Series
Heart failure 1
Lancet 2019; 393: 1034–44
This is the first in a Series of
three papers on heart failure
Centre d’Investigations
Cliniques Plurithématique
1433, Université de Lorraine,
Institut National de la Santé et
de la Recherche Médicale
(Inserm), Centre Hospitalier
Régional Universitaire (CHRU)
de Nancy, Inserm U1116, and
French Clinical Research
Network, Investigation
Network Initiative-
Cardiovascular and Renal
Clinical Trialists (FCRIN
INI-CRCT), Nancy, France
(Prof P Rossignol MD,
F Zannad, MD); Department of
Medicine, Division of
Cardiology, Duke University
Medical Center, Durham,
North Carolina, NC, USA
(A F Hernandez MD); and
Cardiovascular Division,
Brigham and Women’s
Hospital, Boston,
Massachusetts, MA, USA
(S D Solomon MD)
Correspondence to:
Prof Patrick Rossignol, Centre
d’Investigations Cliniques, CHRU
de Nancy,
54500 Vandoeuvre-lès-Nancy,
France
p.rossignol@chru-nancy.fr
1034 www.thelancet.com Vol 393 March 9, 2019
Heart failure drug treatment
Patrick Rossignol, Adrian F Hernandez, Scott D Solomon, Faiez Zannad
Heart failure is the most common cardiovascular reason for hospital admission for people older than 60 years of age.
Few areas in medicine have progressed as remarkably as heart failure treatment over the past three decades. However,
progress has been consistent only for chronic heart failure with reduced ejection fraction. In acutely decompensated
heart failure and heart failure with preserved ejection fraction, none of the treatments tested to date have been
definitively proven to improve survival. Delaying or preventing heart failure has become increasingly important in
patients who are prone to heart failure. The prevention of worsening chronic heart failure and hospitalisations for
acute decompensation is also of great importance. The objective of this Series paper is to provide a concise and
practical summary of the available drug treatments for heart failure. We support the implementation of the
international guidelines. We offer views on the basis of our personal experience in research areas that have insufficient
evidence. The best possible evidence-based drug treatment (including inhibitors of the renin–angiotensin–aldosterone
system and β blockers) is useful only when optimally implemented. However, implementation might be challenging.
We believe that disease management programmes can be helpful in providing a multidisciplinary, holistic approach
to the delivery of optimal medical care.
Introduction estimated 6-month mortality of 17·8%. The International
Heart failure is the most common cardiovascular reason Congestive Heart Failure study13 representing Africa,
for hospital admission among individuals older than China, India, the Middle East, southeast Asia, and South
60 years of age.1 The prevalence of heart failure is increasing America, reported an overall 1-year mortality of 16·5%,
worldwide because of an increasing incidence related to with substantial variation by region (34% in Africa,
population ageing, rising prevalence of poorly controlled 23% in India, 15% in southeast Asia, 9% in South America,
risk factors (ie, hypertension, diabetes, and obesity), and 9% in the Middle East, and 7% in China).
prolonged survival of patients with heart failure due to
implementation of evidence-based treatments.2
Heart failure is a clinical syndrome characterised by NYHA classification
fatigue and dyspnoea, induced by left (or global) ventricular Class III: marked limitation of Class II: slight limitation of
dysfunction, often with signs of congestion. The New York physical activity; comfortable physical activity; comfortable at
Heart Association (NYHA) classification is used to describe at rest, but less than ordinary rest, but ordinary physical
activity causes symptoms of activity results in symptoms of
symptom severity (figure and panel 1). Heart failure carries heart failure heart failure
a poor prognosis; 30 day all-cause readmission rates of
19% have been reported in the USA.9 1-year all-cause Class IV: unable to carry on any Class I: no limitation of physical
mortality for patients with acute heart failure was 17% and physical activity without activity; ordinary physical
symptoms of heart failure, or activity does not cause
stable or ambulatory was 7%, and 12-month hospitalisation symptoms of heart failure at symptoms of heart failure
rates were 44% for patients who were readmitted to rest
hospital and 32% for patients receiving ambulatory care, in
ACC/AHA stage D: refractory ACC/AHA stage C: structural
observational data from Europe.10 Similar data have been heart failure requiring specialised heart disease with previous or
reported in the Asian Sudden Cardiac Death in Heart interventions current symptoms of heart
failure
Failure registry, showing that 19·2% of patients died or
were hospitalised for heart failure within 1 year.11 The Sub- Heart failure with reduced
Saharan Africa Survey of Heart Failure12 reported an ejection fraction (≤40%) or
preserved ejection fraction
Search strategy and selection criteria
We searched MEDLINE and PubMed (search terms: “heart ACC/AHA stage A: at high risk for ACC/AHA stage B: structural
heart failure but without structural heart disease but without signs
failure”, “reduced ejection fraction”, “preserved ejection heart disease or symptoms of heart or symptoms of heart failure
fraction”, “medical therapeutics”, randomised trials”, failure
“pathophysiology”, and “epidemiology”) and references from
relevant articles published in English, in addition to the most Figure: Heart failure presentation at a glance, depicting the spectrum of
recent European Society of Cardiology, and American College heart failure patient population presentation
of Cardiology and American Heart Association guidelines. ACC/AHA=American College of Cardiology and the American Heart Association.
NYHA=New York Heart Association.

For most patients, abnormalities of systolic and
diastolic function coexist, irrespective of the ejection
fraction, which was the most used classifier in clinical
trials to define either heart failure with reduced ejection
fraction (HFrEF) if this parameter is less than 40%, or
heart failure with preserved ejection fraction (HFpEF).
In a European survey, mortality at 1 year was
8·8% for HFrEF and 6·3% for HFpEF.14 The HFrEF
subtype appears to be the most well studied, yielding a
robust body of evidence to support clinical practice
guidelines.4,5
The objective of this Series paper is to provide a concise
and practical summary of the drug treatments available
for heart failure. We support the implementation of the
available international guidelines. These guidelines can
differ in some respects and we offer views on the basis of
our personal expertise when persistent gaps in evidence
exist.
We also identified the priorities for future research in
terms of unmet needs and evidence gaps.
Diuretic and sodium management
Regardless of ejection fraction, heart failure symptoms are
mostly related to congestion,15 which is one of the main
predictors of poor patient outcome.6 Despite no large
randomised outcome trials, loop diuretics are strongly
recommended (grade 1)4,5 for decongestion, albeit with less
evidence (B4 or C5) by the European Society of Cardiology
(ESC) and the American College of Cardiology and
American Heart Association guidelines to improve
symptoms in chronic and acutely decompensated heart
failure.
Diuretic dosing is largely empiric and should be titrated
according to the decongestion target. The use of
inappropriately low doses of diuretics can result in
persistent congestion. Conversely, the use of in-​
appropriately high doses of loop diuretics can trigger
hypokalaemia and hypovolaemia with a related risk of
hypotension and deterioration of renal function,5 which
can lead to down-titration of life-saving drugs (ir, the
inhibitors of the renin–angiotensin–aldosterone system
[RAAS]). Further­ more, this overdosing can further
stimulate RAAS, which can worsen heart failure. Once
optimal decongestion has been achieved, the lowest dose
that maintains euvolaemia should be prescribed and
some heart failure treatment centres should educate
appropriately selected patients to manage symptoms with
diuretics as needed. These patients might be those not
requiring daily diuretic who can be educated to follow the
strategy and will contact clinical staff quickly if symptoms
worsen, although this strategy has not been well studied.
However, deter­ mination of optimal decongestion and
early detection of a recurrent congestion is challenging.
Although numerous clinical scores, imaging and haemo­
dynamic tools, and biological tests are available to assist
physicians in ascertaining and quantifying congestion,
not all are appropriate for use along the course of the
www.thelancet.com Vol 393 March 9, 2019 1035
Series
Panel 1: Heart failure presentation
• Patients at high risk for heart failure (ie, those with hypertension, diabetes,
atherosclerotic disease, or obesity) but without structural heart disease or heart failure
symptoms are considered stage A in the development of heart failure.3
• Stage B describes the development of asymptomatic structural heart disease
(ie, previous myocardial infarction, left ventricular remodelling, left ventricular
hypertrophy, reduced ejection fraction, or asymptomatic valvular disease).3
• Stage C heart failure reflects symptomatic patients who should receive optimal
medical therapy unless contraindicated.3–5 Symptoms are non-specific and dominated
by shortness of breath and fatigue, leading to reduced functional capacity assessed by
clinical scores (New York Heart Association classification I to IV) and 6-min walk
distance or other ergometric tests. The most common signs of heart failure are related
to congestion, whether vascular or interstitial, pulmonary congestion (eg, rales and
pleural effusion), or peripheral congestion (eg, leg oedema, jugular vein dilatation,
and, in more severe cases, liver enlargement and ascites). Stage C patients may be
relatively stable on guideline-directed medical therapy, but ultimately progression of
the disease is marked by episodes of acute decompensation, which can be precipitated
by several cardiovascular and non-cardiovascular factors.
