INTRODUCTION — Treatment of heart failure (HF) is aimed at three goals: improvement in symptoms, slowing of disease progression, and prolongation of survival [1]. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

Investigational and emerging therapies for chronic and acute HF are reviewed here. While beneficial effects have been seen with some of these interventions in preliminary studies, the risk/benefit ratio and true efficacy remain to be proven.

Standard therapies for HF are discussed elsewhere. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

INVESTIGATIONAL THERAPIES FOR CHRONIC HEART FAILURE

Modulation of heart rate or autonomic tone

Parasympathetic stimulation — Decreased parasympathetic nervous system (PNS) activity may contribute to the pathophysiology of HF [2], but the role of PNS stimulation as a treatment of HF is unknown. Based on animal models showing improvement in HF with PNS stimulation, the potential role of increasing PNS activity in the treatment of HF with reduced ejection fraction (HFrEF) is being evaluated in humans. Several trials are underway to examine the effects of increasing PNS activity via vagus nerve stimulation on cardiac structure, function, and clinical outcomes [3].

Other — Use of beta blocker therapy and sinus node inhibition in patients with HF is discussed separately. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Beta blocker'.)

Vasodilators

Sildenafil — Although sildenafil has some beneficial hemodynamic effects, a clinical benefit has not been clearly established. Sildenafil, a selective inhibitor of type 5 phosphodiesterase (PDE-5), lowers pulmonary vascular resistance and systemic arterial load and reduces left ventricular (LV) contractility [4]. A meta-analysis included nine randomized trials comparing sildenafil with placebo in 612 patients with HF [5]. Sildenafil therapy was associated with improvement in peak V_O2 in patients with HF with reduced LVEF but not in patients with HF with preserved ejection fraction. Quality of life was not significantly different with sildenafil therapy. Adverse events were similar in sildenafil and placebo groups.

The largest trial included in the meta-analysis was the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial [6]. The trial enrolled 216 stable outpatients with HF with LVEF ≥50 percent, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity who were randomly assigned to treatment with sildenafil or placebo for 24 weeks. Sildenafil did not improve exercise capacity (peak oxygen consumption or six-minute walk distance) or clinical status rank score compared with placebo.

Potential safety concerns relating to administration of PDE-5 inhibitors in patients with HF are discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

Hawthorn extract — The efficacy of hawthorn extract in the treatment of HF is uncertain since randomized trials have yielded mixed results.

Hawthorn extract is an herbal agent derived from species of the hawthorn plant (Crataegus monogyna or Crataegus laevigata). It is approved for use in Germany for patients with NYHA class II HF. Proposed mechanisms of action include vasodilation, as well as antioxidant activity, inotropy, and lipid lower effects [7].

Although a meta-analysis found that hawthorn extract produced symptomatic and functional benefit in patients with chronic HF, two subsequently published randomized trials in patients with HFrEF found no benefit from hawthorn extract. It is unclear whether this difference in results is related to differences in patient populations (eg, the meta-analysis was not limited to HFrEF while the two later trials were limited to patients with HFrEF), differences in treatment regimens, or the effect of chance.

The meta-analysis included 10 randomized trials enrolling a total of 855 patients with chronic HF (NYHA class I to III) [8]. Most of the included trials did not require systolic dysfunction. Treatment with hawthorn was associated with greater exercise tolerance and maximal achieved workload as well as beneficial reductions in pressure-heart rate product and symptoms of shortness of breath and fatigue. Dosing varied widely (160 to 1800 mg), and impact on mortality was not determined.

Two subsequently published randomized placebo-controlled trials failed to find a benefit from hawthorn extract:

●The SPICE trial randomly assigned 2681 patients with NYHA class II to III HF and LVEF ≤35 percent to hawthorn extract or placebo. No effect of hawthorn was observed on the primary outcome of time until first cardiac event (cardiac death, nonfatal myocardial infarction, and hospitalization due to progressive HF) [9]. Adverse events were comparable in the two groups.

●The HERB CHF trial randomly assigned 120 adults with NYHA class II to III chronic HF and LVEF ≤40 percent to hawthorn extract or placebo. There was no symptomatic or functional benefit from hawthorn extract compared with placebo at six-month follow-up [10]. Adverse events (most noncardiac) were significantly more frequent in the hawthorn group (60 versus 38 percent).

