Heart Failure Pharmacotherapy

Classify the Heart Failure Before Choosing the Regimen

Heart-failure phenotype	Left ventricular ejection fraction (LVEF)
Heart failure with reduced ejection fraction (HFrEF)	≤40%
Heart failure with mildly reduced ejection fraction (HFmrEF)	41–49%
Heart failure with preserved ejection fraction (HFpEF)	≥50%
Heart failure with improved ejection fraction (HFimpEF)	Previous LVEF ≤40%, then >40% with ≥10-point absolute improvement

Stages A and B: Prevention and Pre-HF Matter

Heart-failure pharmacotherapy begins before symptomatic Stage C disease. Stage A describes patients at risk for heart failure (HF) without structural heart disease or HF symptoms; priorities include aggressive treatment of hypertension, diabetes, obesity, dyslipidemia, chronic kidney disease (CKD), and other cardiovascular risk factors. Stage B (pre-HF) includes structural heart disease or another objective cardiac abnormality without current HF symptoms. Therapy is directed at preventing progression to symptomatic HF, including evidence-based renin-angiotensin-aldosterone system (RAAS) inhibition and beta blockade when indicated by reduced left ventricular ejection fraction (LVEF), prior myocardial infarction (MI), or another qualifying condition (Ng & Yeung, 2026).

HFrEF: The Four Foundational Therapies

1.  RAAS inhibition, preferably an angiotensin receptor-neprilysin inhibitor (ARNI) when appropriate; an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) is used when ARNI therapy is not suitable

2.  An evidence-based beta blocker

3.  A mineralocorticoid receptor antagonist

4.  An SGLT2 inhibitor

Current HFrEF management favors early exposure to all 4 mechanisms rather than waiting months to maximize one drug before adding the next. Diuretics are added according to volume status rather than counted as a fifth disease-modifying pillar (Ng & Yeung, 2026).

Common HFrEF Starting and Target Doses

These are common adult HFrEF doses from the 2026 Pharmacotherapy chapter. Start lower or titrate more slowly when blood pressure, kidney function, potassium, recent decompensation, or other patient factors limit tolerance (Ng & Yeung, 2026).

Drug	Common starting dose	Target / usual trial dose
Sacubitril/valsartan	24/26–49/51 mg twice daily	97/103 mg twice daily
Carvedilol	3.125 mg twice daily	25 mg twice daily; 50 mg twice daily if body weight >85 kg
Metoprolol succinate ER	12.5–25 mg once daily	200 mg once daily
Bisoprolol	1.25 mg once daily	10 mg once daily
Spironolactone	12.5–25 mg once daily	25–50 mg once daily
Eplerenone	25 mg once daily	50 mg once daily
Dapagliflozin	10 mg once daily	10 mg once daily
Empagliflozin	10 mg once daily	10 mg once daily

ARNI, ACE Inhibitor, and ARB Therapy

Sacubitril/valsartan combines angiotensin-receptor blockade with neprilysin inhibition. In symptomatic HFrEF, ARNI therapy is preferred over an ACE inhibitor or ARB when tolerated. A 36-hour washout is required between an ACE inhibitor and sacubitril/valsartan because overlapping ACE and neprilysin inhibition increases angioedema risk. Monitor BP, potassium, and renal function (Ng & Yeung, 2026).

Evidence-Based Beta Blockers

• Carvedilol
• Metoprolol succinate
• Bisoprolol

Initiate or titrate beta blockade when the patient is clinically stable and reasonably euvolemic. Metoprolol tartrate is not interchangeable with metoprolol succinate for HFrEF outcome benefit. Carvedilol also blocks alpha1 receptors and may lower BP more, which can influence selection when hypotension limits therapy (Ng & Yeung, 2026).

Mineralocorticoid Receptor Antagonists

Spironolactone and eplerenone reduce aldosterone-mediated sodium retention, fibrosis, and adverse remodeling. In symptomatic HFrEF they reduce morbidity and mortality. Usual safety criteria include potassium <5 mEq/L and eGFR >30 mL/min/1.73 m² (Ng & Yeung, 2026).

Check potassium and renal function before treatment, at approximately day 3 and 1 week after initiation or titration, monthly for the first 3 months, then about every 3 months. Hyperkalemia and renal dysfunction are the major safety concerns. Eplerenone is more selective and causes fewer androgen/progesterone-mediated adverse effects than spironolactone (Ng & Yeung, 2026).

