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Advances in Management of Heart Failure
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Advances in management of heart failure
Paul Heidenreich," Alexander Sandhu?”
checktorvndates] (ABSTRACT
“Diparimentormedane, ——
Heart failure is increasing in prevalence in many countries with aging populations.
‘stanford University School of Fortunately, remarkable scientific advances have been made in the past few years
Medicine, Pao al, A 94306,
us that have led to new treatments and improved prognosis for patients with heart
yA Pao ate Heath Cte
System, Pao, CA USA
failure. This review examines these changes with a focus on the diagnosis and
Comespondence to: medical management of heart failure. The changes include the increase to four
Pligerretch
hoiden@stanford eds
foundational drug classes (pillars of therapy) now recommended for patients
ctotisasenzo2sesx07705 | with heart failure and reduced left ventricular ejection fraction, use of sodium-
Inpeidedovorgf20.11367
tmvosyorreos glucose cotransporter-2 inhibitors for those with a higher ejection fraction, and
sereserpianaton-sateorme | the importance of rapid initiation of life prolonging therapies once a diagnosis of
‘rt Reviews ate commision
Micheswismece: — | heart failure has been made, Device management and other non-drug management
(oacademics and apecalats
‘ne US and intemationly
have also evolved with the publication of new clinical trials. The review emphasizes
Fortnsressonthey zewntten | eyidence published since the recent heart failure guidelines of the European Society
presoninnty by thos.
of Cardiology and American College of Cardiology /American Heart Association/
Heart Failure Society of America in 2021 and 2022. Additional studies are needed to
determine how best to implement these new interventions in clinical practice.
Introduction
Heart failure is a common and growing health
and economic burden for many of the world's
communities. This growth 1s pronounced in
societies with aging populations. Advances in heart
failure care have been dramatic over recent years,
including new drugs, devices, and diagnostic care
stratogies. Clinical guidelines published within
the past few years have included many of these
changes, but even these recent guidelines are
already out of date in their recommendations for
treatment and diagnosis. In light of this rapidly
changing scientific evidence base, we provide an
up-to-date review of the most important aspects of
heart failure care,
Sources and selection criteria
We searched PubMed and the Cochrane Database
of Systematic reviews for articles published
between January 2015 and 7 july 2023 to identify
new randomized controlled trials (RCTs) and
large cohort studies of treatments and diagnostic
strategies for heart failure. We also identified
epidemiologic studies published from 2020 to
2023, We included older studies to provide context.
‘We focused on studies not included in the recent
European Society of Cardiology (ESC) and American
College of Cardiology/American Heart Association/
Heart Failure Society of America (ACC/AHA/HFSA)
guidelines from 2021 and 2022."* We prioritized
RCTS over observational data when reviewing
interventions. We did not consider case reports or
case series in our review.
hob 814/2024385.0077025 | doi: 10 136/bmi 2023.077025
Epidemiology
‘The Global Burden of Disease Study estimated that
57 million people were ling with heart fallure in
2019." although this number has been increasing
jn countries with aging populations, the age
standardized rate has fallen from 7.7 per 1000 in
2010 to 7.1 per 1000 in 2019.* The change over
lume in the age adjusted provalence from 2009 10
2019 (an average 0.3% decline por year during this
Period) nas not been linear, with rates initially falling
Dut then increasing by 0.6% per year between 2016
and 2019.°* The reason for this change in prevalence
4s unclear and requires further investigation. An
Increase in hospital admissions for heat failure has
been noted for young adults (age 18-45) in the US,
with rates increasing from 1.8 per 10000 in 2013 10
2.5 per 10000in 2018.7
Large differences in prevalence are noted across
slobal regions for both men and women (ig 1)."* The
region with the highest prevalence of heart faire
includes the high income countries of North America,
and the lowest prevalence was in central Asta. An
estimated 39% of the US population will have heart
failure by 2030:"The largest declines in age adjusted
rates were noted in high income countries of North
‘America and Australasia regions.
Survival
Survival following a diagnosis of heart failure is
poor and is highly influenced by age. In the UK,
survival approaches 80% at five years for people
aged 45-64 but is closer to 20% at five years for
those aged 285." Fortunately, survival rates have
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Fig 1 Country specific, age adlusted prevalence of hear fallure from 1990 t0 2019 In men (tp) and women (bottom).
Estimates are trom the Global Burden of Disease Study"*
Improved since 2000, particularly among younger
patients.”
