Heart failure with reduced ejection fraction - Emerging treatments

Furosemide (subcutaneous)

A subcutaneous formulation of furosemide has been approved in the US for the treatment of congestion due to fluid overload in adults with NYHA class II/III chronic heart failure. It is self-administered by the patient at home. It is available as a pre-programmed on-body infusor with a prefilled cartridge, and is not recommended for chronic use or use in emergency situations.

Sotagliflozin

Sotagliflozin is a dual inhibitor of both sodium-glucose cotransporter (SGLT)-1 and SGLT2. The US Food and Drug Administration (FDA) has approved sotagliflozin to reduce the risk of cardiovascular death, hospitalisation for heart failure, and urgent heart failure visits in adults with heart failure across the full range of left ventricular ejection fraction, or in adults with type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors.

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.[259] The Optimizer Smart system is an implantable pulse generator that delivers CCM therapy and has been approved by the US FDA for the treatment of patients with chronic, moderate-to-severe HF who are not suited for treatment with other HF devices such as cardiac re-synchronisation 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 HF who are not suited for treatment with other HF devices, such as cardiac re-synchronisation therapy (CRT). Systematic reviews and meta-analysis have found that BAT improves exercise capacity, NYHA class, and quality of life in patients with HFrEF receiving guideline-directed medical therapy.[260][261] Conduction system pacing (His-bundle and left bundle branch area pacing) is an emerging alternative for CRT. In one meta-analysis, conduction system pacing was found to be a feasible and effective alternative to biventricular pacing for CRT; further trials are needed.[262]

Stem-cell therapy

Some trials of stem-cell therapy in both ischaemic and non-ischaemic HF have shown some potential benefit.[263][264] A systematic review on the use of stem-cell therapy for chronic ischaemic heart disease and congestive HF 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.[265]

Gene therapy

An attractive strategy for treatment of HF is by gene therapy.[266] In a small randomised study of patients (n=56) with HF 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.[267] In a larger double-blind placebo-controlled study (n=250), intracoronary infusion of 1 x 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 HFrEF (ejection fraction ≤35%).[268]

Surgical strategies

There have been numerous reports of alternate surgical approaches for the treatment of end-stage HF.[269] 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.[270] However, no controlled studies have evaluated the effects of this procedure on ventricular function, re-hospitalisations, or survival. One single-centre 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.[271] A variant of the aneurysmectomy procedure is now being developed for the management of patients with ischaemic cardiomyopathy, but its role in the management of HF remains to be defined.[272] None of the current surgical reconstruction techniques offer 'rescue therapy' to patients with critical haemodynamic compromise.

Omecamtiv mecarbil

Omecamtiv mecarbil is a novel selective cardiac myosin activator (myotrope). In the GALACTIC-HF phase 3 randomised controlled trial, patients with HF and a reduced ejection fraction (HFrEF) who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo, including those with low systolic blood pressure (≤100 mmHg); however, there was no difference in all-cause mortality.[273] In a pre-specified sub-group analysis of GALACTIC-HF, omecamtiv mecarbil was shown to produce a greater therapeutic benefit as baseline ejection fraction decreased.[274] A post-hoc analysis of GALACTIC-HF found that patients with severe HF (defined as patients with New York Heart Association [NYHA] symptom class III to IV, left ventricular ejection fraction [LVEF] ≤30%, and hospitalisation for HF within the previous 6 months) benefited from treatment with omecamtiv mecarbil for the primary end point of time to first HF event or death from cardiovascular causes, whereas patients without severe HF experienced no significant treatment benefit.[275] The study found omecamtiv mecarbil was well tolerated with no significant changes in blood pressure, kidney function, or potassium level, compared with placebo. The US Food and Drug Administration (FDA) granted Fast Track designation for its development as a potential treatment of chronic HFrEF; however, in December 2022, the FDA voted against approval, noting that the overall treatment effect in the GALACTIC-HF trial was small, and none of the secondary end points were met. In 2023, the application for approval was rejected with a request for more data. An application for marketing authorisation in Europe has also been withdrawn.