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Heart failure 1
Heart failure drug treatment
Patrick Rossignol, Adrian F Hernandez, Scott D Solomon, Faiez Zannad

Lancet 2019; 393: 1034–44 Heart failure is the most common cardiovascular reason for hospital admission for people older than 60 years of age.
This is the first in a Series of Few areas in medicine have progressed as remarkably as heart failure treatment over the past three decades. However,
three papers on heart failure progress has been consistent only for chronic heart failure with reduced ejection fraction. In acutely decompensated
Centre d’Investigations heart failure and heart failure with preserved ejection fraction, none of the treatments tested to date have been
Cliniques Plurithématique
definitively proven to improve survival. Delaying or preventing heart failure has become increasingly important in
1433, Université de Lorraine,
Institut National de la Santé et patients who are prone to heart failure. The prevention of worsening chronic heart failure and hospitalisations for
de la Recherche Médicale acute decompensation is also of great importance. The objective of this Series paper is to provide a concise and
(Inserm), Centre Hospitalier practical summary of the available drug treatments for heart failure. We support the implementation of the
Régional Universitaire (CHRU)
international guidelines. We offer views on the basis of our personal experience in research areas that have insufficient
de Nancy, Inserm U1116, and
French Clinical Research evidence. The best possible evidence-based drug treatment (including inhibitors of the renin–angiotensin–aldosterone
Network, Investigation system and β blockers) is useful only when optimally implemented. However, implementation might be challenging.
Network Initiative- We believe that disease management programmes can be helpful in providing a multidisciplinary, holistic approach
Cardiovascular and Renal
to the delivery of optimal medical care.
Clinical Trialists (FCRIN
INI-CRCT), Nancy, France
(Prof P Rossignol MD, Introduction estimated 6-month mortality of 17·8%. The International
F Zannad, MD); Department of Heart failure is the most common cardiovascular reason Congestive Heart Failure study13 representing Africa,
Medicine, Division of
Cardiology, Duke University
for hospital admission among individuals older than China, India, the Middle East, southeast Asia, and South
Medical Center, Durham, 60 years of age.1 The prevalence of heart failure is increasing America, reported an overall 1-year mortality of 16·5%,
North Carolina, NC, USA worldwide because of an increasing incidence related to with substantial variation by region (34% in Africa,
(A F Hernandez MD); and population ageing, rising prevalence of poorly controlled 23% in India, 15% in southeast Asia, 9% in South America,
Cardiovascular Division,
Brigham and Women’s
risk factors (ie, hypertension, diabetes, and obesity), and 9% in the Middle East, and 7% in China).
Hospital, Boston, prolonged survival of patients with heart failure due to
Massachusetts, MA, USA implementation of evidence-based treatments.2
(S D Solomon MD) Heart failure is a clinical syndrome characterised by NYHA classification
Correspondence to: fatigue and dyspnoea, induced by left (or global) ventricular Class III: marked limitation of Class II: slight limitation of
Prof Patrick Rossignol, Centre
d’Investigations Cliniques, CHRU
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
de Nancy, activity causes symptoms of activity results in symptoms of
54500 Vandoeuvre-lès-Nancy, symptom severity (figure and panel 1). Heart failure carries heart failure heart failure
France 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 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.

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For most patients, abnormalities of systolic and