Myotrope — The efficacy and safety of therapy with a myotrope (inotrope that affects the myocardial molecular motor and scaffolding [11]) is under investigation. Omecamtiv mecarbil is a novel myotrope that improves myocardial contractility by selectively binding to cardiac myosin and increasing the number of myosin heads that can bind to actin filaments. In the GALACTIC-HF trial, 8256 patients (inpatients and outpatients) with chronic HF and LVEF ≤35 percent were randomly assigned to receive omecamtiv mecarbil (25, 37.5, or 50 mg twice daily based on plasma levels of the drug) or placebo, in addition to standard HF therapy [12]. The active drug group experienced a lower incidence of the primary composite outcome of first HF event (hospitalization or urgent visit for HF) or death from cardiovascular causes (37 versus 39.1 percent; HR 0.92, 95% CI 0.86-0.99) at a median of 21.8-month follow-up compared with the placebo group. However, rates of cardiovascular death were similar (19.6 versus 19.4 percent). At week 24, the decline in N-terminal pro-B-type natriuretic peptide level was 10 percent greater, and the median cardiac troponin I level was 4 mg per liter higher in the omecamtiv mecarbil group.

Hormones

Testosterone — The efficacy and safety of testosterone therapy in patients with HF have not been established. Preliminary data suggest that testosterone therapy may improve functional capacity in patients with HF, but data are insufficient to determine safety and effects on clinical events. A meta-analysis of four randomized trials enrolling a total of 198 patients (84 percent male) found that testosterone therapy significantly improved exercise capacity (measured by six-minute walk test, incremental shuttle walk test, or peak V_O2) compared with placebo [13]. No significant effect on cardiovascular events was found.

As discussed separately, disorders including sudden death, hypertension, and left ventricular hypertrophy have been reported in individuals taking androgens, but a causal relationship has not been established. United States Food & Drug Administration-approved labeling includes a warning that edema, with or without HF, may be a complication of androgen treatment in patients with pre-existing cardiac, renal, or hepatic disease [14] (see "Use of androgens and other hormones by athletes"). The 2010 Endocrine Society guidelines on testosterone therapy for men with androgen deficiency recommended against testosterone therapy in patients with uncontrolled or poorly controlled HF [15]. Testosterone was not recommended for treatment of HF by the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines [1]. (See "Drugs that should be avoided or used with caution in patients with heart failure", section on 'Androgens'.)

Growth hormone — The clinical efficacy of growth hormone in the treatment of HF has not been established. Cardiovascular benefits have been observed in patients with growth hormone deficiency but an effect on clinical end points has not been demonstrated in patients who are not growth hormone deficient.

A meta-analysis included 12 studies (eight randomized controlled trials and four uncontrolled studies) with a total of 195 patients with HF without growth hormone deficiency treated with growth hormone for over one month [16]. Pooled data from the randomized trials demonstrated improvement in peak oxygen uptake, increase in interventricular septum thickness, and reduction in left ventricular end-systolic wall stress with growth hormone compared with placebo. Pooled data from all studies suggested additional associations with growth hormone administration, including improvements in LVEF, NYHA functional class, and exercise duration, but there was significant heterogeneity among studies for LVEF.

A later study found that growth hormone deficiency was frequent in patients with HF and that treatment of growth hormone deficiency can improve cardiovascular parameters. Of 158 patients with chronic HF, 40 percent met criteria for hormone deficiency with growth hormone stimulation testing [17]. Of the 63 growth hormone-deficient patients, 56 were randomly assigned to growth hormone plus standard therapy or standard therapy alone. At six months, growth hormone replacement therapy improved quality-of-life score, peak oxygen uptake, and exercise duration compared with standard therapy alone. At four-year follow-up of 17 patients in the growth hormone group and 14 in the control group, growth hormone improved peak oxygen uptake and LVEF while reducing left ventricular end-systolic volume index [18].

The general application of growth hormone administration in dilated cardiomyopathy should be considered with caution. The exact mechanism of benefit is uncertain, as are its impact, clinical outcomes, and the long-term effects of this therapy on myocardial function.

Growth hormone was not recommended as a therapy for HF in the 2013 ACC/AHA guidelines [19].

Cell therapy — Cell therapy involves transfer of cells (stem cells or skeletal myoblasts) to the myocardium to induce therapeutic myocardial regeneration and/or improvement in cardiac function. Clinical studies have investigated use of skeletal myoblasts, bone marrow mononuclear cells, bone marrow progenitor cells, mesenchymal stem cells, and cardiac stem cells to treat patients with chronic HF [20].

