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Cardiac & Cardiovascular Systems
Heart failure with reduced ejection fraction (HFrEF) is a clinical condition associated with cardiac contractility impairment. HFrEF is a significant public health issue with a high morbidity and mortality burden. Pathological left ventricular (LV) remodeling and progressive dilatation are hallmarks of HFrEF pathogenesis, ultimately leading to adverse clinical outcomes. Therefore, cardiac remodeling attenuation has become a treatment goal and a standard of care over the last three decades. Guideline-directed medical therapy mainly targeting the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS) has led to improved survival and a reduction in HF hospitalization in this population.
- heart failure with reduced ejection fraction
- novel medical therapy
- hospitalization
- mortality
- morbidity
1. Introduction
Heart failure (HF) is a significant public health problem affecting millions of individuals globally with high morbidity and mortality rates [1,2]. In people older than 60 years, HF is the leading cardiovascular (CV) reason for hospitalization [3].
HF is differentiated into three major categories based on the left ventricular (LV) ejection fraction (EF). According to the recently released 2021 European Society of Cardiology (ESC) HF guidelines, HF with reduced EF (HFrEF) is defined as HF with EF ≤ 40%. HF with EF between 41% and 49% (previously defined as HF with mid-range HF) is now termed HF with mildly reduced EF (HFmrEF), whereas HF with preserved EF (HFpEF) is defined as HF with EF ≥ 50% (similar to the previous 2016 ESC guidelines) [12,13,14].
HFrEF is often accompanied by pathological LV remodeling and dilatation, which leads to adverse outcomes. Reversing cardiac remodeling became a treatment goal and standard of care more than 20 years ago [15]. These patients are recurrently hospitalized, and not rarely, HF patients may require advanced therapies. Guideline-directed medical therapy has led to an increase in survival rates in these patients, with the main target of treatment being the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS) [16]. Low effective stroke volume, as seen in HFrEF, typically leads to sympathetic nervous system and RAAS activation. The activation of these systems results in vasoconstriction and fluid retention, thereby contributing to adverse remodeling in HF.
2. Traditional Pillar-Directed Medical Therapy
Sympathetic activation has harmful effects on morbidity and mortality in HF [17]. The beta-adrenergic blocker bisoprolol was found to reduce HF hospitalizations and mortality in the Cardiac Insufficiency Bisoprolol Study (CIBIS) [18]. These benefits have only been found in specific beta-blockers, including metoprolol, carvedilol, and bisoprolol, but not as a class effect. The CIBIS-II trial comparing bisoprolol versus placebo in stable HFrEF patients with New York Heart Association (NYHA) III–IV has demonstrated a 5% absolute risk reduction in all-cause mortality [19]. Similarly, results obtained from HFrEF patients treated with metoprolol versus placebo have shown a 34% relative risk reduction in all-cause mortality per patient-year in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), leading to early discontinuation of the trial due to ethical reasons [20]. In 2002, carvedilol was also found to reduce annual mortality rates, HF hospitalizations, and cardiogenic shock compared to placebo in HFrEF patients in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial [21]. Head-to-head trials among the three beta-blockers have shown similar benefits without evidence of a preferred agent over the other [22].
Angiotensin-converting enzyme (ACE) inhibitors inhibit the conversion of angiotensin I to angiotensin II. The CONSENSUS trial has shown an 18% absolute risk reduction in mortality with enalapril compared with placebo among HFrEF patients with NYHA class IV symptoms after six months of follow-up [23]. Subsequent studies have shown consistent results in patients with NYHA class II and III symptoms [24]. A trend towards increased survival has also been noticed with isosorbide dinitrate and hydralazine. However, in two trials, the V-HeFT and the V-HeFT II, treatment with enalapril has reduced mortality by 7% compared to isosorbide dinitrate and hydralazine [25,26]. The SAVE trial has also shown a 19% decreased mortality with captopril compared with placebo as well as a significant reduction in ventricular dysfunction secondary to ischemia [27]. Based on these studies, ACE inhibitors are considered a class I recommendation in patients with HFrEF [16].
Angiotensin receptor blockers (ARBs) inhibit the downstream effects of angiotensin II by blocking its binding to angiotensin I receptors. The Val-HeFT trial has shown that the combination of ACE inhibitors and ARB treatments could cause acute renal failure, and though it resulted in morbidity reduction, no mortality benefit was observed [28]. In 2003, the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) trial demonstrated a significant reduction in the composite outcome of HF hospitalization or CV mortality in NYHA class II to IV HFrEF patients treated with candesartan as compared to those treated with placebo [29,30]. Accordingly, ARBs are considered as a class I recommendation in symptomatic HFrEF patients [16].