diastolic function coexist, irrespective of the ejection Panel 1: Heart failure presentation
fraction, which was the most used classifier in clinical • Patients at high risk for heart failure (ie, those with hypertension, diabetes,
trials to define either heart failure with reduced ejection atherosclerotic disease, or obesity) but without structural heart disease or heart failure
fraction (HFrEF) if this parameter is less than 40%, or symptoms are considered stage A in the development of heart failure.3
heart failure with preserved ejection fraction (HFpEF). • Stage B describes the development of asymptomatic structural heart disease
In a European survey, mortality at 1 year was (ie, previous myocardial infarction, left ventricular remodelling, left ventricular
8·8% for HFrEF and 6·3% for HFpEF.14 The HFrEF hypertrophy, reduced ejection fraction, or asymptomatic valvular disease).3
subtype appears to be the most well studied, yielding a • Stage C heart failure reflects symptomatic patients who should receive optimal
robust body of evidence to support clinical practice medical therapy unless contraindicated.3–5 Symptoms are non-specific and dominated
guidelines.4,5 by shortness of breath and fatigue, leading to reduced functional capacity assessed by
The objective of this Series paper is to provide a concise clinical scores (New York Heart Association classification I to IV) and 6-min walk
and practical summary of the drug treatments available distance or other ergometric tests. The most common signs of heart failure are related
for heart failure. We support the implementation of the to congestion, whether vascular or interstitial, pulmonary congestion (eg, rales and
available international guidelines. These guidelines can pleural effusion), or peripheral congestion (eg, leg oedema, jugular vein dilatation,
differ in some respects and we offer views on the basis of and, in more severe cases, liver enlargement and ascites). Stage C patients may be
our personal expertise when persistent gaps in evidence relatively stable on guideline-directed medical therapy, but ultimately progression of
exist. the disease is marked by episodes of acute decompensation, which can be precipitated
We also identified the priorities for future research in by several cardiovascular and non-cardiovascular factors.
terms of unmet needs and evidence gaps. • Acute decompensation is accompanied by distressing symptoms of congestion and
the potential for end-organ (ie, heart, liver, and kidney) damage.6 Hospitalisation for
Diuretic and sodium management heart failure has a poor prognosis. Among patients with heart failure hospitalised in
Regardless of ejection fraction, heart failure symptoms are the USA from 2008 to 2010, 67·4% were readmitted and 35·8% died within 1 year of
mostly related to congestion,15 which is one of the main the index hospitalisation.7 Data from Europe show consistent results.8
predictors of poor patient outcome.6 Despite no large • Patients with refractory symptoms are considered Stage D, despite optimal
randomised outcome trials, loop diuretics are strongly implementation of best medical care.3 These patients should be considered for