• Acute decompensation is accompanied by distressing symptoms of congestion and
the potential for end-organ (ie, heart, liver, and kidney) damage.6 Hospitalisation for
heart failure has a poor prognosis. Among patients with heart failure hospitalised in
the USA from 2008 to 2010, 67·4% were readmitted and 35·8% died within 1 year of
the index hospitalisation.7 Data from Europe show consistent results.8
• Patients with refractory symptoms are considered Stage D, despite optimal
implementation of best medical care.3 These patients should be considered for
additional interventions (eg, mechanical circulatory support and transplant
evaluation), but these therapies are beyond the scope of this Series.
disease (eg, weight loss scoring lacks sensitivity) and
across all settings of patient presentations (pre-admission
to hospital, admission to the emergency department, in-
hospital management, and discharge and continued
monitoring in the community).6 Medical imaging
(ie, chest x-ray, and B-mode lung ultrasound, inferior
vena cava, and other echocardiography measures) might
be helpful.16 Clinical trials of chronic optimisation of
therapy guided by natriuretic peptide concentrations have
led to conflicting results.17,18
Diuretic resistance can occur in most patients with
severe heart failure. In this clinical setting, specific
pharmacological algorithms encompassing loop diuretic
dose adjustments, inotropes, and the addition of thiazide-
like diuretics can be proposed as an alternative to
extracorporeal ultrafiltration in patients treated in
hospital, whereas none of the approaches showed efficacy
in outcome trials.19 Neurohormonal imbalances created
by heart failure lead to an inability to excrete sodium and
water. Therefore, conventional advice has been to restrict
sodium and fluid intake.20 Major heart failure guidelines
have not reached a consensus on recommendations
for dietary sodium (and fluid) restriction. Four trials
(NCT02467296, NCT02148679, NCT01733017, and
NCT02012179) investigating sodium restriction in heart
failure are in progress, including one large trial
evaluating clinical outcome endpoints.21
 Series
Altogether, we believe in the possibility that detection,
dynamic monitoring, and management of congestion
and decongestion could help to improve heart failure
management. However, we acknowledge that evidence
from robust randomised outcome trials is missing.
One possible exception is a single trial that uses a remote
monitoring of pulmonary artery diastolic pressures with
an implanted device.22 In a randomised controlled trial
that enrolled more than 500 patients with heart failure,
monitoring and managing patients showed improved
clinical outcomes, including reduced hospitalisation for
heart failure. One limitation of the trial is that the control
group did not have a systematic form of disease
management, so whether the trial truly showed benefit
of the invasive technology over and above non-invasive
See Online for appendix disease management is questionable. In addition, the
reduction in the number of patients with the implanted
device admitted to hospital because of heart failure
appeared to be associated with increased use of diuretics
and vasodilators; to what extent this increase in doses
might have contributed to the improved outcomes
remains an open question.
Medical treatment of chronic heart failure with
reduced ejection fraction
The primary pathophysiological cardiac abnormalities in
HFrEF are cardiac chamber enlargement due to cardiac
remodelling, weak contraction (deficient inotropism),
elevated filling pressures (preload), and increased periph­
eral resistance (afterload), leading to an inability to provide
adequate cardiac output at rest or with exercise. These
elevated intracardiac pressures can also cause lung and
peripheral congestion. The number of myocytes and
their function decline, and they are replaced by myocardial
interstitial fibrosis, which stiffens the heart and creates the
anatomical substrate basis for lethal arrhythmias.
Increasingly the disease is viewed as a syndrome with
multiple systemic mechanisms, potentially involving
inflammation and disorders of neurohormonal systems
involving the RAAS, the autonomic nervous system, the
endothelium, the natriuretic peptide system, and the
vasopressin system. Other potential pathophysiological
mechanisms include elevated heart rate, atrial fibrillation,
abnormalities of ventricular–vascular coupling, and com­
plex cardiorenal interactions (ie, cardiorenal syndrome).23
Improved management of acute coronary syndromes
has resulted in less frequent progression to post-myo­
cardial infarction in patients with HFrEF.24 Non-
ischaemic causes account for up to 30% of cases of
HFrEF and include valvular heart disease,25–27 familial
cardiomyopathy, and secondary cardiomyopathies (eg,
inflammatory, cardiotoxic [alcohol or chemotherapy
induced], and infectious).
Treatment guidelines are based on robust evidence
stemming from well designed randomised outcome
trials.4,5 Inhibitors of the RAAS (ie, angiotensin-converting
enzyme inhibitors [ACEs], angiotensin receptor blockers,
1036 www.thelancet.com Vol 393 March 9, 2019
or mineralocorticoid-receptor antagonists [MRAs]), and
β blockers are strongly recommended in international
guidelines (class IA) for improving survival, decreasing
sudden death, and preventing heart failure hospitali­
sations.4 Based on the results of the PARADIGM HF trial,
sacubitril–valsartan is recommended to replace ACE
inhibitors to further reduce the risk of heart failure
hospitalisation and death in ambulatory patients
with HFrEF who remain symptomatic despite optimal
treatment. Unless contraindicated, all symptomatic
patients with HFrEF should receive these medications in
combination, preferably at target maximally tolerated
doses.4,28 The combined optimal use of these class IA
therapies in clinical trials has led to a decline in mortality
among patients with severe and mild-to-moderate cases
of HFrEF (appendix).29 Furthermore, a network meta-
analysis of 58 trials dominated by 15 large-scale trials
with a follow up of 1984–18 898 patient-years showed
that combining evidence-based drugs might produce
cumulative reduction in all-cause mortality up to 60%
and in all-cause hospitalisations with reductions up to
40%, on average. Concomitantly, in patients enrolled in
clinical trials, the annual rate of sudden cardiac death has
declined to less than 5%.30
International registry data showed that physician’s
adherence to guideline-recommended medications in
HFrEF was associated with improved outcomes.31 Un­
fortunately, available guidelines are not being optimally
implemented, both in terms of overall use and under­
dosing,32 most often because of excessive concern
about adverse events.10 Hypotension, hyperkalaemia, and
deterioration of renal function are the most frequently
cited reasons for underdosing, underuse, and dis­
continuation of RAAS inhibitors.10 In a large US database
of electronic health records (Humedica) including more
than 20 000 patients with heart failure, nearly 60% who
discontinued RAAS inhibitors after a hyperkalaemic
episode had an adverse outcome or mortality compared
with 52% of patients on these drugs at submaximal doses
and 44% with patients on maximum doses (all comparisons
p<0·05). Patients on submaximal dose or who discontinued
medication were twice as likely to die as patients on
maximum dose.33 β-blocker use might be hampered by
concerns about hypotension, fatigue, and bradycardia.
However, most of these adverse events are predictable,
reversible, and manageable. Most importantly, occurrence
of these events does not diminish survival benefits.34
Therefore, in our opinion, concerns about adverse events
might be excessive in some cases and might potentially
deprive patients of life-saving therapies. Hypotension if
symptomatic can often be managed by discontinuing
unnecessary vasodilators (eg, calcium channel antagonists,
α blockers, and nitrates), or by reducing diuretic doses to
the lowest dose that maintains euvolaemia, and ultimately
by staggering doses of RAAS inhibitors and β blockers.
