Stable but Progressive Nature of Heart Failure: Considerations for Primary Care Physicians
Stable but Progressive Nature of Heart Failure: Considerations for Primary Care Physicians
Inder Anand 0 1 2
Key Points 0 1 2
0 VA Medical Center , One Veterans Dr., Minneapolis, MN 55417 , USA
1 Cardiovascular Division, University of Minnesota Medical School , Minneapolis, MN 55455 , USA
2 & Inder Anand
Primary care physicians play a significant role in managing heart failure (HF), with the goals of reducing mortality, avoiding hospitalization, and improving patients' quality of life. Most HF-related hospitalizations and deaths occur in patients with New York Heart Association functional class II or III, many of whom are perceived to have stable disease, which often progresses without clinical symptoms due to underlying deleterious effects of neurohormonal imbalance and endothelial dysfunction. Management includes lifestyle changes and stepped pharmacological therapy directed at the four stages of HF, with aggressive uptitration of therapies, including betablockers and inhibitors of the renin-angiotensin-aldosterone system. Recently, two new HF treatments have become available in clinical practice. Ivabradine was approved to reduce the risk of hospitalization for HF in patients with stable, symptomatic HF. Additionally, the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, was found to be significantly superior to enalapril in reducing risks of cardiovascular death and HF-related hospitalization. The respective 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America clinical practice guideline updates recommend that patients taking angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy be switched to ARNI therapy to further reduce morbidity and mortality. For HF management to be maximally effective, physicians must be knowledgeable about the risks and benefits of treatments and stay engaged with patients to identify signs of disease progression. This article provides an overview of the progressive nature of HF in apparently stable patients and describes areas for treatment improvement that may help to optimize patient care.
Heart failure (HF) is a clinical syndrome caused by
structural or functional abnormalities of the heart, resulting in a
reduction in cardiac output or elevation of ventricular
filling pressures at rest or during exercise. The major
manifestations of HF are breathlessness, decreased exercise
tolerance, and fatigue, which may be accompanied by signs
of fluid retention, including peripheral edema, elevated
jugular venous pressure, and crackles in the lungs.
The prevalence of HF increases with age [
in the last several decades, advances in HF treatment have
led to improvements in survival, both in clinical trials and
in the community [
]. These decreases in mortality
extend to very elderly patients (aged [ 80 years) who have
been hospitalized for HF [
Primary care physicians (PCPs) play an important role
in improving outcomes in patients with HF, principally by
implementing guideline-directed evaluation and
management (GDEM) shown to reduce the risks of mortality and
HF hospitalization [
]. In addition, PCPs play an active
role in preventing HF-related hospital readmissions in
accordance with the US Affordable Care Act’s Hospital
Readmission Reduction Program, which penalizes
hospitals with above-average 30-day readmission rates for
Medicare patients .
Despite recent improvements in mortality rates among
patients with HF, the 5-year survival rates remain at about
]. Furthermore, as the US population ages, the
healthcare burden of HF is expected to increase
dramatically. Data from a 2015 report noted that HF affects more
than 5 million Americans, and annual healthcare costs are
more than $US30 billion [
]. By 2030, an estimated
8.5 million adults in the USA will have HF, with annual
costs of $US70 billion [
]. Thus, significant treatment
advances are needed to further improve outcomes.
Improvements in management are especially needed for the
large population of patients with New York Heart
Association (NYHA) class II or III functional status, the largest
population of patients with HF. These patients are often
perceived to have more stable disease. However, sudden
cardiac death remains the leading cause of mortality in
these patients, and they account for the majority of
HFrelated hospitalizations and deaths .
Given their increasing role in managing HF, PCPs are in
a position to work with patients to improve clinical
outcomes. Recent data have highlighted how considerable
further improvement in outcomes in apparently stable
patients with HF is possible if PCPs optimize their care. This
article outlines management recommendations, with a
focus on patients with stable but progressive HF.
1.1 Classification and Management of the Stages of HF
Historically, HF was dichotomized based on measurement
of the left ventricular (LV) ejection fraction (EF) [
Patients with LVEF C 50% were considered to have HF
with normal or preserved EF (HFpEF) and those with
LVEF B 40%, HF with reduced EF (HFrEF) [
left patients with an LVEF in the range of 40–49% in a
‘‘grey area,’’ which has been varyingly defined . Most
recently, the 2016 European Society of Cardiology HF
guidelines defined such patients as having HF with
midrange EF (HFmrEF) [
]. However—as discussed later in
this article—for the sake of management, patients with
HFpEF and HFmrEF are considered collectively.
Epidemiological studies suggest that approximately 50% of
the total HF population have HFrEF and the remainder
have HFpEF and HFmrEF [
]. Therapeutic strategies
for the management of HF differ based on EF classification
because the response to therapy varies between the two
groups . Moreover, recommendations for the use of
pharmacological GDEM have been more extensively
developed for HFrEF than for HFpEF, because clinical
trials have demonstrated benefits with such therapies in
patients with HFrEF but not in patients with HFpEF [
As such, this review focuses primarily on HFrEF
management. GDEM for patients with HFpEF focuses
primarily on managing symptoms and addressing risk factors
and comorbidities for disease progression [
In 2009, the American College of Cardiology (ACC)/
American Heart Association (AHA) further classified HF
into stages that emphasized the progressive nature of the
disease, from risk factors to development of structural heart
disease. The stages complement the NYHA functional
classifications that focus on limitation of exercise capacity
and the symptomatic status of the patient. At each stage of
the new classification, management is aimed at preventing
the development of the next stage.