recommended (grade 1)4,5 for decongestion, albeit with less additional interventions (eg, mechanical circulatory support and transplant
evidence (B4 or C5) by the European Society of Cardiology evaluation), but these therapies are beyond the scope of this Series.
(ESC) and the American College of Cardiology and
American Heart Association guidelines to improve
symptoms in chronic and acutely decompensated heart disease (eg, weight loss scoring lacks sensitivity) and
failure. across all settings of patient presentations (pre-admission
Diuretic dosing is largely empiric and should be titrated to hospital, admission to the emergency department, in-
according to the decongestion target. The use of hospital management, and discharge and continued
inappropriately low doses of diuretics can result in monitoring in the community).6 Medical imaging
persistent congestion. Conversely, the use of in-​ (ie, chest x-ray, and B-mode lung ultrasound, inferior
appropriately high doses of loop diuretics can trigger vena cava, and other echocardiography measures) might
hypokalaemia and hypovolaemia with a related risk of be helpful.16 Clinical trials of chronic optimisation of
hypotension and deterioration of renal function,5 which therapy guided by natriuretic peptide concentrations have
can lead to down-titration of life-saving drugs (ir, the led to conflicting results.17,18
inhibitors of the renin–angiotensin–aldosterone system Diuretic resistance can occur in most patients with
[RAAS]). Further­ more, this overdosing can further severe heart failure. In this clinical setting, specific
stimulate RAAS, which can worsen heart failure. Once pharmacological algorithms encompassing loop diuretic
optimal decongestion has been achieved, the lowest dose dose adjustments, inotropes, and the addition of thiazide-
that maintains euvolaemia should be prescribed and like diuretics can be proposed as an alternative to
some heart failure treatment centres should educate extracorporeal ultrafiltration in patients treated in
appropriately selected patients to manage symptoms with hospital, whereas none of the approaches showed efficacy
diuretics as needed. These patients might be those not in outcome trials.19 Neurohormonal imbalances created
requiring daily diuretic who can be educated to follow the by heart failure lead to an inability to excrete sodium and
strategy and will contact clinical staff quickly if symptoms water. Therefore, conventional advice has been to restrict
worsen, although this strategy has not been well studied. sodium and fluid intake.20 Major heart failure guidelines
However, deter­ mination of optimal decongestion and have not reached a consensus on recommendations
early detection of a recurrent congestion is challenging. for dietary sodium (and fluid) restriction. Four trials
Although numerous clinical scores, imaging and haemo­ (NCT02467296, NCT02148679, NCT01733017, and
dynamic tools, and biological tests are available to assist NCT02012179) investigating sodium restriction in heart
physicians in ascertaining and quantifying congestion, failure are in progress, including one large trial
not all are appropriate for use along the course of the evaluating clinical outcome endpoints.21 Vol 393 March 9, 2019 1035


