Guidelines for Heart Failure with Preserved Ejection Fraction (HFpEF)
Diagnostic Criteria
All major guidelines define HFpEF as clinical signs and symptoms of heart failure with LVEF ≥50%, but require additional objective evidence of cardiac dysfunction. 1
Core Diagnostic Requirements
- Clinical symptoms/signs of heart failure (dyspnea, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema, elevated jugular venous pressure) 1
- LVEF ≥50% on transthoracic echocardiography 1
- Elevated natriuretic peptides: NT-proBNP ≥125 pg/mL (sinus rhythm) or >365 pg/mL (atrial fibrillation) in ambulatory patients; BNP >35 pg/mL (sinus rhythm) or >50 pg/mL (atrial fibrillation) 1
- Echocardiographic evidence of structural/functional abnormalities: 1
- Average E/e' ≥15 (or >14 by some guidelines)
- Left atrial volume index ≥40 mL/m²
- LV mass index ≥95 g/m² (male) or >95 g/m² (female)
- Septal e' <7 cm/s (female) or <10 cm/s (male)
- TR velocity ≥35 mmHg
When Initial Testing is Non-Diagnostic
- Consider cardiovascular magnetic resonance to assess cardiac structure/function or identify specific etiologies 1
- Cardiopulmonary exercise testing should be considered to identify causes of dyspnea when uncertain and quantify functional capacity 1
- Diagnostic scoring systems (H2FPEF or HFA-PEFF) can be utilized when initial investigations are equivocal, though discrepancies exist between scores 1
- Right heart catheterization should be considered to aid diagnosis, monitor pulmonary artery pressure in select patients, or as workup for advanced treatment 1
- Endomyocardial biopsy if specific causes (myocarditis, amyloidosis) are suspected that would influence therapy 1
Disease-Modifying Pharmacotherapy
SGLT2 inhibitors are the cornerstone first-line disease-modifying therapy for HFpEF and should be initiated in all patients regardless of diabetes status. 2
SGLT2 Inhibitors (Class 2a Recommendation)
- Dapagliflozin 10 mg daily or empagliflozin 10 mg daily reduce heart failure hospitalizations and composite cardiovascular outcomes 2
- Dapagliflozin reduced worsening HF and cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92) in DELIVER trial 2
- Empagliflozin reduced hospitalization for HF and cardiovascular death by 21% (HR 0.79,95% CI 0.69-0.90) in EMPEROR-PRESERVED 2
- Ensure eGFR >30 mL/min/1.73m² for dapagliflozin and >60 mL/min/1.73m² for empagliflozin before initiation 2
- Benefits occur independent of glucose-lowering effects 2
Mineralocorticoid Receptor Antagonists (Class 2b Recommendation)
- Spironolactone 12.5-25 mg daily may be considered, particularly in patients with LVEF in the lower preserved range (40-50%) 2
- Reduced heart failure hospitalizations (HR 0.83,95% CI 0.69-0.99) in TOPCAT trial but did not reduce cardiovascular death 2
- Requires careful monitoring of potassium and renal function to minimize hyperkalemia risk 2
Angiotensin Receptor-Neprilysin Inhibitors (Class 2b Recommendation)
- Sacubitril/valsartan may be considered specifically for women and patients with LVEF 45-57% 2
- PARAGON-HF showed potential benefit in these subgroups (rate ratio 0.73,95% CI 0.59-0.90 in women; rate ratio 0.78,95% CI 0.64-0.95 in LVEF 45-57%) 2
- Did not achieve significant reduction in primary endpoint in overall HFpEF population 2
Symptomatic Management
Loop diuretics at the lowest effective dose are the mainstay for managing fluid retention and relieving congestion. 1
Diuretic Strategy
- Furosemide is the conventional first-choice loop diuretic 1
- Titrate diuretic dose upward before considering combination diuretic strategies if initial response is inadequate 1
- For refractory edema, add thiazide or thiazide-like diuretic (e.g., metolazone) for sequential nephron blockade 1
- Close monitoring of renal function and electrolytes is crucial given increased propensity for derangement 1
- Diuretics provide symptomatic relief but have no evidence of prognostic benefit 1
Acute Decompensated HFpEF
- Initial IV furosemide 20-40 mg for new-onset HFpEF with orthopnea/paroxysmal nocturnal dyspnea 2
- For patients on chronic diuretics, initial IV dose should be at least equivalent to oral dose 2
- Loop diuretics are the backbone of acute fluid overload management 1
Prevention and Risk Factor Management
Aggressive control of cardiovascular risk factors through lifestyle modification and pharmacological therapy is essential for preventing HFpEF development. 1
Blood Pressure Control
