Which medications have a Class I recommendation for heart failure with preserved ejection fraction (HFpEF)?

Medications with Class I Recommendation for Heart Failure with Preserved Ejection Fraction

Only two interventions carry Class I recommendations for HFpEF: blood pressure control and diuretics for volume overload. No specific medication class has a Class I recommendation for reducing mortality or morbidity in HFpEF. 1

Class I Recommendations (Strongest Evidence)

1. Blood Pressure Control

• Systolic and diastolic blood pressure should be controlled in patients with HFpEF in accordance with published clinical practice guidelines to prevent morbidity. 1
• This is a Class I, Level of Evidence B recommendation from the 2013 ACC/AHA guidelines. 1
• The specific antihypertensive agents are not mandated—the goal is achieving target blood pressure, not prescribing a particular drug class. 1

2. Diuretics for Symptomatic Relief

• Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF. 1
• This is a Class I, Level of Evidence C recommendation. 1
• Loop diuretics are essential for congestion control but do not reduce mortality—they are purely symptomatic therapy. 2, 3
• Titrate diuretic dose to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 4

Critical Distinction: HFpEF vs. HFrEF

HFpEF patients should NOT be treated like HFrEF patients. 5 The four-drug regimen that provides 61% mortality reduction in HFrEF (ARNI, beta-blocker, MRA, SGLT2 inhibitor) does not have Class I evidence in HFpEF. 4

Emerging Evidence (Not Yet Class I)

While the following medications show promise in HFpEF, they currently lack Class I recommendations:

SGLT2 Inhibitors (Strongest Emerging Evidence)

• SGLT2 inhibitors were the optimal drug class for reducing HF hospitalization in HFpEF in a 2022 network meta-analysis (HR 0.71,95% CrI 0.60-0.83). 6
• Recent 2025 evidence confirms SGLT2 inhibitors reduce cardiovascular death and HF hospitalization regardless of diabetes status in HFpEF. 7
• However, the 2013 ACC/AHA guidelines predate SGLT2 inhibitor trials and do not include Class I recommendations for this drug class. 1

Mineralocorticoid Receptor Antagonists

• MRAs showed modest benefit in reducing HF hospitalization (HR 0.83,95% CrI 0.69-0.99) in HFpEF. 6
• Seven published trials have evaluated MRAs in HFpEF, with mixed results. 2

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

• ARNIs reduced HF hospitalization (HR 0.76,95% CrI 0.61-0.95) in HFpEF. 6
• May be considered for selected HFpEF patients, particularly those with lower-range preserved EF. 7

Special Population: HFpEF with Atrial Fibrillation

If the patient has concurrent atrial fibrillation, rate control becomes a Class I recommendation:

• Control of resting heart rate using either a beta-blocker or nondihydropyridine calcium channel antagonist is recommended for patients with persistent or permanent AF and compensated HFpEF. 1
• This is Class I, Level of Evidence B. 1
• Beta-blockers or nondihydropyridine calcium channel blockers (diltiazem, verapamil) are appropriate for rate control in HFpEF with AF. 1

Common Pitfalls to Avoid

• Do not prescribe ACE inhibitors, ARBs, or beta-blockers solely for the diagnosis of HFpEF without another indication (e.g., hypertension, coronary disease, AF). 1, 5
• Do not withhold diuretics due to concerns about "over-diuresis"—maintaining euvolemia is the primary symptomatic goal. 1, 5
• Do not assume medications proven in HFrEF will work in HFpEF—the pathophysiology differs substantially. 5
• Avoid therapies shown not to be beneficial unless another compelling indication exists. 5

Practical Management Algorithm

1. Confirm HFpEF diagnosis (EF ≥50%, signs/symptoms of HF, elevated natriuretic peptides or objective evidence of diastolic dysfunction). 1

2. Treat blood pressure aggressively to guideline targets using any evidence-based antihypertensive regimen. 1

3. Initiate loop diuretics (furosemide 20-40 mg daily, torsemide 10-20 mg daily, or bumetanide 0.5-1.0 mg daily) and titrate to euvolemia. 4, 3

4. If concurrent AF exists, add beta-blocker or nondihydropyridine calcium channel blocker for rate control. 1

5. Consider SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) based on emerging evidence, though this is not yet a Class I recommendation. 6, 7

6. Treat comorbidities aggressively: obesity, diabetes, coronary disease, atrial fibrillation. 7