Altogether, we believe in the possibility that detection, or mineralocorticoid-receptor antagonists [MRAs]), and
dynamic monitoring, and management of congestion β blockers are strongly recommended in international
and decongestion could help to improve heart failure guidelines (class IA) for improving survival, decreasing
management. However, we acknowledge that evidence sudden death, and preventing heart failure hospitali­
from robust randomised outcome trials is missing. sations.4 Based on the results of the PARADIGM HF trial,
One possible exception is a single trial that uses a remote sacubitril–valsartan is recommended to replace ACE
monitoring of pulmonary artery diastolic pressures with inhibitors to further reduce the risk of heart failure
an implanted device.22 In a randomised controlled trial hospitalisation and death in ambulatory patients
that enrolled more than 500 patients with heart failure, with HFrEF who remain symptomatic despite optimal
monitoring and managing patients showed improved treatment. Unless contraindicated, all symptomatic
clinical outcomes, including reduced hospitalisation for patients with HFrEF should receive these medications in
heart failure. One limitation of the trial is that the control combination, preferably at target maximally tolerated
group did not have a systematic form of disease doses.4,28 The combined optimal use of these class IA
management, so whether the trial truly showed benefit therapies in clinical trials has led to a decline in mortality
of the invasive technology over and above non-invasive among patients with severe and mild-to-moderate cases
See Online for appendix disease management is questionable. In addition, the of HFrEF (appendix).29 Furthermore, a network meta-
reduction in the number of patients with the implanted analysis of 58 trials dominated by 15 large-scale trials
device admitted to hospital because of heart failure with a follow up of 1984–18 898 patient-years showed
appeared to be associated with increased use of diuretics that combining evidence-based drugs might produce
and vasodilators; to what extent this increase in doses cumulative reduction in all-cause mortality up to 60%
might have contributed to the improved outcomes and in all-cause hospitalisations with reductions up to
remains an open question. 40%, on average. Concomitantly, in patients enrolled in
clinical trials, the annual rate of sudden cardiac death has
Medical treatment of chronic heart failure with declined to less than 5%.30
reduced ejection fraction International registry data showed that physician’s
The primary pathophysiological cardiac abnormalities in adherence to guideline-recommended medications in
HFrEF are cardiac chamber enlargement due to cardiac HFrEF was associated with improved outcomes.31 Un­
remodelling, weak contraction (deficient inotropism), fortunately, available guidelines are not being optimally
elevated filling pressures (preload), and increased periph­ implemented, both in terms of overall use and under­
eral resistance (afterload), leading to an inability to provide dosing,32 most often because of excessive concern
adequate cardiac output at rest or with exercise. These about adverse events.10 Hypotension, hyperkalaemia, and
elevated intracardiac pressures can also cause lung and deterioration of renal function are the most frequently
peripheral congestion. The number of myocytes and cited reasons for underdosing, underuse, and dis­
their function decline, and they are replaced by myocardial continuation of RAAS inhibitors.10 In a large US database
interstitial fibrosis, which stiffens the heart and creates the of electronic health records (Humedica) including more
anatomical substrate basis for lethal arrhythmias. than 20 000 patients with heart failure, nearly 60% who
Increasingly the disease is viewed as a syndrome with discontinued RAAS inhibitors after a hyperkalaemic
multiple systemic mechanisms, potentially involving episode had an adverse outcome or mortality compared
inflammation and disorders of neurohormonal systems with 52% of patients on these drugs at submaximal doses
involving the RAAS, the autonomic nervous system, the and 44% with patients on maximum doses (all comparisons
endothelium, the natriuretic peptide system, and the p<0·05). Patients on submaximal dose or who discontinued
vasopressin system. Other potential pathophysiological medication were twice as likely to die as patients on
mechanisms include elevated heart rate, atrial fibrillation, maximum dose.33 β-blocker use might be hampered by
abnormalities of ventricular–vascular coupling, and com­ concerns about hypotension, fatigue, and bradycardia.
plex cardiorenal interactions (ie, cardiorenal syndrome).23 However, most of these adverse events are predictable,
Improved management of acute coronary syndromes reversible, and manageable. Most importantly, occurrence
has resulted in less frequent progression to post-myo­ of these events does not diminish survival benefits.34
cardial infarction in patients with HFrEF.24 Non- Therefore, in our opinion, concerns about adverse events
ischaemic causes account for up to 30% of cases of might be excessive in some cases and might potentially
HFrEF and include valvular heart disease,25–27 familial deprive patients of life-saving therapies. Hypotension if
cardiomyopathy, and secondary cardiomyopathies (eg, symptomatic can often be managed by discontinuing
inflammatory, cardiotoxic [alcohol or chemotherapy unnecessary vasodilators (eg, calcium channel antagonists,
induced], and infectious). α blockers, and nitrates), or by reducing diuretic doses to
Treatment guidelines are based on robust evidence the lowest dose that maintains euvolaemia, and ultimately
stemming from well designed randomised outcome by staggering doses of RAAS inhibitors and β blockers.
trials.4,5 Inhibitors of the RAAS (ie, angiotensin-converting Strategies to achieve optimal use of these therapies include
enzyme inhibitors [ACEs], angiotensin receptor blockers, frequent monitoring (within 3 days of initiation or dose