Strategies to achieve optimal use of these therapies include
frequent monitoring (within 3 days of initiation or dose

adjustments and every 4 months once stable) of estimated
glomerular filtration rate, serum potassium, and blood
pressure; slow uptitration; and avoidance of other con­
comitant, non-essential, interacting drugs (eg, non-steroidal
anti-inflammatory drugs, potassium supple­ments, dietary
potassium, other blood pressure-lowering drugs, and
excessive diuretic doses). Down-titration of doses or
discontinuation of RAAS inhibitors can be considered
temporarily for persistent or severe hyper­ kalaemia,
hypotension, or deterioration of renal function. However,
this temporary discontinuation should not prevent
attempts at reinitiation or uptitration of therapy as soon as
safely possible. The use of potassium binders might
facilitate uptitration in patients prone to hyperkalaemia.35
Whether this treatment can prevent cardio­ vascular
outcome occurrence needs to be shown in a dedicated
outcome trial. Patients with HFrEF are increasingly older
(older than 80 years) and have multiple comorbidities.
Clinical trials have generally excluded patients with these
factors, and, as a result, their response to heart failure
therapy and the best approaches for managing comorbid
conditions and concomitant drug therapies that might
have pharmacodynamic or pharma­cokinetic interactions
with the heart failure regimen is less certain. However,
there is no evidence that such patients would not benefit
from standard heart failure therapy,36 and guidelines should
also be followed in these patients, with individual adjust­
ments in dose or monitoring as clinically indicated
according to comorbidity or interacting medications.
Ivabradine or digoxin prevent heart failure hospitali­
sation in patients with sinus rhythm, if the heart rate
remains above 75 beats per min after β-blocker
administration.4 β blockers and digoxin might help to
control ventricular response in patients with atrial
fibrillation, although benefits of this combined therapy
have not been shown. No consensus has been reached on
an optimal target heart rate in patients with atrial
fibrillation and heart failure, with recommended targets
varying between 60 beats per min and 110 beats
per min.4,37 Amiodarone is not preferred as first line for
heart rate control because of safety concerns. Rhythm
control by use of electrical or pharmacological conversion
could be considered to improve symptoms in patients
with persisting symptoms or signs of heart failure,
despite optimal medical therapy and adequate control of
ventricular rate. Anticoagulation, preferably with direct
oral anticoagulants, should be offered to patients with
heart failure and atrial fibrillation, recognising that
bleeding might be more frequent in these patients than
in those who do not have heart failure, since heart failure
is a component of the CHADS2VASC2 score.38
In the COMMANDER HF trial that enrolled patients
following a recent worsening of chronic HFrEF coronary
artery disease, and typical sinus rhythm, low dose
rivaroxaban did not significantly reduce risk of either the
primary composite outcome of all-cause mortality,
myocardial infarction, or stroke; all-cause mortality
www.thelancet.com Vol 393 March 9, 2019 1037
Series
alone; or the main secondary efficacy outcome of cardio­
vascular death and heart failure hospitalisation.39
Intravenous iron can be used for improving functional
capacity and quality of life in patients with iron deficiency
(serum ferritin<100 mg/L or ferritin between 100 mg/L
and 299 mg/L, and transferrin saturation <20%).4,40,41
However long-term data on the cardiovascular efficacy
and on safety are not yet available.
Medical treatment of heart failure with
preserved ejection fraction
First recognised in the 1980s and initially termed diastolic
heart failure, HFpEF accounts for approximately half of
all hospital admissions for heart failure, is associated with
substantial morbidity and mortality, and is increasing in
prevalence.42 The definition, pathophysiology, and causes
of HFpEF are controversial, but most guidelines agree
that the minimum requirements for the diagnosis of
HFpEF are signs and symptoms of heart failure and a
relatively preserved ejection fraction (ie, ejection fraction
more than 40%).4
Patients with HFpEF tend to be older than those with
HFrEF, and the prevalence of this disorder is increasing as
the population ages.43 Moreover, patients with HFpEF have
more comorbidities than those with HFrEF,44 including
hypertension, diabetes, atrial fibrillation, anaemia, and
chronic obstructive pulmonary disease. For example, a
randomised controlled trial comparing exercise only, diet
only, and combined exercise and diet with a control group
for 20 weeks, in 100 patients with HFpEF, with obesity, and
older than 60 years, showed that a calorie restriction diet or
aerobic exercise training increased peak oxygen con­
sumption.45 Increased adiposity also contributed to worse
NYHA functional class for HFpEF.46,47 The attributable
risk associated with these comorbidities increases with
increasing ejection fraction.48 The high prevalence of
comorbidities in HFpEF has contributed to the notion that
this condition might not exist as an independent entity,
but might simply be a collection of comorbidities. The
concept is countered by the substantially higher number
of events in patients with HFpEF than in patients with
these comorbidities but without heart failure.49 Although
ambulatory patients with HFpEF have substantially lower
morbidity and mortality than patients with HFrEF,50
subsequent hospitalisation and mortality in hospitalised
patients are similar for both conditions.51
Several clinical outcomes trials have been done for
patients with HFpEF yet none have met their primary
endpoint (table 1). All of these trials have so far assessed
inhibitors of the RAAS, either ACE inhibitors,53 angio­
tensin receptor blockers,52,54 or MRAs.55 In the CHARM-
Preserved trial,52 candesartan was associated with an
11% non-significant reduction in cardiovascular death or
heart failure hospitalisation, although post-hoc analyses
suggested a significant reduction in total hospitali­sations.57
The TOPCAT trial58 comparing spironolactone with
placebo, based on the success of MRAs in the treatment of
 Series

Number of Treatment Key inclusion criteria Primary endpoint Findings

patients groups
CHARM- 3023 Candesartan vs NYHA class II–IV, before cardiovascular-related hospitalisation Time until first composite of cardiovascular Primary outcome: HR 0·89
Preserved52 placebo death or heart failure hospitalisation (95% CI 0·77–1·03); p=0·12
PEP-CHF53 850 Perindopril vs Clinical diagnosis of diastolic heart failure with two or more of Time to first all-cause death or heart Primary outcome: HR 0·92
placebo the following symptoms: left atrial enlargement, left failure hospitalisation (95%CI 0·70–1·21); p=0·55
ventricular hypertrophy, impaired left ventricle filling, or atrial
fibrillation
I-PRESERVE54 4128 Irbesartan vs NYHA class II–IV and any corroborating evidence (eg, heart failure Time to first all-cause death or Primary outcome: HR 0·95
placebo sign); left ventricular hypertrophy or left atrial enlargement cardiovascular hospitalisation (95% CI 0·86–1·05); p=0·35
considered optional corroborating evidence; and heart failure
hospitalisation is required unless in NYHA class III–IV
TOPCAT55 3445 Spironolactone Signs and symptoms of heart failure, elevated natriuretic Time to first cardiovascular death, heart Primary outcome: HR 0·89
vs placebo peptide, or heart failure hospitalisation failure hospitalisation, or resuscitated (95% CI 0·77–1·04); p=0·14
sudden death
PARAGON-HF56 Approximately Sacubitril and NYHA class II–IV, elevated NT-proBNP (depending on timing of Cardiovascular death or total heart failure In progress and fully
4800 valsartan vs prior heart failure hospitalisation and atrial fibrillation status), hospitalisation (first and recurrent) recruited
valsartan alone and structural heart disease (left atrial enlargement or left
ventricular hypertrophy)
EMPEROR- Approximately Empaglifozin vs NYHA class II–IV heart failure; ejection fraction more than 40%; Time to first cardiovascular death or heart In progress and recruiting
Preserved 4126 placebo elevated NT-proBNP (depending on atrial fibrillation status); failure hospitalisation
(NCT03057951) structural heart disease (left atrial enlargement or left ventricular
hypertrophy); or documented heart failure hospitalisation
DELIVER 4700 Dapagliflozin vs NYHA class II–IV, elevated NT-proBNP (depending on atrial Cardiovascular death or heart failure In progress and recruiting
(NCT03619213) placebo fibrillation status), and structural heart disease (left atrial event
enlargement or left ventricular hypertrophy)
SPIRRIT 3500 Spironolactone Stable heart failure defined by symptoms and signs of heart Time to death from any cause In progress and recruiting
(NCT02901184) vs standard care failure as assessed by local doctor; left ventricular ejection (information on death from the Swedish
fraction ≥40% recorded in past 12 months; NT-proBNP Causes of death registry)
>300 ng/L in sinus rhythm or >750 ng/L in atrial fibrillation
before atrial discharge
SPIRIT-HF 1300 Spironolactone Heart failure with mid-range or moderately reduced ejection Death from cardiovascular cause or In progress and recruiting
(EudraCT 2017- vs placebo fraction (left ventricular ejection fraction 40–49 %) or with recurrent heart failure hospitalisations
000697-11) preserved ejection fraction (≥50 %) with evidence of impaired over the follow-up period since
left ventricular filling capabilities randomisation
CHARM=Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity. NYHA=New York Heart Association. HR=hazard ratio. PEP-CHF=Perindopril for Elderly People with Heart Failure.
