Target Doses of Medications for HFrEF
Patients with HFrEF should be titrated to the evidence-based target doses proven effective in randomized controlled trials, as these specific doses form the basis for mortality and morbidity reduction—achieving target doses of all four foundational drug classes can reduce all-cause mortality by 73% compared with no treatment. 1
Core Medication Classes and Target Doses
ACE Inhibitors
- Enalapril: 10-20 mg twice daily (target: 20 mg total daily) 1
- Lisinopril: 20-40 mg once daily 1
- Ramipril: 10 mg once daily 1
- Captopril: 50 mg three times daily (150 mg total daily) 1
- Perindopril: 8-16 mg once daily 1
- Quinapril: 20 mg twice daily (40 mg total daily) 1
- Trandolapril: 4 mg once daily 1
- Fosinopril: 40 mg once daily 1
Angiotensin Receptor Blockers (ARBs)
- Candesartan: 32 mg once daily 1
- Valsartan: 160 mg twice daily (320 mg total daily) 1
- Losartan: 50-150 mg once daily (guidelines recommend 150 mg, FDA label maximum 100 mg) 1
Angiotensin Receptor-Neprilysin Inhibitor (ARNI)
- Sacubitril/valsartan: 97 mg sacubitril/103 mg valsartan twice daily (194/206 mg total daily) 1
- Starting dose: 24/26 mg or 49/51 mg twice daily 1
- The 49/51 mg twice daily dose (98/102 mg total daily) meets the 50% of target dose threshold 1
Beta-Blockers
- Metoprolol succinate: 200 mg once daily 1, 2
- Carvedilol: 25 mg twice daily for patients <85 kg; 50 mg twice daily for patients ≥85 kg 1
- Bisoprolol: 10 mg once daily 1
- Carvedilol CR: 80 mg once daily 1
Mineralocorticoid Receptor Antagonists (MRAs)
SGLT2 Inhibitors
- Dapagliflozin: 10 mg once daily (no titration required) 1
- Empagliflozin: 10 mg once daily (no titration required) 1
Additional Therapies
Hydralazine/Isosorbide Dinitrate (for self-identified Black patients)
- Target: 40 mg isosorbide dinitrate/75 mg hydralazine three times daily (120 mg/300 mg total daily) 1
- Fixed-dose combination: 40 mg/75 mg three times daily 1
Ivabradine (for symptomatic patients with heart rate ≥70 bpm on maximally tolerated beta-blocker)
Vericiguat (for recently decompensated patients)
Titration Strategy and Timeline
General Principles
- Start low, go slow: Initiate at low starting doses and uptitrate at specified intervals as tolerated 1
- Titration frequency: Every 1-2 weeks depending on symptoms, vital signs, and laboratory findings 1
- Continue uptitration even if symptoms improve at lower doses—clinical trials demonstrated that reaching target doses provides maximal mortality benefit regardless of symptomatic improvement at intermediate doses 1, 2
- Approximately 70-85% of patients in clinical trials tolerated and achieved target doses 1
Monitoring Parameters During Titration
- Heart rate: Target >60 bpm (avoid uptitration if <60 bpm with symptoms) 2, 3
- Blood pressure: Systolic >90 mmHg preferred (asymptomatic hypotension alone is not a reason to stop uptitration) 2, 3
- Electrolytes: Monitor potassium and renal function, especially with ACEi/ARB/ARNI and MRAs 1
- Signs of worsening heart failure or volume overload 2
Minimum Acceptable Dosing
If target doses cannot be achieved, aim for at least 50% of target dose or the highest tolerated dose. 1 Quality measures define optimal dosing as achieving ≥50% of target doses for ACEi/ARB/ARNI, beta-blockers, and MRAs 1
Dose-Response Relationship and Clinical Outcomes
Evidence for Target Dosing
- Beta-blockers demonstrate clear dose-dependent improvements in LVEF, reduction in HF hospitalizations, and all-cause mortality 1, 2
- Higher doses of ACEi and ARB show lower risk of cardiovascular death or HF hospitalization compared with lower doses in head-to-head trials 1
- Dose de-escalation is associated with worse outcomes: Patients who had doses reduced experienced 60-64% higher all-cause mortality compared with those maintained on target doses 4
- Stable sub-target dosing of beta-blockers was associated with 49% higher cardiovascular mortality or HF hospitalization compared with target dosing 4
Real-World Achievement Rates
Despite guideline recommendations, real-world data reveal suboptimal dosing: only 17-29% of patients on ACEi/ARB, 13-28% on beta-blockers, and 29-77% on MRAs achieve target doses in clinical practice 1. Even more concerning, only 1% of eligible patients achieve target doses of all recommended drugs simultaneously 1.
Common Pitfalls to Avoid
Critical Errors in Dosing
- Do not stop uptitration simply because symptoms improve—the mortality benefit requires reaching target doses proven in trials 1, 2
- Asymptomatic hypotension or bradycardia alone are not contraindications to continued uptitration unless accompanied by symptoms or hemodynamic compromise 2
- Do not discontinue or reduce doses without attempting optimization strategies for common challenges like hyperkalemia, worsening renal function, or hypotension 5
- Avoid clinical inertia—repeated attempts at uptitration can result in optimization even if initial attempts fail 1
Contraindications to Uptitration
- Signs of acute heart failure or volume overload requiring adjustment 2
- Evidence of low output state or increased risk for cardiogenic shock 2
- Heart rate <60 bpm with symptoms 2
- Second- or third-degree AV block without pacemaker 2
- Active asthma or reactive airways disease (for beta-blockers) 2, 6
Special Populations
Renal Impairment
- ACEi dosing adjustments: For creatinine clearance ≤30 mL/min, start enalapril at 2.5 mg once daily and titrate cautiously 7
- HFrEF with renal impairment: Start at 2.5 mg daily under close supervision if serum creatinine >1.6 mg/dL or sodium <130 mEq/L 7
Post-Myocardial Infarction
- Carvedilol: Start at 6.25 mg twice daily after hemodynamic stability, increase to 12.5 mg twice daily after 3-10 days, then to target 25 mg twice daily 8
- Lower starting dose of 3.125 mg twice daily may be used if clinically indicated 8