Therapy and Management of Heart Failure with Preserved Ejection Fraction: New Insights on Treatment

30 May 2024

Therapy and Management of Heart Failure with Preserved Ejection Fraction: New Insights on Treatment

A. SGLT 2 inhibitors:

The mechanism of action of this drug class is complex and not yet fully understood. However, it is known that inhibiting SGLT2 at the proximal convoluted tubule level causes glucose and sodium to be excreted in the urine, which, due to osmotic effects, promotes diuresis.This diuresis, however, is different from that caused by loop diuretics, as it appears to have a selective effect on interstitial volume, with minimal impact on vascular volume. This leads to a reduction in preload and, albeit modestly, blood pressure without triggering compensatory activation of the RAAS.
The efficacy of these molecules was also studied in HFpEF and heart failure with moderately reduced EF (HFmrEF) in the EMPEROR-Preserved and DELIVER clinical trials

In summary, empagliflozin and dapagliflozin significantly reduced the incidence of CV events and worsening HF in HFpEF, demonstrating that SGLT2i improved the prognosis of HF patients across the entire LVEF spectrum

According to new evidence, SGLT2i should be introduced during hospitalisation for acute HF.

B. Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers:

Three large-scale randomised clinical trials tested the safety and efficacy of angiotensin-converting enzyme inhibitors in HFpEF. Two of them, the CHARM-Preserved and the I-PRESERVE used an angiotensin receptor blocker (ARB), the PEP-CHF trial used an angiotensin-converting enzyme inhibitor. The results were fairly similar, confirming no effects on mortality and some effect on HF hospitalisation. A large metanalysis that included the aforementioned clinical trials and other smaller size studies concluded that both ARB and angiotensin-converting enzyme inhibitors have no effect on all-cause mortality, CV death and HF hospitalisation

Based on this evidence, the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines give a class 2b recommendation for ARB use with the aim of reducing HF hospitalisation, especially in the lower end of the LVEF.

C. Mineralocorticoid Receptor Antagonists:

The TOPCAT trial shaped much of our knowledge around the use of MRA in HFpEF, being the only large-scale clinical trial on clinically relevant outcomes. The overall result on the primary outcome of a composite CV death and HF hospitalisation was neutral, as only HF hospitalisations were significantly reduced in the treatment arm New trials are ongoing to better define the role of MRA in HFpEF. SPIRRIT-HFpEF and FINEARTS-HF will hopefully shed light on this

The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines give a class 2b recommendation for MRA use, with the aim of reducing HF hospitalisation, especially in the lower LVEF range.However, the European guidelines do not mention MRA for HFpEF

D. Antagonist Receptor Neprilysin Inhibitors:

The PARAGON-HF trial randomised 4,822 patients with NYHA class II–IV, EF >45%, elevated NP and structural heart disease to valsartan alone or sacubitril/valsartan.67 The primary endpoint of composite of total HF hospitalisation or CV death was missed for a small number of events (just seven events). Splitting the components of the outcomes, a truly neutral effect on CV mortality and a modest positive effect on HF hospitalisations were evident.
Prespecified subgroups analysis highlighted a different response to treatment in women (who benefitted most) compared with men and, in the lower end of the EF spectrum, with an efficacy of the treatment up to an EF of 57%

A recent pool analysis of PARAGLIDE and PARAGON showed that in a population of 5,262 patients, sacubitril/valsartan versus valsartan alone significantly reduced CV death and total worsening heart failure events These data encourage the use of ARNI in HF with mildly reduced or preserved LVEF, particularly in those with a LVEF below normal

E. β-blockers:

The SENIORS trial enrolled HF patients across the entire spectrum of the LVEF and randomised them to nebivolol or a placebo.The subgroup analysis of 752 patients with LVEF >35% is the largest cohort randomised to a placebo we have to date.

A metanalyses suggest that β-blockers could reduce CV mortality or all-cause mortality without significant effect on HF hospitalisation.

F. Treating Cardiac Comorbidities in HFpEF:

1. Ischaemic heart disease and HF are strongly and tightly connected conditions. Ischaemic heart disease includes microvascular dysfunction (MVD), coronary artery disease or previous ‘silent’ MI

MVD contributes to the pathophysiological mechanisms of HFpEF in several ways. The pro-inflammatory state, exacerbated by the multiple comorbidities present in HFpEF, promotes oxidative stress and endothelial dysfunction. The most important mechanisms leading to MVD in HFpEF consist of microvascular inflammation, capillary rarefaction and cardiac fibrosis

SGLT2s have shown beneficial effects of cardiac microvascular endothelial cells on cardiomyocyte function, and demonstrate an improvement in myocardial flow reserve in a single-centre prospective randomised clinical trial

Ranolazine inhibits the late sodium current and reducing intracellular calcium in cardiomyocytes and promotes ventricular relaxation by decreasing diastolic tone and microcirculatory resistance, thus improving coronary blood flow. It also acts on cardiac fibrosis; thus, it could improve the most important physiological mechanisms of MVD in this syndrome

New studies on antidiabetic agents, glucagon-like peptide-1 agonists, are ongoing on the obese HFpEF phenotype, and they could also have a role in chronic inflammation and MVD

2. AF is a highly prevalent cardiac comorbidity in HFpEF, ranging from 32% to 65% in epidemiological studies. An interesting analysis of the HF Long-Term Registry of the European Society of Cardiology, evaluating both ambulatory and hospitalised HF patients, showed that after multivariable adjustment, AF significantly increased long-term mortality and hospitalisation just in the HFpEF and HFmrEF population, but not in the HFrEF population.

3. Diabetes and Metabolism Disorders

Diabetes, excess weight and obesity, typical features of HFpEF patients. visceral and pericardial adipose tissues play a negative, pro-inflammatory role compared with subcutaneous adipose tissue, emphasising that ‘not all fat is equal’.

obesity is associated with obstructive sleep apnoea, contributing to increased right ventricular afterload, promoting functional deterioration, and eventually its failure.

glucagon-like peptide-1 agonists may represent a future therapeutic target for patients with HFpEF, acting on several pathways involved in the pathophysiology of HFpEF, including diabetes and obesity. The LEADER study demonstrated that the rate of the first occurrence of death from CV causes, non-fatal MI or non-fatal stroke among patients with type 2 diabetes was lower with liraglutide than with a placebo

G. Devices for HFpEF:

1. Transcatheter Interatrial Shunt Device

One of the key haemodynamic features of HFpEF is elevated left atrial and pulmonary venous pressure at rest or on exertion, resulting in dyspnoea and reduced exercise capacity. A transcatheter-implanted interatrial shunt device has been developed with the aim of opening an 8 mm large left-to-right atrial shunt and unloading left atrium

The REDUCE LAP-HF I trial, a phase II clinical trial, demonstrated a greater reduction of exercise pulmonary capillary wedge pressure in patients on active treatment compared with patients treated with a sham procedure

2. Cardiac Contractility Modulation

Abnormal myocardial contractility, and pathological atrial and ventricular remodelling is a key feature of HFpEF.

CCM is a new device acting through myocytes stimulation during the absolute refractory period of the action potential, leading to an increase in peak calcium concentration and inducing positive inotropism.CCM has been shown to improve tolerance to exercise and outcome in HFrEF patients, and growing data exist on the benefits of HFmrEf in terms of functional status and QoL