Emerging treatments

Calcium-sensitizing agents

Levosimendan, a novel calcium sensitizer, improves myocardial contractility without causing an increase in myocardial oxygen demand. Its role in acute, decompensated heart failure is more established than in chronic heart failure, but it may reduce overall mortality and length of hospitalization.[176] In the LIDO study, levosimendan improved survival and hemodynamic performance more effectively than dobutamine, in patients with severe, low-output heart failure.[177] The superiority of levosimendan over dobutamine in improving central hemodynamics and left ventricular performance seems in part to be related to its anti-inflammatory and anti-apoptotic effects.[178]

n-3 polyunsaturated fatty acids (n3-PUFA)

The GISSI-HF trial showed that the addition of n3-PUFA produced a small improvement in mortality and hospital admissions in patients with heart failure.[179] However, a 2012 meta-analysis has shown insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease.[180] Omega-3 PUFA supplementation is reasonable to use as adjunctive therapy in patients with New York Heart Association class II to IV symptoms and heart failure, unless contraindicated, to reduce mortality and cardiovascular hospitalizations.

Statins

Statins are not beneficial as adjunctive therapy when prescribed solely for treatment of heart failure in the absence of other indications for their use.[2] Statin therapy has been broadly implicated in prevention of adverse cardiovascular events, including new-onset heart failure. Originally designed to lower cholesterol in patients with cardiovascular disease, statins are known to have beneficial effects on inflammation, oxidative stress, and vascular performance. To date, a sufficient body of evidence does not exist to support the primary prescribing of statins for the treatment of heart failure to improve clinical outcomes.[2]

Nonspecific immunomodulation therapy

Inflammatory mediators are proposed to play a role in heart failure development and progression. In the ACCLAIM trial, nonspecific immunomodulation therapy reduced the risk of hospitalization or death, suggesting that this therapy may be of benefit in heart failure patients.[181]

Recombinant human growth hormone

Preliminary studies suggest that recombinant human growth hormone may have beneficial effects in patients with left ventricular dysfunction, although it may produce an increased risk of arrhythmias.[182][183] Further studies are required to determine the safety and efficacy of this treatment.

Trimetazidine

In a meta-analysis, trimetazidine, which shifts energy production from fatty acid oxidation to glucose oxidation, was shown to have no effect on mortality, but it improves left ventricular ejection fraction (LVEF) and functional class.[184]

Sodium–glucose cotransporter 2 (SGLT2) inhibitors

SGLT2 inhibitors have been investigated for patients with heart failure with and without diabetes. In a phase 3 randomized controlled trial, dapagliflozin was found to reduce the risk of worsening heart failure or death from cardiovascular causes compared with placebo in patients with heart failure and reduced ejection fraction, regardless of whether the patient also had diabetes.[185] The US Food and Drug Administration (FDA) has approved dapagliflozin for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization. In Europe, dapagliflozin and empagliflozin are approved for the treatment of adults with symptomatic chronic heart failure with reduced ejection fraction. Empagliflozin has been granted fast track designation by the FDA for the reduction of risk for cardiovascular death and hospitalization for heart failure in people with chronic heart failure.

Vericiguat

The Food and Drug Administration has approved vericiguat, an orally administered soluble guanylate cyclase stimulator, for treatment of chronic heart failure in patients who are hospitalised for heart failure or need outpatient intravenous diuretics. In Europe, vericiguat is approved for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilised after a recent decompensation event requiring intravenous therapy.

Novel implantable devices

Cardiac contractility modulation (CCM) delivers non-excitatory electrical stimulation to the ventricle during the absolute refractory period to enhance contractile performance without activating extra systolic contractions. CCM works via key calcium regulatory pathways that increase cardiac contractility.[186] The Optimizer Smart system is an implantable pulse generator that delivers CCM therapy and has been approved by the FDA for the treatment of patients with chronic, moderate-to-severe heart failure who are not suited for treatment with other heart failure devices such as cardiac resynchronization therapy to restore a normal timing pattern of the heartbeat. The Barostim Neo System is an implantable device that delivers baroreflex activation therapy (BAT); it has been approved by the FDA for the improvement of symptoms in patients with advanced heart failure who are not suited for treatment with other heart failure devices, such as cardiac resynchronization therapy. In patients with New York Heart Association functional class III heart failure and ejection fraction <35% on chronic stable guideline-directed medical therapy, use of BAT has been shown to improve functional status, quality of life, exercise capacity, and N-terminal pro–brain natriuretic peptide levels.[187]

Stem-cell therapy

Some trials of stem-cell therapy in both ischemic and nonischemic heart failure have shown some potential benefit.[188] A systematic review on the use of stem-cell therapy for chronic ischemic heart disease and congestive heart failure suggests that at both short- and long-term follow-up (≥12 months) the use of autologous bone marrow stem-cell treatment reduces all-cause mortality, although the quality of evidence is low.[189]

Gene therapy

An attractive strategy for treatment of heart failure is by gene therapy.[190] In a small randomized study of patients (n=56) with heart failure and LVEF <40%, intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) increased the LVEF at 4 weeks, with no increase in exercise duration.[191] In a larger double-blind placebo-controlled study (n=250), intracoronary infusion of 1 × 1013 DNase-resistant particle of adeno-associated virus 1 (AAV1)/sarcoplasmic endoplasmic reticulum Ca2 - ATPase (SERCA2a) did not improve the clinical course of patients with heart failure and reduced ejection fraction (ejection fraction ≤35%).[192]

Surgical strategies

There have been numerous reports of alternate surgical approaches for the treatment of end-stage heart failure.[193] Mitral valve repair or replacement has been shown to improve clinical status in patients who have a clinically important degree of mitral regurgitation that is secondary to left ventricular dilation.[194] However, no controlled studies have evaluated the effects of this procedure on ventricular function, rehospitalizations, or survival. One single-center study designed to assess the effects of mitral valve annuloplasty on mortality in patients with mitral regurgitation and left ventricular systolic dysfunction failed to demonstrate any clear survival benefit.[195] A variant of the aneurysmectomy procedure is now being developed for the management of patients with ischemic cardiomyopathy, but its role in the management of heart failure remains to be defined.[196] None of the current surgical reconstruction techniques offer "rescue therapy" to patients with critical hemodynamic compromise.

Intravenous iron

In patients with iron deficiency and systolic heart failure, treatment with intravenous ferric carboxymaltose has been associated with lower rates of recurrent cardiovascular hospitalizations and mortality.[197]

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