The mechanism of benefit from cell therapy is uncertain. Some studies have demonstrated that hematopoietic stem cells do not transdifferentiate into cardiac myocytes [21,22], except for a low rate of cell fusion events [22], and autologous skeletal myoblasts can contract but do not transdifferentiate into cardiomyocytes [23,24]. Studies in animal models found that endogenous cardiac progenitor cells contribute minimal or no cardiomyocytes to the heart [25,26]. The benefit from cellular therapy is likely a paracrine effect in which transplanted cells produce growth factors, cytokines, and other signaling molecules that may improve myocardial function via mechanisms such as increased myocardial perfusion due to angiogenesis, or prolongation of the survival of myocytes or other cells [23,27].

A systematic review and meta-analysis included 38 randomized controlled trials of autologous adult stem/progenitor cells compared with no stem/progenitor cells in 1907 participants with chronic ischemic heart disease and HF [28]. The meta-analysis found low-quality evidence of mortality benefit at ≥12 months (risk ratio [RR] 0.42, 95% CI 0.21 to 0.87) based upon data from nine trials with 491 participants. However, low-quality evidence showed no significant reduction in the risk of hospitalization for HF based on data from six trials with 375 participants (RR 0.63; 95% CI 0.36 to 1.09). Adverse events were infrequent, and no long-term adverse events were reported.

The limited clinical data available do not permit a full assessment of the potential risks of cellular cardiomyoplasty as a therapeutic modality. Three concerns are ventricular arrhythmias (particularly after myoblast injection), myocardial ischemia, and undesired cell differentiation (eg, bone formation [29] or perivascular fibrosis [30]). There are conflicting data as to whether there is an increase in the risk of ischemia and acute coronary syndrome [31,32].

Cell therapy early after acute myocardial infarction is discussed separately. (See "Overview of the non-acute management of ST elevation myocardial infarction", section on 'Hematopoietic stem cell therapy'.)

Gene therapy — Gene therapy approaches to HF are under investigation but have not yet been shown to be of clinical value. Studies of gene therapy for HF are based upon advances in gene transfer technology, including development of safe and efficient vectors and delivery methods as well as identification of appropriate therapeutic targets [33,34]. Potential targets for gene therapy include cardiomyocyte calcium (Ca²⁺) cycling (eg, through restoring activity of the sarcoplasmic reticulum calcium ATPase pump [SERCA2a] or improving S100A1 activity) and altering beta adrenergic system activity (eg, through inhibition of G-protein-couple receptor kinase 2 or improving adenylyl cyclase 6 activity). Further studies are needed to determine the safety and efficacy of gene therapy approaches for HF.

Immunotherapy

Immunosuppressive therapy — Immunosuppressive therapy appears to be of no benefit for an idiopathic dilated cardiomyopathy or myocarditis. However, it may be of value in some patients with a cardiomyopathy due to chronic inflammation, as discussed separately. (See "Treatment and prognosis of myocarditis in adults", section on 'Immunosuppressive therapy'.)

Intravenous immune globulin — The efficacy of intravenous immune globulin in treating dilated cardiomyopathy is uncertain, as discussed separately. (See "Treatment and prognosis of myocarditis in adults", section on 'Dilated cardiomyopathy'.)

Immunoadsorption — The efficacy of immunoadsorption as a therapy for HF or cardiomyopathy has not been established. Antibodies against cardiac cell proteins, including mitochondrial proteins, contractile proteins, and beta receptors, have been identified in dilated cardiomyopathy. (See "Myocarditis: Causes and pathogenesis".)

If cardiac autoantibodies contribute to myocardial dysfunction, their removal with immunoadsorption might improve LV hemodynamics. Several studies have demonstrated the potential benefit of this approach [35-40]:

●One report randomly assigned 18 patients to three sequential days of immunoadsorption with subsequent immunoglobulin IgG substitution or to control, who received no immunoadsorption [35]. After the first treatment, there was a significant decrease in systemic vascular resistance and an increase in stroke volume index and cardiac index from 2.1 to 2.8 L/min/m²; this improvement in hemodynamics persisted for three months. By contrast, there were no changes in the control group.