I-PRESERVE=Irbesartan in Heart Failure with Preserved Ejection Fraction Study. TOPCAT=Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist. PARAGON-HF=Efficacy and
Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction. NT-proBNP=N-terminal B-type natriuretic peptide. EMPEROR=Empagliflozin
outcome trial in patients with chronic heart failure with reduced ejection fraction. SPIRIT(-HF)= SPIRonolactone In the Treatment (of Heart Failure).

Table 1: Completed and ongoing outcomes trials in heart failure with preserved ejection fraction

HFrEF and the possibility that myocardial fibrosis has a
role in the pathophysiology of HFpEF, did not meet its
primary endpoint, with an 11% non-significant reduction
in cardiovascular death or heart rate hospitalisation.
Nevertheless, after unblinding the trial, patients enrolled
in one specific region (Russia and Georgia) had a
substantially lower number of events than those enrolled
in the USA, Canada, Argentina, and Brazil, suggesting
that many patients in that region might not have had heart
failure.58 The 18% nominally significant risk reduction of
the primary outcome in the remaining regions has
encouraged some people to believe that, if properly tested,
spironolactone would improve outcomes in patients with
HFpEF.28
Therapeutic approaches other than RAAS inhibition
have been tested in patients with HFpEF, including
several that have targeted the nitric oxide pathway but did
not show any benefit.59–61 Despite data suggesting the
importance of cGMP in HFpEF and a relative reduction
in intracellular cGMP, the soluble guanylate cyclase
stimulator vericiguat was ineffective in lowering the
N-terminal pro B-type natriuretic peptide (NT-proBNP) or
improving left atrial size in patients with HFpEF.62
although significant improvements in measures for
quality of life were shown. However, data from cardio­
vascular outcome trials are few. In the only positive
primary outcome phase 2 trial in HFpEF, sacubitril–
valsartan increased the reduction of NT-proBNP
compared with valsartan alone and improved left atrial
size and NYHA class.63 These findings provided the
rationale for the PARAGON-HF (NCT01920711) outcomes
trial comparing sacubitril–valsartan to valsartan alone in
4822 patients with HFpEF.56 The results of EMPA-REG
and CANVAS provided the rationale for an outcomes trial
in HFpEF with empagliflozin, an SGLT2 inhibitor
(table 1).64,65 Finally, spironolactone for HFpEF is being
retested in two separate trials (NCT02901184 and SPIRIT-
HF [EudraCT 2017-000697-11]).
The paramount importance to rule out other causes of
symptoms is clear, including ischaemic heart disease,

1038 www.thelancet.com Vol 393 March 9, 2019


Number of Treatments
patients
GALACTIC HF 8000 Omecamtiv
(NCT02929329) mecarbil vs placebo
FAIR-HF2 1200 Intravenous iron (ferric
(NCT03036462) carboxymaltose) vs placebo haemoglobin concentrations of 9·5–14·0 g/dL
HEART-FID 3014 Ferric carboxymaltose vs
(NCT03037931) placebo
EMPEROR Reduced 2850 Empagliflozin vs placebo
(NCT03057977)
DAPA-HF 4500 Dapagliflozin vs placebo
(NCT03036124)
VICTORIA 4872 Vericiguat vs placebo
(NCT02861534)
BNP=B-type natriuretic peptide. NT-proBNP=N-terminal pro-B-type natriuretic peptide. NYHA=New York Heart Association. eGFR=estimated glomerular filtration rate.
Table 2: Ongoing heart failure with reduced ejection fraction outcome trials
overt lung disease, hypertrophic cardiomyopathy, or
infiltrative cardiomyopathies that could mimic signs and
symptoms of HFpEF but which might have specific
alternative therapies. In the absence of evidence-based
therapy, treatment of HFpEF remains empiric and is
based on management of symptoms and comorbidities.66
Although the benefits of diuretic use in HFpEF has not
been rigorously proven in clinical trials, treatment
of congestion with diuretics remains the mainstay of
therapy and appears to improve symptoms. Control of
ventricular rates in patients with atrial fibrillation is also
prudent, particularly because elevated heart rates are
associated with reduced ventricular filling time, but
whether rhythm control is beneficial in HFpEF remains
unclear. Finally, the US guidelines recommend con-​
sideration of spironolactone.28 Because of the challenges
and uncertainty in establishing a definitive diagnosis in
many cases, probability score-based diagnostic
algorithms have been proposed, in which patients are
assessed for the probability of having HFpEF based on
routine clinical and echocardiographic features.67
Acutely decompensated heart failure treatment
Acute heart failure is a common cause of hospitalisation
among individuals aged 65 years or older globally.68–71
These acute events are associated with poor short-term
and long-term prognosis in terms of survival and
rehospitalisation.72–75 The pathophysiology of acute heart
failure is multifactorial, with many potential precipitating
factors (eg, acute coronary syndrome, arrhythmia,
hypertension, renal impairment, infection, and non-
adherence), some of them (acute coronary syndrome or
infection) being associated with an increased mortality.76
www.thelancet.com Vol 393 March 9, 2019 1039
Series
Key inclusion criteria Primary endpoint
History of chronic heart failure, left ventricular ejection fraction ≤35%, Time to cardiovascular-related death or first
NYHA class II-IV, current hospitalisation for heart failure or within the heart failure event
previous year, and elevated BNP or NT-proBNP
Chronic heart failure, confirmed presence of iron deficiency, and serum Combined recurrent hospitalisations for heart
failure and cardiovascular-related death
Stable heart failure on maximum tolerated background therapy; left All-cause mortality or heart failure
ventricular ejection fraction ≤35%; haemoglobin concentrations of hospitalisation at 1 year, or change in 6-min
9·0–13.5 g/dL (women) or <15·0 (men); serum ferritin <100 ng/mL or walk distance
100–300 ng/mL with transferrin saturation <20%; hospitalisation for heart
failure within 12 months; or one of the following screening conditions:
NT-proBNP >600 pg/mL, BNP >200 pg/mL (sinus rhythm), NT-proBNP
>1000 pg/mL, or BNP >400 pg/mL (atrial fibrillation)
Chronic heart failure with reduced ejection fraction, NYHA class II–IV, and Time to first adjudicated cardiovascular death or
elevated NT-proBNP or BNP (at various concentrations, depending on left heart failure hospitalisation
ventricular ejection fraction and cardiac rhythm)
Heart failure with reduced ejection fraction, left ventricular ejection fraction Time to first cardiovascular death, hospitalisation
≤40%, elevated NT-proBNP, and eGFR ≥30 mL/min per 1·73 m² for heart failure, or urgent heart failure visit
Chronic heart failure with reduced ejection fraction; NYHA class II-IV; heart Time to first cardiovascular-related death or
failure hospitalisation within 6 months or intravenous diuretics within heart failure hospitalisation
3 months; elevated BNP or NT-proBNP (specific concentrations dependent
on cardiac rhythm); and left ventricular ejection fraction<45%
Treatment approaches are aimed at treating the
underlying cause (which is often not known) and
relieving symptoms. Despite intensive investigation in
prospective, randomised trials, no treatments for acute
heart failure have been shown to improve clinical
outcomes.77 In the absence of treatments that prolong
survival or reduce morbidity, the goal of initial therapy
is to stabilise the patient and decrease congestion to
produce symptomatic relief and to decrease the
potential for organ impairment secondary to
congestion.78 Specific therapies depend on the
individual patient’s clinical presentation. Most patients
present with evidence of congestion and normal or
elevated systolic blood pressure and are treated with
intravenous diuretics and vasodilators.4,75,79 A smaller
proportion of patients have hypoperfusion, therefore
inotropes or vasopressors might be considered in
patients with systolic blood pressure of less than
90 mm Hg.4 Once the patient is stable, the most
important long-term intervention for patients with
acute heart failure could be to optimise medical
management before discharge80 and plan for early
follow up after discharge in a disease management
programme for heart failure, if available.81
Acutely administered therapies have not been shown
to improve clinical outcome in patients with acute heart
failure. Many factors have been proposed to explain this
failure to improve clinical outcome, including patient
heterogeneity, multiple pathophysiologic mechanisms,
generally rapid response to standard care (ie, diuretics)
in most patients, and the low likelihood that short-term
administration of a treatment can affect long-term
outcomes.77,82 Lessons learned from past trials should
 Series

health plan, remote monitoring and management,

Mechanism of action
enhanced clinic support with rapid access, and emergency
Neladenoson bialanate Adenosine A1 partial agonists and hospital care). Systems of care that include multi­
QCG001 Aminopeptidase A inhibitor disciplinary management have been shown to reduce
GLP-1 agonists (eg, dulaglutide, exenatide, liraglutide, Antidiabetics heart failure hospitalisation and improve survival in
lixisenatide, liraglutide, and semaglutide), SGLT2 inhibitors
(eg, empagliflozin, dapagliflozin, canagliflozin)
patients discharged from hospital.86,87 In France, a regional
Apelin, CLR325 Apelin
heart failure-disease management programme (ICALOR)
Cenderitide, ANX-042, PL-3994 (NPR-A agonist) Atrial natriuretic peptides
was established in 2006, in Lorraine, France,88,89 applying
all major components of recommended Disease
TVR120027 Angiotensin-2 type 1 receptor biased ligands
management programmes as per ESC guidelines. The
Mirabegron b3 agonists
ICALOR programme was proven to decrease both heart
Ranolazine, GSK2193874, TRPV4 Cardiac ion channels modulator
