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May 3, 2022 Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 e950

CLINICAL STATEMENTS AND GUIDELINES

Synopsis HFpEF (LVEF ≥50%) is highly prevalent, accounting for up to 50% of all patients with HF, and is associated with significant morbidity and mortality.14 HFpEF is a heterogenous disorder, contributed to by comorbidities that include hypertension, diabetes, obesity, CAD, CKD, and specific causes such as cardiac amyloidosis.15–17 Clinical trials have used variable definitions of HFpEF (eg, LVEF ≥40%, 45%, or 50%, and the varying need for accompanying evidence of structural heart disease or elevated levels of natriuretic peptides).18 Until recently, clinical trials had been generally disappointing, with no benefit on mortality and marginal benefits on HF hospitalizations.5,8,11,19,20 Currently, recommended management is that used for HF in general with use of diuretics to reduce congestion and improve symptoms (see Section 7.1.1 for recommendations for nonpharmacological management and Section 7.2 for recommendations for diuretics), identification and treatment of specific causes such as amyloidosis, and management of contributing comorbidities such as hypertension, CAD, and AF (see Section 10.2 for recommendations on management of AF). Figure 12 summarizes COR 1, 2a, and 2b for HFpEF. Recommendation-Specific Supportive Text

1.	 The role of blood pressure control is well established for the prevention of HF, as well as for reduction of other cardiovascular events and HF mortality in patients without prevalent baseline HF.1–3,21–24 The SPRINT (Systolic Blood Pressure Intervention) trial and meta-analyses established that more intensive blood pressure control in patients with high cardiovascular risk significantly reduces HF and other cardiovascular outcomes.2,3,25 In recent clinical practice guidelines for hypertension, blood pressure targets in HFpEF are extrapolated from those for treatment of patients with hypertension in general.26 However, the optimal blood pressure goal and antihypertensive regimens are not known for patients with HFpEF. RAAS antagonists including ACEi, ARB, MRA, and possibly ARNi, could be first-line agents given experience with their use in HFpEF trials.8,10,16,20,27,28 Beta blockers may be used to treat hypertension in patients with a history of MI,27 symptomatic CAD, or AF with rapid ventricular response. These effects need to be balanced with the potential contribution of chronotropic incompetence to exercise intolerance in some patients.29 2.	 EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) showed a significant benefit of the SGLT2i, empagliflozin, in symptomatic patients with HF with LVEF >40% and elevated natriuretic peptides.30 The 21% reduction in the primary composite endpoint of time to HF hospitalization or cardiovascular death was driven mostly by a significant 29% reduction in time to HF hospitalization (nonsignificant lower cardiovascular death [HR, 0.91; 95% CI, 0.76-1.0]), with no benefit on all-cause mortality. Empagliflozin also resulted in a significant reduction in total HF hospitalizations, decrease in the slope of the eGFR decline, and a modest improvement in QOL at 52 weeks. Of note, the benefit was similar irrespective of the presence or absence of diabetes at baseline. Although the benefit in the primary endpoint did not have a significant interaction by LVEF subgroups (<50%, 50%–<60%, and >60%),30 in a subgroup analysis by EF, there was a signal for lower benefit on the primary composite endpoint, first and recurrent HF hospitalizations at higher LVEFs >62.5%.31 3.	 Large, randomized clinical trial data are unavailable to specifically guide therapy in patients with HFpEF and AF. Currently, the comprehensive care of AF can be extrapolated from the clinical practice guidelines for AF, with individualization of strategies for rate or rhythm control in patients with HFpEF (see also Section 10.2, “Management of Atrial

Figure 12. Recommendations for Patients With Preserved LVEF (≥50%). Colors correspond to COR in Table 2. Medication recommendations for HFpEF are displayed. ARB indicates angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; and SGLT2i, sodium-glucose cotransporter-2 inhibitor. *Greater benefit in patients with LVEF closer to 50%.

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