SGLT2 Inhibitors

Dapagliflozin and empagliflozin improve HFrEF outcomes even when diabetes is absent. Their HF doses are fixed at 10 mg once daily rather than titrated to a target dose. Dapagliflozin is listed for HFrEF at eGFR ≥25 mL/min/1.73 m² and empagliflozin at eGFR ≥20 mL/min/1.73 m² in the 2026 chapter. Monitor volume status, kidney function, genital mycotic infection, and ketoacidosis risk; loop-diuretic needs may change after initiation. Ketoacidosis can occur without marked hyperglycemia, so compatible symptoms should prompt evaluation regardless of the presenting glucose level. Withhold either agent for at least 3 days, when feasible, before surgery or procedures associated with prolonged fasting, and resume when the patient is clinically stable and oral intake has resumed (AstraZeneca Pharmaceuticals LP, 2026; Boehringer Ingelheim Pharmaceuticals, Inc., 2026; Ng & Yeung, 2026).

Diuretics: Treat Congestion, Not the Ejection Fraction

Loop diuretics improve dyspnea, orthopnea, elevated filling pressures, edema, and other manifestations of volume excess but do not replace disease-modifying HFrEF therapy. Once euvolemia is achieved, use the lowest dose that maintains it. Interpret creatinine changes with BP, perfusion, urine output, weight, and residual congestion (Ng & Yeung, 2026).

Additional HFrEF Therapy for Selected Patients

Hydralazine + Isosorbide Dinitrate

The combination can be added to optimized therapy in self-identified Black patients with persistent New York Heart Association (NYHA) class III–IV HFrEF and can substitute when ARNI/ACE inhibitor/ARB therapy cannot be used because of contraindications or intolerance. Headache, hypotension, reflex tachycardia, and adherence burden are important considerations (Ng & Yeung, 2026).

Ivabradine

Ivabradine may be considered in symptomatic HFrEF with LVEF ≤35%, sinus rhythm, and resting heart rate ≥70 beats/min despite maximally tolerated evidence-based beta-blocker therapy. It does not provide ventricular rate control in atrial fibrillation (Ng & Yeung, 2026).

Digoxin

Digoxin may reduce HF hospitalization in selected patients who remain symptomatic despite optimized therapy but does not improve HFrEF survival. A serum concentration around 0.5–0.9 ng/mL is generally preferred. Renal dysfunction, older age, low lean body mass, hypokalemia, hypomagnesemia, and interacting drugs increase toxicity risk (Ng & Yeung, 2026).

Vericiguat

Vericiguat may be considered in selected patients with HFrEF and recent worsening HF despite foundational therapy. It is adjunctive rather than foundational and should not displace optimization of the 4 primary classes (Ng & Yeung, 2026).

HF with Improved Ejection Fraction

Improved EF usually reflects response to therapy rather than cure. HFrEF guideline-directed therapy should generally be continued after EF improves because withdrawal is associated with substantial relapse risk (Ng & Yeung, 2026).

HFpEF: Contemporary Pharmacotherapy

HFpEF is now treated as a heterogeneous multisystem syndrome rather than a single “diastolic HF” phenotype. Management starts with accurate diagnosis, careful volume control, and treatment of hypertension, atrial fibrillation, coronary disease, CKD, diabetes, obesity, and sleep apnea. SGLT2 inhibitors have established outcome benefit across the preserved-EF spectrum (American College of Cardiology, 2026; Ng & Yeung, 2026).

The 2026 ACC HFpEF pathway incorporates nonsteroidal MRA therapy and phenotype-directed incretin-based therapy in appropriate patients, particularly when obesity or metabolic disease is a major component of the HFpEF phenotype. SGLT2 inhibitors, ARNI/ARB therapy, diuretics, and selected beta-blocker use also remain part of phenotype- and comorbidity-directed care rather than a copied HFrEF regimen (American College of Cardiology, 2026).

Finerenone in HF With LVEF ≥40%

Finerenone is a nonsteroidal mineralocorticoid receptor antagonist with an FDA indication to reduce cardiovascular death, heart-failure hospitalization, and urgent heart-failure visits in adults with heart failure and LVEF ≥40%. The current FDA label starts 20 mg once daily when eGFR is ≥60 mL/min/1.73 m² and 10 mg once daily when eGFR is 25 to <60; initiation is not recommended when eGFR is <25. Do not initiate if serum potassium is >5.0 mEq/L (U.S. Food and Drug Administration, 2026).

After 4 weeks, titrate toward 40 mg once daily when baseline eGFR was ≥60 mL/min/1.73 m² or 20 mg once daily when baseline eGFR was 25 to <60, if potassium and kidney function permit. Recheck potassium and eGFR 4 weeks after initiation and dose changes, then periodically. Strong CYP3A4 inhibitors are contraindicated; avoid grapefruit and strong or moderate CYP3A4 inducers (U.S. Food and Drug Administration, 2026).