‘Although overall survival isan important outcome,
it reflects the combined effects of all the patient's
conditions. The incremental impact of heart failure
on survival is difficult to discern, as most patients
with heart failure have multiple comorbidities. Years
of life lost due to heart failure can be estimated by
examining survival relative to actuarial estimates of
life expectancy. Data from the UK have shown that
heart fallure is associated with a 2.4-fold greater loss
oftimealive than observed in the ageandsexmatched.
general population over 10 years." Length of life lost
with heart failure varies from five months (women)
to one year (men) for people with no comorbidities
and from three years (women) to 4.5 years (men) for
‘those with three or more comorbidities."
‘The impact of covid-19 on the incidence of heatt
failure is uncertain but may be substantial. Studies
from the US Veterans Affairs healthcare system
hhave suggested that covid-19 is associated with an
increased risk of cardiovascular events including
death, myocardial infarction, and stroke."
Prevention, screening, and identification of heat failure
Heart failure can be largely prevented or delayed.
‘with optimal contol of risk factors." Uncontrolled
hypertension remains the most common risk factor
for incident hear failure.""™* Optimal blood pressure
control is associated with a 4096 reduction in heart
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failure events,” and multiple therapies for comorbid
conditions reduce the risk of progression to heart
failure including sodium-glucose cotransporter-2
(SGLT2) inhibitors, which reduce the risk of incident
heart failure in patients with diabetes mellitus."*'*
‘Among patients with chronic kidney disease, both
SGLT2 inhibitors. and finerenone (in those with
diabetes) reduce the risk of incident heart failure."
Several clinical risk models can identify patients
at high risk for progression 0 heart failure.”
Concentrations of natriuretic peptide (B-type
natriuretic peptide (BNP) of N-terminal proBNP (NT-
roBNP)) are also elevated among patients at high
risk of incident heart failure or asymptomatic systolic
dysfunction.“"*” In the STOP-HF (St Vincent's
Screening to Prevent Heart Failure) study, patients
with a cardiovascular risk factor were screened using
BNP. Patients with elevated concentrations had
echocardiography and collaborative cardiology and
primaty cate management. This led toa reduction in
subsequent left ventricular systolic dysfunction and
emergency hospital admissions for cardiovascular
reasons.” Similar results were confirmed in a trial
among patients with diabetes mellitus.” Since these
trials, aditional treatment options are now available
to prevent incident heart failure among people at
high risk"? Expanding natriuretic peptide screening
could lead to earlier diagnosis and treatment,
substantially reducing the morbidity of heart failure,
Given that heart failure isa progressive condition
with high early morbidity, prompt recognition is,
critical. In the UK, more than 8096 of first diagnoses,
of heart failure are made in the hospital, and more
Sepa 409% require additional evidence of increased
filling pressures (at rest or wit exercise) to establish
a diagnosis of near failure.
Diagnosis of HFDEF
‘The diagnosis of HFDEF is particularly challenging,
as determining increased filling pressure can be
dificult. Most definitions of HFPEF exclude patients
with heart failure symptoms due to valve disease,
arhythmia, pericardial constraint, or high cardiac
output. Although invasive testing with cardiac
catheterization is the gold standard for determining
elevated left ventricular filling pressures, the
diagnosis can be made non-invasively. Unfortunately,
no single non-invasive test result has both a high
sensitivity and a high specificity (fig 2)
‘Accordingly, clinical scores have been created
using the results from multiple tests to diagnose
HEDEE. These include H2FPEF (Heavy, 2 of more
Hypertensive drugs, atrial Fibrillation, Pulmonary
hypertension (pulmonary artery systolic pressure>35
‘mim Hig), Elderage>60, elevated Filling pressures, E/e?
29)” and HFA-PEFF (Heart Failure Association—Pre-
test assessment; Echocardiography and natriuretic
peptide score; Functional testing; Final etiology)” A
recent evaluation found that these two scores have
similar prognostic value, although 28% of patients
had discordant findings (HFEF diagnosed by only
one ofthe algorithms).
ethaps as important as making the diagnosis of
hear failure is determining whether the patient will,
benefit from therapy for HEDEF. Thus, clinicians
can use the entollment criteria from clinica trials.
showing benefit to make a diagnosis of HFDEF. The
{wo clinical trials of SGLT2 inhibitors that showed
benefit for patients with HEpEF used the following
enrollment criteria: New York Heart Association
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g/m iftral brillation), and evidence of structural
heart disease (left atrial enlargement, left ventricular
hypertrophy), in the Dapaglilozin Evaluation to
Improve the Lives of Patients with Presarved Ejection
Fraction Heart Failure (DELIVER) trial, or a recent
hospital admission for heart failure.”
