General Treatment of Heart Failure With Preserved Ejection Fraction and Randomized Trials

Introduction

Heart failure (HF) with preserved left ventricular (LV) ejection may constitute up to 50% of HF cases and is increasing in prevalence. Patients with this syndrome also suffer substantial morbidity and mortality. HFpEF is characterized by a morphologically normal, enlarged, and/or hypertrophied left ventricle with EF of 50% and above, impairment to diastolic filling, increasing LV stiffness resulting in elevated left ventricular filling pressures (LVFP), and signs and symptoms of clinical HF. In general, HFpEF excludes HF associated with significant valve disease. Given the absence of specific evidence-based therapy for HFpEF, treatment is geared toward management of volume overload and comorbidities, including hypertension, CAD, diabetes, obesity, sleep apnea, atrial fibrillation (AFib), and renal dysfunction. The reasons why standard therapies effective in HF with reduced EF (HFrEF)—angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, and mineralocorticoid inhibitors (MRAs)—have not been shown to reduce major cardiovascular (CV) events in HFpEF patients remain unclear. Ongoing phase III trials of newer drugs such as the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan and the sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin may identify, at last, effective targeted therapies for HFpEF.

Background

HFpEF is a diagnosis that can be challenging to definitively make. It requires the clinician to establish that signs and symptoms of HF indeed exist, along with corroboration using the following criteria: LV EF of 50% and above, morphologic abnormalities consistent with the diagnosis (LV hypertrophy and/or LA enlargement), and documentation of elevated LV filling pressures (by echocardiography or cardiac catheterization and/or elevated natriuretic peptides). Other causes of HF such as pericardial disease, valvular disease, and high-output HF are usually excluded. In addition, mimickers of HFpEF must be excluded, such as lung disease, obesity, sleep apnea, renal failure, precapillary pulmonary hypertension, and hematologic or metabolic abnormalities.

Earlier placebo-controlled randomized controlled trials (RCTs) in HFpEF patients include the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)–Preserved trial, the Digitalis Investigation Group (DIG) ancillary trial, and the Perindopril in Elderly People with Heart Failure (PEP-CHF) trial. These trials did not demonstrate lower primary end points in the treatment compared to placebo arms; however, some secondary end points (such as HF hospitalization) were decreased in the CHARM trial. The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) trial did demonstrate a reduction in the primary end point in the treatment arm, but in patients with LVEF greater than 35%, and was a subanalysis of a larger trial. More recent RCTs of medical therapy in HFpEF patients include the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) trial, the Japanese Diastolic Heart Failure Trial (J-DHF), the Aldosterone Antagonist Therapy for Adults with Heart Failure and Preserved Systolic Function (TOPCAT) trial, and the Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE) trial. However, none of these trials demonstrated a difference in the primary outcome in treatment compared to placebo arms. Potential reasons these trials were negative include (1) patients were enrolled who did not truly have HFpEF, (2) the therapy was not effective, (3) the numerous comorbidities common in HFpEF patients and their associated adverse outcomes diluted any potential therapeutic effect, (4) the pathophysiology of HFpEF is not well understood and thus treatments targeted at specific disease mechanisms remain elusive, and (5) heterogeneity in HFpEF subtypes may respond differently to therapy. Further complicating the landscape is that different trials used different LV EF cutoff values to connote preserved LV EF (e.g., LV EF > 35% in SENIORS, > 40% in CHARM, and > 45% in I-PRESERVE and TOPCAT).

Therefore current guidelines focus on stages: stage A (prevention of HF), generally with a healthy lifestyle, control of hypertension, and prevention of coronary disease, although newer therapies show promise in reducing the incidence of HF in patients at risk ; for stage C (symptomatic HF), coronary revascularization, treatment of AF, and treatment of hypertension. Regarding specific therapies there are weak recommendations for MRAs (in HFpEF patients fulfilling specific criteria) or ARBs for the goal of reducing HF hospitalizations. Fortunately, there are several phase III RCTs, likely to report results in 1 to 2 years, which may provide targeted therapies to improve clinical outcomes in patients with HFpEF.

Pathophysiology

HFpEF also can be referred to as heart failure with normal EF and diastolic HF. The choice of term sheds much light on the pathophysiology of this syndrome. While the main pathology of HFpEF is impairment to diastolic filing and increased ventricular stiffness (lower ventricular compliance), there is also evidence that systolic function is impaired. Studies with speckle tracking echocardiography have shown impaired longitudinal and circumferential myocardial systolic function in HFpEF patients. Thus even though LV EF is preserved ( > 50%), many HFpEF patients demonstrate abnormalities in systolic function. Nevertheless, there is general agreement that upward and leftward shift of the LV pressure-volume curve is one of the main pathophysiologic abnormalities in HFpEF patients. This results in higher LV pressure for a given volume and leads to elevated LA pressures and pulmonary congestion and/or effort intolerance. To date, RCTs have focused therapy on treating volume overload and ventricular stiffness but have not yet yielded strong results.