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adjustments and every 4 months once stable) of estimated alone; or the main secondary efficacy outcome of cardio­
glomerular filtration rate, serum potassium, and blood vascular death and heart failure hospitalisation.39
pressure; slow uptitration; and avoidance of other con­ Intravenous iron can be used for improving functional
comitant, non-essential, interacting drugs (eg, non-steroidal capacity and quality of life in patients with iron deficiency
anti-inflammatory drugs, potassium supple­ments, dietary (serum ferritin<100 mg/L or ferritin between 100 mg/L
potassium, other blood pressure-lowering drugs, and and 299 mg/L, and transferrin saturation <20%).4,40,41
excessive diuretic doses). Down-titration of doses or However long-term data on the cardiovascular efficacy
discontinuation of RAAS inhibitors can be considered and on safety are not yet available.
temporarily for persistent or severe hyper­ kalaemia,
hypotension, or deterioration of renal function. However, Medical treatment of heart failure with
this temporary discontinuation should not prevent preserved ejection fraction
attempts at reinitiation or uptitration of therapy as soon as First recognised in the 1980s and initially termed diastolic
safely possible. The use of potassium binders might heart failure, HFpEF accounts for approximately half of
facilitate uptitration in patients prone to hyperkalaemia.35 all hospital admissions for heart failure, is associated with
Whether this treatment can prevent cardio­ vascular substantial morbidity and mortality, and is increasing in
outcome occurrence needs to be shown in a dedicated prevalence.42 The definition, pathophysiology, and causes
outcome trial. Patients with HFrEF are increasingly older of HFpEF are controversial, but most guidelines agree
(older than 80 years) and have multiple comorbidities. that the minimum requirements for the diagnosis of
Clinical trials have generally excluded patients with these HFpEF are signs and symptoms of heart failure and a
factors, and, as a result, their response to heart failure relatively preserved ejection fraction (ie, ejection fraction
therapy and the best approaches for managing comorbid more than 40%).4
conditions and concomitant drug therapies that might Patients with HFpEF tend to be older than those with
have pharmacodynamic or pharma­cokinetic interactions HFrEF, and the prevalence of this disorder is increasing as
with the heart failure regimen is less certain. However, the population ages.43 Moreover, patients with HFpEF have
there is no evidence that such patients would not benefit more comorbidities than those with HFrEF,44 including
from standard heart failure therapy,36 and guidelines should hypertension, diabetes, atrial fibrillation, anaemia, and
also be followed in these patients, with individual adjust­ chronic obstructive pulmonary disease. For example, a
ments in dose or monitoring as clinically indicated randomised controlled trial comparing exercise only, diet
according to comorbidity or interacting medications. only, and combined exercise and diet with a control group
Ivabradine or digoxin prevent heart failure hospitali­ for 20 weeks, in 100 patients with HFpEF, with obesity, and
sation in patients with sinus rhythm, if the heart rate older than 60 years, showed that a calorie restriction diet or
remains above 75 beats per min after β-blocker aerobic exercise training increased peak oxygen con­
administration.4 β blockers and digoxin might help to sumption.45 Increased adiposity also contributed to worse
control ventricular response in patients with atrial NYHA functional class for HFpEF.46,47 The attributable
fibrillation, although benefits of this combined therapy risk associated with these comorbidities increases with
have not been shown. No consensus has been reached on increasing ejection fraction.48 The high prevalence of
an optimal target heart rate in patients with atrial comorbidities in HFpEF has contributed to the notion that
fibrillation and heart failure, with recommended targets this condition might not exist as an independent entity,
varying between 60 beats per min and 110 beats but might simply be a collection of comorbidities. The
per min.4,37 Amiodarone is not preferred as first line for concept is countered by the substantially higher number
heart rate control because of safety concerns. Rhythm of events in patients with HFpEF than in patients with
control by use of electrical or pharmacological conversion these comorbidities but without heart failure.49 Although
could be considered to improve symptoms in patients ambulatory patients with HFpEF have substantially lower
with persisting symptoms or signs of heart failure, morbidity and mortality than patients with HFrEF,50
despite optimal medical therapy and adequate control of subsequent hospitalisation and mortality in hospitalised
ventricular rate. Anticoagulation, preferably with direct patients are similar for both conditions.51
oral anticoagulants, should be offered to patients with Several clinical outcomes trials have been done for
heart failure and atrial fibrillation, recognising that patients with HFpEF yet none have met their primary
bleeding might be more frequent in these patients than endpoint (table 1). All of these trials have so far assessed
in those who do not have heart failure, since heart failure inhibitors of the RAAS, either ACE inhibitors,53 angio­
is a component of the CHADS2VASC2 score.38 tensin receptor blockers,52,54 or MRAs.55 In the CHARM-
In the COMMANDER HF trial that enrolled patients Preserved trial,52 candesartan was associated with an
following a recent worsening of chronic HFrEF coronary 11% non-significant reduction in cardiovascular death or
artery disease, and typical sinus rhythm, low dose heart failure hospitalisation, although post-hoc analyses
rivaroxaban did not significantly reduce risk of either the suggested a significant reduction in total hospitali­sations.57
primary composite outcome of all-cause mortality, The TOPCAT trial58 comparing spironolactone with
myocardial infarction, or stroke; all-cause mortality placebo, based on the success of MRAs in the treatment of Vol 393 March 9, 2019 1037