Determining the cause of heart failure
Determining the underlying cause of heart fare
symptoms Is an important second stop after
making a diagnosis, as some conditions have
specific treatments.’ > Additional testing beyond
echocardiography is often needed, and although
routine screening with cardiac magnetic resonance
(CMR) imaging is not clearly beneficial, selected
use of CME offen provides useful information. The
patterns oflate gadolinium enhancement and certain
TH and T2 techniques may suggest a diagnosis of
rnoncompaction, myocarditis, or Chagas discase,
as well as infiltrative cardiomyopathies including
amyloidosis. iron overload, sarcoidosis, and Fabry
discase.* * Patients with ‘dilated cardiomyopathy
and those with significant hypertrophy on
echocardiography may be most likely to benefit from
cor,
Four medication pilars of HFEF therapy
For patients with heart failure and a reduced left
ventricular election fraction to <40% (HFEF), fout
classes of drugs are now known toimprove survival?
These are renin-angiotensin system inhibitors
including angiotensin converting enzyme (ACE)
Inhibitors and angiotensin receptor blockers (ARBs)
orangiotensin receptor/neprilysin inhibitors (ARNT);
8 blockers; mineralocorucoid recoptor antagonists
(O4RAS}; and SGLT2 inhibitors (table 1; fig 3). Using
the relative risk reduction from the clinical trials, it
hhas been estimated thatthe combination of the four
pillars of HFYEF therapy will lead to a 7396 relative
risk reduction in mortality and a number needed to
tweat of four to prevent a death compared with no
treatment?
ARNI
The combination of an ARB and a neprilysin
inhibitor is now recommended as one of the pillars
of HFYEF therapy. The PARADIGM-HF (Prospective
‘Comparison of ARN Inhibitors with ACE Inhibitors to
Determine Impact on Global Mortality and Morbidity
Jn HF) tial randomized 8442 patients with HFYER
1t found a 20%6 reduction in cardiovascular death or
admission to hospital for hear failure with sacubiteil
and valsartan compared with enalapril (hazard
ratio 0.80, 95% confidence interval 0.73 100.87):
Sacubinilvalsartan was also associated with
significant reduction in symptoms, a8 measured by
the Kansas City Cardiomyopathy Clinical Summary
Score (hazard ratio 1.64, 0.63 t0 2.65). A second
CT was conducted in patients admitted to hospital
With heart failure (PIONEER-HES8: Comparison
of SacubitrlValsartan vs Enalapril on Effect of
N-terminal Pro-Brain Natriuretic Peptide [NT-
pro8NP) in Patients Stabilized From an Acute HF
Episode).* This tral in 881 patients showed a
reduction in NF-proBNP concentrations (ratio of
change 0.71, 9596 confidence interval 0.63 to 0.81)
for patients starting sacubitrilwalsartan during
hospital admission compared with those treated with
enalapril. Safety was also demonstrated, with no
significant differences in worsening renal function,
hyperkalemia, and symptomatic hypotension. The
2022 US Heatt Failure Guideline now recommends
ARNT as the fist line agent with ACE inhibitor or ARB
alone for patents unable to take ARN.” Use of ARNI
along with an ACE inhibitors contraindicated.
‘No benefit with ARNI was observed for patients
with advanced heart failure defined as NYHA class
IV symptoms or patients taking chronic inotropic
therapy.” The LIFE (LC2696 in Advanced HF) study
randomized 335 patients with advanced hear failure
and found that after 24 weeks of treatment, changes
Jn NEpCOBNP were not cleariy different’ between
Patient treated with sacubitnil/valsartan and those
treated with valsartan alone (ratio of change 0:95,
0.8410 1.08),
SGLT2 inhibitors
This new class of drugs (Sodium-glucose
cotransporter-2 inhibitors) was originally designed
to improve glycemic regulation in diabetes but was
found to also improve cardiac outcomes, including
the prevention of heart failure. Subsequent trials in
patients with reduced LVEF have consistently shown
a significant reduction in hospital admissions due to
heart failure, with soveral also showing a reduction
in cardiovascular mortalty."* Accordingly, this class
(for example, dapagiffozin and empagiiiozin) is
now one of the four pillars of HFEF therapy.