Stage A patients have risk factors for the development of
HF but do not have structural or functional heart disease
and are asymptomatic. Management of risk factors
prevents the development of HF in patients at this stage. For
example, long-term treatment of hypertension has been
shown to reduce the risk of developing HF by
approximately 50% [
]. Similarly, treatment of
hyperlipidemia with statin therapy reduces the risk of developing
cardiovascular disease (CVD), including HF . In
addition, insulin resistance has been shown to increase the
risk of developing HF [
], and glycated hemoglobin
(HbA1c) concentration C 10.5% was associated with
increased risk for developing HF compared with HbA1c
concentration \ 6.5% [hazard ratio (HR) 3.98; 95%
confidence interval (CI) 2.23–7.14] [
hyperglycemia contributes to the development of HF, its
treatment as a risk factor for CVD has been controversial
because some hypoglycemic medications have been shown
to increase the risk of cardiovascular events [
recent data indicate that sodium–glucose cotransporter-2
(SGLT2) inhibitors reduced the rate of cardiovascular
outcomes, including HF, and may be considered to treat
hyperglycemia in patients at high risk of CVD [
particular, an analysis of data from the EMPA-REG
OUTCOMES (Empagliflozin, Cardiovascular Outcomes,
and Mortality in Type 2 Diabetes; ClinicalTrials.gov
number, NCT01131676) trial has shown that empagliflozin,
an SGLT2 inhibitor, is associated with a reduced risk for
HF-related hospitalization or death compared with placebo
(HR 0.61; 95% CI 0.47–0.79; P \ 0.001) [
]. Thus, the
effective management of these risk factors received a
recommendation [class of recommendation (COR) I, level of
evidence (LOE) A] to prevent the development of HF [
Both pharmacological treatments, such as SGLT2 inhibitors
for patients with diabetes mellitus, and lifestyle
modifications, including sodium restriction in patients with
hypertension, are appropriate strategies to reduce the risk of
developing HF at this stage [
Stage B patients are those who have already developed
structural heart disease, such as myocardial infarction, LV
dysfunction or LV hypertrophy, but are asymptomatic [
These stage B patients with asymptomatic LV dysfunction
(ASLVD) are at an increased risk of experiencing a CV
event (HR 3.32; 95% CI 1.98–5.58; P \ 0.0001) and
mortality (HR 3.47; 95% CI 2.03–5.94; P \ 0.0001) [
To reduce the risk of morbidity and mortality and prevent
progression to symptomatic HF in patients with ASLVD,
the ACC Foundation (ACCF)/AHA Guideline for the
Management of Heart Failure provides a class I (LOE A)
recommendation for the use of the angiotensin-converting
enzyme inhibitor (ACEI) enalapril [
recommendation is based on the results of the SOLVD (Studies of Left
Ventricular Dysfunction) prevention trial, which reported
that treatment with enalapril compared with placebo
reduced the risk of death or hospitalization for congestive
HF by 20% (95% CI 9–30; P \ 0.001) [
an analysis of the 15-year post-trial follow-up data found
that the beneficial effects of initial randomization to
enalapril therapy, compared with placebo, continued to be
seen throughout this period, with an overall absolute
mortality risk reduction (ARR) of 6.5% (P = 0.01) [
These results underscore the importance of the early
initiation of therapy and suggest that delaying treatment in
patients with LV systolic dysfunction increases their risk of
morbidity and mortality. Finally, myocardial
revascularization to correct ischemia has been shown to be associated
with better clinical prognosis [
]. Screening with
noninvasive imaging to detect myocardial ischemia is
recommended for patients with new-onset HFrEF and coronary
artery disease without angina, unless the patient is not
eligible for revascularization of any kind (COR IIA, LOE
Stage C patients have structural heart disease with prior
or current symptoms of HF [
]. Before the recent approval
of the two new HF therapies, ivabradine and
sacubitril/valsartan, the 2013 ACCF/AHA guidelines
recommended that patients with stage C HFrEF receive GDEM,
in addition to management of comorbidities, to reduce their
risk of disease progression (COR I, LOE A) [
mainstay of GDEM for patients with stage C disease at that
time included the use of recommended doses of ACEI—
and if not tolerated, angiotensin receptor blocker (ARB)
therapy (COR I, LOE A)—along with adequate doses of
beta-blocker therapy with bisoprolol, carvedilol, or
sustained-release metoprolol succinate (COR I, LOE A) to
reduce the risk of morbidity and mortality [
]. To further
reduce morbidity and mortality, aldosterone receptor
antagonists are recommended (COR I, LOE A) on top of
ACEI/ARB and beta-blocker therapy in patients with
NYHA class II–IV HFrEF, provided adequate renal
function and potassium concentration \ 5 mEq/dl [
symptomatic African American patients with NYHA class
III–IV HFrEF already receiving optimal doses of ACEI/
ARB and beta-blocker therapy, the combination of
hydralazine and isosorbide dinitrate is recommended (COR I,
LOE A) to further reduce morbidity and mortality [
Although loop diuretics have not been shown to reduce
mortality, they may be initiated in patients with NYHA
class II–IV to reduce volume overload (COR I, LOE C) [
Digoxin is a third-line treatment for HF, usually
restricted as an add-on therapy to GDEM (COR IIA, LOE
B) in patients with NYHA class III or IV HFrEF who
remain symptomatic, to reduce the risk of hospitalization
]. In addition, digoxin is often used in patients with atrial
