Treatment of Chronic Diastolic Heart Failure (HFpEF) versus Chronic Systolic Heart Failure (HFrEF)
For HFrEF (LVEF ≤40%), initiate quadruple guideline-directed medical therapy immediately with an ARNI (preferred over ACE inhibitor), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor, which together provide approximately 73% mortality reduction over 2 years. 1, 2 For HFpEF (LVEF ≥50%), prioritize SGLT2 inhibitors to reduce hospitalizations and cardiovascular mortality, manage blood pressure aggressively, and use diuretics for symptom relief—mortality-reducing therapies proven for HFrEF do not work the same way in HFpEF. 3, 1
HFrEF (LVEF ≤40%): Four-Pillar Approach
Immediate Initiation of Quadruple Therapy
Start all four medication classes simultaneously or in rapid sequence at diagnosis, including during hospitalization—do not wait for "stability" as this delays life-saving therapy 1, 2
ARNI (sacubitril/valsartan) is the preferred renin-angiotensin system inhibitor over ACE inhibitors or ARBs, providing superior mortality reduction of at least 20% 1, 4, 2
Beta-blockers (bisoprolol, carvedilol, or metoprolol succinate) reduce mortality by at least 20% and decrease sudden cardiac death 1, 4, 2
Mineralocorticoid receptor antagonists (spironolactone or eplerenone) provide at least 20% mortality reduction with minimal blood pressure effect, allowing early initiation 1, 2
- Use if eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L 1
SGLT2 inhibitors reduce hospitalizations and cardiovascular mortality regardless of diabetes status with minimal blood pressure effect 1, 2
Additional HFrEF Therapies
Diuretics should be used judiciously to reduce congestion and improve symptoms, not as primary disease-modifying therapy 3, 1
Ivabradine reduces hospitalization risk in patients with LVEF ≤35%, sinus rhythm, resting heart rate ≥70 bpm, and either maximally tolerated beta-blockers or contraindication to beta-blockers 5
ICD therapy is indicated for primary prevention in symptomatic patients (NYHA Class II-III) with LVEF ≤35% despite ≥3 months of optimal medical therapy 4, 2
Cardiac resynchronization therapy (CRT) is indicated for symptomatic HFrEF patients in sinus rhythm with QRS ≥150 msec and LBBB morphology with LVEF ≤35% 2
Critical Management Points for HFrEF
Never discontinue GDMT even if symptoms resolve and EF improves—40% of patients relapse within 6 months of medication withdrawal 1
For symptomatic hypotension, reduce diuretic dose first rather than reducing GDMT, as asymptomatic hypotension is expected and beneficial 4
For hyperkalemia, adjust MRA dose and use potassium binders rather than discontinuing ARNI or beta-blocker to allow continuation of life-saving therapy 4
HFpEF (LVEF ≥50%): Symptom Management and Comorbidity Control
Disease-Modifying Therapy
SGLT2 inhibitors are the cornerstone therapy for HFpEF, decreasing heart failure hospitalizations and cardiovascular mortality 3, 1, 6
- This is the only Class I recommendation with mortality benefit in HFpEF 3
Mineralocorticoid receptor antagonists (particularly spironolactone) showed benefit in the TOPCAT trial for reducing hospitalizations, though results were mixed 3
- Consider in select patients, especially those with lower EF within the HFpEF spectrum 1
ARNI (sacubitril/valsartan) showed modest benefit in PARAGON-HF, particularly in patients with EF closer to 50% and women 3
- Not universally recommended but may be considered in select patients 3
Blood Pressure and Symptom Management
Control blood pressure aggressively to published guideline targets using ACE inhibitors, ARBs, or beta-blockers 1
- Hypertension is present in the vast majority of HFpEF patients and is a primary treatment target 3
Use diuretics judiciously for relief of symptoms due to volume overload—this is the primary symptomatic therapy 3, 1, 7
- Avoid excessive diuresis as HFpEF patients are preload-dependent 7
Comorbidity Management
Aggressively manage diabetes, obesity, atrial fibrillation, coronary artery disease, chronic kidney disease, and obstructive sleep apnea as these drive HFpEF pathophysiology 3, 6
For atrial fibrillation, use beta-blockers or verapamil-type calcium antagonists to control heart rate and increase diastolic filling period 3
- Rate control is mandatory in permanent AF 3
Consider GLP-1 receptor agonists in patients with type 2 diabetes, obesity, and symptomatic HFpEF to reduce symptoms and improve exercise function 1, 6
What NOT to Do in HFpEF
Do not treat HFpEF patients like HFrEF patients—the four-pillar HFrEF approach does not provide the same mortality benefit 3, 7, 8
Historical trials of perindopril, irbesartan, beta-blockers (without specific indication), nitrates, digoxin, ivabradine, sildenafil, and serelaxin were all negative in HFpEF 3
Beta-blockers should only be used in HFpEF if there is a specific indication (prior MI within 3 years, angina, or AF), and exercise tolerance must be monitored due to risk of chronotropic incompetence 3
HFmrEF (LVEF 41-49%): Intermediate Phenotype
SGLT2 inhibitors decrease heart failure hospitalizations in HFmrEF 1
Continue GDMT if the patient previously had HFrEF and improved to HFmrEF 1
Consider MRAs (particularly spironolactone) for patients on the lower end of this EF spectrum 1
Key Distinctions Between HFrEF and HFpEF
Pathophysiology Differences
HFrEF is primarily a disease of systolic dysfunction with proven mortality-reducing therapies targeting neurohormonal activation 3, 2
HFpEF is a heterogeneous syndrome with diastolic dysfunction, but also involves chronotropic incompetence, longitudinal LV systolic dysfunction despite normal EF, pulmonary hypertension, abnormal ventricular-arterial coupling, and systemic comorbidities 9, 10
- Diastolic dysfunction may sometimes be absent in HFpEF 9
Evidence Base Differences
Extensive trial evidence supports quadruple therapy for HFrEF with dramatic mortality reduction 1, 2
HFpEF trials have been largely disappointing until recently, with DELIVER and EMPEROR-PRESERVED showing SGLT2 inhibitor benefit 3, 6