Sotaglilozin is @ combined SGLT1 and SGLT2
Inhibitor, and whether it should be placed inthe same
Tablet [Life prolonging medications Tor hear falure with reduced left ventricular election fracton™
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Edema despite escalating dretics
systole BP 90, rign heart rote
: Prognostic mecizston
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‘Sountivation
Fig 3 | Schemat
pressure; CRT=cardiacresynchronization therapy
branch block: MRA=mineralocorticoid receptor antagonist; NYH
cotransporter 2 inhibitor; TEERetranscatheter edge-to-edge repalr
ection fraction; HF=heart allure; ICO=Implantable cardiac defibrillator; LBBB=let bundle
lew York Heart Association; PA=pulmonary artery; SGLIZI=sodlum glucose linked
class as purer SGLT? inhibitors is unclear. ina study
in 1222 pationts with diabotes and recent hospital
admission for heart failure, initiation of sotaglflozin
before or shortly after discharge reduced death from
cardiovascular causes and hospital admissions and
"urgent visits for heart failure compared with placebo
(hazard ratio 0.67, 0.52 1 0.84). A second study
randomized 10584 patients with diabetes. and
renal dysfunction, 20% of whom had hear failure,
to sotaglilozin or placebo. The combined encipoint
of cardiovascular death, hospital admission for
heart failure, and urgent visits for heart fallure was
reduced by sotagliflzin, with similar effects for
patients with and without heart fatlure (hazard ratio
0.74, 0.63 to 0.88)" The 2021 ESC guideline has
grouped sotagliflozin with the SGLT2 inhibitors in
its recommendations for patients with heart failure
and diabetes.” The drug was only recently approved
in the US and thus was not eligible for inclusion in
the ACC/AHA/HFSA 2022 guideline *
Importance of rapid initiation of therapy
‘The importance of rapid initiation of life prolonging
hhcart failure medication is now recognized owing to
results from the Safety, Tolerability and Etficacy of
Rapid Optimization, Helped by NT-proBNP Testing,
of Heart Failure Therapies (STRONG-HF) ‘twial.”*
This multicenter study with 1078 patients from
87 hospitals in. 14 countries examined rapid up-
titration of guideline directed medication after an
hob 814/2024385.0077025 | doi: 10 136/bmi 2023.077025
admission for acute heart failure. The intervention,
group had their medications up-titrated to 100% of
recommended doses within two weeks of discharge.
‘The primary endpoint of 180 day readmission to
hospital due to heart failure or all cause death was
reduced by an absolute percentage of 8.1% (95%
confidence interval 2.9% to 13.296) with, rapid
titration, We note that the STRONG-HF trial was
conducted before SGLT2 inhibitors became standard.
of car for HFEF therapy.
Further evidence of the benefit of rapid initiation
comes from the Dapaglifozin and Prevention of
‘Adverse Outcomes in Heart Failure (DAPA-HF) tral.”
‘Among 4744 patients in this trial, the time to clinical
Dene was surprisingly fast with a significant
reduction in cardiovascular death or worsening heart
failure observed by 28 days after randomization
to dapagliflozin compared with placebo (hazard
ratio 0.51, 95% confidence interval 0.28 to 0.94).
Similary, in 1222 patients treated with sotaghfiozin,
compared with placebo,” the time toasustained and
significant reduction in the primary endpoint was 27
days (hazard ratio 9.62, 0.39 t0 0.99). However, the
time to benefit was twice as long for patients with,
hear failure and preserved ejection fracion.”*
‘Although the goal isto initiate all four drug classes
ina timely manner, the optimal order and timing of
initiation remains controversial. Investigators have
modeled the potential benefit of different strategies
based on how quickly benefits were observed in
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Continued HFVBF treatments are recommended for
patients whose LVEF improves, although whether
ose escalation or additional medications are
beneficial once sympioms have resolved and LVEF
has improved remains uncertain. In rare cases,
withdrawal of therapy will succeed without relapse
of heart failure. These patients with truly recovered
LVEF include those whose cardiomyopathy is the
result ofa toxin, tachycardia, or other insult that has
deen eliminated. Unfortunately, being certain of the
cause of cardiomyopathy is often dificult, and any
attempt at withdrawal should be gradual with elose
follow-up and should be done only in selected cases
Jn which heart fallure has a specific and reversible
“Treatment of HFmrEF and HFpEF
Asnoted above, an LVEF of 41-4936 is mildly reduced.
(HFMEEF) whereas patients with an LVEF 250%
are considered to have preserved ejection fraction,
(HEPEF). These labels apply only to patients who
hhave not previously had an LVEF <40% (these are
referred to as heart failure with Improved ejection,
fraction). SGLT2 inhibitors are recommended as the
first line medication for patients with mildly reduced.
or preserved LVEF on the basis of the two tials that
enrolled many patients with an LVEF >409%.””
Of the other treatments for HFEF, ARNI, ACE
inhibitors, ARBs, and MRAs are second line
therapies as the evidence for benefit is much
‘weaker than for patients with HFYEF. Accordingly,
MRAS and ACE inhibitors/ARBS/ARNI have a class
2B recommendation for HEmtEF and HEDEF in
guidelines for patients with mildly reduced or
preserved LVEF?