fibrillation to achieve rate control as an adjunct to
]. However, physicians should be aware that
digoxin toxicity may occur (1) with high doses
(0.375–0.50 mg daily) [
]; (2) in patients with
coexisting hypokalemia, hypomagnesemia, or hypothyroidism
]; and (3) with the concomitant use of drugs that
increase digoxin serum concentrations [
]. To prevent
toxicity, concomitant drug interactions and comorbidities
should be considered upon digoxin initiation, and patients
should be continually monitored [
Two types of devices are available for patients with stage
C HFrEF [
]. Implantable cardioverter-defibrillator (ICD)
therapy is recommended (COR I, LOE A) for the primary
prevention of sudden cardiac death in patients with NYHA
class II–III HFrEF receiving GDEM who have either
ischemic cardiomyopathy at least 40 days postmyocardial
infarction or nonischemic dilated cardiomyopathy and a life
expectancy over 1 year [
]. Cardiac resynchronization
therapy (CRT) is recommended for NYHA class II, III, or
ambulatory NYHA class IV HFrEF (COR I, LOE A for
NYHA class III/IV; LOE B for NYHA class II) patients
receiving GDEM who are in sinus rhythm with a left
bundle-branch block and a QRS duration of C 150 ms [
Stage D patients have advanced end-stage refractory HF
and remain persistently symptomatic despite maximum
pharmacological and device therapies [
]. These patients
Potential deaths prevented per year with optimal implementation
ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, ARNI angiotensin receptor–neprilysin inhibitor, CRT cardiac
resynchronization therapy, GDEM guideline-directed evaluation and management, HF heart failure, HFrEF heart failure with reduced ejection
fraction, ICD implantable cardioverter defibrillator
aData are presented as n (%). Estimates are based on the number of patients with HFrEF in the USA (drawn from the 2010 American Heart
Association Heart Disease and Stroke Statistics Update) and the number of patients with HFrEF who are potentially eligible for each of the
guideline-recommended HF therapies (drawn from published HF registries)
bEstimated number of patients with HFrEF who are eligible for ARNI therapy
need to be referred to advanced HF centers for specialized
treatment strategies, such as insertion of mechanical
circulatory assist devices and consideration of cardiac
transplantation or end-of-life care [
Many of the medications commonly prescribed in
patients with HF, including antiarrhythmic drugs, nonsteroidal
anti-inflammatory drugs, and thiazolidinediones, have been
shown to potentially worsen HF [
]. These should be
avoided and discontinued whenever possible (COR III,
LOE B) [
]. Calcium channel-blocking drugs (other than
amlodipine and felodipine) should not be used to treat
patients with HFrEF (COR III, LOE A) because they may
worsen outcomes for these patients [
the long-term use of infused positive inotropic drugs should
be avoided in patients with HFrEF, except when used as
palliation (COR III, LOE C), because they may worsen HF
or precipitate death [
Although GDEM improves patient outcomes, physician
adherence to clinical practice guideline recommendations
is suboptimal [
]. For example,
renin-angiotensinaldosterone system (RAAS) blockers are recommended to
reduce the risk of mortality and hospitalization in patients
with HF [
], but these drugs are underutilized [
Optimal implementation of GDEM has the potential to
prevent thousands of deaths each year based on estimates
from Fonarow and colleagues (Table 1) [
1.2 Patient Monitoring and Management of Fluid
At each patient encounter, vital signs and volume status
should be evaluated, including patient weight, jugular
venous pressure, peripheral edema, and orthopnea (COR I,
LOE B) [
]. For patients with HFrEF who have evidence of
fluid retention, diuretic therapy is recommended in addition
to GDEM for symptomatic management, unless
contraindicated (COR I, LOE C) [
]. Loop diuretics should be
initiated at low doses and uptitrated until weight decreases
by 0.5–1.0 kg daily [
]. Twice-daily administration may be
employed to sustain these effects, if necessary. For patients
who are resistant to diuretics, intravenous administration
or combination with different diuretic classes may be
Because of the risk for electrolyte disturbances,
azotemia, and hypotension with diuretics, aldosterone
antagonists, ACEIs, and ARBs, it is recommended that renal
function and serum electrolytes should be monitored within
2 weeks of initiating or modifying therapy and periodically
thereafter (COR I, LOE C) [
]. Serial measurement of
natriuretic peptide concentrations for the purpose of
improving patient outcomes is not recommended because
supporting evidence is lacking [
1.3 Subclinical Progression in Stable HF
Patients with stable HF typically experience subtle disease
progression that is often not clinically detectable. Even
when patients are receiving GDEM, considerable cardiac
damage and progression of HF can occur over time as a
result of continued deleterious effects of activated RAAS
and sympathetic nervous system pathways as well as
inadequate effects of endogenous compensatory peptides
(e.g., natriuretic peptides, bradykinin) [
]. For example,
many patients with clinically stable HF have elevated
cardiac troponin T concentrations, suggesting continuous
underlying cardiac myocyte injury [
]. Elevated troponin
Repeated (C 2) hospitalizations or emergency department visits for HF in the past year
Progressive deterioration in renal function
Weight loss without other cause
Intolerance to ACEIs due to hypotension and/or worsening renal function