failure hospitalisations and all-cause mortality stabilising
Anakinra Interleukin-1b receptor antagonists
heart failure hospitalisation pro-​gression in Lorraine88,89 in
Elamipretide, perhexilene maleate Mitochondrial targeting peptide
a cost-effective manner, whereas those observed overall in
Finerenone, BR-4628109, CS-3150, LY-2623091, MT-3995 Mineralocorticoid receptor antagonists
France progressed continually. This benefit stopped
GGF (rhNR-1) Neuregulin 1
immediately after the programme was interrupted
ITI-214, CRD-733 Phosphodiesterase inhibitors
because of changes in health policy led regional French
Rifaxamin Probiotics (gut microbiome)
health authorities to stop funding, resulting in a cessation
Riociguat Soluble guanylate cyclase stimulator
of inclusion and follow-up in the heart failure disease
GSK2849466 Selective androgen receptor modulators management programme.87
Urocortin 2 and urocortin 3 Vasodilators Close collaborations and a team-oriented approach to
Tolvaptan and ribuvaptan Vasopressin receptor antagonists heart failure care across the different domains of a
Febuxostat Xanthine oxidase inhibitors health-care system are important to deliver successful
Probenecid Uricosuric programmes. Cardiologists and heart failure nurses need
DNA methyltransferase inhibitors and histone deacetylase Drugs targeting epigenetics to coordinate with general practitioners and primary
inhibitors
care physicians. The heart failure team should include
Table 3: Candidate drugs under early clinical development in chronic heart failure with reduced ejection clinical pharmacists who review complex pharmacological
fraction treatments that might have important drug–drug or
drug–disease interactions to consider. Dietitians and
help to design future study protocols, select candidate exercise physiologists counsel patients on establishing a
therapies, and identify target patient populations.83 healthy lifestyle for heart failure and other preventive
care strategies. Social workers are also crucial team
New drugs in research and development members and ensure patients have appropriate access to
Promising drugs are now in phase 3 outcome trials resources. Psychologists can guide patients through
(tables 1, 2), and many new compounds, most targeting anxiety or depression, which are common in patients
new molecular mechanisms, are in early clinical with heart failure. This integrated care team approach
development (table 3). shifts clinical management towards a proactive system as
opposed to a reactive system.
Enabling life-saving pharmacological treatment A key focus of multidisciplinary teams is to prevent
with multidisciplinary management readmission after a heart failure-related hospitalisation.
The optimisation of available symptom-alleviating and Patients enter a vulnerable period early after discharge.
life-saving pharmacological treatments for patients with Throughout the hospitalisation, a multidisciplinary team
HFrEF should be pursued when patients are discharged. should address potential causes of health deterioration
However, observational studies23 show that this optimi­ during a heart failure event, develop preventive strategies
sation is not routinely done and that prescriptions filled for future events, and coordinate post discharge care.
upon discharge have the highest chance of remaining Systems with early physician follow-up after discharge
unchanged, months after discharge. Therefore, un­ are associated with lower 30-day readmission rates than
fortunately, evidence-based treatments are not being systems without an early follow-up.90
optimally implemented within the current health-care In addition, monitoring strategies can identify potential
systems resulting in under-prescription and under- problems that need to be addressed such as potassium
dosing of drugs in HFrEF. The monitoring of creatinine management (hyperkalaemia or hypokalaemia),91 a major
and potassium after a prescription of MRAs is also poor hurdle toward RAAS inhibitor implementation in
both in the USA84 and EU.85 HFrEF.
More broadly, the recognition of heart failure as a Telemedicine programmes that remotely monitor
complex disorder with multiple comorbidities led to the symptoms and other parameters (such as weight) have
development of multidisciplinary management pro-​ had variable results.92 Although the results of
grammes as a foundation for care (such as personalised meta-analysis suggest clinical benefits,93 large clinical

1040 www.thelancet.com Vol 393 March 9, 2019


trials have not shown benefits consistently. As new
technology evolves with the integration of multiple
sensors, patient self-reported health status, and seamless
home-to-clinic monitoring systems, more consistent
benefits might possibly be achieved.94 Implantable
devices with integrated physiological signals and sensors
designed to alert when patients are at high risk of
hospitalisation for heart failure might provide actionable
data for future telemedicine programmes.95 Trials in
progress are testing whether alert management with
specific treatment protocols could achieve improved
outcomes. Priorities for research to continue advance­
ment of lifestyle interventions (such as exercise and
application of monitoring technologies) for patients with
heart failure are outlined in panel 2.
Heart failure prevention
Prevention is probably the best mechanism to combat
heart failure and its associated clinical and societal
burdens.2 Reducing blood pressure lowers the risk of
new onset of heart failure by as much as 40%, similar to
the effect of lowering blood pressure after stroke and
greater than the effect of lowering blood pressure during
the risk of myocardial infarction.96,97
Diabetes might contribute to the development of
heart failure, although glycaemic control in patients with
type 2 diabetes has not been associated with heart failure
prevention, and might have actually led to worsening
heart failure (eg, with glitazones). However, beyond
glycaemic control, some SGLT2 inhibitors improve
clinical outcomes, including hospitalisation for heart
failure, in patients with type 2 diabetes and pre-existing
cardiovascular disease or cardiovascular risk factors.65,98,99
In primary and secondary cardiovascular prevention
trials, statins can reduce the incidence of heart failure
hospitalisation.100 Adherence to healthy lifestyle factors,
no smoking, regular exercise, healthy weight, moderate
alcohol intake, and consumption of breakfast cereal and
fruits and vegetables was found to be associated with a
lower risk of developing heart failure.101 in men who were
apparently healthy at baseline. Furthermore, observational
data for 11 351 participants in the ARIC (Atherosclerosis
in the Community) study.102 showed that maintenance of
recommended activity levels was associated with the
lowest heart failure risk, and that initiation and increase
of physical activity, even in late middle age (around
60 years), were also linked to lower heart failure risk. The
authors concluded that “augmenting physical activity in
middle age may be an important component of strategies
to prevent heart failure”. However, heart failure
prevention in these observational data could be the result
of better control of risk factors and prevention of
ischaemic heart disease. In patients with ischaemic heart
disease, ACE inhibitors delay the onset of heart failure
and reduce cardiovascular mortality.103
Identification of mechanistic therapeutic targets (eg,
cardiac remodelling, inflammation, fibrosis, diastolic
www.thelancet.com Vol 393 March 9, 2019 1041
Series
Panel 2: Research priorities
• Evidence from randomised trials that lifestyle modifications delay the onset of heart
failure and reduce cardiovascular mortality per se
• Identification of mechanistic therapeutic targets to prevent and treat heart failure
with reduced or preserved ejection fraction
• Define the best monitoring strategies to monitor decongestion or recurrent congestion
• Identification of the most effective components of disease management programmes
• Incorporate digital self-management tools and patient-facing applications for heart
failure management
• Use external (wearables) and internal sensors to identify early signals of worsening
heart failure, including remote imaging and the protocols for managing heart failure
with worsening signals
• Understand whether virtualisation of clinical management of heart failure might be
automated and the benefits or risks for medication titration or alteration based on
multiple, integrated electronic data streams from home and clinic
• Understand whether population management systems can be used for managing and
monitoring patients with heart failure through use of new data science methods such
as machine learning
dysfunction, and vascular dysfunction) might be a more
effective approach for heart failure prevention in the
future. Mechanistic bioprofiling of patients (ie, selecting
subgroups of patients on the basis of biomarker profiles
indicative of underlying mechanisms associated with
heart failure risk) and subsequently matching prevention
strategies to mechanistic biotargets might be a promising
approach to the development of specific heart failure
prevention strategies.104
Conclusion
Few areas in medicine have had a progress as remarkable
as that observed with drug treatment for chronic HFrEF
over the past three decades. Unfortunately, no evidence
basis exists for the treatment of HFpEF or acute heart
failure, beyond management of cardiovascular risk
factors. Therefore, notwithstanding improved outcome
in prevalent heart failure, delaying or preventing this
condition has become increasingly important in patients
at-risk and should be prioritised in future research
programmes. The prevention of chronic heart failure
from worsening and from needing hospital admission
for acute symptoms is also of paramount importance.