●In a second report, immunoadsorption completely eliminated the anti-beta-1 adrenoceptor autoantibodies in the 17 patients undergoing this therapy [36]. After one year, the mean LVEF increased from 22 to 38 percent, LV end-diastolic volume decreased by 14.5 percent, and the autoantibodies did not reappear. At the same time, there were no changes in antibody levels or LV function in the 16 patients undergoing only standard medical therapy.

●Another study indicated that the subclass of immunoglobulin may be important in antibody-mediated dilated cardiomyopathy (DCM). Column immunoadsorption was performed with either protein A columns (which bind to and remove most IgG, but have a low affinity for IgG3) or anti-IgG columns (which have specificity for all IgG subclasses). Only the anti-IgG column was associated with significant improvement in cardiac index with the first treatment and at three months [37]. This result is consistent with data suggesting that elevated IgG3 levels correlate with clinical disease in DCM [41,42]. (See "Myocarditis: Causes and pathogenesis".)

The improvement in LV function with immunoadsorption has been associated with reduced myocardial inflammation and reduced oxidative stress [38,39]. In one study, purification of the eluent collected from the immunoadsorption column found that the cardiodepressant substances are antibodies capable of binding to various myocardial proteins [40].

Thalidomide — Limited evidence is available on the efficacy and safety of thalidomide in patients with HF. Thalidomide is a drug with immunomodulating properties. Since inflammation is involved in the pathogenesis of HF, some studies have explored the effect of thalidomide in patients with HF [43].

The best evidence comes from a single center trial of 56 patients with NYHA class II or III HF and LVEF <40 percent (mean 25 percent), who were randomly assigned to thalidomide (target dose 200 mg daily) or placebo [44]. Patients received standard therapy for HF, including angiotensin converting enzyme inhibitors or angiotensin II receptor blockers and beta blockers. After 12 weeks, patients treated with thalidomide had a significant improvement in LVEF (24 to 32 percent), compared with no change in patients treated with placebo. Patients treated with thalidomide also had a significant reduction in matrix metalloproteinase-2, suggesting a matrix-stabilizing effect. NYHA classification and quality of life were unchanged in both treatment groups. Adverse effects were more common with thalidomide, including vertigo, constipation, and bradycardia.

Pentoxifylline — Limited data are available on the efficacy of pentoxifylline in patients with HF. Pentoxifylline inhibits the production of tumor necrosis factor alpha (TNFa). However, given the lack of apparent benefit with etanercept, a soluble tumor necrosis factor receptor fusion protein that binds to TNFa and functionally inactivates it, a possible improvement with pentoxifylline may be mediated by other mechanisms such as possible vasodilatory properties [45].

A meta-analysis included six randomized controlled trials with a total of 221 patients with HF with LVEF ≤40 percent [46]. No significant mortality benefit was seen in individual trials, but the pooled data showed a significant reduction in mortality (5.4 versus 18.3 percent). However, this finding is uncertain given the low number of events.

Immunomodulation — The role of immunomodulation therapy (IMT) remains to be established, though there is evidence to suggest that some patients may benefit from such therapy.

IMT is a type of immunotherapy that involves removal of a patient's blood, which is then treated and readministered to the patient via intramuscular injection. The treatment is thought to activate immune cells and to increase the elaboration of immune modulators. In an initial double-blind trial, 75 patients with NYHA functional chronic class III to IV HF were randomized to receive either IMT or placebo for six months with continuation of standard HF therapy [47]. Immunomodulation produced significant reductions in the risk of death and the risk of hospitalization. There was nonsignificant improvement in NYHA functional classification and quality of life and no change in LVEF.

In a larger double-blind, placebo-controlled study, 2426 patients with NYHA functional class II to IV HF with reduced ejection fraction were randomized to receive IMT or placebo with a mean follow-up of 10.2 months [48]. There was no significant effect on the primary end point, time to death from any cause, or first hospitalization for cardiovascular reasons. However, in two prespecified subgroups, patients with no history of previous myocardial infarction (n = 919) and patients with NYHA II HF (n = 689), IMT was associated with reductions in the primary end point (odds ratio [OR] 0.74, 95% CI 0.57-0.95 and OR 0.61, 95% CI 0.46-0.8, respectively).