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

1038 Vol 393 March 9, 2019


Number of Treatments Key inclusion criteria Primary endpoint

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


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
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 Vol 393 March 9, 2019


trials have not shown benefits consistently. As new

technology evolves with the integration of multiple Panel 2: Research priorities
sensors, patient self-reported health status, and seamless • Evidence from randomised trials that lifestyle modifications delay the onset of heart
home-to-clinic monitoring systems, more consistent failure and reduce cardiovascular mortality per se
benefits might possibly be achieved.94 Implantable • Identification of mechanistic therapeutic targets to prevent and treat heart failure
devices with integrated physiological signals and sensors with reduced or preserved ejection fraction
designed to alert when patients are at high risk of • Define the best monitoring strategies to monitor decongestion or recurrent congestion
hospitalisation for heart failure might provide actionable • Identification of the most effective components of disease management programmes
data for future telemedicine programmes.95 Trials in • Incorporate digital self-management tools and patient-facing applications for heart
progress are testing whether alert management with failure management
specific treatment protocols could achieve improved • Use external (wearables) and internal sensors to identify early signals of worsening
outcomes. Priorities for research to continue advance­ heart failure, including remote imaging and the protocols for managing heart failure
ment of lifestyle interventions (such as exercise and with worsening signals
application of monitoring technologies) for patients with • Understand whether virtualisation of clinical management of heart failure might be
heart failure are outlined in panel 2. automated and the benefits or risks for medication titration or alteration based on
multiple, integrated electronic data streams from home and clinic
Heart failure prevention • Understand whether population management systems can be used for managing and
Prevention is probably the best mechanism to combat monitoring patients with heart failure through use of new data science methods such
heart failure and its associated clinical and societal as machine learning
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 dysfunction, and vascular dysfunction) might be a more
greater than the effect of lowering blood pressure during effective approach for heart failure prevention in the
the risk of myocardial infarction.96,97 future. Mechanistic bioprofiling of patients (ie, selecting
Diabetes might contribute to the development of subgroups of patients on the basis of biomarker profiles
heart failure, although glycaemic control in patients with indicative of underlying mechanisms associated with
type 2 diabetes has not been associated with heart failure heart failure risk) and subsequently matching prevention
prevention, and might have actually led to worsening strategies to mechanistic biotargets might be a promising
heart failure (eg, with glitazones). However, beyond approach to the development of specific heart failure
glycaemic control, some SGLT2 inhibitors improve prevention strategies.104
clinical outcomes, including hospitalisation for heart
failure, in patients with type 2 diabetes and pre-existing Conclusion
cardiovascular disease or cardiovascular risk factors.65,98,99 Few areas in medicine have had a progress as remarkable
In primary and secondary cardiovascular prevention as that observed with drug treatment for chronic HFrEF
trials, statins can reduce the incidence of heart failure over the past three decades. Unfortunately, no evidence
hospitalisation.100 Adherence to healthy lifestyle factors, basis exists for the treatment of HFpEF or acute heart
no smoking, regular exercise, healthy weight, moderate failure, beyond management of cardiovascular risk
alcohol intake, and consumption of breakfast cereal and factors. Therefore, notwithstanding improved outcome
fruits and vegetables was found to be associated with a in prevalent heart failure, delaying or preventing this
lower risk of developing heart failure.101 in men who were condition has become increasingly important in patients
apparently healthy at baseline. Furthermore, observational at-risk and should be prioritised in future research
data for 11 351 participants in the ARIC (Atherosclerosis programmes. The prevention of chronic heart failure
in the Community) study.102 showed that maintenance of from worsening and from needing hospital admission
recommended activity levels was associated with the for acute symptoms is also of paramount importance.
lowest heart failure risk, and that initiation and increase Implementation of disease management programmes,
of physical activity, even in late middle age (around possibly including modern monitoring technology,
60 years), were also linked to lower heart failure risk. The might, in our opinion, help to achieve this objective.
authors concluded that “augmenting physical activity in Contributors
middle age may be an important component of strategies PR developed the outline of the manuscript. All authors contributed to
to prevent heart failure”. However, heart failure the literature searches and reviews, and assisted in the writing of
sections and figures.
prevention in these observational data could be the result
of better control of risk factors and prevention of Declaration of interests
PR is a co-founder of CardioRenal and declares personal fees
ischaemic heart disease. In patients with ischaemic heart (consulting) from Novartis, NovoNordisk, Relypsa, AstraZeneca,
disease, ACE inhibitors delay the onset of heart failure Grünenthal, Idorsia, Stealth Peptides, Fresenius, Vifor Fresenius
and reduce cardiovascular mortality.103 Medical Care Renal Pharma, Vifor, and Clinical Trials Mobile
Identification of mechanistic therapeutic targets (eg, Application; and lecture fees from Bayer and CVRx. AFH has received
research grants from Amgen, AstraZeneca, Boehringer Ingelheim,
cardiac remodelling, inflammation, fibrosis, diastolic Vol 393 March 9, 2019 1041


