated with
clinical benefits; however, it significantly increased thrombo-
embolic complications and nonsignificantly increased the
rates of fatal and nonfatal strokes. Despite a meta-analysis
(11 studies) showing the benefits of ESAs (i.e., 6-minute walk,
exercise duration, NYHA functional status), the potential
thromboembolic complications associated with this therapy
have led the guidelines to recommend avoiding ESA therapies
in patients with HF and anemia.
Hypertension
Hypertension is an important risk factor for developing HF,
and appropriate therapies should be implemented to avoid
onset. Given the findings of the SPRINT study, the ACC/AHA
HF guidelines advocated tighter blood pressure control in
patients at risk of HF (stage A) (Yancy 2017). Specifically,
patients older than 75 and those with established vascu-
lar disease, chronic renal disease, or a Framingham score
greater than 15% were at a greater risk of HF onset if sys-
tolic blood pressure was greater than 120 mm Hg (SPRINT
Research Group 2015). A recent cohort study showed that
higher baseline diastolic, systolic, and pulse pressures lead
to increased adverse events, further emphasizing the impor-
tance of blood pressure control within this high-risk popula-
tion (Lip 2015). Patients whose disease progresses to stage
C HFrEF with ongoing hypertension should ideally optimize
GDMT, which includes maximizing the doses of RAAS block-
ers. Alternatively, transitioning to carvedilol from metoprolol
succinate can be considered with the titration of mineralo-
corticoid receptor antagonists (MRAs) and diuretic therapy.
In patients who remain hypertensive, adding hydralazine and/
or dihydropyridine calcium channel blockers (CCBs) (e.g.,
amlodipine, felodipine) should be considered because these
agents are all safe in HFrEF. Non-dihydropyridine CCBs (e.g.,
verapamil or diltiazem) should be avoided in HFrEF, given
PSAP 2019 BOOK 1 • Cardiology
their negative inotropic activity, which can worsen HF symp-
toms (discussed later). For patients with heart failure with
preserved ejection fraction (HFpEF), optimizing diuretic ther-
apy to ensure euvolemia is important before considering
additional treatments. Recently, spironolactone reduced hos-
pitalizations in patients with HFpEF and should be consid-
ered in patients with hypertension with this subset of HF (Pitt
2014). Beyond the potential role for spironolactone, data are
sparse to support pharmacotherapy with respect to clinical
outcomes in patients with HFpEF; implementation of therapy
should be driven by comorbidities and tolerability in combina-
tion with patient and provider preferences.
Diabetes
Diabetes is one of the most common comorbidities in patients
with HF and is as a major risk factor for developing new-onset
HF. Although caution should be used when selecting agents,
certain diabetes medications may help prevent HF and play
a pivotal role in reducing CV events. In patients with estab-
lished CV disease, empagliflozin (a sodium-glucose cotrans-
porter 2 [SGLT-2] inhibitor) modestly reduced the composite
outcome (14%, p=0.04 for superiority) of CV mortality, nonfa-
tal myocardial infarction (MI), and nonfatal stroke within the
EMPA-REG OUTCOME study (Zinman 2015) when compared
to placebo. Findings were largely driven by a 38% reduction
in CV death, but the authors also noted a 32% reduction in
all-cause mortality. In addition, HF hospitalizations were sig-
nificantly reduced, but this should be assessed cautiously
because the study did not set rigid criteria to capture the
HF type or cardiac function at baseline. Patients within the
study were noted to have an increase in genitourinary infec-
tions, which resolved with antifungal therapy. Canagliflozin,
another SGLT-2 inhibitor, was evaluated within the CANVAS
program for its potential usefulness in patients at high risk
of CV and diabetes mellitus. Compared with placebo, cana-
gliflozin significantly reduced the risk of the primary compos-
ite outcome of death from CV cause, nonfatal MI, or nonfatal
stroke (26.9 vs. 31.5 participants per 1000 patient-years; HR
0.86; 95% CI, 0.75–0.97; p<0.001 for noninferiority; p=0.02
for superiority) (Neal 2017). Despite a reduction in the pri-
mary composite end point, canagliflozin was not able to rep-
licate a reduction in CV mortality that was found within the
EMPA-REG OUTCOME study. However, despite the observed
benefit of canagliflozin, its use was complicated by a sig-
nificant increase in lower-limb (mainly toe) amputation (6.3
vs. 3.4 participants per 1000 patient-years; HR 1.97; 95% CI,
1.41–2.75; p<0.001). Patients with a history of amputations
or peripheral vascular disease were at highest risk of ampu-
tation within the canagliflozin cohort. A closer evaluation of
patients randomized within the EMPA-REG OUTCOME and
CAVAS studies can potentially explain why empagliflozin
showed a more demonstrable effect on the primary end
point. All patients randomized within the EMPA-REG OUT-
COME study had a prior history of CV disease (secondary
92 Heart Failure
prevention) while only 65% of patients within the CANVAS
study had prior CV disease (both primary and secondary pre-
vention). A difference in patient population could help explain
the significant reduction within the EMPA-REG OUTCOME
study which was not seen in the CANVAS study due the inclu-
sion of an arguably “healthier” study population. Similar to
the CANVAS study, danagliflozin was evaluated in patients
who had or were at risk for atherosclerotic CV disease within
the DECLARE-TIMI 58 study (Wiviott 2018). Unlike the previ-
ously studied medication within this drug class, danagliflozin
did not show a reduction in the primary composite outcome
of CV mortality, nonfatal MI or nonfatal stroke (8.8% vs 9.4%;
HR 0.93; 95% CI, 0.84-1.03; p=0.17). Given the findings of the
EMPA-REG OUTCOME study with respect to reduction in CV
mortality and reduction in hospitalization, the oversight com-
mittee amended the protocol to include an additional primary
composite end point, CV death or hospitalization for HF. With
respect to the added primary outcome, danagliflozin demon-
strated a significant benefit compared to placebo (4.9% vs
5.8%; HR0.83; 95% CI, 0.73-0.95; p=0.005), which was largely
attributed to a reduction in HF hospitalization. The noted dif-
ferences in outcomes amongst the studies evaluating SLT2
inhibitors could reflect a difference in study population as
DECLARE-TIMI 58 included the lowest rate of established CV
disease (40%). Ongoing studies of HF populations are further
explaining the potential risk-benefit of SGLT-2 inhibitors and
will further guide therapy in these complex patients.
Liraglutide and semaglutide (glucagon-like peptide 1 [GLP-
1] agonists) were shown to significantly reduce the compos-
ite primary outcome of death from CV causes, nonfatal MI, or
nonfatal stroke (Marso 2016a, Marso 2016b). Liraglutide was
evaluated in the LEADER trial in patients with CV disease or
patients with one or more CV risk factors. The primary out-
come was largely driven by a significant reduction in CV mor-
tality (p=0.007). Semaglutide was evaluated in the SUSTAIN
study in a similar patient population, where it also signifi-
cantly reduced the primary composite of CV death, nonfatal
MI, and nonfatal stroke (HR 0.74; 95% CI 0.58-0.95; p<0.001 for
noninferiority). Unlike liraglutide, the primary end point was
not driven by a reduction in CV mortality, but nonfatal stroke
was significantly improved with a trend toward a lower inci-
dence of MI. It is unclear whether the overall CV outcomes
with GLP-1 agonists are a class effect or whether certain CV
benefits are provided by individual medications.
Dipeptidyl peptidase 4 (DPP-4) inhibitors have been scru-
tinized, given their variable benefits on CV outcomes and
safety profile. To further understand the concern surrounding
safety of DPP-4 inhibitor use in HF, three CV safety studies
examined saxagliptin (SAVOR-TIMI 53), sitagliptin (TECOS),
and alogliptin (EXAMINE) (Green 2015; Scirica 2013; White
2013). These agents were not associated with reduced CV
outcomes, contrary to results from a previous meta-analy-
sis. Despite meeting the safety information requested by the
FDA, saxagliptin increased HF hospitalizations compared
PSAP 2019 BOOK 1 • Cardiology
with placebo (3.5% vs. 2.8%; p=0.007). Although initial find-
ings did not show an increase in HF hospitalizations in
patients randomized to alogliptin, post hoc analyses sug-
gested that patients with no history of HF at study inclusion
had increased hospitalizations because of HF (HR 1.76; 95%
CI, 1.07–2.90; p=0.026). This CV complication did not occur
with sitagliptin, suggesting that HF hospitalizations is not a
class effect.
Metformin continues to be used cautiously in patients with
HF, especially in those with NYHA class III–IV symptoms,
because this agent has been associated with an increased
risk of lactic acidosis in patients with renal or hepatic impair-
ment. Although careful monitoring of kidney and liver func-
tion is warranted with metformin, data analyses support its
use in this patient population because it modestly reduced
morbidity and mortality. Despite the initial report that 47
patients developed lactic acidosis in association with met-
formin use (38% having concomitant HF diagnosis), several
evaluations have failed to replicate this association. In a
large observational study (n=2952) evaluating diabetes ther-
apies in patients with HF, no associated hospitalizations or
deaths were attributed to metformin-associated lactic acido-
sis (Andersson 2010). Several small case series have shown
a poor correlation between mortality in patients with lactic
acidosis receiving metformin and their associated metformin
and lactate serum concentrations. Finally, in a literature eval-
uation of 47 patients with lactic acidosis, neither metformin
nor lactate concentrations correlated with mortality (Stades
2004). Given the information to date, metformin appears safe
in patients with HF and should be considered, given its abil-
ity to significantly reduce macrovascular events and diabe-
tes-related mortality.
RENIN-ANGIOTENSIN-
ALDOSTERONE SYSTEM
Angiotensin II (AngII) is a key hormone within the RAAS path-
way that can worsen HF through arterial vasoconstriction,
stimulation of sodium and water reabsorption, promotion
of cellular proliferation, and evocation of an inflammatory
response. Traditional therapies designed to blunt these effects
include angiotensin-converting enzyme inhibitors (ACEIs),
angiotensin receptor blockers (ARBs), and MRAs.
ACE Inhibitors
Angiotensin-converting enzyme inhibitors form the foun-
dation for HFrEF management and are recommended as
first-line therapy, given their ability to reduce morbidity and
mortality. Therapy with ACEIs should be initiated according to
the starting doses used in clinical trials, with a goal of titrating
to the target doses that showed mortality benefit (Table 2).
The beneficial outcomes of ACEI therapy are considered a
class effect, unlike other drug classes used in HF therapy.
93 Heart Failure
 Table 2. Approved HF Medications

Drug Starting Dose Target Dose Mean Dose Achieved in Clinical Trial

ACEI (Class I; LOE A)

Captopril 6.25 mg TID 50 mg TID 122.7 mg total daily dose

Enalapril 2.5 mg BID 10–20 mg BID 16.6 mg total daily dose

Lisinopril 2.5–5 mg QD 20–40 mg QD 32.5–35 mg total daily dose

ARBs (Class I; LOE A)

Candesartan 4–8 mg QD 32 mg QD 24 mg total daily dose

Losartan 25–50 mg QD 50–150 mg QD 129 mg total daily dose

Valsartan 20–40 mg BID 160 mg BID 254 mg total daily dose

ARNI (Class I; LOE B)

Sacubitril/valsartan 49/51 mg BID 97/103 mg BID 375 mg total daily dosea

MRAs (Class I; LOE A)

Spironolactone 12.5–25 mg QD 25 mg QD or BID 26 mg total daily dose

Eplerenone 25 mg QD 50 mg QD 42.6 mg total daily dose

β-Blocker (Class I; LOE A)

Bisoprolol 1.25 mg QD 10 mg QD 8.6 mg total daily dose

Carvedilol 3.125 mg BID 25 mg BID 37 mg total daily dose

50 mg BID (if ≥ 85 kg)

Metoprolol succinate 12.5–25 mg QD 200 mg QD 159 mg total daily dose

Isosorbide dinitrate/hydralazine (Class I; LOE A) b

Fixed-dose combination 20 mg of isosorbide 40 mg of isosorbide 90 mg of isosorbide dinitrate/~175 mg

dinitrate/37.5 mg of dinitrate/75 mg of of hydralazine QD
hydralazine TID hydralazine TID

Isosorbide dinitrate and 20–30 mg of isosorbide 40 mg of isosorbide Not studied

hydralazine dinitrate/25–50 mg of dinitrate TID with 100 mg
hydralazine TID or QD of hydralazine TID

If channel inhibitor (Class IIa; LOE B)

Ivabradine 5 mg BID 7.5 mg BID 6.4 mg BID (28 days) and 6.5 mg BID
(1 year)

a
Total dose of both components as defined in the PARADIGM-HF study.
b
African American patients who remain symptomatic despite receiving GDMT.
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin
inhibitor; BID = twice daily; GDMT = guideline-directed management and therapy; HF = heard failure; LOE = level of evidence; MRA =
mineralocorticoid receptor antagonist; QD = once daily; QID = four times daily; TID = three times daily.
Information from: Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for
the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137-61.

