Investigational therapies for management of heart failure

INTRODUCTION — The treatment of heart failure (HF) is designed to prolong survival, reduce morbidity, slow the progression of disease, and improve symptoms [1]. While conclusive trials established the efficacy of many HF therapies, other plausibly effective therapies remain investigational due to inconclusive evidence.

Investigational therapies for HF are reviewed here.

Standard therapies for HF are discussed elsewhere:

●(See "Overview of the management of heart failure with reduced ejection fraction in adults".)

●(See "Treatment and prognosis of heart failure with preserved ejection fraction".)

DEVICE-BASED THERAPIES

Parasympathetic stimulation — In patients with HF, the decrease in parasympathetic nervous system (PNS) activity may contribute to the pathophysiology of HF [2], but it is unknown whether PNS stimulation is an effective treatment for HF. 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 [3-5].

Enhanced external counterpulsation — Enhanced external counterpulsation (EECP) is a technique that increases arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation). EECP is applied by wrapping cuffs around the patient’s legs and applying sequential air pressure (300 mmHg) from the lower legs to the thighs in early diastole, which propels blood back to the heart.

In patients with HF, EECP is an unproven therapy; there are only limited data from subgroup analyses of trials and registries that show variable effects on exercise tolerance.

As an example, the PEECH trial directly evaluated the possible benefit of EECP in 187 patients with mild to moderate HF [6]. Patients were randomly assigned to 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 VO₂. 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 the placebo effect. Further research will be necessary to define the impact of EECP in the treatment of HF.

The use of EECP to treat angina is discussed elsewhere. (See "New therapies for angina pectoris", section on 'External counterpulsation'.)

Cardiac contractility modulation — Cardiac contractility modulation (CCM) involves applying biphasic electric stimulation to the right ventricular septum during the cardiac absolute refractory period to induce a mild augmentation of left ventricular (LV) contraction that may lead to reverse LV remodeling and improve LV ejection fraction (LVEF) [7].

CCM may improve functional measures but has an unclear effect on long-term clinical outcomes and a relatively high risk of complications. However, the trials that tested the efficacy of CCM showed minimal or no effect of CCM on all-cause mortality, survival free of hospitalization, and changes in functional capacity. CCM was associated with a relatively high complication rate of approximately 10 percent. Accordingly, cardiac resynchronization therapy (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 and choice of system".)

Studies and trials of CCM include:

●A meta-analysis of three randomized controlled trials that included a total of 641 participants with HF found that CCM improved peak oxygen consumption (mean difference +0.7, 95% CI 0.2-1.2 mL/kg/min) and quality of life measured by Minnesota Living With Heart Failure Questionnaire (mean difference -7.2, 95% CI -10.4 to -4.0) but had an uncertain effect on six-minute walk test distance (mean difference +14 m, 95% CI -0.1 to 27.9 m) when compared with sham treatment or usual care [8].

●A subsequent randomized trial (FIX-HF-5C) enrolled 160 patients with New York Heart Association (NYHA) functional class III or IV symptoms, QRS duration <130 ms, and LVEF between 25 and 45 percent [9]. Survival free of cardiac death and HF hospitalization was significantly improved with CCM compared with usual care (97.1 versus 89.2 percent at 24 weeks). However, overall survival and survival free of any hospitalization were similar in the CCM and usual care groups. 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 improved in the group assigned to CCM. There was a 10.3 percent rate of device- or procedure-related complications with CCM.

Combined data from FIX-HF-5C and FIX-HF-5 trials showed that peak oxygen consumption was significantly improved at 24 weeks with CCM compared with usual care (mean difference +0.84 mL/kg/min, 95% CI 0.12-1.55) [9].

While the benefits of CCM are unclear and possibly affected by the placebo effect, CCM is approved by the US Food and Drug Administration for use in patients with HFrEF who have NYHA functional class III or IV symptoms despite optimal medical therapy and who cannot undergo placement of a CRT device. There are ongoing trials and registries of CCM in patients with HF due to reduced or preserved ejection fraction [10-15].

STEM CELL THERAPY — Cell therapy involves transfer of less-differentiated cells (eg, cardiac stem cells, skeletal myoblasts) to the myocardium to induce therapeutic myocardial regeneration and/or improvement in cardiac function. The benefit of cell therapy is uncertain in patients with HF [16,17].

●Theoretical basis – The most likely mechanism of benefit is 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 [18,19]. It is unclear if cell therapies can incorporate into the myocardium and differentiate into functional myocardial tissue; some studies have demonstrated that hematopoietic stem cells do not transdifferentiate into cardiac myocytes [20,21], while autologous skeletal myoblasts can contract but do not transdifferentiate into cardiomyocytes [18,22]. Studies in animal models found that endogenous cardiac progenitor cells contribute minimal or no cardiomyocytes to the heart [23,24].

