What is the pharmacological management of Heart Failure (HF)?

Pharmacological Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

Core Foundation: Quadruple Therapy for All Patients

All patients with HFrEF should be initiated on four foundational medication classes simultaneously as soon as possible after diagnosis to reduce mortality and morbidity: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), along with diuretics for volume management. 1

This represents a paradigm shift from the traditional sequential approach. The primary goal is neurohormoral blockade to reduce morbidity and mortality, while simultaneously improving symptoms, functional capacity, and quality of life. 2

First-Line Medications (Start All Four Classes Early)

1. SGLT2 Inhibitors (Dapagliflozin or Empagliflozin)

• Start first due to minimal blood pressure effect, making them ideal initial agents 1
• Reduce cardiovascular death and HF hospitalization regardless of diabetes status 1
• Unique among HFrEF medications: no effect on blood pressure, heart rate, or potassium levels; require no dose adjustment or up-titration 3
• Effective in patients with moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin) 3
• Treatment benefits occur within weeks of initiation, independent of age, sex, or background medical therapy 3
• High-certainty evidence demonstrates improved quality of life 3

2. Mineralocorticoid Receptor Antagonists (Spironolactone or Eplerenone)

• Start early alongside SGLT2 inhibitor due to minimal blood pressure effect 1
• Provide at least 20% mortality reduction and reduce sudden cardiac death 1
• Indicated for all symptomatic patients with LVEF ≤35% 1
• Require monitoring of renal function and serum potassium levels 1
• Continue when initiating sacubitril/valsartan as cornerstone therapy 4

3. Beta-Blockers (Carvedilol, Metoprolol Succinate, or Bisoprolol)

• Use only evidence-based beta-blockers that reduce mortality by at least 20% and decrease sudden cardiac death 1
• Preferred agents for achieving rate control in patients with atrial fibrillation due to favorable effect on morbidity and mortality 3
• Initiate in clinically stable patients at low dose and gradually up-titrate to maximum tolerated dose 1
• Critical: Non-evidence-based beta-blockers should not be used 1

4. Renin-Angiotensin System Inhibitors

Sacubitril/Valsartan (ARNI) - Preferred Option:

• Superior to ACE inhibitors with at least 20% mortality reduction 1
• Replace ACE inhibitors in symptomatic patients to further reduce hospitalization and death risk 4, 2
• High-certainty evidence demonstrates improved quality of life compared to ACE inhibitors 3
• All HFrEF patients on ACE inhibitors or ARBs are candidates for switching, without needing to wait for patients to "fail" optimal medical therapy first 4

Dosing Strategy for Sacubitril/Valsartan:

• Standard patients: Start 49/51 mg twice daily if previously on high-dose ACE inhibitors 4
• High-risk patients (severe renal impairment with eGFR <30 mL/min/1.73 m², moderate hepatic impairment, or age ≥75 years): Start 24/26 mg twice daily 4
• Target dose: 97/103 mg twice daily, doubling dose every 2-4 weeks as tolerated 4
• Switching from ACE inhibitor: Mandatory 36-hour washout period to avoid angioedema 2
• Switching from ARB: No washout period required 2

ACE Inhibitors (if ARNI not tolerated):

• Enalapril indicated for symptomatic congestive heart failure, usually in combination with diuretics and digitalis 5
• Improves symptoms, increases survival, and decreases frequency of hospitalization 5
• Also indicated for asymptomatic left ventricular dysfunction (ejection fraction ≤35%) to decrease rate of development of overt heart failure 5

ARBs (if ACE inhibitor and ARNI not tolerated):

• High-certainty evidence demonstrates improved quality of life 3
• Effective alternative when ACE inhibitors or ARNI cannot be used 1

Diuretics for Volume Management

• Loop diuretics essential for congestion control but do not reduce mortality 1
• Starting doses: Furosemide 20-40 mg once or twice daily, torsemide 10-20 mg once daily, or bumetanide 0.5-1.0 mg once or twice daily 1
• Adjust dose based on fluid status and symptoms 1
• Diuretic doses may need reduction due to enhanced natriuresis when using sacubitril/valsartan 4

Titration Strategy: Achieving Target Doses

Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved, starting with SGLT2 inhibitor and MRA first. 1

Specific Titration Sequence:

1. Start SGLT2 inhibitor and MRA simultaneously (minimal BP effect) 1
2. Add beta-blocker, starting low and titrating slowly 1
3. Add ARNI or ACE inhibitor/ARB, titrating to target dose 1
4. For sacubitril/valsartan: Double dose every 2-4 weeks as tolerated to reach target of 97/103 mg twice daily 4

Managing Low Blood Pressure During Titration:

• Do not withhold therapy for asymptomatic low BP with adequate perfusion 1
• Start SGLT2 inhibitor and MRA first (no BP effect), then add beta-blocker or very low-dose ARNI 1
• Asymptomatic hypotension is not a reason to avoid switching to sacubitril/valsartan; it provides mortality benefit even with lower BP 4
• If symptomatic hypotension occurs: Reduce diuretic dose first or temporarily reduce sacubitril/valsartan dose, then re-titrate 4
• Symptomatic hypotension in chronic HFrEF can usually be managed through patient education and counseling without reducing HF pharmacotherapy 4