The adverse effect profile of ACEIs is primarily reflected
in direct or indirect inhibition of AngII formation or because
of increased bradykinin concentrations (Table 3). Common
adverse events include hypotension, hyperkalemia, worsen-
ing renal function, and dry cough. The most severe, albeit
rare, complication of ACEI therapy is angioedema. Within the
ONTARGET clinical trial, angioedema occurred in only 0.3%
of 8500 patients treated with ramipril (ONTARGET Investiga-
tors 2008). Patients who develop angioedema while receiv-
ing ACEI therapy should avoid being rechallenged, given the

PSAP 2019 BOOK 1 • Cardiology 94 Heart Failure

 Table 3. Traditional HF Therapies: Mechanism of Action, Adverse Effects, and Monitoring

Compensatory
Mechanism
Affected Drug Class Mechanism of Action Adverse Effects (common) Monitoring Values

RAAS ACEIs Competitive inhibitor of ACE • Hypotension • K

leading to a reduction in the • Hyperkalemia • SCr
conversion of AngI to AngII • Worsening renal function • BP
• Dry cough
• Angioedema (rare)

ARBs Inhibition of the AngII type 1 • Hypotension • K

receptor • Hyperkalemia • SCr
• Worsening renal function • BP

MRAs Inhibition of the aldosterone • Hyperkalemia • K

receptor • Worsening renal function • SCr
• Gynecomastia
(spironolactone)

Sympathetic β-Blockers Inhibition of β-adrenoreceptor • Bradycardia • Heart rate

nervous system and potentially α-adrenergic • Hypotension • BP
activity • Dizziness

Nitrates Increased cGMP concentrations • Headache • BP

leading to smooth muscle • Dizziness
relaxation • Hypotension

Hydralazine Direct vasodilation of arterioles • Headache • BP

• Dizziness
• Hypotension

AngII = angiotensin II; BP = blood pressure; cGMP = guanosine 3’5’-monophosphate; HF = heart failure; RAAS = renin-angiotensin-al-
dosterone system.

concern for recurrence. To limit the risk of adverse effects,
ACEI therapy should be titrated after at least 2 weeks. Clinical
laboratory values and adverse effects should be monitored
after each titration.
ARB Therapy
Angiotensin receptor blockers were developed with the idea
that inhibiting AngII through blockade of the AngII type 1
receptor could further improve HF. The current guidelines
recommend that either an ACEI or an ARB be used, with
ARBs preferred if patients cannot tolerate an ACEI. Unlike
ACEI therapy, whose benefits are considered universal
across the drug class, the following ARBs are listed for use
within the current guidelines: candesartan, valsartan, and
losartan.
Angiotensin receptor blockers are generally well toler-
ated and have an adverse effect profile similar to ACEIs, with
a noted reduction in the rates of cough and angioedema
but an apparent increased rate of hypotension. Titration of
ARBs should be similar to that of ACEIs, with initiation at low
doses and increasing doses similar to those used in clinical
trials. Monitoring should occur after initiating therapy and
after dose escalations.
Aldosterone Receptor Antagonist Therapy
Mineralocorticoid receptor antagonists have been used
across the HF spectrum, providing benefits through inhibit-
ing aldosterone’s activities. Clinical studies have shown sur-
vival benefits when MRAs are used in patients with advanced
HF (spironolactone) and patients after an MI with a reduced
EF (eplerenone). Use of MRAs in patients with mild-moderate
HF was studied in the EMPHASIS-HF study. Patients were
well matched at randomization, with 93% of study partici-
pants taking an ACEI or an ARB (or both) and 86% receiving
β-blockers. Like within the RALES study, the overwhelm-
ing benefit of eplerenone in addition to GDMT prompted
the study to be prematurely terminated because of a 37%
reduction in the composite primary end point: risk of death
and hospitalization for HF compared with placebo (Zannad
2011). Patients were initiated on eplerenone 25 mg/day with
a dose increase at 4 weeks to a goal dose of 50 mg/day (or in
patients with an estimated glomerular filtration rate [eGFR]
of 30–49 mL/minute/1.73 m2, study investigators initiated