It has recently been suggested that phenotyping in HFpEF patients is necessary as heterogeneity in HFpEF is common, and this may be one of the reasons that helps explain lack of response to prior RCTs. A study utilizing machine learning has identified three phenotypes: (1) younger patients with moderate diastolic dysfunction with relatively normal natriuretic peptide levels, (2) obese, diabetic patients with a high prevalence of obstructive sleep apnea with the poorest LV relaxation, and (3) older patients with chronic kidney disease, electrical and myocardial remodeling, pulmonary hypertension, and right ventricular dysfunction. Outcomes (including hospitalization and death) have been shown to vary by phenogroup, with an increase in risk from group 1 to group 3, suggesting different therapy may work for different phenotypes.

In addition, an emerging pathophysiologic model that has been proposed for HFpEF suggests that a proinflammatory condition exists, leading to systemic microvascular endothelial inflammation, increases in oxidative stress, decreases in nitric oxide–cyclic guanosine monophosphate, microvascular dysfunction, and rarefaction. These processes result in increased myocyte stiffness, cardiomyocyte hypertrophy, and fibrosis, leading to global cardiac remodeling and dysfunction, impaired coronary flow reserve, impaired oxygen delivery, uptake, and utilization in skeletal muscle signaling.

For future HFpEF therapies to show promise it is possible that they may need to be targeted to a specific HFpEF phenotype and/or target the proinflammatory process (and its downstream effects) in HFpEF patients.

General Treatment Guidelines

Currently, the principles underlining the management of patients presenting with HFpEF involve identification and treatment of the underlying etiology, treatment of comorbid conditions that may play a role in both the development and the exacerbation of HF symptoms, and a focus on symptom management. Patient education is also paramount, with instruction on the importance of self-care, weight management, aerobic exercise programs, sodium restriction and fluid status, and regular clinical follow-up being emphasized.

Optimization of fluid status is an initial focus of therapy (Class of Recommendation [COR] Ia, Level of Evidence [LOE] C) in current guidelines . Aside from decreasing pulmonary venous congestion and LV filling pressures, diuretic therapy prevents plasma volume expansion, which has been implicated in the pathophysiology of patients with HFpEF. In a cohort of patients with HFpEF it was shown that capillary wedge pressure increases with plasma volume expansion. This phenomenon is thought to be secondary to pericardial restraint from right heart dilation and/or increased total heart volumes. Loop diuretic therapy remains the most effective therapy to optimize fluid status and avoid plasma volume expansion. Diuretic therapy should be tailored to the patient’s body weight, symptoms, and electrolyte status. The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial was designed to investigate the utility of noninvasive LV filling pressure monitors in a group of HF patients, 20% of whom had preserved EF. Optimal filling pressures were achieved primarily with increasing doses of both loop and thiazide diuretics and resulted in a reduction in HF hospitalizations. The addition of thiazide and thiazide-like diuretics, administered before the dose of loop diuretics, can be a helpful addition in patients with excessive volume overload or diuretic resistance. Careful monitoring should be applied when considering adjunctive diuretics as volume depletion, loss of urinary electrolytes, and renal dysfunction can occur. Although evidence is limited, restricting dietary sodium to less than 2 g per day is currently recommended by most guidelines. Further, sodium restriction may play a more significant role in patients with recurrent episodes of refractory episodes of volume overload. In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) trial of 7020 diabetic patients without clinical HF, randomization to empagliflozin (an SGLT2 inhibitor) was associated with a relative risk reduction of 35% in HF hospitalization, which may at least in part be due to the osmotic diuresis. Diuretic therapy to optimize volume status and maintain euvolemia plays a central role in symptom management and is a reasonable first step in improving the functional status in patients with HFpEF.

Treatment of Comorbidities

Comorbid conditions are highly prevalent in HFpEF patients. Comorbidities, including CAD, hypertension, diabetes, renal dysfunction, and others, contribute to the underlying physiopathology of HFpEF; in addition, the absolute number of comorbidities has been associated with an increased risk of all-cause hospitalization. Thus treatment of these comorbidities plays a key role in the management of HFpEF patients. These comorbidities are reviewed in detail in other chapters but are briefly covered here.