Implementation of disease management programmes,
possibly including modern monitoring technology,
might, in our opinion, help to achieve this objective.
Contributors
PR developed the outline of the manuscript. All authors contributed to
the literature searches and reviews, and assisted in the writing of
sections and figures.
Declaration of interests
PR is a co-founder of CardioRenal and declares personal fees
(consulting) from Novartis, NovoNordisk, Relypsa, AstraZeneca,
Grünenthal, Idorsia, Stealth Peptides, Fresenius, Vifor Fresenius
Medical Care Renal Pharma, Vifor, and Clinical Trials Mobile
Application; and lecture fees from Bayer and CVRx. AFH has received
research grants from Amgen, AstraZeneca, Boehringer Ingelheim,
 Series
Bristol-Myers Squibb (BMS), Daiichi, GlaxoSmithKline (GSK), Janssen,
Luitpold, Merck, US National Lung, Heart, and Blood Institute, Novartis,
PCORI, and Portola; and consultation fees from Amgen, AstraZeneca,
Bayer, Boston Scientific, Merck, Novartis, Pfizer. SDS has received
research grants from Alnylam, Amgen, AstraZeneca, Bellerophon,
Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis
Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, The National
Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos;
and consultation fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer,
BMS, Cardior, Corvia, Cytokinetics, Gilead, GSK, Ironwood, Merck,
Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion,
AoBiome, Janssen, and Cardiac Dimensions. FZ is the founder of
Cardiovascular Clinical Trialists and of CardioRenal and declares
personal fees for steering committee membership and consultancy from
Amgen, Janssen, Bayer, Novartis, Boston Scientific, Resmed, Takeda,
General Electric, Boehringer Ingelheim, AstraZeneca, CVRx, Quantum
Genomics, Relypsa, and ZS Pharma.
Acknowledgments
The authors acknowledge the contributions of Wendy Gattis Stough,
who was funded by Centre Hospitalier Régional Universitaire de Nancy,
for editing and assisting with the preparation of the manuscript. PR and
FZ are supported by the French National Research Agency (Fight heart
failure programme ANR-15-RHU-0004 and GEENAGE Impact
programme Lorraine University d’Excellence ANR-15-IDEX-04-LUE),
the Contrat de Plan Etat Région Lorraine and FEDER IT2MP.
References
1 Braunwald E. Heart failure. JACC Heart Fail 2013; 1: 1–20.
2 Zannad F. Rising incidence of heart failure demands action.
Lancet 2018; 391: 518–19.
3 Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline
update for the diagnosis and management of chronic heart failure
in the adult: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines
(writing committee to update the 2001 guidelines for the evaluation
and management of heart failure): developed in collaboration with
the American College of Chest Physicians and the International
Society for Heart and Lung Transplantation: endorsed by the Heart
Rhythm Society. Circulation 2005; 112: e154–235.
4 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 Heart J 2016; 37: 2129–200.
5 Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline
for the management of heart failure: executive summary: a report of
the American College of Cardiology Foundation/American Heart
Association Task Force on practice guidelines. Circulation 2013;
128: 1810–52.
6 Girerd N, Seronde MF, Coiro S, et al. Integrative assessment of
congestion in heart failure throughout the patient journey.
JACC Heart Fail 2018; 6: 273–85.
7 Ziaeian B, Fonarow GC. The prevention of hospital readmissions in
heart failure. Prog Cardiovasc Dis 2016; 58: 379–85.
8 Senni M, Gavazzi A, Oliva F, et al. In-hospital and 1-year outcomes
of acute heart failure patients according to presentation
(de novo vs worsening) and ejection fraction. Results from IN-HF
Outcome Registry. Int J Cardiol 2014; 173: 163–69.
9 Bergethon KE, Ju C, DeVore AD, et al. Trends in 30-day readmission
rates for patients hospitalized with heart failure: findings from the
get with the guidelines-heart failure registry. Circ Heart Fail 2016;
9: e002594.
10 Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational
Research Programme: regional differences and 1-year follow-up
results of the Heart Failure Pilot Survey (ESC-HF Pilot).
Eur J Heart Fail 2013; 15: 808–17.
11 Tromp J, Tay WT, Ouwerkerk W, et al. Multimorbidity in patients
with heart failure from 11 Asian regions: a prospective cohort study
using the ASIAN-HF registry. PLoS Med 2018; 15: e1002541.
12 Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment,
and outcome of acute heart failure in 1006 Africans from 9 countries.
Arch Intern Med 2012; 172: 1386–94.
1042 www.thelancet.com Vol 393 March 9, 2019
13 Dokainish H, Teo K, Zhu J, et al. Global mortality variations in
patients with heart failure: results from the International
Congestive Heart Failure (INTER-CHF) prospective cohort study.
Lancet Glob Health 2017; 5: e665–72.
14 Crespo-Leiro MG, Anker SD, Maggioni AP, et al. European Society
of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year
follow-up outcomes and differences across regions. Eur J Heart Fail
2016; 18: 613–25.
15 Van Aelst LNL, Arrigo M, Placido R, et al. Acutely decompensated
heart failure with preserved and reduced ejection fraction present
with comparable haemodynamic congestion. Eur J Heart Fail 2018;
20: 738–47.
16 Harjola VP, Parissis J, Brunner-La Rocca HP, et al. Comprehensive
in-hospital monitoring in acute heart failure: applications for
clinical practice and future directions for research. A statement
from the Acute Heart Failure Committee of the Heart Failure
Association (HFA) of the European Society of Cardiology (ESC).
Eur J Heart Fail 2018; 20: 1081–99.
17 Ibrahim NE, Januzzi JL Jr. The future of biomarker-guided therapy
for heart failure after the guiding evidence-based therapy using
biomarker intensified treatment in heart failure (GUIDE-IT) study.
Curr Heart Fail Rep 2018; 15: 37–43.
18 Felker G, Anstrom KJ, Adams KF, et al. Effect of natriuretic
peptide-guided therapy on hospitalization or cardiovascular mortality
in high-risk patients with heart failure and reduced ejection fraction:
a randomized clinical trial. JAMA 2017; 318: 713–20.
19 Costanzo MR, Ronco C, Abraham WT, et al. Extracorporeal
ultrafiltration for fluid overload in heart failure: current status
and prospects for further research. J Am Coll Cardiol 2017;
69: 2428–45.
20 Houston BA, Kalathiya RJ, Kim DA, Zakaria S. Volume overload in
heart failure: an evidence-based review of strategies for treatment
and prevention. Mayo Clin Proc 2015; 90: 1247–61.
21 Colin-Ramirez E, Ezekowitz JA. Salt in the diet in patients with heart
failure: what to recommend. Curr Opin Cardiol 2016; 31: 196–203.