Antiviral therapy — There is evidence of viral genome in endomyocardial biopsy specimens by the polymerase chain reaction in patients with chronic dilated cardiomyopathy. A possible role for antiviral therapy with beta interferon or alpha interferon has been investigated, as discussed separately. (See "Treatment and prognosis of myocarditis in adults", section on 'Antiviral therapy'.)

Device therapies — Enhanced external counterpulsation (EECP) and cardiac contractility modulation are discussed here. The role of ventricular assist devices in acute and chronic settings is discussed separately. (See "Short-term mechanical circulatory assist devices" and "Intermediate- and long-term mechanical circulatory support".)

Enhanced external counterpulsation — Limited data are available on the efficacy of EECP in patients with chronic HF. EECP is a technique that increases arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation). Cuffs are wrapped around the patient’s legs and, using compressed air, sequential pressure (300 mmHg) is applied (from the lower legs to lower and upper thighs) in early diastole to propel blood back to the heart. EECP has been most commonly evaluated in the treatment of refractory angina. (See "New therapies for angina pectoris", section on 'External counterpulsation'.)

Trials and registries of EECP included some patients with HF, some of whom had improvements in their exercise capacity following EECP therapy. The PEECH trial directly evaluated the possible benefit of EECP in patients with mild to moderate HF [49]. One hundred and eighty-seven patients were randomly assigned standard medical therapy with seven to eight weeks of EECP or standard medical therapy alone. Patients assigned to EECP were slightly more likely to increase their total exercise time by more than 60 seconds (35 versus 25 percent with standard medical therapy). However, EECP did not have any effect on peak V_O2. (See "Exercise capacity and VO2 in heart failure".)

Thus, this study did not achieve positive results for one of its two primary end points. In addition, the results of this single-blind trial are subject to placebo effect. Further research will be necessary to define the impact of EECP in the treatment of HF.

Cardiac contractility modulation — Cardiac contractility modulation (CCM) is a device-based therapy for HF that mildly improves functional measures but an effect on long-term clinical outcomes has not been established and there is a significant risk of complications. This therapy involves applying biphasic electric stimulation to the right ventricular septum during the cardiac absolute refractory period; these signals induce an acute mild augmentation of left ventricular (LV) contraction and may induce reverse LV remodeling and improve LVEF over time [50].

●A meta-analysis including three randomized controlled trials enrolling 641 participants with HF (with longest follow-up 24 to 50 weeks) found that CCM improved peak oxygen consumption (mean difference +0.71, 95% CI 0.20-1.21 mL/kg/min), six-minute walk test distance (mean difference +13.92, 95% CI -0.08 to 27.91 m) and quality of life measured by Minnesota Living With Heart Failure Questionnaire (mean difference -7.17, 95% CI -10.38 to -3.96) compared to sham treatment or usual care [51].

●A later randomized trial (FIX-HF-5C) enrolled 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms and LVEF ≥25 and ≤45 percent [52]. Survival free of cardiac death and HF hospitalization was significantly improved with CCM compared to usual care (97.1 versus 89.2 percent at 24 weeks). However, overall survival and survival free of any hospitalization was not significantly changed. In an analysis that combined data from FIX-HF-5C and FIX-HF-5 trials, peak oxygen consumption was significantly improved at 24 weeks with CCM compared to usual care (mean difference +0.84, 95% CI 0.12-1.55 mL/kg/min). In the FIX-HF-5C cohort, six-minute walk test distance, quality of life measured by Minnesota Living With Heart Failure Questionnaire and NYHA functional class were improved with CCM. There was a 10.3 percent rate of device- or procedure-related complications with CCM.

CCM is an option in patients with HFrEF with NYHA functional class III or IV symptoms despite optimal medical therapy. However, there are several limitations to the widespread use of CCM: the data regarding outcomes with CCM are limited and there is risk of bias due to lack of full blinding (ie, control subjects did not receive a generator implant), and outcomes less susceptible to lack of blinding such as all-cause death and survival free of hospitalization were not improved. Accordingly, CRT, which has more extensive supporting data, is the preferred approach in patients who qualify for CRT. (See "Cardiac resynchronization therapy in heart failure: Indications".)

Nutritional supplements

Coenzyme Q10 — A multicenter randomized trial found that coenzyme Q10 therapy reduced mortality and hospitalization in patients with moderate to severe HF, as described below [53]. Further data are needed to establish the efficacy and safety of coenzyme Q10 therapy in patients with HF.