PSAP 2019 BOOK 1 • Cardiology 95 Heart Failure

25 mg every other day with an increase to 25 mg daily at
4 weeks) if serum potassium concentrations remained
below 5 mEq/L. After 5 months of therapy, the mean doses
achieved in the eplerenone and placebo groups were 39.1
mg (±13.8) and 40.8 mg (±12.9), respectively.
Because of findings from the EMPHASIS-HF trial, the
guidelines state that MRAs should be implemented in
patients with NYHA classes II–IV receiving GDMT with a
CrCl greater than 30 mL/minute/1.73 m2 and a K less than
5.0 mEq/L. Pharmacists play an essential role in ensuring
that MRAs are added to patients’ HF regimens because stud-
ies have shown a continued underuse of this highly effective
medication class.
In clinical studies, MRAs were well tolerated, with study
drug discontinuation rates similar to placebo. Most nota-
bly, MRAs have consistently significantly increased the risk
of hyperkalemia. Male patients randomized to spironolac-
tone had a significant increase in the development of gyne-
comastia, which did not occur with eplerenone because of
its different molecular moiety. Caution with MRAs should be
used in patients whose baseline potassium concentrations
are greater than 5 mEq/L or with impaired renal function
(SCr greater than 2.5 mg/dL in men or greater than 2 mg/dL
in women or eGFR less than 30 mL/minute/1.73 m2) because
both characteristics were excluded from the original studies.
Patient Care Scenario
A 35-year-old African American man was referred to
cardiology for newly diagnosed HF thought to be con-
genital, given that both of his parents and his older sister
had previously been given a diagnosis of HF. The patient
denies active concerns but states that he recently has
felt increased shortness of breath with an inability to lie
flat when he goes to bed at night. He still performs his
activities of daily living without issues. Echocardiography
(ECHO) reveals moderately reduced ventricular function
ANSWER
This unique scenario shows a significant complication
resulting from ACEI use. Development of angioedema with
ACEI use should preclude future use within this specific
drug class because of the significant risk of recurrence.
The best option for the patient, given the reduced risk
of angioedema associated with ARB therapy, would be a
transition to a medication within this drug class. Although
the likelihood is significantly reduced, patients receiving
ARBs have reported episodes of angioedema, and careful
1. C ohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med
2001;345:1667-75.
2. M cMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
3. P feffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left
ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.
4. Y ancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart
failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the
Heart Failure Society of America. Circulation 2017;136:e137-61.
PSAP 2019 BOOK 1 • Cardiology
Given the overt risk of hyperkalemia with MRAs, careful
monitoring of potassium concentrations and renal function
is warranted when initiating therapy and particularly within
the first few months, or when doses are adjusted.
SYMPATHETIC ACTIVATION
In patients with HF having NYHA class II–IV symptoms,
bisoprolol, carvedilol, or metoprolol (controlled release or
extended release), when combined with ACEI, digoxin, and
diuretics, reduced the composite end point of hospital admis-
sion and mortality by over 30%. The current guidelines only
recommend metoprolol succinate, bisoprolol, and carve-
dilol because these are the only three β-blockers proven to
reduce mortality; the benefits are not thought to be a class
effect. Data are limited comparing the relative efficacies of
the currently approved β-blockers for HFrEF. Carvedilol may
be advantageous in patients with HF having baseline hyper-
tension versus bisoprolol or metoprolol in patients with mar-
ginal blood pressure at initiation.
In β-blocker–naive individuals, starting doses should
be low and therapy initiated when patients are clinically
compensated, with the goal of titrating to maximally tol-
erated doses or the target doses used in clinical trials. In
patients who present with acute decompensated HF pre-
viously receiving β-blocker therapy, continued therapy is
with a reported EF of 35%. Following guideline recommen-
dations, the patient is initiated on enalapril 5 mg twice
daily, metoprolol succinate 25 mg daily, and spironolac-
tone 25 mg daily. Three days after starting therapy, the
patient begins to have worsening shortness of breath with
a swelling sensation of the lips, mouth, and throat. The
resident is concerned about ACEI-induced angioedema
and seeks your recommendation. What is best to recom-
mend for this patient?
monitoring should ensue to ensure patients do not have
cross-reactivity. Transitioning to sacubitril/valsartan
would be ideal, given the mortality benefits associated
with this new agent; however, because of a high likelihood
of angioedema, its use is contraindicated. Use of alter-
native medication classes (CCBs or hydralazine/nitrates)
should be reserved as second-line therapies if a similar
reaction occurs with ARBs.
96 Heart Failure
recommended unless hemodynamic compromise is evident
through requirement of inotropes or mechanical circulatory
support.
Patients should be monitored closely after initiating (or
dose titrating) β-blocker therapy to assess for potentially
worsening symptoms of HF because of the β-blocker’s neg-
ative inotropic properties. At least 2 weeks is recommended
between dose titrations, and some patients may require
extended titration intervals. Patients who are decompen-
sated or hypervolemic at initiation are at a higher risk of
worsening HF. Bradycardia, hypotension, dizziness, and
bronchospasms are additional adverse effects that should
be closely monitored after β-blocker initiation and subse-
quent dose titrations. Patients who develop symptomatic
hypotension while taking carvedilol should be changed to
metoprolol succinate or bisoprolol. Alternatively, a dose
reduction can be considered.
ALTERNATIVE AGENTS
Nitrates/Hydralazine
Hydralazine plus oral nitrates is generally reserved for
patients who have a contraindication to or cannot tolerate
first-line agents (ACEIs, ARBs, angiotensin receptor-nepri-
lysin inhibitors [ARNIs]) or in the setting of ongoing NYHA
class III–IV HF symptoms despite receiving optimal GDMT
in patients of African American descent.
Adherence should be a factor when considering adding
hydralazine/nitrates to a patient’s pharmacotherapy plan.
Given their short half-lives, these drugs are given three
times daily. As with other dose titrations, patients should
be evaluated for at least 2 weeks before increasing the
doses to target doses. Long-acting once-daily isosorbide
mononitrate (40–120 mg daily) has been suggested as an
alternative to the dinitrate formulation to overcome adher-
ence concerns, but direct evidence is lacking. Even though
the fixed-dose combination of hydralazine/nitrate was ben-
eficial in clinical studies, its overall cost has prompted cli-
nicians to individually dose hydralazine and isosorbide
dinitrate, even though this will increase overall pill burden.
Common adverse effects of hydralazine/nitrates include
headache, dizziness, and hypotension. A significantly
greater risk of headaches (48% vs. 19%) and dizziness was
noted in 29% of patients (placebo 12%) within the A-HeFT
trial (Taylor 2007). If symptomatic hypotension occurs,
reduction in hydralazine/nitrate is advocated, but concur-
rent first-line therapies (β-blocker, ACEI, or ARB) should be
continued, if possible. In rare cases, patients may develop
drug-induced lupus syndrome (hydralazine) or vasculitis
(noted by hematuria, SCr elevation, and edema). If either
syndrome develops, immediate evaluation is warranted, in
addition to prompt discontinuation of hydralazine/nitrate.
PSAP 2019 BOOK 1 • Cardiology
NOVEL HF THERAPIES
Angiotensin Receptor-Neprilysin Inhibitors
Natriuretic peptides (NPs) play an important role in HF, serv-
ing as potential targets in managing the disease. Histori-
cally, augmenting NPs with nesiritide (synthetic BNP) did not
have long-term beneficial effects when assessed in patients
with acute HF (O’Connor 2011). Preventing the breakdown of
endogenous NPs as a target led to the development of sacu-
bitril, a neutral endopeptidase that blocks neprilysin, the
enzyme responsible for degrading NPs. Inhibition of nepri-
lysin may lead to improved fluid homeostasis and reduced
neurohormonal activation. Neprilysin is also responsible for
degrading several other vasoactive peptides, including AngII.
Thus, inhibiting neprilysin alone results in increased con-
centrations of both natriuretic peptides and AngII. As such,
neprilysin must be combined with a RAAS blocker to negate
elevated AngII concentrations. Combining valsartan (an ARB)
with a neprilysin inhibitor prodrug sacubitril created sacubi-
tril/valsartan (formerly LCZ 696 [Entresto]), the first ARNI in
its class.
The PARADIGM-HF study was a phase III randomized trial
including 8399 patients with NYHA class II–IV HF symptoms,
EF of 40% or less (changed to 35% or less 1 year into enroll-
ment), and elevated NT-proBNP concentrations receiving
GDMT for HF. The investigators hypothesized that sacubitril/
valsartan would better reduce morbidity and mortality than
enalapril (goal dose 20 mg/day) (McMurray 2014). Interim
safety and efficacy data analyses showed that sacubitril/val-
sartan resulted in a 20% relative risk reduction in the com-
posite end point (CV death and hospitalization for HF) as well
as a 16% relative risk reduction in all-cause mortality, and
the study was terminated early because of the overwhelm-
ing efficacy of sacubitril/valsartan. Because of the results
of the PARADIGM-HF study, the HF guidelines recommend
that in patients currently tolerating ACEI or ARB therapy,
sacubitril/valsartan replacement should be used to further
reduce morbidity and mortality. The guidelines do not cur-
rently recommend sacubitril/valsartan in patients with de
novo HF because this population was not included in PAR-
ADIGM-HF, but the recently published PIONEER study evalu-
ated the safety and efficacy of sacubitril/valsartan in patients
hospitalized for acute decompensated HF (Velazquez 2018).
Once hemodynamically stable patients were randomization
to receive enalapril (initial dose: 2.5 mg or 5 mg twice daily;
target dose: 10 mg twice daily) or sacubitril/valsartan (initial
dose: 24 mg of sacubitril with 26 mg of valsartan or 49 mg of
sacubitril with 51 mg of valsartan twice daily; target dose 97
mg of sacubitril with 103 mg of valsartan twice daily). The pri-
mary efficacy outcome was the time-averaged proportional
change in NT-proBNP from baseline through weeks 4 and 8.
A significant reduction in the NT-proBNP concentration were
seen amongst patients randomized to sacubitril/valsartan
(n=440) as opposed to enalapril (n=441) (percent change,
97 Heart Failure
-46.7% vs -25.3%; ratio of change with sacubitril/valsartan vs
enalapril, 0.71; 95% CI, 0.63-0.81; p<0.001). Safety outcomes
which included risk for worsening real function, hyperkalemia
development, and hypotension, were not different amongst
the study groups. It is important to note the benefits demon-
strated with sacubitril/valsartan were seen in patients irre-
spective of history of HF or previous use of ACEi or ARB,
suggesting that the use of sacubitril/valsartan can likely be
utilized safely and effectively in de novo HF patients. A sub-
sequent analysis of the PARADIGM data showed that sacu-
bitril/valsartan was associated with an incremental benefit
over enalapril on the nonfatal progression of HF (intensifica-
tion of therapy [HR 0.84; 95% CI, 0.74–0.94; p=0.003]) (Packer
2015). Sacubitril/valsartan significantly reduced the risk of a
first ED visit (HR 0.66; 95% CI, 0.52–0.85; p=0.001) or hospital-
ization (HR 0.79; 95% CI, 0.52–0.94); p=0.017), in addition to
decreasing the need for repeated visits for HF compared with
enalapril. Moreover, a noted intensification of background
therapies within the enalapril group testified to improvements
in HF with sacubitril/valsartan. The benefits with sacubitril/
valsartan were noted as early as 30 days after randomization,
further highlighting the importance of this new medication.
Despite the overwhelming benefit shown within the PAR-
ADIGM-HF study, questions surrounding its study design
and conclusions have emerged. A run-in period was used
to establish the tolerability of the study drug, but this tech-
nique may create results that represent a subset of a larger
patient population. To better quantify the generalizability of
the PARADIGM-HF results, an analysis was performed using
patient characteristics from pre-randomization exclusions
for the treatment effect of the primary composite end point
(death from CV causes or first hospitalization for HF) (Desai
2016). A total of 2079 patients (19.8%) did not complete the
run-in phase, with most unable to be randomized because of
adverse events (12%) or withdrawal of consent (2.6%). Reanal-
ysis using inverse probability weighting confirmed the benefit
of sacubitril/valsartan over enalapril.
Overall, sacubitril/valsartan was well tolerated with fewer
study medication discontinuations compared with enal-
april (17.8% vs. 19.8%). Within the sacubitril/valsartan group,
patients were at a higher risk of developing symptomatic
hypotension (14% vs. 9.2%, p<0.001), which did not influence
the need for permanent therapy discontinuation. In addition,
hypotension within the run-in phase did not differentially
affect the relative efficacy of sacubitril/valsartan compared
with enalapril after randomization (Vardeny 2018). Of interest,
these hypotensive effects did not correlate with worsening
renal function (SCr greater than 2.5 mg/dL: 3.3% sacubitril/
valsartan vs. 4.5% enalapril, p=0.07). A lower risk of serum
potassium elevations greater than 6 mEq/L (4.3% vs. 5.6%,
p=0.07) and a reduction in cough episodes (11.3% vs. 14.3%,
p<0.001) occurred with sacubitril/valsartan. A secondary
analysis directed at further explaining the risk of hyperkale-
mia showed that among patients receiving MRAs at baseline,
PSAP 2019 BOOK 1 • Cardiology
those randomized to enalapril had a higher rate of severe
hyperkalemia (greater than 6 mEq/L) (3.1 vs. 2.2 per 100
patient-years; p=0.02) than did those randomized to sacubi-
tril/valsartan (Desai 2016). Patients naive to MRAs at base-
line of the PARADIGM-HF study had similar rates of severe
hyperkalemia, irrespective of randomization group. Because
concerns for hyperkalemia often limit the use of MRAs in
chronic HF, the lower risk of hyperkalemia with sacubitril/val-
sartan may be reassuring to providers.
Patients new to ARNI therapy or previously taking low-
dose ACEI therapy (less than 10 mg/day of enalapril or equiv-
alent) or ARB therapy (less than 160 mg/day of valsartan or
equivalent) should be initiated on sacubitril/valsartan 24/26
