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

Heart Failure Treatment: Recommended Regimen

All patients with heart failure and reduced ejection fraction (HFrEF, LVEF ≤40%) should receive four foundational medication classes simultaneously: ACE inhibitor (or ARNI), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor, as this quadruple therapy reduces both mortality and hospitalization. 1

Initial Pharmacological Approach for HFrEF

First-Line Therapy: ACE Inhibitors

• Start ACE inhibitors immediately in all patients with reduced left ventricular systolic function, beginning with low doses and titrating gradually to target maintenance doses proven effective in clinical trials 2, 3
• Use only ACE inhibitors with proven mortality benefit: captopril, enalapril, lisinopril, or ramipril 4
• Target high doses rather than low doses—the ATLAS trial demonstrated that high-dose lisinopril (32.5-35 mg daily) reduced death or hospitalization by 12% and heart failure hospitalizations by 24% compared to low doses (2.5-5 mg daily), despite no significant mortality difference alone 5
• 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, then every 6 months 2, 3

Second Pillar: Beta-Blockers

• Add beta-blockers for all stable patients (NYHA class II-IV) already on ACE inhibitors and diuretics 2, 3
• Use only evidence-based agents: carvedilol, metoprolol succinate, or bisoprolol, which reduce mortality by at least 20% 1
• Critical timing: Ensure the patient is relatively stable without intravenous inotropic support or marked fluid retention before initiation 6
• Start with very low doses and double every 1-2 weeks if tolerated, targeting maintenance doses from large trials 6
• Common pitfall: If worsening symptoms occur during titration, first increase diuretics or ACE inhibitors before reducing beta-blocker dose 6
• For hypotension during titration, reduce vasodilators first rather than the beta-blocker 6
• Refer to specialist care for: severe heart failure (NYHA III/IV), bradycardia, low blood pressure, or suspected asthma/bronchial disease 6

Third Pillar: Mineralocorticoid Receptor Antagonists

• Add spironolactone in advanced heart failure (NYHA III-IV) despite ACE inhibitor and diuretic therapy to improve survival and reduce morbidity 2, 1
• Start with 25 mg daily only if serum potassium <5.0 mmol/L and creatinine <250 μmol/L 6
• Check potassium and creatinine after 4-6 days 6
• Critical monitoring: If potassium ≥5.5 mmol/L at any time, reduce dose by 50% or stop if persistently elevated 6
• After 1 month, if symptoms progress and potassium remains normal, increase to 50 mg daily 6

Fourth Pillar: SGLT2 Inhibitors

• Initiate SGLT2 inhibitors early regardless of diabetes status, as they reduce cardiovascular death and heart failure hospitalization 1
• This represents the newest pillar of therapy with strong evidence across all HFrEF patients 1

Advanced Therapy Options

ARNI (Sacubitril/Valsartan)

• Replace ACE inhibitors with sacubitril/valsartan in ambulatory patients who remain symptomatic despite optimal triple therapy (ACE inhibitor, beta-blocker, MRA) 3
• The PARADIGM-HF trial demonstrated superiority over enalapril, with hazard ratio 0.80 for the composite endpoint of cardiovascular death or heart failure hospitalization (p<0.0001) 7
• Sacubitril/valsartan reduced cardiovascular death (HR 0.80), heart failure hospitalizations (HR 0.79), and all-cause mortality (HR 0.84, p=0.0009) 7
• Do not combine ACE inhibitor, ARB, and MRA due to increased risk of renal dysfunction and hyperkalemia 3

Digoxin

• Reserve digoxin for patients in sinus rhythm with persistent symptoms despite ACE inhibitor and diuretic treatment 6
• Usual dose: 0.25-0.375 mg daily with normal renal function; reduce to 0.125-0.25 mg in elderly patients 6
• No loading dose needed for chronic conditions 6
• Contraindications include bradycardia, second- or third-degree AV block, sick sinus syndrome, and electrolyte abnormalities (hypokalemia, hypercalcemia) 6

Ivabradine

• Consider ivabradine in patients with stable NYHA class II-IV heart failure, LVEF ≤35%, and resting heart rate ≥70 bpm despite maximally tolerated beta-blocker doses 8
• The SHIFT trial showed reduced risk of hospitalization for worsening heart failure or cardiovascular death (HR 0.82, p<0.0001), driven entirely by reduced hospitalizations 8
• Start at 5 mg twice daily, titrating to maintain heart rate between 50-60 bpm 8

Diuretic Management

• Diuretics are essential for symptomatic relief when fluid overload (pulmonary congestion or peripheral edema) is present 2, 3
• Always administer loop diuretics or thiazides in combination with ACE inhibitors, never as monotherapy 2
• Avoid thiazides in reduced renal function except when used synergistically with loop diuretics 2

Device Therapy Considerations

• Implantable cardioverter-defibrillators (ICDs) reduce sudden death and all-cause mortality in symptomatic HF patients (NYHA II-III) with LVEF ≤35% despite ≥3 months of optimal medical therapy 3
• Critical timing: Do not implant ICDs within 40 days of myocardial infarction, as this does not improve prognosis 3
• Cardiac resynchronization therapy (CRT) is indicated for symptomatic patients in sinus rhythm with QRS ≥150 msec, LBBB morphology, and LVEF ≤35% 3

Treatment by Ejection Fraction Category

HFmrEF (LVEF 41-49%)

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

HFpEF (LVEF ≥50%)

• SGLT2 inhibitors are the cornerstone of HFpEF treatment, reducing cardiovascular death and heart failure hospitalization 1
• Definite benefit from ACE inhibitors in all HFpEF patients has not been demonstrated 4

Non-Pharmacological Management

• Control sodium intake, especially in severe heart failure 2, 3, 1
• Avoid excessive fluid intake in severe heart failure 2, 3
• Recommend daily physical activity in stable patients to prevent muscle deconditioning 2, 3
• Implement team-based care with cardiologists, primary care physicians, nurses, and pharmacists to reduce mortality and hospitalization 1

Critical Contraindications and Warnings

• Avoid diltiazem or verapamil in HFrEF as they increase risk of heart failure worsening 3
• Beta-blocker absolute contraindications: asthma bronchiale, severe bronchial disease, symptomatic bradycardia or hypotension 6
• If inotropic support is needed in a patient on beta-blockade, use phosphodiesterase inhibitors as their effects are not antagonized by beta-blockers 6