- Target blood pressure <130/80 mmHg in patients with high cardiovascular disease risk 1, 2
- Six guidelines strongly recommended tight control of hypertension 1
- Use RAAS antagonists (ACE inhibitors or ARBs) as first-line agents if additional blood pressure control is needed beyond HF medications 2
Diabetes Management
- Initiate SGLT2 inhibitors in patients with type 2 diabetes and high cardiovascular disease risk 1
- SGLT2 inhibitors provide dual benefit for glycemic control and heart failure outcomes 1
- Finerenone (non-steroidal MRA) recommended in type 2 diabetes with concomitant chronic kidney disease 1
Lifestyle Modifications
- Weight reduction for obesity 1
- Smoking cessation 1
- Salt and fluid restriction for symptom management 1
- Regular physical activity 1
Non-Pharmacological Interventions
Supervised exercise training programs should be prescribed to improve functional capacity and quality of life (Class 1 recommendation). 2
Exercise Training
- 3 sessions per week for 1-8 months at 40-90% of exercise capacity using walking, stationary cycling, or high-intensity interval training 2
- Improves aerobic exercise capacity by 12-14% with clinically meaningful quality of life benefits 2
- Five guidelines recommended cardiac rehabilitation, though further research is needed specifically in HFpEF 1
Multidisciplinary Care
- Involvement of wider multidisciplinary team to provide holistic, personalized care 1
- Early palliative care involvement should start early in disease trajectory, with referral to specialist palliative care if patient needs are unmet 1
Comorbidity Management
Managing comorbidities significantly impacts outcomes in HFpEF and is a critical component of comprehensive care. 2
Key Comorbidities to Address
- Hypertension: Achieve target <130/80 mmHg 2
- Diabetes mellitus: Prioritize SGLT2 inhibitors 1
- Obesity: Weight reduction strategies 1
- Atrial fibrillation: Rate control and anticoagulation based on CHA₂DS₂-VASc score 3
- Coronary artery disease: Appropriate revascularization and medical therapy 4
- Chronic kidney disease: Monitor renal function closely with medication adjustments 4
- Obstructive sleep apnea: Screening and treatment 4
Critical Medications to AVOID
Certain medications can worsen HFpEF outcomes and should be avoided. 2
- Nondihydropyridine calcium channel blockers (diltiazem, verapamil) have negative inotropic effects and increase risk of heart failure worsening and hospitalization 2
- Nitrates are associated with a signal of harm in HFpEF 2
- Beta-blockers are not recommended as primary HFpEF therapy unless specific indications exist (e.g., rate control for atrial fibrillation, post-myocardial infarction) 4
Advanced Heart Failure Management
Referral to advanced heart failure specialist team should be considered for patients with advanced HFpEF refractory to standard therapies. 1
When to Refer
- Refractory symptoms despite optimal medical therapy 1
- Consideration for advanced therapies 1
- Cardiac transplantation can be considered in eligible patients with advanced HFpEF 1
Common Pitfalls to Avoid
- Do not treat HFpEF patients the same as those with reduced ejection fraction – response to therapies differs significantly between populations 2
- Avoid excessive diuresis which may lead to hypotension and worsening renal function 2
- Do not overlook comorbidity management which significantly impacts outcomes 2
- Avoid inadequate dose titration of medications, which results in subtherapeutic dosing and reduced efficacy 4
- Do not use medications proven only for HFrEF without evidence in HFpEF 4
Areas of Ongoing Research
Several therapeutic areas require further investigation to establish definitive recommendations. 1
- Combined SGLT2/SGLT1 inhibition 1
- GLP-1 receptor agonists for prognostic benefit 1
- Non-steroidal MRAs in prevention 1
- Efficacy of cardiac rehabilitation specifically in HFpEF 1
- Population-based screening strategies 1
Mortality Reduction Evidence
No pharmacological agent has definitively proven to reduce mortality as a standalone endpoint in HFpEF. 2
- SGLT2 inhibitors reduce composite cardiovascular outcomes driven primarily by reductions in heart failure hospitalizations rather than mortality alone 2
- Multiple agents (perindopril, irbesartan, beta-blockers, nitrates, digoxin, ivabradine, sildenafil, serelaxin) have failed to show mortality benefit 2
- Current treatment goals focus on alleviating symptoms, improving quality of life, and reducing hospitalizations 2