Intolerance to beta-blockers due to worsening HF or hypotension
Frequent systolic blood pressure of \ 90 mmHg
Persistent dyspnea with dressing or bathing, requiring rest
Inability to walk one block on level ground due to dyspnea or fatigue
Recent need to escalate diuretics to maintain volume status, often reaching daily furosemide-equivalent dose of [ 160 mg/day and/or use of
supplemental metolazone therapy
Progressive decline in serum sodium, usually to \ 133 mEq/l
Frequent implantable cardioverter-defibrillator shocks
ACEI angiotensin-converting enzyme inhibitor, HF heart failure
concentrations in patients with stable HF are associated
with increased risk of cardiovascular mortality and
]. Disease progression can also occur as a
result of prolonged endothelial dysfunction and alterations
in the nitric oxide pathway, which promote increased
vascular stiffness, myocardial damage, and vascular
Table 2 summarizes some clinical characteristics of
patients with advanced HF that indicate clinically obvious
disease progression [
]. For example, weight loss without
other causes may indicate cardiac cachexia, which is
associated with poor prognosis [
]. Although these
features of disease progression are often clear in patients with
advanced HF, predicting which clinically stable patients
may decompensate is challenging. This difficulty is
highlighted by studies such as PARADIGM-HF (Prospective
Comparison of ARNI (angiotensin receptor–neprilysin
inhibitor) with ACEI to Determine Impact on Global
Mortality and Morbidity in Heart Failure; NCT01035255),
in which 26.5% of patients with apparently stable HF who
received standard-of-care therapy, including enalapril,
experienced a primary event of cardiovascular death or first
hospitalization for worsening HF (WHF) during the trial
(median duration of follow-up, 27 months) [
]. Indeed, no
simple means exist for physicians to predict when a
seemingly stable patient will decompensate. Thus, it is
important for physicians to remain aware of the significant
risks associated with all stages of HF and to recognize
therapies that may improve the underlying
pathophysiology of HF for patients with stable yet progressive disease.
2 Potential Impact of New Therapies
Two new therapies have the potential to improve outcomes
for patients with stable, symptomatic HF [
]. In April
2015, ivabradine became the first new medication in nearly
a decade to be approved by the US FDA for the treatment
of chronic HF [
]; in July 2015, the FDA also approved
the ARNI sacubitril/valsartan for the same condition [
Ivabradine is a specific inhibitor of the
hyperpolarizationactivated cyclic nucleotide-gated channel, which is
responsible for diastolic depolarization of pacemaker cells
in the sinoatrial node [
]. Ivabradine is therefore a pure
heart-rate–reducing agent with no other cardiovascular
effects, indicated to reduce the risk of hospitalization for
]. The approval of ivabradine was based on results
of the randomized, double-blind SHIFT (Systolic Heart
Failure Treatment With the If Inhibitor Ivabradine Trial;
NCT02441218) that compared ivabradine versus placebo
in 6558 patients with symptomatic HFrEF [
Eligible patients were required to have stable, symptomatic HF
with a baseline EF of B 35%; to be in sinus rhythm with a
resting heart rate of at least 70 beats per minute (bpm); to
have been hospitalized for HF within the last year; and to
be receiving stable background treatment, including a
betablocker, at the maximally tolerated dose or have a
contraindication to beta-blocker use [
]. Over a median
follow-up period of 22.9 months, significantly fewer
patients in the ivabradine group [793/3268 (24%)] than in
the placebo group [937/3290 (29%)] experienced the
primary endpoint of cardiovascular death or hospitalization
for WHF (HR 0.82; 95% CI 0.75–0.90; P \ 0.001) [
The effects were primarily driven by hospital admissions
for WHF [672 (21%) placebo vs. 514 (16%) ivabradine;
HR 0.74; 95% CI 0.66–0.83; P \ 0.0001] and deaths due
to HF [151 (5%) vs. 113 (3%); HR 0.74; 95% CI
0.58–0.94; P = 0.014] [
]. Overall, findings from SHIFT
indicated that heart rate reduction has the potential to
improve clinical outcomes for patients with stable, chronic
]. However, ivabradine has been shown to increase
the risk of atrial fibrillation [
]. It should be used only
in patients with normal sinus rhythm and discontinued if
patients develop atrial fibrillation [
Sacubitril/valsartan is a novel, first-in-class drug that
combines a neprilysin inhibitor with an ARB [
Sacubitril is a prodrug that is metabolized to LBQ657,
which inhibits neprilysin endopeptidase. Neprilysin
inhibition prevents the degradation of B-type natriuretic
peptide (BNP) and other compensatory peptides (e.g.,
bradykinin, adrenomedullin), thus increasing plasma levels
of these peptides and enhancing their beneficial effects,
which include vasodilation, natriuresis, diuresis, and
inhibition of pathogenic growth and fibrosis [
counterbalances the increase of angiotensin II that also
results from neprilysin inhibition, while simultaneously
exerting the beneficial effects of ARBs seen in previous HF
]. Unlike previous neprilysin inhibitors, such as
omapatrilat, ARNI therapy does not inhibit
angiotensinconverting enzyme, which allows for the degradation of
bradykinin and thus lowers the risk for angioedema [
In the PARADIGM-HF trial, the safety and efficacy of
sacubitril/valsartan were compared with that of enalapril,
the standard-of-care ACEI shown to reduce mortality in
patients with chronic HFrEF [
]. The mean dose