Mineralocorticoid receptor antagonists (MRAs) inhibit the aldosterone receptor, thus hindering sodium and water retention. The Randomized Aldactone Evaluation Study (RALES) has demonstrated an 11% absolute risk reduction in all-cause mortality and a 35% relative risk reduction in HF hospitalization in HFrEF patients when treated with spironolactone versus placebo. This trial has also shown an improved functional capacity in patients with an LVEF < 35% and NYHA class III and IV [31].
The combination of isosorbide dinitrate and hydralazine has shown a trend towards improved survival in the Vasodilator Heart Failure Trial (V-HeFT) compared with prazosin or placebo in HFrEF patients [34].
The SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine) involving NYHA II–IV HFrEF patients with a resting heart rate ≥ 70 and at least one HF hospitalization in the previous year demonstrated an 18% relative risk reduction in the composite outcome of HF mortality or hospitalization for HF [36]. The addition of ivabradine is considered a class IIa recommendation by the European Society of Cardiology (ESC) to reduce HF hospitalization in symptomatic patients with NYHA II–III HFrEF [37].
3. Novel Pillar-Directed Medical Therapy
A quarter of HF patients will still suffer severe symptoms, hospitalizations, and mortality despite optimal treatment. Consequently, novel pharmacological approaches to HF management are pivotal [9,39,40]. Novel pharmacologic therapies targeting unique pathways involved in the pathogenesis of HFrEF have increasingly become a part of the standard-of-care medical therapy in the past few years. Neprilysin is an endopeptidase responsible for the degradation of natriuretic and other vasoactive peptides under normal conditions. Neprilysin inhibition increases natriuretic peptide levels and other vasodilatory substances and leads to natriuretic and vasodilatory effects. The administration of synthetic natriuretic peptides has not improved outcomes in acute HF [41]. Early trials failed to prove improved outcomes with neprilysin inhibition alone or when combined with ACE inhibitors [42,43]. The combination of neprilysin with ACE inhibitors showed an increased incidence of angioedema, leading to early termination of the trial [44]. The formerly known LCZ696 molecule of sacubitril/valsartan (ARNi) had a unique design of blocking both the renin–angiotensin system and neprilysin activity [45,46,47]. The Prospective Comparison of ARNi with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, involving NYHA class II–IV HFrEF patients, was terminated early due to a 20% relative risk reduction in the composite outcome of CV mortality or HF hospitalization, and a 16% relative risk reduction in all-cause mortality with ARNi compared with enalapril in addition to standard therapies in HFrEF [48]. The Comparison of Sacubitril–Valsartan versus Enalapril on Effect on N-terminal (NT) pro B-type-natriuretic peptide (BNP) (NT-proBNP) in Patients Stabilized from an Acute Heart Failure Episode (PIONEER-HF) trial has shown that this treatment is safe and more effective in reducing NT-proBNP levels than ACE inhibitors among patients hospitalized for acute decompensated HF, including ACE inhibitor/ARB-naïve patients [49].
Patients with HFrEF receiving ACE inhibitors or ARBs should be transferred to ARNi when possible, given the greater clinical benefit with ARNi use. ACE inhibitors should be held for 36 h before starting ARNi, while there is no need for this interruption in treatment with ARBs. The initial dosage of ARNi depends on the preceding ACEi/ARB dose, but it is strongly recommended to achieve a maximal dose of 200 mg (sacubitril/valsartan 97/103 mg) twice daily. A lower dose (sacubitril/valsartan 24/26 mg twice daily) should be considered in patients at the age of 75 years or older, with low blood pressure (systolic pressure of 100 to 110 mmHg), estimated GFR < 60 mL/min/1.73 m2, or those with significant liver disease. Dosage can be doubled every 2–4 weeks up to the maximally tolerated dose. In an analysis of high-risk patients in the PIONEER-HF study, the reduction in cardiovascular death or rehospitalization after hospitalization for acute decompensated heart failure was similar to the significant risk reduction in the original trial. Compared to enalapril, the initiation of sacubitril/valsartan does not increase adverse events including symptomatic hypotension, worsening renal function, and hyperkalemia [50].
3.1. Sodium–Glucose Cotransporter-2 Inhibitors (SGLT2i)
Sodium–glucose cotransporter-2 inhibitors (SGLT2i) target the sodium–glucose cotransporter-2 expressed in the early proximal tubules in the kidney, which is responsible for most renal glucose filtration (Figure 1). These medications were initially used as antihyperglycemic agents in patients with type 2 diabetes [51,52]. The mechanisms of the benefits of SGLT2 inhibition are still being elucidated and are likely multifactorial. Besides glycemic control, SGLT2i have additional favorable effects on blood pressure, weight, uric acid concentrations, albuminuria, lipid profile, and hematocrit, as well as direct cardiac effects, including CV and HF benefits [51,53,54,55,56].