22 Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary
artery haemodynamic monitoring in chronic heart failure:
a randomised controlled trial. Lancet 2011; 377: 658–66.
23 Zannad F, Rossignol P. Cardiorenal syndrome revisited. Circulation
2018; 138: 929–44.
24 Gerber Y, Weston SA, Berardi C, et al. Contemporary trends in
heart failure with reduced and preserved ejection fraction after
myocardial infarction: a community study. Am J Epidemiol 2013;
178: 1272–80.
25 Bonow RO, Leon MB, Doshi D, Moat N. Management strategies
and future challenges for aortic valve disease. Lancet 2016;
387: 1312–23.
26 Nishimura RA, Vahanian A, Eleid MF, Mack MJ. Mitral valve
disease—current management and future challenges. Lancet 2016;
387: 1324–34.
27 Rodés-Cabau J, Taramasso M, O’Gara PT. Diagnosis and treatment
of tricuspid valve disease: current and future perspectives.
Lancet 2016; 388: 2431–42.
28 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.
J Am Coll Cardiol 2017; 70: 776–803.
29 Burnett H, Earley A, Voors AA, et al. Thirty years of evidence on the
efficacy of drug treatments for chronic heart failure with reduced
ejection fraction: a network meta-analysis. Circ Heart Fail 2017;
10: e003529.
30 Shen L, Jhund PS, Petrie MC, et al. Declining risk of sudden death
in heart failure. N Engl J Med 2017; 377: 41–51.
31 Komajda M, Cowie MR, Tavazzi L, Ponikowski P, Anker SD,
Filippatos GS. Physicians’ guideline adherence is associated with
better prognosis in outpatients with heart failure with reduced
ejection fraction: the QUALIFY international registry.
Eur J Heart Fail 2017; 19: 1414–23.
32 Ouwerkerk W, Voors AA, Anker SD, et al. Determinants and
clinical outcome of uptitration of ACE-inhibitors and beta-blockers
in patients with heart failure: a prospective European study.
Eur Heart J 2017; 38: 1883–90.

33 Epstein M, Reaven NL, Funk SE, McGaughey KJ, Oestreicher N,
Knispel J. Evaluation of the treatment gap between clinical
guidelines and the utilization of renin-angiotensin-aldosterone
system inhibitors. Am J Manag Care 2015; 21 (suppl 11): S212–20.
34 Rossignol P, Menard J, Fay R, Gustafsson F, Pitt B, Zannad F.
Eplerenone survival benefits in heart failure patients
post-myocardial infarction are independent from its diuretic and
potassium-sparing effects. Insights from an EPHESUS (Eplerenone
Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival
Study) substudy. J Am Coll Cardiol 2011; 58: 1958–66.
35 Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F,
Huang IZ. Evaluation of the efficacy and safety of RLY5016,
a polymeric potassium binder, in a double-blind, placebo-controlled
study in patients with chronic heart failure (the PEARL-HF) trial.
Eur Heart J 2011; 32: 820–28.
36 Eschalier R, McMurray JJ, Swedberg K, et al. Safety and efficacy of
eplerenone in patients at high risk for hyperkalemia and/or
worsening renal function: analyses of the EMPHASIS-HF study
subgroups (Eplerenone in Mild Patients Hospitalization And
SurvIval Study in Heart Failure). J Am Coll Cardiol 2013;
62: 1585–93.
37 Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the
management of atrial fibrillation developed in collaboration with
EACTS. Eur Heart J 2016; 37: 2893–962.
38 Ferreira JP, Girerd N, Alshalash S, Konstam MA, Zannad F.
Antithrombotic therapy in heart failure patients with and without
atrial fibrillation: update and future challenges. Eur Heart J 2016;
37: 2455–64.
39 Zannad F, Anker SD, Byra WM, et al. Rivaroxaban in patients with
heart failure, sinus rhythm, and coronary disease. N Engl J Med
2018; 379: 1332–42.
40 Anker SD, Comin CJ, Filippatos G, et al. Ferric carboxymaltose in
patients with heart failure and iron deficiency. N Engl J Med 2009;
361: 2436–48.
41 Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al.
Beneficial effects of long-term intravenous iron therapy with ferric
carboxymaltose in patients with symptomatic heart failure and iron
deficiencydagger. Eur Heart J 2015; 36: 657–68.
42 Komajda M, Lam CS. Heart failure with preserved ejection fraction:
a clinical dilemma. Eur Heart J 2014; 35: 1022–32.
43 Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL,
Redfield MM. Trends in prevalence and outcome of heart failure
with preserved ejection fraction. N Engl J Med 2006; 355: 251–59.
44 Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with
preserved ejection fraction in a population-based study. N Engl J Med
2006; 355: 260–69.
45 Kitzman DW, Brubaker P, Morgan T, et al. Effect of caloric
restriction or aerobic exercise training on peak oxygen consumption
and quality of life in obese older patients with heart failure with
preserved ejection fraction: a randomized clinical trial. JAMA 2016;
315: 36–46.
46 Dalos D, Mascherbauer J, Zotter-Tufaro C, et al. Functional status,
pulmonary artery pressure, and clinical outcomes in heart failure
with preserved ejection fraction. J Am Coll Cardiol 2016;
68: 189–99.
47 Kitzman DW, Shah SJ. The HFpEF obesity phenotype: the elephant
in the room. J Am Coll Cardiol 2016; 68: 200–03.
48 Wolsk E, Claggett B, Kober L, et al. Contribution of cardiac and
extra-cardiac disease burden to risk of cardiovascular outcomes
varies by ejection fraction in heart failure. Eur J Heart Fail 2018;
20: 504–10.
49 Campbell RT, McMurray JJ. Comorbidities and differential
diagnosis in heart failure with preserved ejection fraction.
Heart Fail Clin 2014; 10: 481–501.
50 Solomon SD, Anavekar N, Skali H, et al. Influence of ejection
fraction on cardiovascular outcomes in a broad spectrum of heart
failure patients. Circulation 2005; 112: 3738–44.
51 Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved,
borderline, and reduced ejection fraction: 5-year outcomes.
J Am Coll Cardiol 2017; 70: 2476–86.
52 Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in
patients with chronic heart failure and preserved left-ventricular
ejection fraction: the CHARM-Preserved Trial. Lancet 2003;
362: 777–81.
www.thelancet.com Vol 393 March 9, 2019 1043
Series
53 Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L,
Taylor J. The perindopril in elderly people with chronic heart failure
(PEP-CHF) study. Eur Heart J 2006; 27: 2338–45.
54 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.
55 Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure
with preserved ejection fraction. N Engl J Med 2014; 370: 1383–92.
56 Solomon SD, Rizkala AR, Gong J, et al. Angiotensin receptor
neprilysin inhibition in heart failure with preserved ejection
fraction: rationale and design of the PARAGON-HF trial.
JACC Heart Fail 2017; 5: 471–82.
57 Rogers JK, Pocock SJ, McMurray JJ, et al. Analysing recurrent
hospitalizations in heart failure: a review of statistical methodology,
with application to CHARM-Preserved. Eur J Heart Fail 2014;
16: 33–40.
58 Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in
patients and outcomes in the Treatment of Preserved Cardiac
Function Heart Failure With an Aldosterone Antagonist (TOPCAT)
trial. Circulation 2015; 131: 34–42.
59 Hoendermis ES, Liu LC, Hummel YM, et al. Effects of sildenafil 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.
60 Redfield MM, Chen HH, Borlaug BA, et al. Effect of
phosphodiesterase-5 inhibition on exercise capacity and clinical
status in heart failure with preserved ejection fraction:
a randomized clinical trial. JAMA 2013; 309: 1268–77.
61 Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate
in heart failure with preserved ejection fraction. N Engl J Med 2015;
373: 2314–24.
62 Pieske B, Maggioni AP, Lam CSP, et al. Vericiguat in patients with
worsening chronic heart failure and preserved ejection fraction:
results of the SOluble guanylate Cyclase stimulatoR in heArT
failurE patientS with PRESERVED EF (SOCRATES-PRESERVED)
study. Eur Heart J 2017; 38: 1119–27.
63 Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor
neprilysin inhibitor LCZ696 in heart failure with preserved ejection
fraction: a phase 2 double-blind randomised controlled trial.
Lancet 2012; 380: 1387–95.