(18.9 mg/day) of enalapril used in this trial was the highest
dose achieved in any of the large outcome trials . This
randomized, double-blind, phase III trial enrolled 8442
patients with stable HFrEF (EF B 40%) and NYHA class
II, III, or IV functional status who were receiving adequate
doses of current standard-of-care HF medications,
including an ACEI or ARB, beta-blockers, and mineralocorticoid
]. Patients were randomly assigned 1:1 to
receive enalapril 10 mg twice daily or sacubitril/valsartan
200 mg twice daily in addition to comprehensive
concomitant background HF therapy. Patients were followed
for a median of 27 months. Evaluation of the primary
endpoint showed that, compared with enalapril, use of
sacubitril/valsartan was associated with a 20% reduction in
the composite of cardiovascular death or first
hospitalization for HF (HR 0.80; 95% CI 0.73–0.87; P \ 0.001), a
16% reduction in death from any cause (HR 0.84; 95% CI
0.76–0.93; P \ 0.001), and significant improvements in
HF symptoms and physical limitations as measured by the
Kansas City Cardiomyopathy Questionnaire
(betweengroup difference 1.64; 95% CI 0.63–2.65; P = 0.001) [
Additionally, sudden cardiac death was significantly
reduced with sacubitril/valsartan compared with enalapril
(HR 0.80; 95% CI 0.68–0.94; P = 0.008) [
Sacubitril/valsartan was generally well tolerated; the adverse
events hypotension and nonserious angioedema were more
common with sacubitril/valsartan, whereas renal
impairment, hyperkalemia, and cough were more common with
]. Significantly fewer patients in the
sacubitril/valsartan group stopped treatment because of renal
impairment compared with the enalapril group (0.7 vs.
1.4%; P = 0.002) [
As mentioned, one in four patients in the control group
of PARADIGM-HF trial receiving GDEM had a primary
clinical event (cardiovascular death or HF hospitalization)
]. Thus, these apparently stable patients receiving
adequate treatment remained at a high risk for serious adverse
clinical outcomes. The benefit of sacubitril/valsartan was
observed in these stable patients (75% of patients
randomized to treatment had NYHA class I or II functional
status). The beneficial effects of sacubitril/valsartan
compared with enalapril were consistent across all subgroups,
regardless of patient baseline demographics and clinical
characteristics [e.g., age, sex, ethnicity, geographic region,
NYHA class, comorbidities, EF, N-terminal pro-BNP
(NTproBNP) level, HF treatment history, or hospitalization
]. Moreover, a recent analysis showed that
optimal implementation of ARNI therapy in the
appropriate community-based population of patients with NHYA
class II–III HFrEF who tolerate ACEI/ARB therapy would
prevent approximately 28,000 deaths per year [
A separate analysis of data from the PARADIGM-HF
trial performed in surviving patients showed that those who
received sacubitril/valsartan were significantly less likely
to require intensification of HF treatment (P = 0.003) or
emergency-department treatment for WHF (P = 0.001)
than patients who received enalapril [
]. Patients treated
with sacubitril/valsartan were also less likely to have WHF
requiring the addition of a new drug, intravenous therapy,
or an increase in the daily dose of diuretic for [ 1 month
(P = 0.003); to be evaluated and treated for WHF in the
emergency department but discharged without hospital
admission (P = 0.001); to be hospitalized for WHF
(P \ 0.001); to be hospitalized for any reason (P \ 0.001);
to be hospitalized for HF more than once (P = 0.001); to
receive intravenous inotropic agents (P \ 0.001); to
require intensive care (P = 0.019); or to require HF device
implantation or heart transplantation (P = 0.07) [
these patients, sacubitril/valsartan treatment was associated
with lower levels of NT-proBNP and troponin, which are
biomarkers for myocardial wall stress and injury, than was
2.3 Guideline Update
The remarkable results of the SHIFT and PARADIGM-HF
trials led the ACC/AHA/Heart Failure Society of America
(HFSA) to release an update to the guideline for the
management of HF in May 2016 [
]. The recommendations
provided in the 2016 guideline update have been carried
over to the most recent 2017 guideline update [
guideline recommended that ivabradine ‘‘can be beneficial
to reduce HF hospitalization for patients with symptomatic
(NYHA class II, III) stable chronic HFrEF (LVEF B 35%)
who are receiving GDEM, including a beta-blocker at the
maximum-tolerated dose, and who are in sinus rhythm with
a heart rate of 70 bpm or greater at rest’’ (COR IIA, LOE
]. The update noted that only 25% of patients in
the trial were receiving optimal doses of beta-blocker
therapy and encouraged efforts to maximize the use of
these agents in this setting. The second specific
recommendation in the update related to the ARNI class of drugs,
of which only sacubitril/valsartan is currently available and
]. The update added the ARNI class to an
existing recommendation (alongside ACEIs or ARBs) for a
management strategy to reduce morbidity and mortality in
patients with chronic HFrEF (COR I, LOE B–R) [
specifically noted that patients with chronic, symptomatic
HFrEF who have NYHA class II or III disease should be
switched from an ACEI or ARB to the ARNI,
sacubitril/valsartan, to further reduce morbidity and mortality
(COR I, LOE B–R) [
]. This particular
recommendation represents a clear departure from the previous
guideline that only recommended adding newly approved
drugs to existing standard-of-care therapy and never
recommended switching one class of therapy for another.