HFmrEF Pharmacotherapy

HFmrEF occupies the 41–49% LVEF range. SGLT2 inhibitors have outcome benefit across this range. ARNI, ACE inhibitor, ARB, beta blocker, and MRA therapy may also be considered, particularly as EF approaches the HFrEF range and when another indication is present (Ng & Yeung, 2026).

Acute Decompensated Heart Failure

Acute treatment begins with the physiologic profile: congestion, perfusion, blood pressure, and evidence of cardiogenic shock. IV loop diuretics are primary therapy for substantial congestion. IV vasodilators can be considered when blood pressure is adequate. Positive inotropes such as dobutamine or milrinone are not routine congestion therapy and are generally reserved for cardiogenic shock, bridge therapy, or selected palliative situations (Ng & Yeung, 2026).

Medications That Can Precipitate or Worsen Heart Failure

Medication reconciliation is part of HF treatment because several common drugs can worsen congestion, contractility, or myocardial injury. High-yield examples include nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors, which promote sodium retention and can blunt diuretic response; thiazolidinediones such as pioglitazone and rosiglitazone, which promote fluid retention; verapamil and diltiazem in HFrEF because of negative inotropy; selected antiarrhythmics with negative inotropic or proarrhythmic effects; and systemic glucocorticoids or other sodium-retaining therapies. New or worsening HF should trigger review of medications and substances before disease progression is assumed (Ng & Yeung, 2026).

Iron Deficiency as a Treatable HF Comorbidity

Iron deficiency is common in HF and can contribute to impaired functional capacity even when overt anemia is absent. The 2026 Pharmacotherapy chapter defines iron deficiency in HF as ferritin <100 ng/mL, or ferritin 100–300 ng/mL with transferrin saturation <20%. Intravenous iron replacement can improve exercise tolerance and quality of life in appropriately selected patients. Consider iron studies when symptoms or functional limitation seem disproportionate, especially when anemia, nutritional deficiency, or recurrent HF decompensation is present (Ng & Yeung, 2026).

Self-Management and Patient Education

Teach patients to track daily weight trends and recognize worsening dyspnea, orthopnea, edema, abdominal congestion, or declining exercise tolerance. Reinforce medication adherence, individualized sodium guidance, fluid restriction only when clinically indicated, tobacco cessation, alcohol limitation, appropriate exercise/cardiac rehabilitation, and recommended immunizations. Patients should know which OTC drugs can destabilize HF—especially NSAIDs—and when a change in symptoms or weight warrants clinician contact. Self-monitoring is part of maintaining compensation, not an optional add-on to pharmacotherapy (Ng & Yeung, 2026).

High-Yield Distinctions

• HFrEF disease modification is built around ARNI/RAAS inhibition, evidence-based beta blockade, MRA, and SGLT2 inhibition.
• A 36-hour washout is required between ACE inhibitor and sacubitril/valsartan.
• Carvedilol, metoprolol succinate, and bisoprolol are evidence-based HFrEF beta blockers.
• MRAs require structured potassium and renal-function monitoring.
• Dapagliflozin and empagliflozin use fixed 10-mg daily HF doses.
• Loop diuretics treat congestion but do not replace outcome-improving guideline-directed medical therapy.
• Iron deficiency can contribute to HF symptoms with or without overt anemia; IV iron can improve exercise tolerance and quality of life in appropriately selected patients.
• Continue GDMT in HFimpEF unless a contraindication develops.
• HFpEF therapy is phenotype-directed; SGLT2 inhibitors and nonsteroidal MRA therapy now have important outcome roles.
• Routine inotrope use in acute HF is inappropriate without low-output shock or another advanced-HF indication.
• SGLT2 inhibitors should generally be withheld for at least 3 days before surgery or prolonged fasting and restarted only after clinical stability and oral intake resume.

Related YourDNP Resources

• Heart Failure
• Case Study: Cardiorenal Decompensation
• Chronic Kidney Disease
• Arrhythmias

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References

American College of Cardiology. (2026, July 23). Updated ACC expert consensus decision pathway addresses management of HFpEF. https://www.acc.org/latest-in-cardiology/journal-scans/2026/07/22/17/25/updated-acc-ecdp-addresses-management-of-hfpef

AstraZeneca Pharmaceuticals LP. (2026). Farxiga (dapagliflozin) prescribing information. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef9e9c8c-5460-4193-952a-0c249dd071bd

Boehringer Ingelheim Pharmaceuticals, Inc. (2026). Jardiance (empagliflozin) prescribing information. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59ed43d9-b4e0-72a2-e063-6394a90a327d

Ng, T. M. H., & Yeung, S. L. (2026). Heart failure. In M. A. Chisholm-Burns, P. M. Malone, J. M. Kolesar, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed., pp. 184–238). McGraw Hill.

U.S. Food and Drug Administration. (2026). Kerendia (finerenone) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215341s011lbl.pdf