64 Fitchett D, Butler J, van de Borne P, et al. Effects of empagliflozin
on risk for cardiovascular death and heart failure hospitalization
across the spectrum of heart failure risk in the EMPA-REG
OUTCOME(R) trial. Eur Heart J 2018; 39: 363–70.
65 Radholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart
failure in type 2 diabetes mellitus: results from the CANVAS
program (Canagliflozin Cardiovascular Assessment Study).
Circulation 2018; 138: 458–68.
66 Redfield MM. Heart failure with preserved ejection fraction.
N Engl J Med 2016; 375: 1868–77.
67 Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA.
A simple, evidence-based approach to help guide diagnosis of heart
failure with preserved ejection fraction. Circulation 2018; published
online May 23. DOI:10.1161/CIRCULATIONAHA.118.034646
(preprint).
68 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.
69 Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact
of heart failure in the United States: a policy statement from the
American Heart Association. Circ Heart Fail 2013; 6: 606–19.
70 Christ M, Stork S, Dorr M, et al. Heart failure epidemiology
2000–2013: insights from the German Federal Health Monitoring
System. Eur J Heart Fail 2016; 18: 1009–18.
71 Omersa D, Farkas J, Erzen I, Lainscak M. National trends in heart
failure hospitalization rates in Slovenia 2004–2012. Eur J Heart Fail
2016; 18: 1321–28.
72 Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal
hospitalization for heart failure on subsequent mortality in patients
with chronic heart failure. Circulation 2007; 116: 1482–87.
 Series
73 Kristensen SL, Jhund PS, Kober L, et al. Comparison of outcomes
after hospitalization for worsening heart failure, myocardial
infarction, and stroke in patients with heart failure and reduced and
preserved ejection fraction. Eur J Heart Fail 2015; 17: 169–76.
74 Crespo-Leiro MG, Anker SD, Maggioni AP, et al. European Society
of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year
follow-up outcomes and differences across regions. Eur J Heart Fail
2016; 18: 613–25.
75 Chioncel O, Mebazaa A, Harjola VP, et al. Clinical phenotypes and
outcome of patients hospitalized for acute heart failure: the ESC
Heart Failure Long-Term Registry. Eur J Heart Fail 2017;
19: 1242–54.
76 Arrigo M, Gayat E, Parenica J, et al. Precipitating factors and 90-day
outcome of acute heart failure: a report from the intercontinental
GREAT registry. Eur J Heart Fail 2017; 19: 201–08.
77 Ferrari R, Bueno H, Chioncel O, et al. Acute heart failure: lessons
learned, roads ahead. Eur J Heart Fail 2018; 20: 842–50.
78 Harjola VP, Mullens W, Banaszewski M, et al. Organ dysfunction,
injury and failure in acute heart failure: from pathophysiology to
diagnosis and management. A review on behalf of the Acute Heart
Failure Committee of the Heart Failure Association (HFA) of the
European Society of Cardiology (ESC). Eur J Heart Fail 2017;
19: 821–36.
79 Mebazaa A, Yilmaz MB, Levy P, et al. Recommendations on
pre-hospital & early hospital management of acute heart failure:
a consensus paper from the Heart Failure Association of the
European Society of Cardiology, the European Society of Emergency
Medicine and the Society of Academic Emergency Medicine.
Eur J Heart Fail 2015; 17: 544–58.
80 Gayat E, Arrigo M, Littnerova S, et al. Heart failure oral therapies
at discharge are associated with better outcome in acute heart
failure: a propensity-score matched study. Eur J Heart Fail 2018;
20: 345–54.
81 Cheema B, Ambrosy AP, Kaplan RM, et al. Lessons learned in acute
heart failure. Eur J Heart Fail 2018; 20: 630–41.
82 Packer M. Acute heart failure is an event rather than a disease:
plea for a radical change in thinking and in therapeutic drug
development. JACC Heart Fail 2018; 6: 73–75.
83 Mebazaa A. Acute heart failure deserves a log-scale boost in
research support: call for multidisciplinary and universal actions.
JACC Heart Fail 2018; 6: 76–79.
84 Cooper LB, Hammill BG, Peterson ED, et al. Consistency of
laboratory monitoring during initiation of mineralocorticoid
receptor antagonist therapy in patients with heart failure. JAMA
2015; 314: 1973–75.
85 Nilsson E, De Deco P, Trevisan M, et al. A real-world cohort study
on the quality of potassium and creatinine monitoring during
initiation of mineralocorticoid receptor antagonists in patients with
heart failure. Eur Heart J Qual Care Clin Outcomes 2018; published
online May 2. DOI:10.1093/ehjqcco/qcy019 (preprint).
86 McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary
strategies for the management of heart failure patients at high risk
for admission: a systematic review of randomized trials.
J Am Coll Cardiol 2004; 44: 810–19.
87 Alla F, Agrinier N, Lavielle M, et al. Impact of the interruption of a
large heart failure regional disease management programme on
hospital admission rates: a population-based study. Eur J Heart Fail
2018; 20: 1066–68.
88 Laborde-Casterot H, Agrinier N, Zannad F, et al. Effectiveness of a
multidisciplinary heart failure disease management programme on
1-year mortality: prospective cohort study. Medicine (Baltimore)
2016; 95: e4399.
1044 www.thelancet.com Vol 393 March 9, 2019
89 Agrinier N, Altieri C, Alla F, et al. Effectiveness of a multidimensional
home nurse led heart failure disease management program—a French
nationwide time-series comparison. Int J Cardiol 2013; 168: 3652–58.
90 Hernandez AF, Greiner MA, Fonarow GC, et al. Relationship
between early physician follow-up and 30-day readmission among
Medicare beneficiaries hospitalized for heart failure. JAMA 2010;
303: 1716–22.
91 Sarwar CM, Papadimitriou L, Pitt B, et al. Hyperkalemia in heart
failure. J Am Coll Cardiol 2016; 68: 1575–89.
92 Anker SD, Koehler F, Abraham WT. Telemedicine and remote
management of patients with heart failure. Lancet 2011;
378: 731–39.
93 Yun JE, Park JE, Park HY, Lee HY, Park DA. Comparative
effectiveness of telemonitoring versus usual care for heart failure:
a systematic review and meta-analysis. J Card Fail 2018; 24: 19–28.
94 Fraiche AM, Eapen ZJ, McClellan MB. Moving beyond the walls of
the clinic: opportunities and challenges to the future of telehealth in
heart failure. JACC Heart Fail 2017; 5: 297–304.
95 Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor
algorithm predicts heart failure events in patients with implanted
devices: results from the MultiSENSE study. JACC Heart Fail 2017;
5: 216–25.
96 Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of
different blood-pressure-lowering regimens on major cardiovascular
events: results of prospectively-designed overviews of randomised
trials. Lancet 2003; 362: 1527–35.
97 Thomopoulos C, Parati G, Zanchetti A. Effects of blood
pressure-lowering treatment. 6. Prevention of heart failure and
new-onset heart failure—meta-analyses of randomized trials.
J Hypertens 2016; 34: 373–84.
98 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular
outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;
373: 2117–28.
99 Butler J, Hamo CE, Filippatos G, et al. The potential role and
rationale for treatment of heart failure with sodium-glucose
co-transporter 2 inhibitors. Eur J Heart Fail 2017; 19: 1390–400.
100 Preiss D, Campbell RT, Murray HM, et al. The effect of statin
therapy on heart failure events: a collaborative meta-analysis of
unpublished data from major randomized trials. Eur Heart J 2015;
36: 1536–46.
101 Djousse L, Driver JA, Gaziano JM. Relation between modifiable
lifestyle factors and lifetime risk of heart failure. JAMA 2009;
302: 394–400.
102 Florido R, Kwak L, Lazo M, et al. Six-year changes in physical
activity and the risk of incident heart failure: ARIC study.
Circulation 2018; 137: 2142–51.
103 Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S.
Angiotensin-converting-enzyme inhibitors in stable vascular
disease without left ventricular systolic dysfunction or heart
failure: a combined analysis of three trials. Lancet 2006;
368: 581–88.
104 Ferreira JP, Machu JL, Girerd N, et al. Rationale of the
FIBROTARGETS study designed to identify novel biomarkers of
myocardial fibrosis. ESC Heart Fail 2018; 5: 139–48.
© 2019 Elsevier Ltd. All rights reserved.