HFnrEF management

LVEF >40% — encompasses what was previously called HFmrEF and HFpEF. Accounts for ~50% of all HF, particularly older patients, women, and those with HTN, DM, obesity, and OSA. No therapy has demonstrated mortality reduction. The goal is to reduce HF hospitalisations and improve symptoms. SGLT2i and MRA form the pharmacologic backbone.

key differences from HFrEF

	HFrEF (≤40%)	HFnrEF (>40%)
mortality benefit from GDMT	yes — quadruple therapy	no intervention reduces mortality
primary treatment goal	reduce death + HF hospitalisation	reduce HF hospitalisation + symptoms
quadruple therapy	standard of care	not applicable as a bundle
beta-blockers	mortality benefit	no HF-specific benefit (use for rate control / HTN only)
comorbidity burden	variable	typically high — HTN, DM, AF, obesity, CKD, OSA

pharmacotherapy

recommended (strong evidence for reducing HF hospitalisation)

Agent	Evidence	Notes
SGLT2i (dapa or empa)	EMPEROR-Preserved (2021), DELIVER (2022)	for all HFnrEF; no dose titration; do not start if eGFR <20
MRA	TOPCAT (2014), FINEARTS-HF (2024)	favour non-steroidal MRA (finerenone) — see below; spironolactone/eplerenone if finerenone unavailable

steroidal vs non-steroidal MRAs — not interchangeable

Same receptor target, different drugs, different patients. Steroidal MRAs (spironolactone, eplerenone) have proven mortality benefit in HFrEF but equivocal data in HFpEF (TOPCAT). Non-steroidal MRAs (finerenone) have more even heart/kidney tissue distribution, higher MR antagonism potency, and fewer off-target effects (less gynecomastia and hyperkalaemia). Finerenone is the preferred MRA for HFnrEF based on FINEARTS-HF (2024). Favour finerenone especially if concurrent diabetic kidney disease. — Harrington et al. JACC Heart Fail. 2025

suggested (moderate evidence or specific subgroups)

Agent	Evidence	Notes
ARNI	PARAGON-HF (2019)	primary endpoint narrowly missed; benefit signal in LVEF <57% and in women; suggest if low risk of hypotension
GLP-1RA (semaglutide)	STEP-HFpEF (2024)	if LVEF ≥45% + BMI ≥30; improves symptoms, exercise capacity, weight; HF hospitalisation benefit emerging

symptom management

loop diuretics for euvolaemia — lowest effective dose; no mortality benefit
treat comorbidities aggressively: HTN, AF (rate/rhythm), OSA (CPAP), obesity, diabetes

comorbidity-driven approach

HFnrEF is a comorbidity-driven syndrome

Unlike HFrEF where the myocardial disease is central, HFnrEF is often driven by systemic inflammation from metabolic comorbidities → endothelial dysfunction → myocardial fibrosis and stiffness. Treating comorbidities IS treating the HF.

Comorbidity	Action
HTN	aggressive BP control — single most important modifiable factor
AF	rate or rhythm control; OAC per CHADS₂-VASc (or CHADS-65 in Canada)
obesity	GLP-1RA (semaglutide) if BMI ≥30; weight loss improves symptoms and exercise capacity
diabetes	SGLT2i first-line; GLP-1RA additive benefit
OSA	screen (high prevalence); CPAP improves symptoms
iron deficiency	IV iron if ferritin <100 or ferritin 100–299 + TSAT <20% (extrapolated from HFrEF data)
CKD	SGLT2i beneficial for both HF and renal outcomes; finerenone for DKD
coronary disease	standard secondary prevention; revascularisation if ischaemia-driven symptoms

what NOT to do

do not reflexively use beta-blockers for HFnrEF — no HF-specific benefit; may worsen exercise intolerance (chronotropic incompetence is common)
do not assume “diastolic HF is benign” — 5-year mortality approaches HFrEF
do not neglect volume assessment — these patients are highly preload-sensitive; over-diuresis causes low output symptoms