In contrast to sGC activators, sGC stimulators (e.g., vericiguat and riociguat) potentiate endogenous NO by binding directly to sGC (Figure 2) [84]. In the SOCRATES-Reduced dose defining phase 2b clinical trial, vericiguat was evaluated in 456 participants with worsening HFrEF. At 12 weeks of follow-up, the primary endpoint of decreased NT-proBNP levels was not met, yet a prespecified secondary analysis demonstrated a dose–response relationship. Furthermore, an improvement in the rate of CV death and HF hospitalization as well as a significant improvement in LVEF was noticed in a dose–response manner [87]. The VICTORIA study, a phase 3 RCT, has examined the efficacy and safety of vericiguat in 5050 patients with HF and EF < 45%, elevated NT-proBNP, and recent clinical worsening. Over 10.8 months of follow-up, the primary composite endpoint of CV death or first HF hospitalization was significantly lower in the vericiguat versus the placebo arms (35.5% vs. 38.5%, p = 0.02). The difference was mainly driven by a reduction in HF hospitalization, while the difference in the CV death was not significantly different between the two groups. Symptomatic hypotension and syncope rates did not differ between the treatment and control groups (9.1% vs. 7.9%, p = 0.12; and 4% vs. 3.5%, p = 0.3, respectively) [88]. Following the results of the VICTORIA study, vericiguat received regulatory approval by the FDA for patients with symptomatic chronic HFrEF.
3.3. Omecamtiv Mecarbil
Myocardial contraction is a result of chemical energy transformation into mechanical energy. Actin, myosin, and other regulatory proteins generate the force needed for contraction. It also involves ATP hydrolysis and myosin–actin cross bridging, which both play a key role in cardiac contractility [89]. Inotropic drugs increase myocardial contractility through the increase in intracellular cAMP and calcium through different mechanisms. However, the use of inotropes is associated with increased myocardial oxygen consumption and tachyarrhythmia, which may increase mortality as shown in previous studies [89,90,91].
Omecamtiv mecarbil, formerly known as CK-1827452, was the first agent developed to accelerate the transition of the actin–myosin complex from weakly bound to a firmly bound configuration (Figure 3) [90,91,92]. Omecamtiv mecarbil was found to improve cardiac function in patients with HFrEF. However, higher infused doses have led to cardiac ischemia in some cases [92,93]. Safety and tolerability were tested and found not to be different from placebo, including time to angina, exercise duration, or ischemic ECG changes [94].
In the ATOMIC-AHF study, patients with reduced ejection fraction admitted with acute decompensated HF were randomized to receive intravenous omecamtiv mecarbil vs. placebo for 48 h. There was no significant effect on dyspnea relief at 6, 24, and 48 h compared with the pooled cohort. There was a benefit on dyspnea relief at 48 h in a supplemental prespecified analysis compared with the paired placebo. There was no effect on 30-day mortality or worsening HF, length of hospitalization, or NT-proBNP levels [95].
The management of HF patients includes four major pillars of pharmacological treatment. The ideal patient will be managed with ARNi, beta-blockers, MRAs, and an SGLT2 inhibitor (Table 1). Beta-blockers and MRAs are longstanding class I recommendations for the treatment of HFrEF. ARNi became a class I recommendation in the 2016 ESC guidelines for the treatment of chronic heart failure for patients with reduced EF [99]. In the 2021 European Society of Cardiology (ESC) HF guidelines, SGLT2 inhibitors became the fourth crucial pillar of treatment for patients with reduced EF (and HFpEF) with or without diabetes mellitus. An emerging new approach will be tailored treatment for HFrEF patients based on their phenotype (Figure 4) [14]. The tailored treatment approach is applied as a general approach. Clinicians can put more emphasis on one of the pillars depending on the clinical scenario. Patients with marked hypertension might benefit from emphasis on treatment with ARNi. Patients with chronic kidney disease (CKD) with hyperkalemia and hypotension might benefit from emphasizing the SGLT2 inhibitors pillar.
4. Future Perspectives and Conclusions
Based on a large series of clinical trials, it appears that SGLT2i have the largest effect, hence they have become a class I recommendation in the recent ESC guidelines for chronic HFrEF. Omecamtiv mecarbil and vericiguat have provided less striking results, probably directing their clinical use to specific clinical scenarios, such as omecamtiv mecarbil’s use for patients with lower systolic blood pressure. The future holds tremendous and exciting pharmacologic avenues to be explored. The role of inflammation in morbidity and mortality outcomes in HF patients is a primary area of interest. Genetic analysis of HF patients might shed light on the variation in responses to specific medications, and personalized therapeutic regimens may be suited accordingly. Increasing efforts to improve adherence to optimal medical therapy for HFrEF patients is mandatory to achieve maximal clinical benefits.
This entry is adapted from the peer-reviewed paper 10.3390/jcm10194409
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