Of note, 6 blockers are not recommended for
patients with HEpEF (2B recommendation for
HmrEF)? Lack of benefit for HFpEF was noted in
2 meta-analysis of randomized trials of f blockers,
‘which reported a non-significant trend toward
increased cardiovascular and. all cause mortality
in patients with preserved LVEF and sinus rhythm.
(hazard ratio 1.70, 0.78 to 4.10).
LVEF and benefit of medical therapy
LVEF can be difficult to quantify with
echocardiography, but it has been routinely used t0
dotermine eligibility for clinical trials in heart failure.
Given the growing evidence for treatment benefit in
patients with higher LVEF levels, some authors have
questioned the continued use of the LVEF to classify
patients with heart failure. Multiple drug therapies
hhave been tested across the ejection fraction
spectrum: f blockers, ACE inhibitors/ARBs, ARNI,
MBAS, and SGLT2 inhibitors, Traditionally, trials
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24096. However, most therapies have shown abeneft
at higher thresholds than the traditional cutoff of
reduced LVEF at 40%. For P blockers, a reduction
in cardiovascular mortality was abserved with LVEF
<50y4** For MRA therapy, alargertteatmentbenefitis
‘more likely for patients with LVEF 41-49% than with
LVEF 25074" The teatment benefit of sacubiti/
valsartan was observed with LVEF <6096," For SGLT2
Inhibitor therapy, the relauve treatment effect was
similar across the LVEF spectrum." Overall, these
results suggest that the LVEF threshold for systolic
dysfunction used in treatment ils may benefit from
reclassification but that LVEF will remain important
for determining optimal management.
‘The association of LVEF with the benefit of early
initiation and titration was evaluated in a sub-study
of the STRONG-HF trial This study showed the
consistency of the rapid implementation of guideline
based! medical therapy across the entire spectrum of
LVEF after an admission for heart failure.
Other drug treatments,
Several additional medications can be used 10
improve outcomes among patients with HEE
This section discusses soveral of these therapies:
hydralazine isosorbidedinitrate therapy, ivabradine,
vericiguat, intravenous iron, and glucagon-like
peptide-1" receptor agonists. We discuss their
evidence and contemporary role.
‘SQLT2 inhibitors
1 DELIVER ta conrmed benef of SGLT2 inhibitors for
patents wth HF and HFSEF
1 Sotaaiozin approved for HF teatmentin US
ARN for HFDEF
1 Pooled PARAGLIDE-HF ang PARAGON tle snow tat
‘ARNT reduces worsening HF everts and CV death in
patents with HF =7/HFSEF
Intravenous iron for HFEF
1 Meta-analyses of intravenous ton find reduction in
hospital admissions for HF and improved HROOL,
Diuretic therapy
1 Acunetve resis wih acetalozarie Improved
fig Ny" Woy PepEOLUNOR “FZOZ IMdY 0} UO 40%,” the
STRONG-HF tral showing benefit of rapid initiation
and titration of medications for those with HEYER,"”
and a trial showing that pulmonary pressure
‘monitoring using the CardioMEMS device improved
outcome.” Future guidelines will likely incorporate
hob 814/2024385.0077025 | doi: 10 136/bmi 2023.077025
the trial results into revised recommendations. Figure
4 shows. summary of new evidence published since
the 2022 ACC/AHA/HFSA and 2021 ESC hear failure
guidelines." An update to the 2021 ESC guideline
was recently published,” and this incorporates new
clinical trials of SGLT2 inhibitors, finerenone, and.
Intravenous iron therapy.
Emerging treatments
Continued progress in treatment remains critical
given the residual morbidity for patients with heart
failure, Omecamtiv mecarbil is a cardiac myosin
activator that improves cardiac contractility. In the
GALACTIC-HF (Global Approach to Lowering Adverse
Cardiac Outcomes through improving Contractility
in Heart Failure) trial, 8258 pationts with HFEF
who received omecamtiv mecarbil showed an
{8% relative reduction (0.92, 0.86 to 0.99) in the
risk of cardiovascular death or heart failure event
(hospital admission or urgent vist) The benefit
was driven by the difference in heart failure events.
Multiple secondary analyses have illustrated larger
therapeutic benefit among patients with more severe
hear failure based on LVEF, systolic blood pressure,
NYHA class, ornatriureticpeptides."”?"”* Omecamtiv
rmecarbil is not avaiable as it was denied approval
by the US Food and Drug Administration and is still
pursuing approval in Europe.
Several trials will help to clarify the role of existing
hear failure therapies. The VICTOR trial is evaluating
the efficacy of vericiguat among patients with heart
failure who have not had a recent worsening heart
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