It is important to point out that the American Academy
of Family Physicians (AAFP) has not completely endorsed
these guideline recommendations because of concerns that
sacubitril/valsartan was tested only in one study and that
postmarketing data in the American population on potential
harm and adverse side effects are limited [
]. However, it
should be emphasized that the patients enrolled in the
PARADIGM-HF trial from the USA were typical of
patients seen in primary care practice: Approximately 26%
were African American and nearly 60% had an ICD [
In patients from the USA, a somewhat greater beneficial
effect with sacubitril/valsartan compared with enalapril on
the primary outcome was observed (HR 0.66; 95% CI
0.47–0.92) compared with that of the entire cohort (HR
0.80; 95% CI 0.73–0.87) [
]. Similar patient
characteristics and outcomes were observed in the prespecified
subgroup analyses for North America (including both Canada
and the USA); 54% of these patients had an ICD, 19% were
Black, and a somewhat greater beneficial effect with
sacubitril/valsartan compared with enalapril on the primary
outcome was observed (HR 0.67; 95% CI 0.50–0.90)
compared with that of the entire cohort (HR 0.80; 95% CI
0.73–0.87) sacubitril/valsartan [
]. Because the evidence
for the 20% reduction in the primary endpoint (P \ 0.001)
and for the 20% lower risk of cardiovascular death
(P \ 0.001) with sacubitril/valsartan compared with
enalapril was very strong [
], randomizing patients to
treatment with enalapril to replicate PARADIGM-HF trial
results would not be ethical [
In PARADIGM-HF, sacubitril/valsartan was very well
tolerated, and fewer patients taking sacubitril/valsartan
discontinued study medication because of adverse effects
compared with those taking enalapril [
that required dose reduction was seen more often with
sacubitril/valsartan, but renal dysfunction, hyperkalemia,
and cough requiring discontinuation of study medication
were more common with enalapril [
]. Few cases of
angioedema were reported, with no significant difference
between study groups [
]. Furthermore, in a meta-analysis
of six hypertension and HF trials involving 11,821 patients,
sacubitril/valsartan was associated with significantly lower
risk of treatment discontinuation for any adverse event than
was an ACEI/ARB or placebo [
]. Therefore, based on a
critical examination of the available literature on
sacubitril/valsartan, it is difficult to understand the reluctance of
the AAFP to fully endorse the AHA/ACC/HFSA guideline
recommendations to replace ACEI or ARB therapy with
sacubitril/valsartan in patients with HFrEF.
The guideline update also offers two important safety
recommendations with respect to the ARNI class: ‘‘ARNI
should not be administered concomitantly with ACEIs or
within 36 hours of the last dose of an ACEI’’ (COR III,
LOE B–R) and ‘‘ARNI should not be administered to
patients with a history of angioedema’’ (COR III, LOE
]. These safety recommendations address the
potential risk for angioedema that was observed with
omapatrilat (a dual neprilysin inhibitor/ACEI), which
halted the clinical development of this drug [
higher incidence of angioedema was because both
pharmacodynamic effects of omapatrilat result in bradykinin
accumulation. Because ARBs do not inhibit bradykinin
degradation, the substitution of an ARB agent (such as
valsartan) for the ACEI should mitigate the risk for
angioedema. Indeed, the overall incidence of angioedema
in the PARADIGM-HF trial was low and nonsignificant
compared with enalapril (19 vs. 10; P = 0.13) [
]. It is
also important to note that because one component of
ARNI therapy is an ARB agent (i.e., valsartan in
sacubitril/valsartan), ARNI should also not be used concomitantly
with another ARB [
3 Areas for Improvement in the Treatment of HF
3.1 Uptitration of Pharmacologic Therapies
The ACCF/AHA guideline for the management of HF
recommends uptitration of GDEM to the target or
highesttolerated doses (Table 3) shown to improve outcomes in
Starting dose, mg
Target dose, mg
25 od or bid
Doses are presented as mg
ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, ARNI angiotensin receptor–neprilysin inhibitor, bid twice
daily, CR controlled release, od once daily, tid three times daily, XL extended release
aSuggested target doses were not studied in clinical trials
clinical trials [
]. Optimized GDEM for stage C HFrEF
decreased the relative risk of mortality by 17–43% and the
relative risk of HF hospitalization by 31–41% against the
comparator arms in randomized controlled trials [
However, HF medication doses are not always escalated as
]. There are several possible reasons for this
observation. One explanation may be that patients with HF
are not seen often enough to allow for adjustments. Some
physicians perceive that escalated doses of HF drugs may
negatively affect patients or higher doses of ACEIs, ARBs,
and aldosterone receptor antagonists may worsen renal
function . Thus, physicians may be hesitant to increase
doses when renal function cannot be carefully monitored.
