Dr. Ihab Ramzy,
Heart failure (HF) is a major public health concern affecting as many as 23 million people worldwide . Furthermore, the hospitalisation rate and costs of care are enormous. The goals of treatment in patients with HF are to improve their clinical status, functional capacity and quality of life, prevent hospital admission and reduce mortality.
There has been substantial progress in the management of HF with drugs. One ongoing challenge is to ensure that proven HF therapies are used at tolerated target doses. Because of high morbidity and mortality, there is an overwhelming need for new therapies that are safe in improving outcomes in HF patients.
ACE: angiotensin-converting enzyme
ACEI: angiotensin-converting enzyme inhibitor
ADHF: acute decompensated heart failure
AF: atrial fibrillation
AHF: acute heart failure
ANP: A-type natriuretic peptide
ARB: angiotensin receptor blocker
ARNI: angiotensin receptor neprilysin inhibitor
BEAUTIFUL: morBidity-mortality EvAlUaTion of the If inhibitor Ivabradine in patients with coronary disease and left ventricULar Systolic Dysfunction study
BNP: B-type natriuretic peptide
bpm: beats per minute
CKD: chronic kidney disease
EMA: European Medicines Agency
FDA: Food and Drug Administration
HARMONIZE: Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients study
HF: heart failure
HFrEF: heart failure with reduced ejection fraction
HR: heart rate
LV: left ventricular/left ventricle
LVEF: left ventricular ejection fraction
MRA: mineralocorticoid receptor antagonist
NP: natriuretic peptide
NT-proBNP: N-terminal pro-B type natriuretic peptide
NYHA: New York Heart Association
PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial
RAAS: renin-angiotensin-aldosterone system
RCT: randomised controlled trial
SHIFT: Systolic Heart failure treatment with the If inhibitor ivabradine Trial
Neurohormonal antagonists have been shown to improve survival in patients with heart failure with reduced ejection fraction (HFrEF) and are recommended for the treatment of every patient with HFrEF, unless contraindicated or not tolerated. A new compound (LCZ696) that combines the moieties of an angiotensin receptor blocker (ARB; valsartan) and a neprilysin inhibitor (sacubitril) has recently been shown to be superior to an angiotensin-converting enzyme inhibitor (ACEI;enalapril) in reducing the risk of death and of hospitalisation for HF in a single trial with strict inclusion/exclusion criteria . LCZ696 is therefore recommended to replace ACEIs in ambulatory HFrEF patients who remain symptomatic despite optimal therapy. ARBs have not been consistently proven to reduce mortality in patients with HFrEF, and their use should be restricted to patients intolerant of an ACEI or those who take an ACEI but are unable to tolerate a mineralocorticoid receptor antagonist (MRA). Ivabradine reduces the elevated heart rate often seen in HFrEF and has also been shown to improve outcomes, and should be considered when appropriate. The above medications should be used in conjunction with diuretics in patients with symptoms and/or signs of congestion.
ACEIs have been shown to reduce mortality and morbidity in patients with HFrEF  and are recommended unless contraindicated or not tolerated in all symptomatic patients. ACEIs should be up-titrated to the maximum tolerated dose in order to achieve adequate inhibition of the renin-angiotensin-aldosterone system (RAAS). ACEIs are also recommended in patients with asymptomatic left ventricular (LV) systolic dysfunction to reduce the risk of HF development, HF hospitalisation and death.
Beta-blockers reduce mortality and morbidity in symptomatic patients with HFrEF, despite treatment with an ACEI and, in most cases, a diuretic , but have not been tested in congested or decompensated patients. It is known that beta-blockers and ACEIs are complementary, and can be started together as soon as the diagnosis of HFrEF is made. There is no evidence favouring the initiation of treatment with a beta-blocker before an ACEI has been started . Beta-blockers should be initiated in clinically stable patients at a low dose and gradually up-titrated to the maximum tolerated dose. In patients admitted due to acute HF (AHF), beta-blockers should be cautiously initiated in hospital, once the patient is stabilised. Beta-blockers should be considered for rate control in patients with HFrEF and atrial fibrillation (AF), especially in those with a high heart rate.
Beta-blockers are recommended in patients with a history of myocardial infarction and asymptomatic LV systolic dysfunction to reduce the risk of death.
MRA (spironolactone and eplerenone) block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormone (e.g., corticosteroids, androgens) receptors. Spironolactone or eplerenone is recommended in all symptomatic patients (despite treatment with an ACEI and a beta-blocker) with HFrEF and left ventricular ejection fraction (LVEF) ≤35%, to reduce mortality and HF hospitalisation .