mg twice daily. The recommended starting dose for patients
receiving moderate- to high-dose ACEI or ARB therapy is
49/51 mg twice daily. Patients with moderate hepatic impair-
ment (Child-Pugh class B) or severe renal impairment (eGFR
less than 30 mL/minute/1.73 m2) should also be considered
for a starting low dose of sacubitril/valsartan 24/26 mg twice
daily. Patients should be monitored for 2–4 weeks before
doubling the dose to the target maintenance dose of 97/103
mg twice daily. Patients should be monitored for hypoten-
sion, worsening renal function, and hyperkalemia after dose
adjustments and periodically while receiving treatment. Of
importance, as shown in the PARADIGM-HF study, BNP con-
centrations increase while patients are receiving sacubitril/
valsartan therapy because of reduced BNP degradation by
neprilysin (McMurray 2014). However, given that NT-proBNP
is not a substrate for the neprilysin enzyme, it is appropriate
for use as a marker of HF severity while sacubitril/valsartan
therapy is used. In PARADIGM-HF, higher BNP concentrations
but lower NT-proBNP concentrations were noted at 4 weeks
and 8 months compared with placebo group (Packer 2015).
Before initiating sacubitril/valsartan and when interchang-
ing sacubitril/valsartan and an ACEI, a washout period of 36
hours should occur to avoid the development of angioedema.
Sacubitril/valsartan is contraindicated in patients with a his-
tory of angioedema.
Ivabradine
The premise that heart rate is an important factor associ-
ated with HF mortality led to the development of ivabra-
dine. Unlike β-blockers, which are often dose limited by
hypotensive episodes, ivabradine reduces heart rate with-
out compromising blood pressure. By directly inhibiting the
funny channel (sodium channel) within the sinoatrial node,
ivabradine prolongs the slow depolarization phase and sub-
sequently reduces heart rate. Ivabradine failed to show mor-
tality or hospital admission benefit when originally evaluated
in chronic stable coronary artery disease in the BEAUTIFUL
trial; however, a subgroup analysis showed a treatment bene-
fit in patients with a baseline heart rate greater than 70 beats/
minute. The subsequent SHIFT study evaluated ivabradine in
6500 patients with HF (EF of 35% or less), NYHA classes II–IV,
98 Heart Failure
and a resting heart rate of 70 beats/minute or more (Swed-
berg 2010). After a 23-month follow-up, ivabradine reduced
the composite end point (CV death or hospitalization) by 18%
(24% vs. 29%, p<0.0001). These findings were largely driven by
a reduction in hospitalizations (16 vs. 21%; p<0.001). Although
no difference occurred in all-cause (16% vs. 17%, p=0.092) or
CV mortality (14% vs. 15%, p=0.128), HF mortality was reduced
with ivabradine (3% vs. 5%, p=0.014).
A detailed examination of the SHIFT baseline characteris-
tics merits further discussion. Although 89% of patients were
reportedly receiving β-blocker therapy, 14% were receiving
an agent that did not follow the current ACC/AHA guideline
recommendations (e.g., nebivolol, metoprolol tartrate). A key
limitation of the study was related to the dosing of β-blocker
therapy. Only 56% of patients received one-half the recom-
mended target dose, and only 26% received the target dose.
In about 75% of patients, the target dose was not achieved
because of hypotension or fatigue. Sub-target β-blocker use
raises questions about the benefit of ivabradine in patients
receiving optimal GDMT. Furthermore, the profound mortality
benefits of β-blockers in several clinical trials warrant more
aggressive measures to reach target doses before prescrib-
ing ivabradine, which has not yet shown a mortality benefit.
Given the many benefits with β-blocker therapy, the cur-
rent guidelines recommend that ivabradine be considered
in patients with stable HFrEF in sinus rhythm and a resting
heart rate of 70 beats/minute or more who are receiving max-
imum tolerated β-blocker therapy or who have a contraindi-
cation to β-blocker use. Patients should be initiated on 5 mg
twice daily; however, an initial dose of 2.5 mg twice daily may
be considered in patients for whom bradycardia could lead
to hemodynamic compromise. After initiating therapy, in
patients who remain asymptomatic with a heart rate greater
than 60 beats/minute, titration to a target dose of 7.5 mg
twice daily is recommended. If not receiving maximum ther-
apy and heart rate is 50–60 beats/minute, patients should be
maintained on the current dose. If the heart rate is less than
50 beats/minute or the patient has signs or symptoms con-
sistent with bradycardia, a reduction to 2.5 mg twice daily is
recommended.
Symptomatic bradycardia and visual effects were more
common in the ivabradine group (5% vs. 1%, and 3% vs. 1%,
respectively) within the SHIFT study. Patients taking ivabra-
dine developed luminous phenomena or sensations of
enhanced brightness, which likely resulted from inhibition
of the Ih ion channel in the retina. These symptoms typically
presented an average of 40 days after starting ivabradine
and were considered mild, transient, and fully reversible on
discontinuation. The risk of developing atrial fibrillation (AF)
within the ivabradine cohort was 9%, with 4% requiring with-
drawal from the study because of this complication. After
publication of the SHIFT trial, a growing concern surround-
ing the underreporting of AF development when initiating
ivabradine began to surface. In 2014, a meta-analysis using
PSAP 2019 BOOK 1 • Cardiology
available safety data showed a 15% increased risk of develop-
ing AF with ivabradine compared with control, which is asso-
ciated with a number needed to harm (NNH) of 208 (Martin
2014). Looking specifically at data from the BEAUTIFUL and
SHIFT trials, patients with a baseline heart rate of 70 beats/
minute or greater had an even higher rate of AF, with an NNH
of 58. Of note, patients at highest risk of AF are also the most
likely to benefit from ivabradine. To further investigate the
association of ivabradine treatment and AF development, a
meta-analysis (n=40,437) was completed using three ran-
domized controlled trials and data from the European Med-
icines Agency. The incidence of AF was 5.34% in patients
receiving ivabradine and 4.56% in patients receiving placebo,
correlating with a statistically significant 24% relative risk
increase in patients receiving ivabradine therapy (Tanboga
2016). Given these findings, careful consideration should be
given to initiating ivabradine therapy, and this agent should
be considered contraindicated in patients with AF.
In a certain subset of patients with HF, despite maximum
GDMT, the severity of symptoms will become recurrent and
persistent. Patients who require an increasing level of care
and treatment intensity with the noticeable failure of oral
therapies have been categorized as patients with advanced
HF (Allen 2012). Patients whose disease progresses to stage
D HF should be referred to centers that specialize in advanced
therapies, including inotropic therapy, left ventricular assist
devices (LVADs), and heart transplantation.
INOTROPIC THERAPY
Inotropic therapy can significantly increase the risk of mor-
tality. Given that studies showing worse outcomes were con-
ducted when implantable internal cardiac defibrillator or
chronic resynchronization therapy (ICD/CRT) devices and rou-
tine β-blocker therapy were not in common practice, inotropic
therapy has resurfaced as a potential therapeutic modality in
patients with advanced HF. Patients with systolic dysfunc-
tion, hemodynamic compromise including low blood pres-
sure, impaired perfusion, and significantly depressed cardiac
output should be considered for inotropic therapy. Patients
presenting in cardiogenic shock should be considered for
inotropic therapy, with a definitive therapy (coronary revascu-
larization, mechanical circulatory support, or heart transplan-
tation) as the ultimate treatment goal. Long-term continuous
infusion therapy in patients whose condition is refractory
to GDMT can be used as a “bridge” strategy while awaiting
permanent therapy (LVAD, transplantation). In advanced HF
patients receiving ambulatory intravenous inotropic therapy,
a recent systemic review and meta-analysis demonstrated an
improvement in NYHA functional without a significant differ-
ence in the risk of mortality. While the data within the analysis
were too limited to be stratified by indication (e.g., palliation,
bridge to transplant), there appears to be a role for patients
who have progressed to stage D HF without the previously
conceived increase in mortality (Nizamic 2018).
99 Heart Failure
 Dobutamine and milrinone remain the most commonly
used inotropic therapies within this setting. Dobutamine,
a β-agonist, and milrinone, a phosphodiesterase inhibitor,
increase cardiac contractility, which subsequently increases
cardiac output.
Use of inotropic agents can be limited by the ensuing
adverse effects. Because both dobutamine and milrinone
alter cardiac contractility, arrhythmias often develop, with
rates as high as 50%, necessitating careful monitoring.
Furthermore, peripheral activation of β-receptors and inhi-
bition of phosphodiesterase can lead to vasodilation, which
can in turn lead to extreme hypotension. Milrinone is elimi-
nated renally and should be carefully monitored in patients
with developing renal dysfunction, given its normal half-life
of 2.5 hours.
ADVANCED THERAPY MODALITIES
ICD/CRT Devices
As part of the compensatory mechanisms in HF, patients
often develop hypertrophy of the myocardium in an effort to
increase cardiac output. Alterations within the cardiac mus-
cles can predispose patients to ventricular tachyarrhythmias
and, ultimately, sudden cardiac death (SCD). Neurohormonal
antagonists have helped reverse cardiac remodeling and the
risk of arrhythmias; however, patients with HF are still at a
significant risk of SCD. Several randomized controlled trials
have evaluated ICD therapy for primary prevention, showing
a reduction in all-cause mortality of 23%–31% (Bardy 2005).
Smaller trials have replicated these findings, except in patients
with a recent MI (less than 40 days previously), in which no
survival benefit was shown. The current guidelines recom-
mend that primary prevention be considered in patients with
an LVEF of less than 35% while receiving optimal GDMT for at
least 3–6 months. Because GDMT has potentially improved
EF after therapy initiation, repeat ventricular function assess-
ment is important to ensure that ICD implantation is still war-
ranted. Use of ICD therapy is not without consequences, and
shocks may be inappropriate (because of the presence of
artifact or AF) or appropriate but unnecessary (self-terminat-
ing ventricular tachycardia), which can lead to reduced qual-
ity of life or posttraumatic stress syndrome (Sears 2011). In
addition, in rare cases, patients may develop complications
from the implant surgery, including hematomas or infections.
In a certain subset of patients with HF (30%), progression
of HF can lead to a prolongation of the QRS interval, which
can in turn lead to worse outcomes. Use of CRT or biventricu-
lar pacing reverses ventricular remodeling and improves ven-
tricular contraction. The initial studies evaluating the use of
CRT therapy were in patients with NYHA class III or ambu-
latory class IV symptoms with a QRS greater than 120–130
milliseconds. The results showed a reduction in rehospital-
ization as well as all-cause mortality of 24%–36% (Cleland
2005). Increasing evidence suggests that patients with a QRS
PSAP 2019 BOOK 1 • Cardiology
of at least 150 milliseconds and left bundle branch block pat-
tern are most likely to improve with CRT therapy (Stavrakis
2012). When CRT therapy was extended to include patients
with milder HF (NYHA class I–II) symptoms, the results indi-
cated a reversing or halting in LV remodeling in addition to a
reduction in hospitalizations (Moss 2009).
LVAD and Transplantation
Patients with advanced HF (stage D) should be considered
for advanced therapies, including LVAD implantation or car-
diac transplantation. Cardiac transplantation remains the
only definitive treatment for patients with HF unless signif-
icant contraindications exist (Figure 1). However, the num-
ber of available organ donors does not match the number of
potential needed recipients. Development of long-term LVAD
therapy has provided an alternative therapeutic modality for
patients whose disease is refractory to GDMT and ICD/CRT
devices. Improved technology and treatment of patients with
LVADs has ensured that patients can successfully be bridged
to transplantation or be maintained on these devices as des-
tination therapy. Patients who have relative or absolute con-
traindications to transplantation are considered destination
therapy candidates, whereas patients who are eligible for
transplantation can be bridged with an LVAD until a suitable
donor is available.
CURRENT HF MEDICATIONS
The dramatic benefit of using pharmacotherapy in patients
with HFrEF has not been replicated in patients with HFpEF.
Because of the limited results within HFpEF, most recommen-
dations focus on management strategies to alleviate symp-
toms and treat concomitant conditions.
Aldosterone Receptor Antagonists
The TOPCAT study evaluated the MRA spironolactone in
patients with symptomatic HF and an LVEF greater than 45%
with respect to the composite primary end point of death from
CV causes, aborted cardiac arrest, or hospitalization for HF
(Pitt 2014). The study randomized 3445 patients to receive
placebo or spironolactone. Although the primary outcome
rates did not differ (18.6% vs. 20.4%, p=0.14), spironolactone
reduced HF hospitalization rates (12% vs. 14.2%, p=0.04) after
a mean follow-up of 3.3 years. However, in a post hoc analysis,
regional variations potentially skewed the study results (Pfef-
fer 2015). Study patients in Russia/Georgia were younger and
had a lesser incidence of AF/diabetes mellitus, a higher like-
lihood of MI or hospitalization, and a lower baseline EF. The
analysis showed a significant difference in primary compos-
ite event rates for the spironolactone and placebo groups in
the Americas (10.4 and 12.6 per 100 patient-years) and Rus-
sia/Georgia (2.5 and 2.3 per 100 patient-years) (p<0.001 for
comparison of rates between regions). Given the large vari-
ance in event rates amongst study centers, an assessment of
100 Heart Failure
 Figure 1. Heart failure treatment algorithm.
AA = African American; ARNI = angiotensin receptor-neprilysin inhibitor; BB = β-blocker; BNP = B-type natriuretic peptide; GDMT =
guideline-directed management and therapy; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with
reduced ejection fraction; ICD/CRT = internal cardiac defibrillator or chronic resynchronization therapy; LVAD = left ventricular
assist device; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist.
Information from: Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for
the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137-61.