However, considerable evidence suggests that despite mild
worsening of renal function, uptitration of RAAS blockers
and aldosterone antagonists is associated with better
]. The development of hypotension may
prevent uptitration due to concerns of advanced pump
failure, but other causes of hypotension should be
considered before adjusting HF medications. These other
causes include overdiuresis, dehydration, acute coronary
syndrome, ischemia, arrhythmia, autonomic dysfunction,
gastrointestinal bleeding, infection, or use of drugs for
conditions other than HF [
]. Typically, hypotension
resolves spontaneously after diuretic dose reduction in
euvolemic patients or after management of other
medications and/or comorbidities [
]. Moreover, vasodilators
such as RAAS blockers and the combination of hydralazine
and isosorbide often improve blood pressure with
continued use [
]. Some physicians are concerned that
intensification of beta-blocker therapy may lower cardiac
output short term and worsen HF; however, the author is
aware of no evidence to date that uptitration of
betablockers is associated with hospitalization in the
subsequent 30 days .
Interestingly, evidence suggests that patients having
telephone consultations at 1- to 3-week intervals with
registered nurses or cardiologists may efficiently optimize
dose escalation of HF medication, improving clinical
]. Analysis of data from the Train-the-Trainer
trial also found that increasing the self-confidence of PCPs
in treating HF by using educational interventions improved
evidence-based prescription of RAAS blockers [
However, other studies do not support such interventions
], and more studies are required to confirm these
The GUIDE-IT (Guiding Evidence-based Therapy
Using Biomarker Intensified Treatment in Heart Failure;
NCT01685840) study aimed to assess whether natriuretic
peptide (i.e., NT-proBNP)-guided treatment improved
clinical outcomes versus usual care in high-risk patients
with HFrEF [
]. The data and safety monitoring board
recommended stopping the study when only 894 of the
planned 1100 patients had been enrolled, with follow-up
for a median of 15 months, because of futility [
primary outcome of the composite of time-to-first HF
hospitalization or death from cardiovascular causes
occurred in 164 patients (37%) in the biomarker-guided
group and 164 patients (37%) in the usual-care group [
None of the secondary endpoints, nor the decreases in the
NT-proBNP levels achieved, differed significantly between
]. Hence, the natriuretic peptide-guided strategy
to uptitrate HF medications cannot be recommended.
Additional research is necessary to improve
implementation of evidence-based therapy into clinical practice.
Meanwhile, physicians are encouraged to optimize
guideline-recommended uptitration of HF medications.
3.2 Switching Therapies
As mentioned, previous guideline recommendations
focused on stacking newer therapies on older approved
drugs and have not considered it appropriate to switch a
patient’s existing pharmacologic regimen [
]. This is
because all previous trials have compared the active drug
on top of the standard of care against a placebo [
However, the PARADIGM-HF trial tested the ARNI
sacubitril/valsartan against the active comparator ACEI
enalapril and found it to be superior [
]. Hence, the
guidelines recommend switching from ACEI/ARB therapy
to ARNI therapy [
Unfortunately, physicians are often hesitant to even
intensify therapies when patients appear to be stable and
lack clinical evidence of progression [
physicians may be even more diffident to switch to a new
therapy in stable patients. Considerable efforts may be
required to educate physicians about the benefits of
switching from ACEI/ARB to ARNI therapy. In many
cases, physicians may find it easier to implement new HF
treatment strategies with new patients than to switch
therapy in seemingly stable patients.