Caution should be exercised when MRA are used in patients with impaired renal function and in those with serum potassium levels>5.0 mmol/L. Regular checks of serum potassium levels and renal function should be performed according to clinical status.
Diuretics are recommended to reduce the signs and symptoms of congestion in patients with HFrEF, but their effects on mortality and morbidity have not been studied in randomised controlled trials (RCTs). Loop diuretics produce a more intense and shorter diuresis than thiazides, although they act synergistically and the combination may be used to treat resistant oedema. However, adverse effects are more likely and these combinations should only be used with care. The aim of diuretic therapy is to achieve and maintain euvolaemia with the lowest achievable dose. The dose of the diuretic must be adjusted according to individual needs over time. In selected asymptomatic euvolaemic/hypovolaemic patients, the use of a diuretic drug might be (temporarily) discontinued.
Currently, blockade of the RAAS is the cornerstone of the treatment of HF. However, the combination of RAAS blockade with inhibition of neprilysin, an enzyme that degrades natriuretic peptides (NPs), has recently emerged as a potentially superior treatment strategy . In July 2015, the Food and Drug Administration (FDA) approved sacubitril/valsartan (previously known as LCZ696) for use in patients who have chronic and stable but symptomatic HF and who have an LVEF of less than 40%. The drug should be used in conjunction with other HF therapies but in place of ACE inhibitors or ARBs, and is contraindicated in patients with a history of ACE inhibitor or ARB-induced angioedema.
The first in class is LCZ696, which is a molecule that combines a neprilysin inhibitor (sacubitril) and an ARB (valsartan) in a single substance. Neprilysin is a zinc-dependent neutral endopeptidase that is responsible for the degradation of several vasoactive peptides such as NPs, bradykinin, and adrenomedullin and contributes to the breakdown of angiotensin II . High circulating A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) exert physiologic effects through binding to NP receptors and the augmented generation of cGMP, thereby enhancing diuresis, natriuresis and myocardial relaxation and anti-remodelling. ANP and BNP also inhibit renin and aldosterone secretion. Selective AT1-receptor blockade reduces vasoconstriction, sodium and water retention and myocardial hypertrophy .Neprilysin inhibition is thought to be the therapeutic target for counteracting the neurohormonal activation and complementarily inhibiting the RAAS.
The PARADIGM trial
The PARADIGM-HFtrial was conducted in 8,399 patients who had New York Heart Association (NYHA)Class II-IV HF and an LVEF of not more than 40% (this was changed to ≤35% during the study) and who were randomly assigned to LCZ696 or enalapril . The trial was stopped early because of an overwhelming benefit with LCZ696 therapy. The composite primary endpoint, including cardiovascular mortality and hospitalisation for HF, occurred significantly more often in patients receiving LCZ696 compared with those receiving enalapril (hazard ratio [HR] 0.80, 95% confidence interval [CI]: 0.73-0.87, p<0.001). LCZ696 was also associated with significant reductions in all-cause mortality, cardiovascular mortality, and hospitalisation for worsening HF. Furthermore, those patients who received LCZ696 had lower levels of the biomarkers NT-proBNP and troponin compared with those receiving enalapril. These differences were apparent within four weeks of treatment and were maintained when patients were assessed again eight months later. Interestingly, levels of BNP actually increased: this is consistent with the mechanisms of action of neprilysin inhibition . This trial provided strong evidence for superiority of the ARNI in patients with HFrEF .
Despite the superiority of LCZ696 over enalapril in the PARADIGM-HF trial, some relevant safety issues remain when initiating therapy with this drug in clinical practice. Symptomatic hypotension was more often present in the sacubitril/valsartan group (in those ≥75 years of age, it affected 18% in the sacubitril/valsartan group vs. 12% in the enalapril group), although there was no increase in the rate of discontinuation . The risk of angioedema in the trial was reduced by recruiting only those who tolerated therapy with enalapril 10 mg b.i.d. and sacubitril/valsartan during an active run-in phase of five to nine weeks (it resulted in a 0.4% rate of angioedema in the sacubitril/valsartan group vs. 0.2% in the enalapril group). Also, the number of African American patients, who are at a higher risk of angioedema, was relatively small in this study. To minimise the risk of angioedema caused by overlapping ACE and neprilysin inhibition, the ACEI should be withheld for at least 36 hrs before initiating sacubitril/valsartan. Combined treatment with an ACEI (or ARB) and sacubitril/valsartan is contraindicated.