PSAP 2019 BOOK 1 • Cardiology 101 Heart Failure

canrenone concentrations (an active metabolite of spirono-
lactone) was completed in 366 patients (206 from the Ameri-
cas and 160 from Russia) randomized within the TOPCAT Trial
(de Denus 2017). Despite higher rates of reported medication
continuation at the 12-month visit (Russia: 94.3% vs Ameri-
cas: 75.2%), a significantly higher proportion of participants
from Russia had undetectable canrenone concentrations as
compared to Americas participants (30% vs 3%, p<0.001).
These findings, coupled with the a higher incidence of hyper-
kalemia and creatinine changes in the Americas (post hoc
analysis) raises concerns regarding adherence with study
medication at some sites in Russia. While further studies are
warranted to evaluate potential regional differences noted
within the post hoc analysis and subsequent concentration
analysis, the TOPCAT study demonstrated a reduction in hos-
pital admissions in patients randomized to spironolactone.
Given the study’s results, the current guidelines recommend
that patients with HF with an EF greater than 45%, an elevated
BNP, or hospitalization within 1 year should be considered for
MRAs for potential reduction in hospitalization.
β-Blockers
Little evidence suggests benefit with β-blocker therapy in
patients with HFpEF, except for nebivolol. The SENIORS study
evaluated nebivolol in patients 70 and older regardless of EF
with a composite of all-cause mortality or hospital admis-
sion (Flather 2005). After 21 months of therapy, the primary
outcome occurred in 332 patients (31.1%) receiving nebivo-
lol and in 375 patients (35.3%) receiving placebo (p=0.039).
The primary outcome was not influenced by EF, suggesting
that nebivolol can play a role in patients with HFpEF. Even
though the SENIORS study was not powered to show nebiv-
olol’s effect in EF subgroups, the authors maintain that given
similar hazard ratios with no apparent treatment interaction,
the benefit is similar in patients with impaired and preserved
EF (van Veldhuisen 2009). Although the European Society of
Cardiology provides commentary regarding nebivolol’s role in
reduced deaths and CV hospitalizations, the ACC/AHA guide-
lines only recommend this agent for patients with hyper-
tension as a treatment option for blood pressure lowering
(Ponikowski 2016).
Diuretics
Diuretic therapy should be used to help improve symptoms
associated with congestion and volume overload. Man-
agement should be influenced by fluctuations in daily body
weights, symptoms, and electrolyte status. Although loop
diuretic therapy is typically used in these patients, thia-
zide-like diuretics (e.g., metolazone) can be used to augment
and help maximize fluid removal in those with difficult-to-man-
age fluid balances. Caution should be used with aggressive
diuresis because clinically significant hypotension can result
from the relationship between LV diastolic pressure and vol-
ume status. Specifically, patients with HFpEF are extremely
PSAP 2019 BOOK 1 • Cardiology
preload-dependent, leading to underfilling of the LV and
potential hypotension if water removal occurs too rapidly.
ACEI/ARB Therapy
Despite evidence within HFrEF for ACEI/ARB therapy, evi-
dence is lacking for use of this therapy for morbidity or
mortality benefits in patients with HFpEF. In the CHARM-Pre-
served study (n=3023), patients randomized to candesartan
had significantly fewer HF hospitalizations (p=0.017) and a
trend toward reduction in the primary composite end point
(HF hospitalization and cardiac death) (Yusuf 2003). How-
ever, when irbesartan was evaluated in HFpEF (I-PRESERVE),
it had no noted benefits over placebo for any of the measured
outcomes after almost 50 months of therapy (Massie 2008).
Given the potential benefits with candesartan, ARBs may be
considered to help reduce HF hospitalizations.
ARNI Therapy
The PARAMOUNT trial was a phase II, double-blind study com-
paring sacubitril/valsartan with valsartan in 308 patients for
36 weeks (Solomon 2017). Sacubitril/valsartan provided fur-
ther NT-proBNP reduction compared with valsartan at 12
weeks. These positive findings have led to further investigation
within the phase III PARAGON-HF trial, which has completed
enrollment (estimated completion May 2019) (Solomon 2017).
Sildenafil
Initial findings with sildenafil use in HFpEF were significant
improvements in mean pulmonary arterial pressure, right
atrial pressure, and right ventricular function, with an addi-
tional improvement in quality of life in 44 patients (Guazzi
2011). To validate these findings, a multicenter randomized,
double-blind, placebo-controlled study was conducted. The
RELAX study (n=216 patients) investigated sildenafil 20 mg
three times daily (target dose 60 mg three times daily) com-
pared with placebo for improvement in exercise capacity or
clinical status (Redfield 2013). At the end of the study, no
demonstrable difference had occurred in the investigated
outcomes. In line with these results, a subsequent study
specifically evaluating HFpEF and concomitant pulmonary
hypertension also reported that sildenafil within this patient
subset with HF provided no benefits with respect to clinical
or exercise parameters (Hoendermis 2015). Given these data,
sildenafil should not be used solely to improve HFpEF.
Nitrates
Nitrates are generally not recommended in patients with
HFpEF, given the lack of evidence. In addition, within the
NEAT-HFpEF study, patients randomly assigned to isosor-
bide mononitrate (target dose 60–120 mg/day) had a nonsig-
nificant trend toward lower daily activity, with a significant
decrease in hours of activity per day. Reduction in activity
was shown irrespective of isosorbide mononitrate dosing,
with significant reductions in activity levels with increasing
102 Heart Failure
doses. Given these findings, use of nitrates for symptomatic
improvement for HFpEF is not currently recommended.
HF THERAPIES WITH LIMITED
BENEFIT OR POTENTIAL HARM
Because of the burden of HF on the health care system, addi-
tional medications have been evaluated to circumvent the
harmful aspects of worsening HF. However, many of the medi-
cations described in the text that follows have failed to provide
additional, if any, benefit toward improving HF symptoms, hos-
pitalizations, or mortality. These agents should thus be used
cautiously, when alternative options have been exhausted,
and only when the potential benefits outweigh the risk.
Digoxin
Digoxin is one of the oldest medications within the HF phar-
macotherapy spectrum, but its use remains controversial
(Table 4). Use of digoxin in patients with mild to moderate
HF is associated with improved symptoms and exercise tol-
erance but has failed to show a mortality benefit. In addition,
digoxin’s true efficacy is difficult to determine, given the lack
of therapies used within the DIG trial (e.g., β-blockers, MRAs,
and device therapy [ICD, CRT]). Therefore, digoxin should only
be considered once GDMT has been optimized.
Atrial fibrillation is often concomitant in patients with HFrEF,
but given the limited evidence, digoxin use in AF remains
Table 4. Comparison of Digoxin and Ivabradine
Digoxin
Indication HFrEF
SVT or AF
Mechanism of HFrEF: Inhibition of Na/K channel leading to
action increased intracellular calcium and contractility
Arrhythmias: AV nodal suppression
Dosing 0.125–0.25 mg QD
Adverse effects GI, CNS, arrhythmias
Consideration Renal function
Drug interactions
Digoxin concentrations
Clinical benefits HFrEF: Improvement in symptoms and exercise
tolerance with reduction in HF hospitalizations
Appropriate use Consider in symptomatic patients who are
currently treated with ACEI/ARB and β-blocker
May be considered in patients with symptomatic
HFrEF with concomitant AF when alternative
options cannot be pursued
AF = atrial fibrillation; AV = atrioventricular; HFrEF = heart failure with reduced ejection fraction; NSR = normal sinus rhythm; SVT =
supraventricular tachycardia.
PSAP 2019 BOOK 1 • Cardiology 103
controversial. Meta-analyses showed a 21% increased risk
of mortality (n=318,000 patients) and a 29% increase in mor-
tality (n=235,000 patients) when patients were treated with
digoxin therapy (Vamos 2015). This is in contrast to a subse-
quent meta-analysis that performed a post hoc defined sen-
sitivity analysis and showed no significant effect on mortality
in patients with HF and AF (Ziff 2015). Given the controversy
surrounding digoxin, the current guidelines recommend that
it be used for heart rate reduction in patients with AF when
other therapeutic options cannot be used.
Digoxin dosing is 0.125–0.25 mg/day, but a starting dose
of 0.125 mg/day is recommended, given the propensity for
increased toxicity with the higher dose and the therapeu-
tic benefit with lower serum concentrations. Further dose
reductions are warranted in patients with impaired renal
function or concomitant drug interaction (e.g., amiodarone)
and in older patients. Use of digoxin concentrations to guide
therapy has been debated because the literature supporting
this practice is limited to retrospective assessments. Most
clinicians target drug concentrations of 0.5–0.9 ng/mL,
given the correlation between digoxin concentration and sur-
vival, as noted in a post hoc analysis of the DIG trial (Digitalis
Investigation Group 1997). Patients with digoxin concentra-
tions greater than 1.2 ng/mL had increased mortality, which
led to the recommendation to target lower serum digoxin
concentrations.
Ivabradine
HFrEF with heart rate ≥ 70 beats/min on maximally
tolerated β-blocker
Inhibition of the If channels within the sinoatrial node
leading to prolonged diastolic depolarization and a
reduction in heart rate
2.5–7.5 mg BID
AF, bradycardia
Contraindicated in AF
Patient needs to be stable in NSR
HFrEF: Reduce the risk of hospitalizations in patients
with stable HF with heart rate ≥ 70 beats/min in NSR
Patient with stable HFrEF in NSR with heart rate ≥
70 beats/min on maximally tolerated β-blocker
Heart Failure
n-3 Polyunsaturated Fatty Acids
Mainly used for their benefits on hypertriglyceridemia, n-3
polyunsaturated fatty acids (PUFAs) had a small benefit in
patients with HF (Tavazzi 2008). In a trial evaluating around
7000 patients with HF in cardiology and internal medicine
centers in Italy, patients were randomized to n-3 PUFAs 1 g/
day or placebo with a primary composite end point of time to
death, or time to death or hospital admission related to a CV
cause. Within the intention-to-treat analysis, death from any
cause was slightly lower in the n-3 PUFA group (27%) than in
placebo (29%, p=0.041). Despite these findings, the authors
also noted that the number needed to treat to avoid one death
was 56 patients requiring treatment for a median of 3.9 years.
Given the currently available information, the use of PUFA are
deemed safe in HF patients and may provide some benefit.
Oral Anticoagulants and Antiplatelets
In patients with HF having a clear indication for anticoagu-
lation therapy (AF, history of a thromboembolic event), anti-
coagulation therapy should be individualized depending on
the clinical scenario. In patients without a clear indication
for anticoagulation therapy, the decision to initiate therapy is
more controversial. Patients with HFrEF have an inherently
increased risk of blood stasis because of hypokinetic or aki-
netic heart chambers, which can lead to thrombus develop-
ment. In clinical studies, patients with HFrEF remained at
low risk (1%–3%) of thromboembolism, even those with a
severely reduced EF. Initiation of warfarin in these cases has
had mixed results, with a reduction in major CV events and
death in some trials that was not replicated in other cases.
To further ascertain potential benefits of anticoagulation in
these high risk patients, the COMMANDER-HF study evalu-
ated rivaroxaban in HFrEF patients with no history of AF. Par-
ticipants were randomized to rivaroxaban (2.5 mg twice daily)
or placebo with the hypothesis that the study medication
would lead to a reduction in death and CV events. Following a
median follow-up period of 21.1 months, the authors found no
difference in the rate of death, MI or stroke (rivaroxaban: 25%
vs placebo: 26.2%, HR 0.94, 95% CI 0.84-1.05; p=0.27). There
was no difference in the primary composite safety outcome
(fatal bleeding or bleeding into a critical space) but a signifi-
cant increase in the risk of ISTH-defined major bleeding was
noted within the rivaroxaban cohort (3.3% vs 2%, HR 1.68, 95%
CI 1.18-2.39; p=0.003). Overall, current data do not support the
routine use of anticoagulation in patients with HFrEF and no
other compelling indication. Of greater concern is the risk of
complications, specifically the risk of major bleeding without
a significant benefit for therapy.
As with warfarin, no available evidence suggests any ben-
efit of antiplatelet therapy in patients with HF without con-
comitant disease necessitating therapy (e.g., coronary
artery disease). Because of the associated increased risk of
GI bleeding when using antiplatelet therapy, its routine use,
except in ischemic cardiomyopathy, is not recommended.
PSAP 2019 BOOK 1 • Cardiology
Renin Inhibitors
Renin serves as the starting point within the RAAS pathway
by cleaving the peptide angiotensinogen into AngI, which is
converted to AngII. Inhibition of renin would theoretically be
an additional target to decrease circulating AngII concen-
trations; however, the direct renin inhibitor aliskiren failed to
reduce CV deaths or rehospitalizations for patients at 6 or 12
months. Adding aliskiren to the current RAAS agents used in
the ASTRONAUT trial led to increased episodes of hyperkale-
mia, hypotension, and renal impairment failure (Gheorghiade
2013). Given the increased risk without benefits, aliskiren is
not currently recommended for patients with HF.
Statins
Statin therapy is widely used in various clinical scenarios
for its beneficial effects on inflammation, oxidative stress,
and immunologic activities. After reported benefits from
small observational or post hoc analyses within patients
with HF, two randomized controlled trials studied the poten-
tial usefulness of statin therapy. Rosuvastatin was evalu-
ated for its potential long-term benefits in patients receiving
optimal GDMT. The CORONA and GISSI-HF trials failed to
show any merit for the routine use of statin therapy in HFrEF
(Kjekshus 2007; Tavazzi 2008). In the absence of a compel-
ling indication, statin use alone in HF has not been proven
beneficial.
Calcium Channel Blockers
Patients should avoid non-dihydropyridine CCBs (diltiazem,
verapamil) because of their potential harm in those with symp-
tomatic HFrEF. Patients in the Multicenter Diltiazem Post
Infarction Trial (MDPIT) initiated on diltiazem were at a sig-
nificant risk of developing congestive HF compared with pla-
cebo (p=0.0017) (Goldstein 1991). The dihydropyridine CCBs
amlodipine and felodipine appear to be safe in both patient
subsets with HF, but given their lack of benefit, they should be
reserved for select patients already receiving GDMT (HFrEF)
or in patients whose hypertension is inadequately controlled
with an ACEI/ARB or β-blocker.
OTC Medications
Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs are commonly used
in the general population because of their anti-inflammatory
and analgesic properties. Inhibition of renal prostaglandins
leads to vasoconstriction of the afferent arteriole and sub-
sequent increase in sodium and water resorption. Although
generally well tolerated in healthy individuals, NSAIDs should
be avoided in patients with HF, given their propensity to
worsen kidney function and raise blood pressure (through
sodium and water retention), thereby opposing the diuretic
therapy. Heart failure exacerbations and increased mortality
have occurred in observational cohort studies that evaluated
selective or nonselective NSAID therapy.
104 Heart Failure
Decongestants
Pseudoephedrine is an OTC medication that is often used as
a decongestant in combination with select cough and cold or
anti-allergy medications. In addition to pseudoephedrine’s pri-
mary role of vasoconstriction within the respiratory mucosa
and relaxation of the bronchial tree, its adrenergic activation
can lead to systemic responses, increasing contractility and
pulse. Patients with HF may not tolerate the added catechol-
amine surge, which can worsen HF symptoms. Moreover, stim-
ulation of α-receptors in the vasculature can increase afterload,