Bristol-Myers Squibb (BMS), Daiichi, GlaxoSmithKline (GSK), Janssen, 13 Dokainish H, Teo K, Zhu J, et al. Global mortality variations in
Luitpold, Merck, US National Lung, Heart, and Blood Institute, Novartis, patients with heart failure: results from the International
PCORI, and Portola; and consultation fees from Amgen, AstraZeneca, Congestive Heart Failure (INTER-CHF) prospective cohort study.
Bayer, Boston Scientific, Merck, Novartis, Pfizer. SDS has received Lancet Glob Health 2017; 5: e665–72.
research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, 14 Crespo-Leiro MG, Anker SD, Maggioni AP, et al. European Society
Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year
Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, The National follow-up outcomes and differences across regions. Eur J Heart Fail
2016; 18: 613–25.
Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos;
and consultation fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, 15 Van Aelst LNL, Arrigo M, Placido R, et al. Acutely decompensated
heart failure with preserved and reduced ejection fraction present
BMS, Cardior, Corvia, Cytokinetics, Gilead, GSK, Ironwood, Merck,
with comparable haemodynamic congestion. Eur J Heart Fail 2018;
Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, 20: 738–47.
AoBiome, Janssen, and Cardiac Dimensions. FZ is the founder of
16 Harjola VP, Parissis J, Brunner-La Rocca HP, et al. Comprehensive
Cardiovascular Clinical Trialists and of CardioRenal and declares in-hospital monitoring in acute heart failure: applications for
personal fees for steering committee membership and consultancy from clinical practice and future directions for research. A statement
Amgen, Janssen, Bayer, Novartis, Boston Scientific, Resmed, Takeda, from the Acute Heart Failure Committee of the Heart Failure
General Electric, Boehringer Ingelheim, AstraZeneca, CVRx, Quantum Association (HFA) of the European Society of Cardiology (ESC).
Genomics, Relypsa, and ZS Pharma. Eur J Heart Fail 2018; 20: 1081–99.
Acknowledgments 17 Ibrahim NE, Januzzi JL Jr. The future of biomarker-guided therapy
for heart failure after the guiding evidence-based therapy using
The authors acknowledge the contributions of Wendy Gattis Stough,
biomarker intensified treatment in heart failure (GUIDE-IT) study.
who was funded by Centre Hospitalier Régional Universitaire de Nancy, Curr Heart Fail Rep 2018; 15: 37–43.
for editing and assisting with the preparation of the manuscript. PR and
18 Felker G, Anstrom KJ, Adams KF, et al. Effect of natriuretic
FZ are supported by the French National Research Agency (Fight heart peptide-guided therapy on hospitalization or cardiovascular mortality
failure programme ANR-15-RHU-0004 and GEENAGE Impact in high-risk patients with heart failure and reduced ejection fraction:
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