One novel potential therapeutic option for HF is heart rate (HR) control. An elevated HR, probably reflecting activation of the sympathetic nervous system, is associated with worse cardiovascular outcomes. Although beta-blockers are used mainly for reducing HR in HF treatment, up-titration of beta-blockers can be associated with an increased risk of adverse reactions . Ivabradine, which acts by directly and selectively inhibiting the If current in the sinoatrial node and therefore should only be used for patients in sinus rhythm, has potential benefits of pharmacologic modification of HR in HF. The European Medicines Agency (EMA) approved ivabradine for use in Europe in patients with HFrEF with LVEF ≤35% and in sinus rhythm with a resting heart rate ≥75 bpm, because in this group ivabradineconferred a survival benefit  based on a retrospective subgroup analysis requested by the EMA.
Ivabradine lowers HR by inhibiting a specific sinus node pacemaker If current without affecting the myocardial contractility or relaxation, ventricular repolarisation, or intracardiac conduction. This is rather different from the mechanism induced by beta-blockers, which acts wherever beta-adrenergic receptors are present, causing negative inotropism and vasoconstriction in the bronchi; and calcium channel blockers act on the calcium channels of the heart and smooth muscle, causing negative inotropism, hypotension, and constipation.
The BEAUTIFUL trial
The BEAUTIFUL trial was an RCT to test the efficacy of ivabradine in 10,917 patients with stable coronary disease and an LVEF of less than 40% and an HR of more than 60 beats per minute (bpm) . In this trial, ivabradine reduced HR but had no effect on the primary endpoint of cardiovascular death or admission to a hospital for new-onset or worsening HF. However, in a subgroup of patients with an HR of at least 70 bpm, ivabradine revealed a clear benefit with respect to the secondary endpoints of admission to a hospital for a fatal or non-fatal myocardial infarction and coronary revascularisation .
The SHIFT trial
The SHIFT trial was an RCT in 6,558 patients with stable symptomatic HF and an LVEF of not more than 35% in sinus rhythm with an HR of at least 70 bpm . In this trial, ivabradine significantly reduced the primary endpoint of a composite of cardiovascular death or hospital admission for worsening HF and deaths due to HF . The effect was consistent across all pre-specified subgroups, including the elderly . Further analyses proved that high HR as a risk factor in HF and lowering HR improve outcomes . Other analyses showed that ivabradine reduces the risk of rehospitalisation for HF and is associated with an improvement in quality of life. HR targeted below a threshold rather than HR reduction itself has demonstrated potential benefits. One problem with interpreting the results of the SHIFT trial is that many patients were not on target doses of beta-blockers. If indeed these patients were intolerant of higher doses of beta-blockers, then these results are quite important for clinical care. Given its promising therapeutic value, ivabradine is clearly desirable in patients with symptomatic LV systolic dysfunction, elevated HR, and an intolerance to beta-blockers.
ARB are recommended only as an alternative in patients intolerant of an ACEI.Candesartan has been shown to reduce cardiovascular mortality .Valsartan showed an effect on hospitalisation for HF (but not on all-cause hospitalisations) in patients with HFrEF receiving background ACEIs. The combination of ACEI/ARB for HFrEF was reviewed by the EMA, which suggested that the benefits are thought to outweigh the risks only in a select group of patients withHFrEF in whom other treatments are unsuitable. Therefore, ARBsare indicated for the treatment of HFrEF only in patients who cannot tolerate an ACEI because of serious side effects. The combination of ACEI/ARB should be restricted to symptomatic HFrEF patients receiving a beta-blocker who are unable to tolerate an MRA, and must be used under strict supervision.
There is no clear evidence to suggest the use of this fixed-dose combination therapy in all patients with HFrEF. Evidence on the clinical utility of this combination is scanty and comes from one relatively small RCT conducted exclusively in men and before ACEIs or beta-blockers were used to treat HF.
Additionally, a combination of hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who can tolerate neither ACEI nor ARB (or they are contraindicated) to reduce mortality. However, this recommendation is based on the results of the Veterans Administration Cooperative Study, which recruited symptomatic HFrEF patients who received only digoxin and diuretics .
Table 1 summarises the above recommended treatments in selected patients with symptomatic heart failure with reduced ejection fraction.
Table1. Pharmacological treatments recommended in selected patients with symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction.
