What is the recommended management for a patient with heart failure with preserved ejection fraction?

Management of Heart Failure with Preserved Ejection Fraction (HFpEF)

Establish the Diagnosis and Exclude Mimics

Before initiating HFpEF-specific therapy, you must exclude primary non-cardiovascular causes of congestion (kidney failure, liver failure, chronic venous insufficiency) and special cardiomyopathies (infiltrative/restrictive disease, hypertrophic cardiomyopathy, significant valvular disease, pericardial disease) that require distinct treatment approaches. 1

• Obtain a detailed history focusing on musculoskeletal issues (carpal tunnel, lumbar stenosis), neuropathy, family history of cardiomyopathy, prior chest radiation or pericarditis, and extracardiac manifestations (pulmonary, ocular, dermatologic symptoms) that suggest specific mimics 1
• Order monoclonal protein screening (serum/urine immunofixation electrophoresis and serum free light chains) if left ventricular wall thickness is increased to evaluate for cardiac amyloidosis 1
• Consider cardiac magnetic resonance imaging when echocardiography suggests infiltrative disease, hypertrophic cardiomyopathy, sarcoidosis, or pericardial disease 1
• Measure ferritin, transferrin, and consider HFE genetic testing if hemochromatosis is suspected based on diabetes, erectile dysfunction, or transfusion history 1

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First-Line Disease-Modifying Pharmacotherapy

Initiate an SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) immediately upon confirming HFpEF diagnosis, regardless of diabetes status—this is the single most important disease-modifying intervention. 2, 3

SGLT2 Inhibitor Selection and Evidence

• Dapagliflozin 10 mg daily reduces the composite of worsening heart failure and cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92) and heart failure hospitalizations by 23% (HR 0.77,95% CI 0.67-0.89) in the DELIVER trial 2, 3, 4
• Empagliflozin 10 mg daily reduces heart failure hospitalization or cardiovascular death by 21% (HR 0.79,95% CI 0.69-0.90) in EMPEROR-PRESERVED 2, 3
• Verify eGFR >30 mL/min/1.73m² for dapagliflozin or >60 mL/min/1.73m² for empagliflozin before initiation 2, 3
• Benefits occur within weeks, are independent of diabetes status, and require no dose titration 2

Critical caveat: No pharmacologic agent has demonstrated definitive mortality reduction as a standalone endpoint in HFpEF; the benefit of SGLT2 inhibitors is driven primarily by reduction in heart failure hospitalizations 2, 5

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Acute Symptom Management with Diuretics

Use loop diuretics at the lowest effective dose to relieve orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema—these are the only agents that reliably address fluid retention in HFpEF. 2, 3

Diuretic Dosing Strategy

• For new-onset congestion, start with furosemide 20-40 mg IV (or equivalent); for patients already on chronic diuretics, use an IV dose at least equivalent to their oral dose 2
• If inadequate response despite dose escalation, add hydrochlorothiazide for sequential nephron blockade (CLOROTIC trial showed greater weight loss and diuresis, though with higher creatinine elevation) 2
• Consider adding IV acetazolamide if response remains inadequate 2
• Once euvolemia is achieved, taper to the lowest dose that maintains volume balance 2
• Monitor serum electrolytes, blood urea nitrogen, and creatinine serially during diuretic titration 2

Common pitfall: Excessive diuresis precipitates hypotension and worsening renal function, compromising tolerance of other guideline-directed therapies 2

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Blood Pressure Control

Target systolic blood pressure <130 mmHg and diastolic <80 mmHg using agents that provide additional heart failure benefits. 2, 3

• Use ACE inhibitors or angiotensin receptor blockers as first-line antihypertensive therapy after volume status is optimized; they effectively lower blood pressure and modestly reduce HF hospitalizations, though they do not confer mortality benefit 2
• Consider nebivolol when additional blood pressure control is needed; it reduces the combined endpoint of mortality or cardiovascular hospitalization by approximately 19% in HFpEF 2

Medications to avoid:

• Never use non-dihydropyridine calcium channel blockers (diltiazem, verapamil) due to myocardial depressant effects and association with worsened clinical outcomes 2, 3
• Avoid nitrates due to potential signal of harm in HFpEF 2, 3

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Additional Pharmacologic Options for Selected Patients

Mineralocorticoid Receptor Antagonists

Consider adding spironolactone 12.5-25 mg daily specifically in patients with LVEF in the lower preserved range (40-50%). 2, 3

• Spironolactone reduces heart failure hospitalizations (HR 0.83,95% CI 0.69-0.99) in TOPCAT but did not reduce the primary composite outcome of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization 2
• Monitor potassium, renal function, and diuretic dosing carefully to minimize hyperkalemia and worsening renal function 2

Angiotensin Receptor-Neprilysin Inhibitors

Sacubitril/valsartan may be considered specifically for women and patients with LVEF 45-57%, as these subgroups showed benefit in PARAGON-HF post-hoc analyses. 2, 3

• The overall PARAGON-HF trial did not achieve a significant reduction in the primary composite endpoint (rate ratio 0.87,95% CI 0.75-1.01, p=0.06) 2
• Prespecified subgroup analyses showed potential benefit in patients with LVEF 45-57% (rate ratio 0.78,95% CI 0.64-0.95) and women (rate ratio 0.73,95% CI 0.59-0.90) 2

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Management of Key Comorbidities

Diabetes Mellitus

Prioritize SGLT2 inhibitors for glycemic control given their dual benefit on glucose and heart failure outcomes. 2, 3

Atrial Fibrillation (Present in 4-40% of HFpEF Patients Depending on NYHA Class)

Rate control is the preferred initial strategy over rhythm control in HFpEF patients with atrial fibrillation. 6

• Use beta-blockers as the preferred agents for achieving rate control due to favorable effects on controlling ventricular response 6
• Non-dihydropyridine calcium channel antagonists (diltiazem) can be effective for rate control when combined with digoxin, though they should generally be avoided as monotherapy in HFpEF 6
• Anticoagulate according to CHA₂DS₂-VASc score 2
• Consider AV node ablation and cardiac resynchronization therapy device placement only when rate control cannot be achieved due to drug inefficacy or intolerance—never perform AV node ablation without a pharmacological trial first 6

Chronic Kidney Disease

• Monitor renal function and electrolytes regularly, particularly when MRAs or diuretics are prescribed 2, 3
• Ensure eGFR thresholds are met before starting SGLT2 inhibitors 2, 3

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Non-Pharmacological Interventions

Prescribe supervised exercise training programs (3 sessions per week for 1-8 months at 40-90% of maximal capacity) to improve functional capacity by 12-14% and quality of life. 2, 3

• Recommend dietary sodium restriction to <2-3 g per day to lessen congestive symptoms and support diuretic effectiveness 2, 3
• Advise weight reduction for obese patients 7

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Advanced Therapies for Refractory Disease

Consider referral to an advanced heart failure specialist team for patients with recurrent hospitalizations and persistent congestion despite optimal medical therapy. 2

• Ultrafiltration may be employed as a last-resort strategy to achieve euvolemia in patients with persistent congestion despite maximal diuretic therapy 2
• Wireless, implantable pulmonary artery pressure monitors can be considered in selected patients with prior decompensated HF admissions to facilitate volume-status optimization 2
• Cardiac transplantation can be considered in eligible patients with advanced HFpEF 2

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Monitoring and Follow-Up

• Regularly assess volume status, renal function, and electrolytes, especially with MRA therapy 2, 3
• Monitor symptoms and functional capacity to guide treatment adjustments 2

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Common Pitfalls to Avoid

• Do not treat HFpEF patients the same as those with reduced ejection fraction—response to therapies differs significantly between these populations 2
• Do not delay initiation of SGLT2 inhibitors, which have the strongest evidence for reducing heart failure hospitalizations 6
• Do not overlook the importance of managing comorbidities (hypertension, diabetes, obesity, atrial fibrillation), which significantly impact outcomes in HFpEF 2, 3, 8