Coenzyme Q10 is a vitamin-like, fat soluble quinone found in high concentrations in the mitochondria of the heart, liver, and kidney, where it is involved in electron and proton transfer during oxidative phosphorylation. It is also an antioxidant and free radical scavenger with membrane-stabilizing properties. Myocardial biopsies from patients with HF have demonstrated depletion of coenzyme Q10, an observation that provided the rationale for randomized controlled trials.

A systematic review included seven randomized trials with a total of 914 patients with HF comparing coenzyme Q10 with placebo [54]. Information on clinical end points was lacking. Pooled analysis suggested that coenzyme Q10 had no significant effect on LVEF or exercise capacity, but data were limited. Based on similar observations, coenzyme Q10 and other nutritional supplements were not recommended as a therapy for HF in the 2013 American College of Cardiology/American Heart Association guidelines [19].

However, a subsequent randomized trial provided evidence of clinical benefit from coenzyme Q10. In the Q-SYMBIO trial, 420 patients with chronic NYHA functional class III or IV HF were randomly assigned to either coenzyme Q10 100 mg three times daily or placebo, in addition to standard therapy [53]. Patients assigned to coenzyme Q10 had lower rates of cardiovascular mortality (9 versus 16 percent), all-cause mortality (10 versus 18 percent), and incidence of hospitalization for HF at two years. In addition, NYHA class was improved in the coenzyme Q10 group. The rates of adverse events were similar in the two treatment groups (13 and 19 percent).

Evidence is lacking to support use of other antioxidants in the treatment of HF [55,56].

Remote hemodynamic monitoring via device — The efficacy of remote hemodynamic monitoring using either existing cardiac resynchronization therapy (CRT) or implantable cardioverter-defibrillator (ICD) devices or implantable hemodynamic monitoring devices is of uncertain efficacy as discussed below.

Implantable hemodynamic monitoring — We suggest not using implantable hemodynamic monitoring as the efficacy of this approach is uncertain. The wireless CardioMEMS pulmonary artery monitoring device has been approved by the US Food and Drug Administration to monitor pulmonary artery pressure and heart rate in patients with NYHA class III HF who have been hospitalized during the previous year [57]. Further study is needed to determine the efficacy and safety of this device [58]. The 2016 ESC HF guidelines included only a very weak recommendation stating that this device may be considered in symptomatic patients with HF with previous HF hospitalization [59].

The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes In NYHA Class III Heart Failure Patients (CHAMPION) randomized single-blind trial of 550 patients found that transmission of pulmonary artery pressure data from the device reduced HF-related hospitalizations at six months (31 versus 44 percent, HR 0.70, 95% CI 0.60-0.84) [60]. There was a 1.5 percent rate of device- or system-related complications. An exploratory subgroup analysis found that device-guided management reduced HF-related hospitalization in patients with preserved LVEF (LVEF ≥40 percent or LVEF ≥50 percent), as well as in patients with LVEF <40 percent [61,62]. Another exploratory analysis found that device-guided management reduced respiratory hospitalization rates as well as HF hospitalization rates in the entire cohort, as well as in a subgroup of 187 patients with chronic obstructive pulmonary disease [63].

A later analysis reported sustained reduction in HF-related hospitalization in the device-guided management group compared with the control at 18-month average follow-up (46 versus 68 percent, HR 0.67, 95% CI 0.55 to 0.80) [64]. During a subsequent open access period (mean duration 13 months), pulmonary artery pressure information was made available to guide therapy in the former control group; the rate of admission was reduced compared with that in the control group during the randomized access period (36 versus 68 percent; HR 0.52, 95% CI 0.40 to 0.69). The rate of device- or system-related complications was 1 percent and the rate of procedure-related adverse events was 1 percent.

However, the efficacy of the CardioMEMS device is uncertain given concerns raised about potential bias introduced in the conduct of the CHAMPION trial (including interaction between the trial sponsor and clinical investigators on certain treatment group subjects) and the analysis of data [58,65].

Diagnostics using an existing device — We recommend against use of existing cardiac implantable electronic device diagnostics for remote hemodynamic monitoring in the management of HF given the lack of evidence of efficacy of this approach. Remote hemodynamic monitoring using existing CRT or ICD devices as a means to remotely guide outpatient HF therapy has been investigated in at least four large RCTs involving a total of 3852 patients, none of which showed reduction in mortality or HF-related hospitalizations [66-68]. The 2016 ESC guidelines included only a very weak recommendation that monitoring based on ICD (IN-TIME approach) may be considered in symptomatic patients with HF with reduced ejection fraction (with LVEF ≤35 percent) [59].