Class of recommendation
Level of evidence
Diuretics are recommended in order to improve symptoms and exercise capacity in patients with signs and/or symptoms of congestion.
Diuretics should be considered to reduce the risk of HF hospitalisation in patients with signs and/or symptoms of congestion.
Angiotensin receptor neprilysin inhibitor
Sacubitril/valsartan is recommended as a replacement for an ACEI to reduce further the risk of HF hospitalisation and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACEI, a beta-blocker and an MRAa.
Ivabradine should be considered to reduce the risk of HF hospitalisation and cardiovascular death in symptomatic patients with LVEF ≤35%, in sinus rhythm and a resting heart rate ≥70 bpm despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACEI (or ARB), and an MRA (or ARB).
Ivabradine should be considered to reduce the risk of HF hospitalisation and cardiovascular death in symptomatic patients with LVEF ≤35%, in sinus rhythm and a resting heart rate ≥70 bpm who are unable to tolerate or have contraindications for a beta-blocker. Patients should also receive an ACEI (or ARB) and an MRA (or ARB).
An ARB is recommended to reduce the risk of HF hospitalisation and cardiovascular death in symptomatic patients unable to tolerate an ACEI (patients should also receive a beta-blocker and an MRA).
An ARB may be considered to reduce the risk of HF hospitalisation and death in patients who are symptomatic despite treatment with a beta-blocker who are unable to tolerate an MRA.
Hydralazine and isosorbide dinitrate
Hydralazine and isosorbide dinitrate should be considered in self-identified black patients with LVEF ≤35% or with an LVEF <45% combined with a dilated LV in NYHA Class III-IV despite treatment with an ACEI, a beta-blocker and an MRA, to reduce the risk of HF hospitalisation and death.
Hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who can tolerate neither an ACEI nor an ARB (or they are contraindicated) to reduce the risk of death.
Other treatments with less certain benefits
Digoxin may be considered in symptomatic patients in sinus rhythm despite treatment with an ACEI (or ARB), a beta-blocker and an MRA, to reduce the risk of hospitalisation (both all-cause and HF-hospitalisations).
aPatient should have elevated natriuretic peptides (plasma BNP ≥150 pg/mL or plasma NT-proBNP ≥600 pg/mL, or, if HF hospitalisation within the last 12 months, plasma BNP ≥100 pg/mL or plasma NT-proBNP ≥400 pg/mL) and be able to tolerate enalapril 10 mg b.i.d.
ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BNP: B-type natriuretic peptide; bpm: beats per minute; HF: heart failure; HFrEF: heart failure with reduced ejection fraction; LVEF: left ventricular ejection fraction; MRA: mineralocorticoid receptor antagonist; NT-proBNP: N-terminal pro-B type natriuretic peptide; NYHA: New York Heart Association. OMT: optimal medical therapy (for HFrEF this mostly comprises an ACEI or sacubitril/valsartan, a beta-blocker and an MRA).
Digoxin may be considered in patients in sinus rhythm with symptomatic HFrEF to reduce the risk of hospitalisation (both all-cause and HF hospitalisations),although its effect on top of beta-blockers has never been tested. The effects of digoxin in patients with HFrEF and AF have not been studied in RCTs, and recent studies have suggested a potentially higher risk of events (mortality and HF hospitalisation) in patients with AF receiving digoxin.
In patients with symptomatic HF and AF, digoxin may be useful to slow a rapid ventricular rate, but it is only recommended for the treatment of patients with HFrEF and AF with rapid ventricular rate when other therapeutic options cannot be pursued. Of note, the optimal ventricular rate for patients with HF and AF has not been well established, but the prevailing evidence suggests that strict rate control might be deleterious. A resting ventricular rate in the range of 70-90 bpm is recommended based on current opinion.
Digitalis should always be prescribed under specialist supervision. Given its distribution and clearance, caution should be exerted in females, in the elderly and in patients with reduced renal function. In the latter patients, digitoxin should be preferred.
As the use of RAAS inhibitors and MRA in patients with HF increases, hyperkalaemia has become a more common electrolyte disturbance in clinical practice, especially in patients with chronic kidney disease (CKD). Moreover, hyperkalaemia is a major limiting factor to titrate these drugs fullyin these patients who are most likely to benefit from treatment. Currently, non-invasive treatment of hyperkalaemia is limited by a lack of safety, efficacy, and tolerability. Thus, agents to control reliably the plasma concentration of potassium while maintaining the use of RAAS inhibitors or MRA are needed. Now, there are two novel potassium absorbents, patiromer calcium and zirconium silicate (ZS-9), that are designed to increase potassium loss via the gastrointestinal tract. Although they have not yet been approved by the FDA, both have demonstrated efficacy and safety in recent trials.
