Heart Failure With Preserved Ejection Fraction Management: 5 Things to Know

Daniel N. Silverman, MD; Sheldon E. Litwin, MD; Ryan J. Tedford, MD, FACC


October 07, 2020

Editorial Collaboration

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2. Managing comorbid conditions is important.

Although HFpEF is frequently characterized by its phenotypic heterogeneity, most patients also present with a host of other discrete, treatable medical comorbidities, such as hypertension, valvular heart disease, and atrial fibrillation. Management of hypertension is one of the highest-yield mechanisms for reducing CV morbidity and mortality, including HF-associated hospitalizations. The presence of underlying valvular heart disease or coronary artery disease should be considered and pursued to identify potential therapeutic targets. Atrial fibrillation is highly common in patients with HFpEF and often increases the likelihood of hospitalization. Rhythm control strategies, such as catheter ablation, may be more beneficial than rate control, though data from prospective randomized controlled trials are needed.

Hypothesized to be at the core of the HFpEF "metabolic phenotype" is a chronic, systemic proinflammatory state affecting multiple organs and the microvasculature. With increasing prevalence of an obesity/metabolic HFpEF phenotype, weight loss and aerobic exercise are critical interventions proven to improve exercise tolerance and reduce body weight in patients with HFpEF. In cases wherein traditional weight loss strategies have failed, pharmacologic adjunctive therapies and/or bariatric surgery may be considered.

Management of diabetes offers an adjunctive target for reduction of systemic inflammation, and there is hope that sodium-glucose cotransporter 2 inhibitors may simultaneously offer blood glucose control, reduced systemic inflammation, and additive diuresis. Whether this class of medications will prove to be effective in reducing cardiovascular outcomes in HFpEF as they have been in HFrEF remains to be seen when results from the EMPEROR-Preserved Trial and others become available.

3. Most medications used to treat HFrEF have not shown conclusive benefit in HFpEF.

There is no convincing evidence that the major components of guideline-directed medical therapy for HFrEF are effective in treating HFpEF. Clinical trials involving aldosterone antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNi), beta-blockers, and nitrates all failed to meet primary efficacy endpoints. In addition, studies involving digoxin, inorganic nitrites, phosphodiesterase 5 inhibitors, and soluble guanylyl cyclase stimulators also failed to show significant benefit in HFpEF. Despite these overall disappointing results, a handful of these studies merit closer discussion.

The CHARM-Preserved study failed to show reduction in mortality, but the ARB candesartan resulted in a reduction in hospitalizations, suggesting ARBs as a good first-line agent for treating HFpEF in patients with hypertension. Although the TOPCAT trial of the mineralocorticoid receptor antagonist spironolactone failed to meet its primary endpoint (composite of cardiovascular death, aborted cardiac arrest, or HF hospitalization), there was some reduction in hospitalizations. In addition, poststudy investigations of TOPCAT found several trial-related irregularities related to study drug administration and diagnosis by region of enrollment. Analysis of the trial data suggested that in the North American study cohort, spironolactone reduced mortality and hospitalizations. For this reason, spironolactone is a staple treatment for patients with HFpEF who have preserved renal function (glomerular filtration rate > 30 mL/min/1.73 m2) and normal potassium levels.

Several medications should be considered carefully before use in HFpEF. For example, the NEAT-HFpEF trial showed that the use of nitrates in the absence of a compelling coexisting indication (eg, stable angina) decreased levels of physical activity among patients with HFpEF. In addition, multiple studies, including ELANDD, SENIORS, and J‐DHF, showed no benefit of beta-blockers in HFpEF. Of note, however, these studies included patients who by contemporary definition would be categorized as having HFrEF (LVEF < 40%) and HF with mid-range EF (LVEF ≥ 40% and < 50%). Secondary analyses have suggested that there may in fact be an associated increase in HF hospitalizations with use of beta-blockers in HFpEF (LVEF ≥ 50%), hypothesized to be due to the production of elevated filling pressures at lower heart rates, elevated central blood pressures, and worsening of chronotropic incompetence (an inadequate heart rate response to stress or demands). Although these considerations are related to secondary endpoints and post hoc analyses, they nonetheless provide some guidance in selecting therapeutic agents.


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