When considering a switch in medication, physicians
should confirm that patients are receiving therapeutically
appropriate doses of their current treatments and that
aggressive efforts have been made to reach target doses
(Table 3). Analysis of data from the IMPROVE-HF
(Registry to Improve the Use of Evidence-based Heart
Failure Therapies in the Outpatient Setting;
NCT00303979) showed that, prior to implementation of a
practice-based performance improvement intervention at
outpatient cardiology clinics, only 36.1, 20.5, and 74.4% of
patients were receiving recommended target doses of
ACEIs/ARBs, beta-blockers, and aldosterone antagonists,
]. Similarly, data from the OPTIMIZE-HF
(Organized Program to Initiate Lifesaving Treatment in
Hospitalized Patients With Heart Failure; NCT00344513)
indicated that target doses of the beta-blockers carvedilol
and metoprolol succinate, used for 60–90 days after
hospital discharge, were achieved only by 17.5 and 7.9% of
patients, respectively [
3.3 Improving Adherence
Although GDEM is recommended to reduce the risk of
disease progression, it is not always appropriately initiated
in clinical practice. A survey of 1378 specialists in family
medicine, internal medicine, and general cardiology found
that referral practices for an ICD for primary prevention are
often discordant with evidence-based guideline
recommendations from the ACC/AHA/Heart Rhythm Society
]. Survey results observed that 28% of respondents
reported that they never refer patients for consideration of
an ICD, 15% believed ventricular arrhythmia is required
before an ICD is indicated, and 36% believed an EF[ 40%
warrants an ICD [
]. Of the respondents, the specialists
most likely to give responses that were inconsistent with
guideline recommendations were family practice
physicians, as demonstrated by multivariate analyses of survey
Similarly, telephone interviews with clinicians at US
Department of Veterans Affairs healthcare systems found
that many physicians believe HF guideline
recommendations are less applicable in the very elderly (aged
[80 years) and in those with multiple comorbidities that
increase clinical complexity and risk of adverse medication
]. Practitioners reported having concerns about
the validity of evidence-based HF guideline
recommendations in these higher-risk patient populations, despite
evidence that these subgroups may receive greater absolute
benefit from HF medications [
findings from the HART (Heart Failure Adherence Retention
Trial) showed that physicians are significantly less likely to
follow evidence-based guideline recommendations for
ACEIs/ARBs and beta-blockers—which include not
prescribing therapy when contraindicated—in patients with
multiple comorbidities, older patients, patients with higher
NYHA class, and ethnic minorities [
3.4 HF Management in Primary Care
The quality of the PCP–patient relationship is essential for
the optimal management of HF. To reduce the risk of poor
outcomes, physicians must be able to identify the
oftensubtle symptoms of WHF in seemingly stable patients [
Thus, physicians need to establish a trusting relationship
with patients to whom they provide information about the
progressive nature of HF along with reassurances to
alleviate patient fears and concerns. Patients should feel
comfortable having honest conversations with their PCPs
and should feel confident that their providers are
knowledgeable about HF. However, a recent study by Zickmund
et al. [
] found that about three in ten patients expressed
complaints about their physicians, including poor
interpersonal skills, lack of confidence in their medical
competence to diagnosis and treat congestive HF, and inability
to provide sufficient medical information. Therefore,
initiatives are needed to train physicians in ways to improve
the PCP–patient relationship [
]. To improve patient
confidence, physicians should have strong knowledge of
current HF guideline recommendations and stay abreast of
new therapies and strategies to improve patient care.
PCPs should also collaborate with other healthcare
professionals as part of a multidisciplinary network of care
because team approaches that include input from
cardiologists, nurses, pharmacists, physical therapists, dietitians,
and PCPs have been shown to improve patient survival,
decrease readmission rates, and improve patient quality of
]. For example, Lee et al.  found that
collaboration between a PCP and a cardiologist within
30 days of a patient’s hospital discharge improved rates of
follow-up testing, use of GDEM, and survival compared
with PCP care alone. Moreover, multidisciplinary HF
disease-management programs are recommended to facilitate
the implementation of GDEM, prevent readmissions to
hospital, and address barriers to behavior change (COR I,
LOE B) [
Although HF management has considerably improved in
the past several years, mortality rates remain high, with
only about 50% of patients surviving more than 5 years
after diagnosis [
]. Fortunately, recent clinical studies of
ivabradine and sacubitril/valsartan suggest that, for the first
time in more than a decade, patient outcomes for HF could
be further improved. These new therapies were tested in
patients with apparently stable HF, who often experience
subclinical disease progression in the absence of symptoms
or signs of decompensation. Data from these trials
underscore the fact that the apparently stable patient with chronic
HF remains at increased risk of asymptomatic progression
of HF, death, and hospitalization. However, we now have
new therapies that have been shown to be particularly
beneficial for such patients.
In conclusion, physicians need to stay informed about
advances in HF treatment and strive to improve HF
management strategies for their patients. Early therapeutic
intervention with aggressive uptitration of GDEM is
important to reduce poor outcomes, and new therapies are
likely to prevent disease progression. Physicians must also
stay engaged with patients to identify subtle signs of
disease progression and maintain an open dialogue with
patients to ensure their needs are being met.
Compliance with Ethical Standards
Funding Technical assistance with editing and styling of the
manuscript for submission was provided by Oxford PharmaGenesis
Inc., Newtown, Pennsylvania, USA, and was funded by Novartis
Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Conflict of interest The author was fully responsible for all content
and editorial decisions and received no financial support or other
form of compensation related to the development of this manuscript.
Dr. Anand is a consultant to, and has received honoraria from, Amgen,
Arca, AstraZeneca, Boehringer Ingelheim, Cyberonics, and Zensun.
Statement of human and animal rights This article does not
contain any studies with human participants performed by the author.
Open Access This article is distributed under the terms of the
Creative Commons Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits any noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons
license, and indicate if changes were made.
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