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Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 May 3, 2022 e939 CLINICAL STATEMENTS AND GUIDELINES

Recommendation-Specific Supportive Text

1.	 The use of these specific medications for HFrEF should involve initiation at low-starting doses, uptitration at specified intervals as tolerated, and achieving-maintaining the target doses shown to be effective in major clinical trials. Every effort should be made by clinicians to achieve and maintain the clinical trial–defined target doses (Table 13) of guideline-directed medications, as long as they are well tolerated by the patient. Patients should be monitored for changes in heart rate, blood pressure, electrolytes, renal function, and symptoms during this uptitration period. Planned uptitration of a HF medication should be delayed until any adverse effects observed with lower doses have resolved. When such a strategy is used for dose titration, most patients (approximately 70%–85%) enrolled in clinical trials who received these medications were able to tolerate short-, intermediate-, and long-term treatment with these agents and achieve and maintain the trial defined target dose.1–9,11–14 Repeated attempts at uptitration can result in optimization, even if initial attempts may fail. In patients with HFrEF, beta blockers provide dose-dependent improvements in LVEF, reduction in HF hospitalizations, and reduction in all-cause mortality.17 Trials of lower versus higher dose of ACEi and ARB have shown lower risk of cardiovascular death or HF hospitalization with higher doses, with similar safety and tolerability.17,18 2.	 Initiation and titration should be individualized and optimized without delay according to patient’s symptoms, vital signs, functional status, tolerance, renal function, electrolytes, comorbidities, specific cause of HF, and ability of follow-up. In patients with HFrEF, simultaneous initiation or sequencing, and order of guideline-directed medications are usually individualized according to patient’s symptoms, vital signs, functional status, tolerance, renal function, electrolytes, comorbidities, specific cause of HF, and ability of follow-up, and does not necessarily need to be done according to the sequence of trial publications and should not be delayed.

7.3.9 Additional Medical Therapies

7.3.9.1 Management of Stage C HF: Ivabradine

Recommendation for the Management of Stage C HF: Ivabradine Referenced studies that support the recommendation are summarized in the Online Data Supplements.

COR LOE Recommendation

2a B-R 1.	 For patients with symptomatic (NYHA class II to III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDMT, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of ≥70 bpm at rest, ivabradine can be beneficial to reduce HF hospitalizations and cardiovascular death.1,2

Synopsis Heart rate is a strong predictor of cardiovascular outcomes in the general population and in patients with CVD, including HF. The SHIFT (Ivabradine and Outcomes in Chronic Heart Failure) trial tested the hypothesis that reducing heart rate in patients with HF improves cardiovascular outcomes.1 SHIFT demonstrated the efficacy of ivabradine, a sinoatrial node modulator that selectively inhibits the If current, in reducing the composite endpoint of cardiovascular death or HF hospitalization in patients with HF. See Figure 7 for a summary of additional medical therapy recommendations.

Table 15.  Benefits of Evidence-Based Therapies for Patients With HFrEF3–6,8,10–14,23,31–42

Evidence-Based Therapy Relative Risk Reduction in All-Cause Mortality in Pivotal RCTs, % NNT to Prevent All-Cause Mortality Over Time* NNT for All-Cause Mortality (Standardized to 12 mo) NNT for All- Cause Mortality (Standardized to 36 mo) ACEi or ARB 17 22 over 42 mo 77 26 ARNi† 16 36 over 27 mo 80 27 Beta blocker 34 28 over 12 mo 28 9 Mineralocorticoid receptor antagonist 30 9 over 24 mo 18 6 SGLT2i 17 43 over 18 mo 63 22 Hydralazine or nitrate‡ 43 25 over 10 mo 21 7 CRT 36 12 over 24 mo 24 8 ICD 23 14 over 60 mo 70 23 ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor neprilysin inhibitor; CRT, cardiac resynchronization therapy; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator; NNT, number needed to treat; RCT, randomized controlled trial; and SGLT2i, sodium-glucose cotransporter-2 inhibitor. *Median duration follow-up in the respective clinical trial. †Benefit of ARNi therapy incremental to that achieved with ACEi therapy. For the other medications shown, the benefits are based on comparisons to placebo control.

‡Benefit of hydralazine-nitrate therapy was limited to African American patients in this trial. Downloaded from http://ahajournals.org by on October 7, 2026