which may be difficult for a failing heart to overcome, leading to
reduced cardiac output. Given the concerns for worsening HF,
pseudoephedrine is generally not recommended for patients
with HF, especially those with symptomatic HF.
CONCLUSION
Preventing hospital readmissions through optimizing transi-
tions of care is crucial to improving HF outcomes in addition
to reducing hospital readmissions, morbidity, mortality, and
costs. Use of pharmacy services as part of a multidisciplinary
HF service has been shown beneficial for medication recon-
ciliation and education and has reduced medication errors as
well as hospital costs. However, even with the proven bene-
fits of HF teams, recent findings within the CHAMP-HF study
suggest that more involvement is needed (Greene 2018). To
identify potential gaps between guideline recommendations
and real-world management, the CHAMP-HF study character-
ized medication use and doses within clinical practice. Spe-
cifically evaluating patients with HF in the outpatient setting,
Practice Points
• In patients with risk factors for HF, appropriate measures
should be taken to aggressively manage comorbidities to
prevent the onset of HF.
• Patients with HF should be assessed and actively treated
for concomitant diabetes, hypertension, or anemia to help
improve quality of life (anemia) and reduce CV complica-
tions (diabetes).
• Ensure that patients with HFrEF are receiving a RAAS
inhibitor (ACEI, ARB, or ARNI) in combination with β-block-
ers and MRAs.
• For patients with HFrEF who are currently tolerating an
ACEI/ARB, transition to an ARNI is recommended to reduce
the risk of mortality.
• Medication therapy should be dose adjusted to maximally
tolerated doses before adding secondary agents (e.g.,
hydralazine/isosorbide, digoxin).
• In patients receiving maximally tolerated β-blockers with
a heart rate of 70 beats/minute or greater (in normal sinus
rhythm), ivabradine should be considered.
• In patients who develop HFpEF, spironolactone should be
considered to reduce the risk of HF hospitalizations.
• Careful consideration should be given when adding medi-
cations with no proven benefits to HF regimens.
PSAP 2019 BOOK 1 • Cardiology
ACEI/ARB/ARNI, β-blocker, and MRA therapy were not pre-
scribed for 27%, 33%, and 67% respectively. Of these patients,
target doses were seldom achieved with an ACEI/ARB (17%),
an ARNI (14%), and a β-blocker (28%), whereas patients
receiving MRAs more commonly received the doses achieved
in clinical studies (77%). Using adjusted models, lower medi-
cation dosing or use occurred in patients of older age, those
with lower blood pressure, hospitalized patients, and patients
with renal insufficiency.
As medication experts, pharmacists are pivotal in this
challenging puzzle of HF medication optimization. Pharma-
cists must work with clinicians to ensure that appropriate HF
medications are initiated with strategies to titrate toward tar-
get doses that have shown beneficial morbidity and mortal-
ity results.
REFERENCES
Allen LA, Stevenson LW, Grady KL, et al. Decision making
in advanced heart failure: a scientific statement from the
American Heart Association. Circulation 2012;125:1928-52.
Andersson C, Olesen JB, Hansen PR, et al. Metformin treat-
ment is associated with a low risk of mortality in diabetic
patients with heart failure: a retrospective nationwide
cohort study. Diabetologia 2010;53:2546-53.
Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implant-
able cardioverter-defibrillator for congestive heart failure.
N Engl J Med 2005;352:225-37.
Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease
and stroke statistics-2018 update: a report from the Ameri-
can Heart Association. Circulation 2018;137:e67-e492.
Cleland JG, Daubert JC, Erdmann E, et al. The effect of car-
diac resynchronization on morbidity and mortality in heart
failure. N Engl J Med 2005;352:1539-49.
ClinicalTrials.gov [homepage on the Internet]. A Service of
the U.S. National Institutes of Health. Study to Compare
Ferric Carboxymaltose with Placebo in Patients with Acute
Heart Failure and Iron Deficiency (AFFIRM-AHF).
ClinicalTrials.gov [homepage on the Internet]. A Service of
the U.S. National Institutes of Health. Intravenous Iron
Treatment in Patients with Heart Failure and Iron Defi-
ciency: IRONMAN.
de Denus S, O’Meara E,Desai AS, et al. Spironolactone
metabolites in TOPCAT – New insights into regional varia-
tion. N Engl J Med 2017;367:1690-92.
Desai AS, Solomon S, Claggett B, et al. Factors associ-
ated with noncompletion during the run-in period before
randomization and influence on the estimated bene-
fit of LCZ696 in the PARADIGM-HF Trial. Circ Heart Fail
2016;9:e002735.
Digitalis Investigation Group. The effect of digoxin on mor-
tality and morbidity in patients with heart failure. N Engl J
Med 1997;336:525-33.
105 Heart Failure
Doust JA, Pietrzak E, Dobson A, et al. How well does B-type
natriuretic peptide predict death and cardiac events
in patients with heart failure: systematic review. BMJ
2005;330:625.
Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to
determine the effect of nebivolol on mortality and cardio-
vascular hospital admission in elderly patients with heart
failure (SENIORS). Eur Heart J 2005;26:215-25.
Ghali JK, Anand IS, Abraham WT, et al. Randomized dou-
ble-blind trial of darbepoetin in patients with symptomatic
heart failure and anemia. Circulation 2008;117:526-35.
Gheorghiade M, Bohm M, Greene SJ, et al. Effect of aliskiren
on postdischarge mortality and heart failure readmissions
among patients hospitalized for heart failure: the ASTRO-
NAUT randomized trial. JAMA 2013;309:1125-35.
Goldstein RE, Boccuzzi SJ, Cruess D, et al. Diltiazem
increases late-onset congestive heart failure in post
infarction patients with early reduction in ejection frac-
tion. The Adverse Experience Committee; and the Mul-
ticenter Diltiazem Post-infarction Research Group.
Circulation 1991;83:52-60.
Green JB, Bethel MA, Armstrong PW, et al.; for the TECOS
Study Group. Effect of sitagliptin on cardiovascular out-
comes in type 2 diabetes. N Engl J Med 2015;373:232-42.
Greene SJ, Butler J, Albert NM, et al. Medical therapy
for heart failure with reduced ejection fraction: the
CHAMP-HF Registry. J Am Coll Cardiol 2018;72:351-66.
SPRINT ResearchGroup, Wright JT Jr, Williamson JD, et al. A
randomized trial of intensive versus standard blood pres-
sure control. N Engl J Med 2015;373:2103-16.
Guazzi M, Vicenzi M, Arena R, et al. Pulmonary hypertension
in heart failure with preserved ejection fraction: a target of
phosphodiesterase-5 inhibition in a 1-year study. Circula-
tion 2011;124:164-74.
Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the
impact of heart failure in the United States: a policy state-
ment from the American Heart Association. Circ Heart Fail
2013;6:606-19.
Hoendermis ES, Liu LC, Hummel YM, et al. Effects of silde-
nafil on invasive haemodynamics and exercise capacity in
heart failure patients with preserved ejection fraction and
pulmonary hypertension: a randomized controlled trial.
Eur Heart J 2015;36:2565-73.
ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisar-
tan, ramipril, or both in patients at high risk for vascular
events. N Engl J Med 2008;358:1547-59.
Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of
intravenous iron therapy in iron-deficient patients with
systolic heart failure: a meta-analysis of randomized con-
trolled trials. Eur J Heart Fail 2016;18:786-95.
Kjekshus J, Apetrei E, Barrios V, et al; for the CORONA Group.
Rosuvastatin in older patients with systolic heart failure.
N Engl J Med 2007;357:2248-61.
PSAP 2019 BOOK 1 • Cardiology
Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic pep-
tide-based screening and collaborative care for heart fail-
ure: the STOP-HF randomized trial. JAMA 2013;310:66-74.
Lip GY, Skjoth F, Overvad K, et al. Blood pressure and prog-
nosis in patients with incident heart failure: the diet,
cancer and health (DCH) cohort study. Clin Res Cardiol
2015;104:1088-96.
Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type
natriuretic peptide assay for identifying patients at high
risk of re-admission after decompensated heart failure.
JACC 2004;43:635-41.
Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid mea-
surement of B-type natriuretic peptide in the emergency
diagnosis of heart failure. N Engl J Med 2002;347:161-7.
Marso SP, Bain SC, Consoli A, et al.; for the SUSTAIN-6
Investigators. Semaglutide and cardiovascular out-
comes in patients with type 2 diabetes. N Engl J Med
2016;375:1834-44.
Marso SP, Daniels GH, Brown-Frandsen K, et al.; for the
LEADER Steering Committee on behalf of the LEADER
Trial Investigators. Liraglutide and cardiovascular out-
comes in type 2 diabetes. N Engl J Med 2016b;375:311-22.
Martin RI, Pogoryelova O, Koref MS, et al. Atrial fibrillation
associated with ivabradine treatment: meta-analysis of
randomised controlled trials. Heart 2014;100:1506-10.
Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in
patients with heart failure and preserved ejection fraction.
N Engl J Med 2008;359:2456-67.
McMurray JJ, Packer M, Desai AS, et al. Angiotensin-nepri-
lysin inhibition versus enalapril in heart failure. N Engl J
Med 2014;371:993-1004.
Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchroni-
zation therapy for the prevention of heart-failure events.
N Engl J Med 2009;361:1329-38.
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and car-
diovascular and renal events in type 2 diabetes. N Engl J
Med 2017;377:644-57.
Nizamic T, Murad H, Allen LA, et al. Ambulatory inotrope infu-
sions in advanced heart failure: a systematic review and
meta-analysis. JACC Heart Fail 2018;6:757-67.
O’Connor CM, Starling RC, Hernandez AF, et al. Effect of
nesiritide in patients with acute decompensated heart fail-
ure. N Engl J Med 2011;365:32-43.
Okonko DO, Mandal AK, Missouris CG, et al. Disordered iron
homeostasis in chronic heart failure: prevalence, predic-
tors, and relation to anemia, exercise capacity, and sur-
vival. J Am Coll Cardiol 2011;58:1241-51.
Packer M, McMurray JJ, Desai AS, et al. Angiotensin recep-
tor neprilysin inhibition compared with enalapril on the
risk of clinical progression in surviving patients with heart
failure. Circulation 2015;131:54-61.
106 Heart Failure
Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation
in patients and outcomes in the treatment of preserved
cardiac function heart failure with and aldosterone antag-
onist (TOPCAT) trial. Circulation 2015;131:34-42.
Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for
heart failure with preserved ejection fraction. N Engl J
Med 2014;370:1383-92.
Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines
for the diagnosis and treatment of acute and chronic heart
failure: the task force for the diagnosis and treatment of
acute and chronic heart failure of the European Society of
Cardiology (ESC). Developed with the special contribution
of the Heart Failure Association (HFA) of the ESC. Eur J
Heart Fail 2016;18:891-975.
Rahimi K, Bennett D, Conrad N, et al. Risk prediction in
patients with heart failure: a systematic review and analy-
sis. JACC Heart Fail 2014;2:440-6.
Redfield MM, Chen HH, Borlaug BA, et al. Effect of phospho-
diesterase-5 inhibition on exercise capacity and clinical
status in heart failure with preserved ejection fraction: a
randomized clinical trial. JAMA 2013;309:1268-77.
Scirica BM, Bhatt DL, Braunwald E, et al.; for the SAVOR-TIMI
53 Steering Committee and Investigators. Saxagliptin and
cardiovascular outcomes in patients with type 2 diabetes
mellitus. N Engl J Med 2013;369:1317-26.
Sears SF, Hauf JD, Kirian K, et al. Posttraumatic stress and
the implantable cardioverter-defibrillator patient: what the
electrophysiologist needs to know. Circ Arrhythm Electro-
physiol 2011;4:242-50.
Solomon SD, Rizkala AR, Gong J, et al. Angiotensin receptor
neprilysin inhibition in heart failure with preserved ejec-
tion fraction: rationale and design of the PARAGON-HF
Trial. JACC Heart Fail 2017;5:471-82.
Stades AM, Heikens JT, Erkelens DW, et al. Metformin and
lactic acidosis: cause or coincidence? A review of case
reports. J Intern Med 2004;255:179-87.
Stavrakis S, Lazzara R, Thadani U. The benefit of cardiac
resynchronization therapy and QRS duration: a meta-anal-
ysis. J Cardiovasc Electrophysiol 2012;23:163-8.
Swedberg K, Komajda M, Bohm M, et al. Ivabradine and out-
comes in chronic heart failure (SHIFT): a randomised pla-
cebo-controlled study. Lancet 2010;376:875-85.
Tanboga IH, Topcu S, Aksakal E, et al. The risk of atrial fibril-
lation with ivabradine treatment: a meta-analysis with trial
sequential analysis of more than 40000 patients. Clin Car-
diol 2016;39:615-20.
Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 poly-
unsaturated fatty acids in patients with chronic heart
failure (the GISSI-HF trial): a randomised, double-blind,
placebo-controlled trial. Lancet 2008;37:1223-30.
Taylor AL, Ziesche S, Yancy CW, et al. Early and sustained
benefit on event-free survival and heart failure hospi-
talization from fixed-dose combination of isosorbide
dinitrate/hydralazine: consistency across subgroups
PSAP 2019 BOOK 1 • Cardiology
in the African-American heart failure trial. Circulation
2007;115:1747-53.
Taylor CJ, Ryan R, Nichols L, et al. Survival following a
diagnosis of heart failure in primary care. Fam Pract
2017;34:161-8.
Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mor-
tality: a systematic review and meta-analysis of the litera-
ture. Eur Heart J 2015;36:1831-8.
van Veldhuisen DJ, Cohen-Solal A, Bohm M, et al. Beta-block-
ade with nebivolol in elderly heart failure patients with
impaired and preserved left ventricular ejection fraction:
data from SENIORS (study of effects of nebivolol inter-
vention on outcomes and rehospitalization in seniors with
heart failure). JACC 2009;53:2150-8.
Vardeny O, Claggett B, Kachadourian J, et al. Incidence, pre-
dictors, and outcomes associated with hypotensive epi-
sodes among heart failure patients receiving sacubitril/
valsartan or enalapril: the PARADIGM-HF Trial (prospec-
tive comparison of angiotensin receptor neprilysin inhib-
itor with angiotensin-converting enzyme inhibitor to
determine impact on global mortality and morbidity in
heart failure). Circ Heart Fail 2018;11:e004745.
Velazquez EJ, Morrow DA, DeVore AD, et al; for the PIO-
NEER-HF Investigators. Angiotensin-neprilysin inhibi-
tion in acute decompensated heart failure. N Engl J Med
2018;Nov 11 [Epub ahead of print].
White WB, Cannon CP, Heller SR, et al.; for the EXAM-
INE Investigators. Alogliptin after acute coronary syn-
drome in patients with type 2 diabetes. N Engl J Med
2013;369:1327-35.
Wiviott SD, Raz I, Bonaca MP, et al.; for the DECLARE-TIMI 58
Investigators. Dapagliflozin and cardiovascular outcomes
in type 2 diabetes. N Engl J Med 2018; Nov 10 [Epub ahead
of print].
Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA
focused update of the 2013 ACCF/AHA guideline for the
management of heart failure: a report of the American Col-
lege of Cardiology/American Heart Association Task Force
on Clinical Practice Guidelines and the Heart Failure Soci-
ety of America. Circulation 2017;136:e137-61.
Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesar-
tan in patients with chronic heart failure and preserved
left-ventricular ejection fraction: the CHARM-Preserved
trial. Lancet 2003;362:777-81.
Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients
with systolic heart failure and mild symptoms. N Engl J
Med 2011;364:11-21.
Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of
digoxin: systematic review and meta-analysis of observa-
tional and controlled trial data. BMJ 2015;351:h4451.
Zinman B, Wanner C, Lachin JM, et al.; for the EMPA-REG
OUTCOME Investigators. Empagliflozin, cardiovascular
outcomes, and mortality in type 2 diabetes. N Engl J Med
2015;373:2117-28.
107 Heart Failure
Self-Assessment Questions
16. A 43-year-old man (weight 240 lb) with no significant
medical history routinely sees his primary physician
for an annual examination because of an ongoing con-
cern for elevated blood pressure. He is reluctant to start
taking blood pressure medications, and given his blood
pressure of 135/86 mm Hg and lack of additional risk fac-
tors, his physician agrees to first try diet, exercise, and
lifestyle changes. Subsequently, the patient presents to
the ED with fever and difficulty breathing. Pneumonia
is initially diagnosed, and the patient is discharged on