This approach to remote hemodynamic monitoring involves transmission of data such as intrathoracic impedance and heart rate variability obtained from existing CRT or ICD systems [69]. Intrathoracic impedance is inversely related to lung water. Impedance and other diagnostic parameters from existing cardiac implantable electronic devices are predictive of HF events [70-74].

However, despite this theoretical potential benefit, four randomized trials have shown no benefit on death or hospitalizations:

●The DOT-HF trial randomly assigned 335 patients with chronic HF with LVEF ≤35 percent to either receive an audible patient alert based upon crossing a programmed intrathoracic impedance threshold or routine follow-up [66]. The audible alert did not lead to reduction in the composite end point of all-cause mortality and HF hospitalization and instead increased HF hospitalization and outpatient visits.

●A randomized trial of 1002 patients in Germany with newly implanted ICDs assigned half to telemetry alerts based on intrathoracic fluid index threshold crossing, an early measure of volume overload [75]. There was no difference in the composite of death or cardiovascular hospitalization (HR 0.87, 95% CI 0.72-1.04), or in mortality or admission taken individually.

●The MORE-CARE trial enrolled 865 patients in Europe and Israel, who were randomized within eight weeks of CRT device implantation to remote checks in addition to office visits or office visits alone. The trial found no significant difference between the groups in a composite of death or cardiovascular hospitalization (HR 1.02, 95% CI 0.80-1.30).

●A trial in England randomly assigned 1650 patients with an existing cardiac implanted electronic device to remote follow-up or usual care and found no difference in a composite of death or cardiovascular hospitalization (HR 1.01, 95% CI 0.87-1.18) [67].

INVESTIGATIONAL THERAPIES FOR ACUTE HEART FAILURE — The following investigational therapies have shown some promise but are not considered appropriate for routine treatment.

Investigational vasodilators

Serelaxin — Relaxin is a naturally occurring human peptide vasodilator. Although an international randomized controlled trial comparing 48-hour intervenous infusion of serelaxin (recombinant human relaxin-2) with placebo in patients with acute decompensated HF (ADHF; with any LVEF) found improvements in some clinical outcomes (including reductions in cardiovascular and all-cause mortality at six months), a subsequent larger trial failed to confirm a clinical benefit:

●The RELAX-AHF trial enrolled 1161 patients with ADHF and systolic blood pressure >125 mmHg [76]. Serelaxin improved one measure of dyspnea (the visual analogue scale area under the curve) through day 5 and reduced average length of index hospital stay but did not improve the proportion of patients with moderate or marked improvement in dyspnea measured by Likert scale during the first 24 hours or readmission to the hospital within 60 days. The serelaxin group experienced a significantly lower rate of cardiovascular death (hazard ratio [HR] 0.63, 95% CI 0.41-0.96) and all-cause mortality (HR 0.83, 95% CI 0.43-0.93) at six months [77].

●The RELAX-AHF-2 trial enrolled 6545 patients with ADHF and systolic blood pressure ≥125 mmHg [78,79]. Cardiovascular mortality (8.7 and 8.9 percent) and all-cause mortality (11.2 and 11.9 percent) rates at six months were similar for serelaxin and placebo. Rates of worsening HF through day 5 ( 6.9 and 7.7 percent) and lengths of index hospital stay (6.8 and 6.9 days) were similar in the two treatment groups.

Ularitide — Ularitide is a synthetic analogue of the renal vasodilatory natriuretic peptide urodilatin. A randomized trial found that ularitide caused short-term hemodynamic effects but did not improve clinical outcomes [80]. The TRUE-AHF trial randomly assigned 2157 patients with ADHF (and systolic blood pressure between 116 and 180 mmHg) to receive a 48-hour infusion of ularitide or placebo. There was no significant difference in clinical outcomes at 48 hours based upon a hierarchical composite end point. Cardiovascular mortality rates were similar in the ularitide and placebo groups (21.7 versus 21.0 percent) at a median follow-up of 15 months. Greater reductions in systolic blood pressure and N-terminal probrain natriuretic peptide (NT-proBNP) level were seen with ularitide, but there was no impact on change in cardiac troponin T levels. Patients in the ularitide group had higher rates of hypotension and had slightly higher transient increases in serum creatinine levels.