Patiromer is a non-absorbable polymer that binds potassium in exchange for calcium throughout the gastrointestinal tract. This agent, which is an orally administered drug, increases faecal excretion of potassium and consequently decreases plasma potassium levels. Prior patiromer clinical trials have also demonstrated the drug’s utility in treating hyperkalaemia in at-risk populations for periods ranging from a few days to up to 12 weeks .
2. Zirconium cyclosilicate (ZS-9)
ZS-9 is a high-specificity inorganic crystal that entraps potassium in the intestinal tract. Instead of exchanging calcium, ZS-9 exchanges sodium and hydrogen ions for potassium. Dose-dependent excretion of potassium occurs in the faeces, whereas urinary excretion decreases with dose.
The HARMONIZE study
The HARMONIZE study was an RCT evaluating the long-term efficacy and safety of ZS-9 in 258 patients with hyperkalaemia . Patients achieving normokalaemia (3.5 to 5.0 mEq/l) were randomly assigned to different doses of ZS-9 (5, 10, or 15 g) or placebo for 28 days in the maintenance phase. Mean baseline potassium was 5.6 mEq/l and declined to 4.5 mEq/l after 48 hours of 10g ZS-9 treatment in the acute phase. A significant reduction in potassium was observed within one hour of ZS-9 administration, and 84% of patients achieved normokalaemia at 24 hours and 98% at 48 hours . Furthermore, studies assessing the long-term efficacy and safety profile of this novel drug are ongoing.
Serelaxin is a recombinant form of the human hormone relaxin, which is a naturally occurring hormone that is produced by the corpus luteum and placenta in pregnancy. Recent studies have shown that relaxin is also produced by the vasculature and failing myocardium.
Relaxin interacts with a G protein-coupled receptor, leading to increased cyclic adenosine monophosphate (cAMP). As a result, nitric oxide production is increased. Additionally, relaxin upregulates the activity of vascular matrix metalloproteinase-2 (MMP-2), which can activate endothelin-1, leading to endothelin-B receptor activation and subsequent nitric oxide production. Activation of the endothelin-B receptor is probably involved in the relaxin-mediated increases in renal blood flow . Thus, relaxin increases cardiac output, arterial compliance, and renal blood flow, supporting important physiological changes during pregnancy. Given its potent vasodilator properties as well as its ability to increase renal perfusion, relaxin became of interest as a potential therapy for acute HF.
Decongestion is an important part of managing both acute and chronic HF, and retention of fluid and sodium metabolism play a fundamental role in this. NPs are activated in HF and exert compensatory effects by inhibiting the RAAS and inducing vasodilation and natriuresis. Therefore, NPs have received much interest as a potential therapy in acute decompensated heart failure (ADHF). NPs consist of ANP, BNP, C-type NP (CNP), D-type NP (DNP), and urodilatin.
Urodilatin was first isolated from human urine in 1988 as a modified version of pro-ANP. It is produced mainly by distal renal tubule cells and is secreted into urine and is involved in renal sodium handling . Synthetic NPs such as carperitide (a recombinant form of ANP) and nesiritide (a recombinant form of BNP) are currently used to treat congestive HF (carperitide is available only in Japan). When it is administered to patients with ADHF, a rapid reduction of pulmonary capillary pressure and consequent relief of dyspnoea often result because of natriuresis, diuresis, and venous and arterial dilation. In contrast to ANP and BNP, urodilatin is effective in more distal parts of the renal tubular system because of its slower elimination rate.
The treatment of heart failure has evolved rapidly over the past few years and many aspects of this are considered in this article. Patients are often complex, with multiple comorbidities, and being under specialist care has been shown to be associated with greater use of evidence-based therapies and improved survival. Future clinical trials with adequately powered, more appropriate study designs, optimal clinical endpoints, and proper patient selection are mandatory to assess the true efficacy of these treatments.
Dr Ihab S.Ramzy, MD, PhD, FESC
Northwick Park Hospital, London, United Kingdom
Address for correspondence:
Dr Ihab S. Ramzy
Specialty Doctor in Cardiology,Cardiology Department, Northwick Park Hospital,
Watford Road, Harrow, London, HA1 3UJ, United Kingdom
The author has no conflicts of interest to declare.
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