What is the recommended treatment regimen for patients with heart failure?

Heart Failure Treatment Regimen

Foundational Four-Drug Therapy for HFrEF (LVEF ≤40%)

All patients with heart failure and reduced ejection fraction must receive four medication classes simultaneously: ACE inhibitors (or ARNIs), beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, as this combination reduces mortality and hospitalization. 1, 2

ACE Inhibitors (or ARNIs) - First Pillar

• Start ACE inhibitors immediately in all patients with reduced left ventricular systolic function, beginning with low doses and gradually titrating to target maintenance doses proven effective in clinical trials 3, 2
• Target doses from major trials are: lisinopril 20-35 mg daily, enalapril 10-20 mg twice daily, or ramipril 5-10 mg daily 2
• Before initiating ACE inhibitors, review and potentially reduce diuretic doses for 24 hours to avoid excessive hypotension 2
• Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, at 3 months, and subsequently at 6-month intervals 3, 2
• High doses of ACE inhibitors (e.g., lisinopril 32.5-35 mg daily) result in 12% lower risk of death or hospitalization and 24% fewer heart failure hospitalizations compared to low doses (2.5-5 mg daily), though mortality reduction alone was not statistically significant 4
• ARNIs (sacubitril-valsartan) are superior to ACE inhibitors alone: in the PARADIGM-HF trial, sacubitril-valsartan 200 mg twice daily reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril 10 mg twice daily (HR 0.80, p<0.0001) 5

Beta-Blockers - Second Pillar

• Initiate beta-blockers in all stable patients already on ACE inhibitors and diuretics, ensuring the patient has no intravenous inotropic support requirements or marked fluid retention 1, 2
• Evidence-based beta-blockers with proven mortality benefit are: bisoprolol (target 10 mg daily), metoprolol succinate CR (target 200 mg daily), carvedilol (target 50 mg daily), or nebivolol (target 10 mg daily) 2
• Start with very low doses (bisoprolol 1.25 mg, metoprolol 12.5-25 mg, carvedilol 3.125 mg) and double every 1-2 weeks if tolerated 1, 2
• Beta-blockers reduce mortality by at least 20% and decrease hospitalizations 1, 2
• If worsening symptoms occur during beta-blocker titration, first increase diuretics or ACE inhibitors before reducing beta-blocker dose 1
• For hypotension during beta-blocker titration, reduce vasodilators first rather than the beta-blocker 1
• Absolute contraindications include asthma bronchiale, severe bronchial disease, symptomatic bradycardia or hypotension 1

Mineralocorticoid Receptor Antagonists (MRAs) - Third Pillar

• Add spironolactone or eplerenone for patients who remain symptomatic (NYHA Class III-IV) despite ACE inhibitor and beta-blocker therapy to reduce mortality and hospitalization 1, 3, 2
• Start spironolactone 12.5-25 mg daily only if serum potassium <5.0 mmol/L and creatinine <250 μmol/L 1, 2
• Check potassium and creatinine after 4-6 days of spironolactone initiation 1
• If potassium levels are elevated, reduce the spironolactone dose by 50% or stop it if persistently elevated 1
• Monitor serum potassium and creatinine carefully when initiating therapy and during dose adjustments 3

SGLT2 Inhibitors - Fourth Pillar

• Initiate SGLT2 inhibitors early in all HFrEF patients regardless of diabetes status to reduce cardiovascular death and heart failure hospitalization 1, 2
• SGLT2 inhibitors represent the fourth pillar of therapy and should be started simultaneously with the other three medication classes 1

Diuretic Therapy (Symptomatic Relief)

• Diuretics are essential for symptomatic treatment when fluid overload is present, and loop diuretics or thiazides should always be administered in addition to an ACE inhibitor 3
• For patients with reduced renal function, avoid thiazides except when used synergistically with loop diuretics 3

Additional Pharmacological Considerations

• Reserve digoxin for patients in sinus rhythm with persistent symptoms despite ACE inhibitor and diuretic treatment, with a usual dose of 0.25-0.375 mg daily 1
• Avoid digoxin in patients with bradycardia, second- or third-degree AV block, sick sinus syndrome, and electrolyte abnormalities 1
• Avoid combining ACE inhibitors, ARBs, and MRAs due to increased risk of renal dysfunction and hyperkalemia 1
• If inotropic support is needed in a patient on beta-blockade, use phosphodiesterase inhibitors as their effects are not antagonized by beta-blockers 1

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF, LVEF 41-49%)

• Treat HFmrEF similarly to HFrEF with the same four-drug foundational therapy, though the evidence level is lower 1

Heart Failure with Preserved Ejection Fraction (HFpEF, LVEF ≥50%)

• SGLT2 inhibitors are the cornerstone of HFpEF treatment, reducing cardiovascular death and heart failure hospitalization 1

Adjunctive Therapy for Specific Populations

• Ivabradine can be added in patients with HFrEF, LVEF ≤35%, heart rate ≥70 bpm despite maximally tolerated beta-blocker doses, and recent heart failure hospitalization 6
• Ivabradine reduced the composite endpoint of hospitalization for worsening heart failure or cardiovascular death (HR 0.82, p<0.0001), driven entirely by reduction in heart failure hospitalizations with no mortality benefit 6

Device Therapy

• ICD is recommended for primary prevention in symptomatic HF (NYHA Class II-III) with LVEF ≤35% despite ≥3 months of optimal medical therapy in patients with ischemic heart disease or dilated cardiomyopathy 2
• ICD is also indicated for secondary prevention in patients who survived ventricular arrhythmia causing hemodynamic instability 2

Non-Pharmacological Management

• Control sodium intake, especially in severe heart failure, and avoid excessive fluid intake 1, 3, 2
• Daily physical activity is recommended in stable patients to prevent muscle deconditioning and improve exercise tolerance 1, 2
• Provide patient education about heart failure, symptom recognition, and self-management 3, 2
• Team-based care with cardiologists, primary care physicians, nurses, and pharmacists reduces mortality and hospitalization 1, 2

Critical Monitoring Parameters

• When starting ACE inhibitors, avoid excessive diuresis before treatment, and consider reducing or withholding diuretics for 24 hours 3, 2
• Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment of ACE inhibitors or MRAs, at 3 months, and subsequently at 6-month intervals 3, 2
• Refer patients to specialist care for severe heart failure, bradycardia, low blood pressure, or suspected asthma/bronchial disease 1