antibiotics and steroids. However, the patient does not
improve and is sent to the hospital for a further workup.
Chest radiography reveals pulmonary edema versus
infection. Given his ongoing shortness of breath, car-
diology is consulted. An ECHO is unremarkable, with a
reported left ventricular ejection fraction (LVEF) greater
than 55%. The patient has no evidence of dyspnea on
exertion, orthopnea, or lower-extremity swelling. Which
one of the following best classifies this patient with
respect to ACC/AHA and NYHA?
A. ACC/AHA stage C and NYHA class II
B. ACC/AHA stage A and NYHA class III
C. ACC/AHA stage B and NYHA class IV
D. ACC/AHA stage A with no accompanying NYHA
classification
Questions 17 and 18 pertain to the following case.
G.K. is a 64-year-old African American man with a medical
history of ischemic cardiomyopathy (EF 25%) because of
an MI in 1999 requiring three-vessel coronary artery bypass
grafting. He was initiated, and has remained, on appropriate
medical therapy that includes aspirin 81 mg daily, carvedilol
12.5 mg twice daily, atorvastatin 80 mg daily, and lisinopril
10 mg daily. G.K. continues to be seen by cardiology but indi-
cates that he has recently been more short of breath, requir-
ing 2 or 3 pillows at night to help him sleep. He denies the
use of diuretic therapy recently because there is no overt
lower-extremity edema. G.K. checks his weight three or four
times per week; until a week ago, his weight had remained
around 84 kg, but since then, it has increased to 90 kg. He
denies any change in diet and continues trying to exercise;
however, it is becoming more difficult. G.K. cannot walk up a
flight of steps without stopping and can only walk about the
one-half the length of the school track. Today’s vital signs
include heart rate 83 beats/minute, blood pressure 104/67
mm Hg, and respiratory rate 19 breaths/minute with Sao2
95%. G.K.’s basic metabolic panel is unremarkable, but his
NT-proBNP is significantly elevated at 6000 pg/mL (baseline
540 pg/mL).
PSAP 2019 BOOK 1 • Cardiology
17. Which one of the following best describes G.K.’s NYHA
functional class?
A. I
B. II
C. III
D. IV
18. G.K. is diuresed to his “normal” weight, and after his
HF medications are titrated, he is almost ready for dis-
charge. His current weight is 79 kg, with correlating vital
signs as follows: heart rate 65 beats/minute, blood pres-
sure 100/68 mm Hg, and respiratory rate 15 breaths/min-
ute with 100% saturation. Relevant laboratory values are
K 4.6 mEq/L, SCr 1.1 mg/dL (baseline 0.9 mg/dL), Na 141
mEq/L, and BNP 600 pg/mL. His current drug regimen is
aspirin 81 mg daily, carvedilol 12.5 mg twice daily, ator-
vastatin 80 mg daily, lisinopril 20 mg daily, and bumeta-
nide 2 mg daily. Which one of the following is best to add
to G.K.’s regimen before discharge?
A. Hydralazine/isosorbide (37.5 mg/20 mg combination
tablet) three times daily
B. Digoxin 0.25 mcg daily
C. Spironolactone 12.5 mg daily
D. Sacubitril/valsartan 24/26 mg twice daily
19. A 54-year-old white man has a medical history signifi-
cant for nonischemic cardiomyopathy (NICM) caused
by viral myocarditis. He has no other significant medi-
cal history and currently has been treated on an HF regi-
men consistent with sacubitril/valsartan 2426 mg twice
daily, metoprolol succinate 50 mg daily, spironolactone
25 mg daily, and as-needed bumetanide 1 mg daily. He is
seen in the clinic and admitted to the hospital with fail-
ure to thrive and reduced ability to perform daily activi-
ties. His weight has decreased from 74 kg (3 months ago)
to 64 kg as his admission weight. His admission labora-
tory values are unremarkable and unchanged from pre-
vious clinic visits: Hgb 8.9 g/dL, SCr 1.3 mg/dL, and K
4.1 mEq/L, with NT-proBNP 335 pg/mL and serum iron
19 mcg/dL (range 50–170 mcg/dL). His vital signs on
admission are heart rate 75 beats/minute, blood pres-
sure 115/76 mm Hg, and respiratory rate 17 breaths/min-
ute with 98% saturation. Given his decreased activity
level and weight loss, which one of the following is best
to recommend for this patient?
A. Initiate intravenous iron sucrose 200 mg daily x 5
days.
B. Give darbepoetin.
C. Reduce metoprolol succinate to 25 mg daily.
D. Initiate continuous intravenous milrinone 0.25 mcg/
kg/minute.
108 Heart Failure
20. A 35-year-old African American man recently received
a diagnosis of HF because of ischemia (history of an
ST-segment elevation MI). The patient underwent per-
cutaneous coronary intervention with drug-eluting stent
placement to his left anterior descending and left circum-
flex arteries (x 2) and was initiated on appropriate med-
ications, including HF medications, because an ECHO
revealed an EF less than 35%. He is seen in the clinic
with worsening HF symptoms and describes increased
weight gain, bloating, and general fatigue. Physical
examination reveals cool, clammy extremities, with jugu-
lar venous distention and an elevated heart rate. He has
been adherent to his medications, which include losar-
tan 50 mg daily, metoprolol succinate 50 mg daily, spi-
ronolactone 25 mg daily, aspirin 81 mg daily, ticagrelor
90 mg twice daily, atorvastatin 80 mg daily, bumetanide 1
mg twice daily, and nitroglycerin as needed. He is admit-
ted to the hospital for concern for HF exacerbation. Vital
signs on admission are heart rate 88 beats/minute, blood
pressure 121/67 mm Hg, and respiratory rate 19 breaths/
minute with 100% saturation. To optimize his care, the
physician seeks your recommendation for medical ther-
apy. Which one of the following is best to recommend for
this patient?
A. Initiate lisinopril 5 mg daily.
B. Increase losartan 100 mg daily.
C. Initiate isosorbide dinitrate 20 mg and hydralazine
37.5 mg three times daily.
D. Change losartan to sacubitril/valsartan 24/26 mg
twice daily.
Questions 21 and 22 pertain to the following case.
F.G. is a 55-year-old white woman with a medical history
significant for diabetes and hypertension. Despite her
medical history, she does not actively take medications
and has not been adherent to medical advice or with clinic
follow-ups. F.G. presents to the ED with profound volume
overload, as evidenced by a 10-kg weight gain over the past
7–10 days; difficulty breathing; 3+ pitting edema in her
lower extremities; and swelling in her abdomen. Her lab-
oratory results are normal except for Na 131 mEq/L, K 4.8
mEq/L, SCr 2.4 mg/dL (baseline 1.1 mg/dL), and NT-proBNP
13,000 pg/mL. Given the concern for cardiac involvement,
an ECHO is done that reveals severely reduced cardiac
function, with an LVEF of less than 20% with an enlarged
LV cavity. F.G.’s vital signs are blood pressure 144/84 mm
Hg, heart rate 102 beats/minute, Sao2 98%; and respiratory
rate 20 breaths/minute. She is admitted to the HF service
for treatment.
PSAP 2019 BOOK 1 • Cardiology
21. The resident treating F.G. comes to you for advice regard-
ing the patient’s pharmacotherapy. Which one of the fol-
lowing is best to recommend first for F.G.’s treatment?
A. Lisinopril
B. Carvedilol
C. Bumetanide
D. Hydrochlorothiazide
22. After being initiated on appropriate HF therapy, F.G. is
discharged on the following medication regimen: lisino-
pril 10 mg daily, carvedilol 6.25 mg twice daily, spirono-
lactone 12.5 mg daily, and torsemide 20 mg daily with an
extra tablet in the afternoon as needed for weight gain.
Six months later, F.G. presents to the clinic with the fol-
lowing medication list: lisinopril 20 mg daily, metoprolol
succinate 150 mg daily, spironolactone 25 mg daily, and
torsemide 10 mg as needed. Her vital signs on admission
are blood pressure 114/64 mm Hg, heart rate 68 beats/
minute in normal sinus rhythm, Sao2 99%, and respiratory
rate 19 breaths/minute. All laboratory values are within
normal limits except for SCr 1.8 mg/dL. F.G. has worsen-
ing shortness of breath, with difficulty lying flat at night
and increased pillows to help her sleep. The resident
wants to add ivabradine to her drug regimen. Which one
of the following is best to recommend regarding ivabra-
dine use in F.G.?
A. Initiate 5 mg twice daily.
B. Initiate 2.5 mg twice daily.
C. Initiate 7.5 mg twice daily.
D. Therapy is not indicated.
23. A 67-year-old African American woman has longstand-
ing heart failure with reduced ejection fraction (HFrEF)
(stage C). Her other medical history consists of diabetes
mellitus, hypertension, several genitourinary infections,
and a remote history of intravenous drug use (more than
20 years ago). The patient’s condition has been well con-
trolled on lisinopril 20 mg daily, carvedilol 25 mg twice
daily, eplerenone 50 mg daily, and furosemide 20 mg twice
daily. In the clinic today, she reports feeling well but indi-
cates that her diet has not been the best and that her blood
glucose readings have been a little high. An A1C reading is
8.1%, significantly increased from 6.5% 6 months ago. She
is currently not receiving any medications for diabetes.
Understanding the risks of uncontrolled diabetes (given
her family history), she seeks medication therapy to bet-
ter prevent cardiovascular (CV) complications. Which one
of the following is best to recommend for this patient?
A. Metformin 500 mg twice daily
B. Empagliflozin 10 mg daily
C. Saxagliptin 2.5 mg daily
D. Glyburide 10 mg daily
109 Heart Failure
24. T.A., a 74-year-old man, presents to the ED with the chief
concern of a racing heart. He describes it as if his heart
is beating through his chest. Initial heart rate shows that
he is tachycardiac at 114–132 beats/minute, with blood
pressure 104/65 mm Hg. T.A. states that he has long-
standing HFrEF with a current drug regimen of sacubi-
tril/valsartan 49/51 mg twice daily, bisoprolol 2.5 mg
daily (intolerant of higher doses), spironolactone 25
mg twice daily, and ivabradine 5 mg twice daily. He was
recently given a diagnosis of diabetes and instructed to
start empagliflozin, given the benefits of empagliflozin
for patients with his condition. His laboratory values
are all within normal limits, with SCr 0.89 mg/dL and K
4.6 mEq/L. Given his heart rate, an ECG is done, which
reveals the patient is likely in atrial fibrillation (AF). T.A. is
given a dose of intravenous metoprolol 5 mg to help con-
trol his heart rate and is admitted for further evaluation.
T.A.’s care team is searching for treatment options for his
new AF. Which one of the following is best to recommend
for T.A.?
A. Digoxin 125 mcg daily, goal 0.5–0.9 ng/mL
B. Digoxin 125 mcg every other day, goal greater than
1.2 ng/mL
C. Diltiazem IR 30 mg three times daily
D. Metoprolol tartrate 25 mg twice daily
25. A 67-year-old African American man has a medical his-
tory significant for NICM 2/2 viral myocarditis, hyperten-
sion, and ventricular tachycardia. His HF is well managed
with sacubitril/valsartan 49–51 mg twice daily, metopro-
lol succinate 150 mg daily, eplerenone 50 mg daily, and
furosemide 40 mg twice daily. The patient underwent
an internal cardiac defibrillator implantation with car-
diac resynchronization therapy (ICD/CRT) upgrade for
his history of ventricular tachycardia. He asks whether
any OTC medications are safe that might improve his HF.
Which one of the following is best to recommend for this
patient?
A. Fish oil
B. Aspirin
C. Ibuprofen
D. Caffeine
Questions 26 and 27 pertain to the following case.
H.M. is a 65-year-old white man with a medical history of MI
(15 years ago) that required stent placements and subse-
quent three-vessel bypass surgery. Additional medical his-
tory includes diabetes and gout. After his MI, H.M.’s heart
function slowly deteriorated until he developed systolic dys-
function. He has been seen in the HF clinic for several years
and has been doing well with ongoing optimization of his
HF regimen. The patient reports that he was admitted to the
hospital for 2 days because of decompensation with volume
PSAP 2019 BOOK 1 • Cardiology
overload. H.M. was treated with intravenous diuretics and
later discharged. His most recent EF was 15% during hospital-
ization. His vital signs today are heart rate 86 beats/minute,
blood pressure 114/58 mm Hg, respiratory rate 17 breaths/
minute, and Sao2 99%. H.M.’s home drugs include losartan 50
mg daily, metoprolol succinate 100 mg daily, spironolactone
25 mg daily, potassium chloride 20 mEq twice daily, atorvas-
tatin 80 mg daily, aspirin 81 mg daily, and bumetanide 2 mg
daily. The resident treating H.M. decides to initiate ivabradine
5 mg twice daily.
26. H.M. is seen 2 weeks after ivabradine initiation and
reports significant fatigue and lightheadedness. His vital
signs are heart rate 61 beats/minute, blood pressure
101/54 mm Hg, and respiratory rate 16 breaths/minute.
Which one of the following is best to recommend regard-
ing ivabradine for H.M.?
A. Continue current regimen.
B. Decrease to 2.5 mg twice daily.
C. Increase to 7.5 mg twice daily.
D. Discontinue.
27. H.M. continues to be seen by the HF service as an out-
patient. Overall, he is doing well but is beginning to have
more frequent hospitalizations because of HF. On review-
ing the patient’s medication profile, the attending physi-
cian wants make adjustments to better compensate the
patient and reduce hospitalizations. Which one of the fol-
lowing is best to recommend for H.M.?
A. Substitute eplerenone 25 mg daily for
spironolactone.
B. Discontinue losartan and initiate sacubitril/
valsartan 24/26 mg twice daily without a washout
period.
C. Add isosorbide dinitrate 20 mg and hydralazine
37.5 mg three times daily.
D. Discontinue losartan and initiate irbesartan 300 mg
daily.
28. A 45-year-old man has newly diagnosed HF and a med-
ical history of hypertension and diabetes. His initial
ECHO reveals heart failure with preserved ejection frac-
tion (HFpEF) (LVEF 55%). His current medication ther-
apy includes hydrochlorothiazide 25 mg daily, metformin
1000 mg twice daily, furosemide 20 mg daily (as needed),
and aspirin 81 mg daily. His diabetes and hyperten-
sion have been well controlled with this regimen, with
an A1C of 6.5% and blood pressure of 114–125 systolic
and 65–75 diastolic. Important laboratory values include
K 4.1 mEq/L and SCr 1.1 mg/dL. The patient reports
increased swelling with a 3-lb weight gain over the past
2–3 days, for which he has taken three doses of furo-
semide. He denies significant shortness of breath but
reports he has to stop more often while walking. He can
110 Heart Failure
 still walk 1–2 miles a day. Which one of the following is C. Initiate hydralazine 25 mg three times daily in
best to recommend for this patient? combination with isordil dinitrate 10 mg three times
daily.
A. Irbesartan 150 mg daily
D. Discontinue lisinopril; wait 36 hours and initiate
B. Isosorbide mononitrate 30 mg ER daily
sacubitril/valsartan 24/26 mg twice daily.
C. Spironolactone 25 mg daily
D. Nebivolol 5 mg daily 30. A 67-year-old woman has a medical history significant
for NICM (HFpEF), hypertension, and diabetes mellitus.
29. A 34-year-old man with no medical insurance has a
She has managed her disease states well and been vigil-
medical history that includes viral myocarditis at age
iant about her diet and exercise. However, her blood pres-
31 leading to HFrEF, drug and alcohol use disorder, and
sure has steadily increased, and today, it is 154/88 mm
hypertension. He has been nonadherent to medical ther-
Hg with heart rate 91 beats/minute. She denies chang-
apy and medications over the past 1–2 years. Overall,
ing her diet or exercise regimen. Her current medica-
he feels well without concerns and presents to the car-
tion regimen consists of aspirin 81 mg daily, fish oil 1 g
diology clinic for a routine clinic visit. His current drug
twice daily, and loratidine 10 mg as needed for allergies.
regimen includes lisinopril 40 mg daily, carvedilol 25 mg
Which one of the following is best to recommend for this
twice daily, spironolactone 50 mg daily, and bumetanide
patient?
1 mg daily, but he states that he has been more compliant
since his last cinic visit. His vital signs on presentation A. Sacubitril/valsartan 24/26 mg twice daily
today are as follows: heart rate 69 beats/minute, blood B. Amlodipine 5 mg daily
pressure 154/95 mm Hg, respiratory rate 15 breaths/min- C. Isosorbide mononitrate ER 60 mg daily
ute, and Sao2 99%; his weight is 65 kg (unchanged from D. Irbesartan 150 mg daily
previous visits). Which one of the following would best
reduce this patient’s risk of complications?
A. Increase carvedilol to 50 mg twice daily.
B. Discontinue lisinopril; wait 36 hours and initiate
sacubitril/valsartan 49/51 mg twice daily.