●Efficacy – Clinical studies have investigated the efficacy of skeletal myoblasts, bone marrow mononuclear cells, bone marrow progenitor cells, mesenchymal stem cells, and cardiac stem cells to treat patients with chronic HF [25]. A systematic review and meta-analysis evaluated 38 randomized controlled trials that included 1907 participants with chronic ischemic heart disease and HF and that compared autologous adult stem/progenitor cells with no stem/progenitor cells [26]. The meta-analysis ultimately included nine trials with 491 participants and found low-quality evidence of mortality benefit at ≥12 months (risk ratio [RR] 0.42, 95% CI 0.21-0.87). Based on data from six trials with 375 participants, there was no significant reduction in the risk of hospitalization for HF (RR 0.63; 95% CI 0.36-1.09). Adverse events were infrequent, and no long-term adverse events were reported.

●Safety – The delivery of cell therapies via cellular cardiomyoplasty (ie, direct injection or implantation of cells into the myocardium) raises concerns for safety, though data are limited. Three concerns are ventricular arrhythmias (particularly after myoblast injection), myocardial ischemia, and undesired cell differentiation (eg, intramyocardial bone formation [27] or perivascular fibrosis [28]). There are conflicting data as to whether there is an increase in the risk of ischemia and acute coronary syndrome [29,30].

GENE THERAPY — Gene therapy is under investigation for the treatment of HF [31], but published studies have not established the clinical value of this approach. Studies of gene therapy for HF are based upon advances in appropriate gene targets and in gene transfer technology, which include development of safe and efficient vectors and delivery methods [32,33]. Potential targets for gene therapy include cardiomyocyte calcium 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).

NUTRITIONAL SUPPLEMENTS

Hawthorn extract — Hawthorn extract is an herbal agent derived from species of the hawthorn plant (Crataegus monogyna or Crataegus laevigata). Proposed mechanisms of action include vasodilation, as well as antioxidant activity, inotropy, and lipid effects [34].

The efficacy of hawthorn extract in the treatment of HF is uncertain; randomized trials have yielded mixed results. 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 HF with reduced ejection fraction (HFrEF) found no benefit. It is unclear whether the 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.

●A meta-analysis included 10 randomized trials enrolling a total of 855 patients with chronic HF (New York Heart Association [NYHA] class I to III); most of the trials did not require systolic dysfunction [35]. Treatment with hawthorn was associated with greater exercise tolerance and maximal achieved workload as well as reductions in pressure-heart rate product and symptoms of dyspnea and fatigue. Dosing varied widely (160 to 1800 mg), and the trials did not report data on mortality or HF hospitalization.

●Two trials published after the meta-analysis found similar rates of death, hospitalization, and symptom improvement in the hawthorn and placebo groups:

•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) [36]. 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 [37]. Adverse events (most noncardiac) were significantly more frequent in the hawthorn group (60 versus 38 percent).

Coenzyme Q10 — 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 coenzyme Q10 depletion.

The role of coenzyme Q10 as a treatment for HF is unclear. The trials of coenzyme Q10 are small, subject to bias, and, in aggregate, suggest a wide range of efficacy that includes no effect:

●A systematic review and meta-analysis of randomized trials concluded that trials of coenzyme Q10 were subject to substantial bias and that there was an uncertain benefit of coenzyme Q10 when compared with placebo for the outcome of mortality (relative risk 0.68, 95% CI 0.45-1.03) and unclear or minimal effect on HF symptoms [38].

●One of the randomized trials included in the meta-analysis 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 [39]. 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 improved in the coenzyme Q10 group. The rates of adverse events were similar in the two treatment groups (13 and 19 percent).

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

●Investigational therapies – The treatment of heart failure (HF) is designed to prolong survival, reduce morbidity, slow the progression of disease, and improve symptoms [1]. While the efficacy of many HF therapies has been established by conclusive trials, other plausibly effective therapies remain investigational due to inconclusive evidence.

This topic reviews the following investigational therapies:

•Parasympathetic simulation. (See 'Parasympathetic stimulation' above.)

•Enhanced external counterpulsation. (See 'Enhanced external counterpulsation' above.)

•Cardiac contractility modulation (CCM). (See 'Cardiac contractility modulation' above.)

•Stem cell therapies. (See 'Stem cell therapy' above.)

•Gene therapy. (See 'Gene therapy' above.)

•Nutritional supplements including hawthorn extract and coenzyme Q10. (See 'Hawthorn extract' above and 'Coenzyme Q10' above.)

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