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7 6 Table 5. Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations (2017) COR LOE Recommendations I e clinical strategy of inhibition of the renin-angiotensin system with: A ACE inhibitors, OR A ARBs, OR B-R ARNI in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HFrEF to reduce morbidity and mortality. I A e use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality. I A e use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE inhibitors because of cough or angioedema. I B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. III: Harm B-R ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor. III: Harm C-EO ARNI should not be administered to patients with a history of angioedema. Table 6. Ivabradine: Recommendation (2017) COR LOE Recommendation IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of ≥70 bpm at rest. Treatment Table 7. Drugs Commonly Used for Stage C HFr EF (2017) Drug Initial Daily Dose(s) Maximum Daily Doses(s) Mean Daily Doses Achieved in Clinical Trials ACE Inhibitors Captopril 6.25 mg tid 50 mg tid 122.7 mg qd Enalapril 2.5 mg bid 10–20 mg bid 16.6 mg qd Fosinopril 5–10 mg qd 40 mg qd N/A Lisinopril 2.5–5 mg qd 20–40 mg qd 32.5–35.0 mg qd Perindopril 2 mg qd 8–16 mg qd N/A Quinapril 5 mg bid 20 mg bid N/A Ramipril 1.25–2.5 mg qd 10 mg qd N/A Trandolapril 1 mg qd 4 mg qd N/A ARBs Candesartan 4–8 mg qd 32 mg qd 24 mg qd Losartan 25–50 mg qd 50–150 mg qd 129 mg qd Valsartan 20–40 mg bid 160 mg bid 254 mg qd ARNI Sacubitril/valsartan 49/51 mg bid (therapy may be initiated at 24/26 mg bid) 97/103 mg bid 375 mg qd; target dose: 24/26 mg, 49/51 mg OR 97/103 mg bid I f channel inhibitor Ivabradine 5 mg bid 7.5 mg bid 6.4 mg bid (at 28 d) 6.5 mg bid (at 1 y) Aldosterone Antagonists Spironolactone 12.5–25 mg qd 25 mg qd or bid 26 mg qd Eplerenone 25 mg qd 50 mg qd 42.6 mg qd Beta Blockers Bisoprolol 1.25 mg qd 10 mg qd 8.6 mg qd Carvedilol 3.125 mg bid 50 mg bid 37 mg qd Carvedilol CR 10 mg qd 80 mg qd N/A Metoprolol succinate extended release (metoprolol CR/XL) 12.5–25 mg qd 200 mg qd 159 mg qd Isosorbide dinitrate and hydralazine Fixed-dose combination 20 mg isosorbide dinitrate/37.5 mg hydralazine tid 40 mg isosorbide dinitrate/75 mg hydralazine tid 90 mg isosorbide dinitrate/~175 mg hydralazine qd Isosorbide dinitrate and hydralazine 20–30 mg isosorbide dinitrate/25–50 mg hydralazine tid or qd 40 mg isosorbide dinitrate tid with 100 mg hydralazine tid N/A Modified (Table 15) from the 2013 HF guideline