Managing Renal Function Changes:

• Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment 4
• Monitor renal function and electrolytes, particularly when using aldosterone antagonists 4

Additional Therapies for Selected Patients

Ivabradine

• Indication: Heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 1
• Starting dose: 2.5-5 mg twice daily 1
• Target: Maintain resting heart rate between 50-60 bpm 6
• Reduces hospitalizations but survival benefit is modest or negligible in broad HFrEF population 1
• High-certainty evidence demonstrates improved quality of life 3
• Effective in stable NYHA class II-IV heart failure with LVEF ≤35% and resting heart rate ≥70 bpm 6

Hydralazine/Isosorbide Dinitrate

• Indication: Self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 1
• Starting dose: Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 1
• High-certainty evidence demonstrates improved quality of life 3
• Can prolong survival but may be inferior to ACE inhibitors for mortality 1

Digoxin

• May be effective adjunct to beta-blocker for rate control in atrial fibrillation 3
• Useful for symptom reduction but does not reduce mortality 7
• Particularly useful in patients with atrial fibrillation 8

Intravenous Iron (Ferric Carboxymaltose)

• Indication: Iron deficiency in HFrEF patients 3
• High-certainty evidence demonstrates improved quality of life 3
• Consider in selected patients with documented iron deficiency 3

Vericiguat and Omecamtiv Mecarbil

• Can be considered in selected patients with persistent symptoms despite optimal therapy 3
• Evidence-based therapies for specific clinical scenarios 3

Special Populations and Considerations

Patients with Atrial Fibrillation

• Rate control strategy: Beta-blockers are preferred agents due to favorable effect on morbidity and mortality 3
• Rhythm-control strategy has not been shown superior to rate-control strategy 3
• Digoxin may be effective adjunct to beta-blocker 3
• Non-dihydropyridine calcium antagonists (diltiazem) should be used with caution due to negative inotropic effect 3
• If rhythm control chosen, amiodarone is most effective antiarrhythmic with lower proarrhythmic risk 3

Patients with HFpEF

• SGLT2 inhibitors have proven beneficial in HFpEF 9
• Non-dihydropyridine calcium antagonists can be effective for rate control, more effective when combined with digoxin 3

Hospitalized Patients

• Resolution of acute pulmonary congestion required before initiating sacubitril/valsartan 4
• Continue MRA as cornerstone therapy when initiating sacubitril/valsartan 4
• Recent data support direct initiation of sacubitril/valsartan without pretreatment period with ACEIs or ARBs as safe and effective strategy 4

Critical Contraindications and Drug Interactions

Absolute Contraindications:

• Never combine ACE inhibitor with ARNI 1
• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 1
• History of angioedema related to previous ACE inhibitor or ARB therapy is precaution for sacubitril/valsartan use 4
• Pregnancy or lactation contraindicated for sacubitril/valsartan 4
• Severe hepatic impairment contraindicated for sacubitril/valsartan 4

Medications to Avoid:

• Diltiazem or verapamil in HFrEF increase risk of worsening heart failure and hospitalization 1
• Non-evidence-based beta-blockers should not be used 1

Drug Interactions:

• Sacubitril/valsartan may increase levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters 4
• Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when combined with sacubitril/valsartan 4

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes simultaneously 1
2. Accepting suboptimal doses without attempting titration to target 1
3. Stopping medications for asymptomatic hypotension with adequate perfusion 1
4. Inadequate monitoring of renal function and electrolytes 1
5. Using non-evidence-based beta-blockers instead of carvedilol, metoprolol succinate, or bisoprolol 1
6. Failure to titrate to target doses due to asymptomatic hypotension or mild laboratory changes 4
7. Permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate 4
8. Treating heart failure less aggressively than other life-threatening conditions despite similar mortality risks 4
9. Believing medium-range doses provide most benefits of target doses (they do not) 4

Evidence Base and Quality of Life Impact

The contemporary approach to HFrEF pharmacotherapy is supported by high-certainty evidence demonstrating both mortality reduction and quality of life improvement. Meta-analyses confirm that ARBs, ARNIs, SGLT2 inhibitors, ivabradine, hydralazine-nitrate, and intravenous iron all improve health-related quality of life in HFrEF patients. 3 The PARADIGM-HF trial demonstrated sacubitril/valsartan reduced cardiovascular death or HF hospitalization by 20% compared to enalapril, with meta-analysis confirming mortality benefit (RR 0.86,95% CI 0.79-0.94). 4

Patients commencing comprehensive therapy at age 55 years gain an additional 8.3 years free of cardiovascular mortality or first HF hospitalization compared to conventional therapy. 3 This underscores the critical importance of early, aggressive implementation of all four foundational medication classes rather than sequential, delayed initiation.