Hypertonic saline plus furosemide — Several studies have suggested benefits from combined intravenous hypertonic saline solution plus intravenous furosemide as compared with intravenous furosemide alone in treating acute decompensated HF. However, the safety and effectiveness of this approach is uncertain.

The rationale for using hypertonic saline solution includes an osmotic effect that might help optimize refilling of the intravascular compartment during intravenous diuretic therapy and increases in renal blood flow that might promote diuretic action [81,82].

A meta-analysis included nine randomized controlled trials comparing intravenous hypertonic saline solution plus intravenous furosemide with intravenous furosemide alone with the following results [81]:

●Analysis for all-cause mortality included five trials and found a survival benefit with combined hypertonic saline solution plus furosemide compared with furosemide alone (risk ratio [RR] = 0.57, 95% CI 0.44-0.74). However, there was substantial heterogeneity among the studies (I² = 66 percent) and no significant benefit remained if either of two trials [83,84] was excluded.

●Based upon pooled results from four trials, combined hypertonic saline solution plus furosemide decreased HF-related hospital readmission compared with furosemide alone (RR = 0.51, 95% CI 0.35-0.75). However, there was moderate heterogeneity among studies (I² = 58 percent), and no significant benefit remained if either of two trials [83,84] was excluded.

●Analyses of length of hospital stay (seven trials), weight loss (eight trials), and preservation of renal function (serum creatinine) all favored therapy with combined hypertonic saline solution plus furosemide versus furosemide alone, although there was marked heterogeneity among studies for each of these outcomes.

Continuous aortic flow augmentation — Continuous aortic flow augmentation (CAFA) appears to improve cardiac performance but a clinical benefit has not been established and risk of major bleeds is associated with the device. CAFA does not increase cardiac output directly. Instead, arterial blood is drawn from a peripheral artery and recirculated through the aorta via an extracorporeal pump that then returns blood through a second arterial access site. The system provides continuous flow through the aorta that augments pulsatile cardiac output. Increased aortic flow is postulated to stimulate favorable hemodynamic changes, primarily through cardiac unloading and peripheral vasodilation.

In the MOMENTUM trial, 168 patients hospitalized with HF with reduced LVEF were randomly assigned to CAFA plus medical therapy or medical therapy alone [85]. Participants had elevated pulmonary capillary wedge pressure (PCWP), and renal impairment or substantial diuretic requirement despite intravenous inotropes/vasopressors. The primary composite efficacy end point included PCWP and days alive out of hospital off mechanical support over 35 days and was similar in the two treatment groups. CAFA improved cardiac index and PCWP. CAFA resulted in improved cardiac performance, as reflected in an upward-leftward shift in the stroke work versus PCWP relationship compared with the control group [86]. Major bleeds occurred in 16.5 percent in the device group and 5.1 percent in the control group.

High-dose mineralocorticoid receptor antagonist — A randomized trial found no benefit from the addition of high-dose spironolactone (100 mg per day for four days) to usual care in patients with acute HF [87]. A total of 360 patients were randomly assigned to high-dose spironolactone plus usual care or to usual care alone (including placebo or continued low-dose spironolactone [25 mg per day] for patients already taking low-dose spironolactone). There was no significant difference in the log NT-proBNP reduction between the two treatment groups. There were no significant differences in clinical congestion score, dyspnea assessment, net urine output, net weight change, 30-day mortality, or HF hospitalization rate in the two groups. Changes in serum potassium and estimated glomerular filtration rate were similar in the two groups.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)

SUMMARY AND RECOMMENDATIONS

●Investigational and emerging therapies for patients with heart failure (HF) include vasodilators, hormones, cell therapy, gene therapy, immunotherapy, antiviral therapy, and mechanical therapies. While beneficial effects have been seen with some of these interventions in preliminary studies, the risk/benefit ratio and true efficacy remain to be proven.

●Various types of immunotherapy have been investigated in patients with HF but such therapy does not have an established clinical benefit except for specific indications in patients with myocarditis. (See 'Immunotherapy' above and "Treatment and prognosis of myocarditis in adults", section on 'Management of specific disorders'.)

●Standard therapies for HF with reduced ejection fraction and the management of HF with preserved ejection fraction are discussed elsewhere. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)