PSAP 2019 BOOK 1 • Cardiology 111 Heart Failure

Learner Chapter Evaluation: Heart Failure.

As you take the posttest for this chapter, also evaluate the Use the 5-point scale to indicate whether this chapter pre-
material’s quality and usefulness, as well as the achievement pared you to accomplish the following learning objectives:
of learning objectives. Rate each item using this 5-point scale:
29. Apply treatment strategies to reduce the progression of
heart failure (HF) through assessing functional class.
• Strongly agree
30. Evaluate and justify traditional and newer treatment

• Agree strategies for patients with stage C HF, specifically as
• Neutral they relate to the 2017 guideline updates.
• Disagree 31. Develop treatment strategies for patients with stage D
• Strongly disagree HF.
32. Evaluate treatment strategies for potential benefit/harm
18. The content of the chapter met my educational needs.
for the patient with HF with preserved ejection fraction.
19. The content of the chapter satisfied my expectations.
20. The author presented the chapter content effectively.
OTHER COMMENTS
21. The content of the chapter was relevant to my practice 33. Please provide any specific comments relating to any
and presented at the appropriate depth and scope. perceptions of bias, promotion, or advertisement of
22. The content of the chapter was objective and balanced. commercial products.
23. The content of the chapter is free of bias, promotion, or 34. Please expand on any of your above responses, and/or
advertisement of commercial products. provide any additional comments regarding this chapter:
24. The content of the chapter was useful to me.
25. The teaching and learning methods used in the chapter
were effective.
26. The active learning methods used in the chapter were
effective.
27. The learning assessment activities used in the chapter
were effective.
28. The chapter was effective overall.

PSAP 2019 BOOK 1 • Cardiology 112 Heart Failure