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May 3, 2022 Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 e940

CLINICAL STATEMENTS AND GUIDELINES

Recommendation-Specific Supportive Text

1.	 Although the primary outcome in SHIFT was a composite of hospitalization and cardiovascular death, the greatest benefit was a reduction in HF hospitalization. SHIFT included patients with HFrEF and LVEF ≤35% who were in sinus rhythm with a resting heart rate of ≥70 bpm. Participants were predominantly NYHA class II and III. Participants had been hospitalized for HF in the preceding 12 months and were on stable GDMT for 4 weeks before initiation of ivabradine therapy.1–4 The target of ivabradine is heart rate, and the benefit of ivabradine results from a reduction in heart rate. However, only 25% of patients studied in SHIFT were on optimal doses of beta-blocker therapy. Given the well-proven mortality benefits of beta-blocker therapy, these agents should be initiated and uptitrated to target doses, as tolerated, before assessing the resting heart rate for consideration of ivabradine initiation.5,6 7.3.9.2 Pharmacological Treatment for Stage C HFrEF: Digoxin

Recommendation for the Pharmacological Treatment for Stage C HFrEF: Digoxin Referenced studies that support the recommendation are summarized in the Online Data Supplements.

COR LOE Recommendation

2b B-R 1.	 In patients with symptomatic HFrEF despite GDMT (or who are unable to tolerate GDMT), digoxin might be considered to decrease hospitalizations for HF.1,2

Synopsis To date, there has been only 1 large-scale, RCT of digoxin in patients with HF.1 This trial, which predated current GDMT, primarily enrolled patients with NYHA class II to III HF and showed that treatment with digoxin for 2 to 5 years had no effect on mortality but modestly reduced the combined risk of death and hospitalization. The trial also found no significant effect on health-related QOL in a subset of the trial patients.3 The effect of digoxin on hospitalizations has been supported by retrospective analyses and meta-analyses.2,4–6 Additionally, observational studies and retrospective analyses have shown improvement in symptoms and exercise tolerance in mild to moderate HF; however, they have mostly shown either lack of mortality benefit or increased mortality associated with digoxin.7 The benefit in patients on current GDMT is unclear because most trials preceded current GDMT. Thus, use of digoxin requires caution in patients with HF and is reserved for those who remain symptomatic despite optimization of GDMT.

Recommendation-Specific Supportive Text

1.	 Digoxin is usually initiated at a low dose because higher doses are rarely required in the management of HF and are potentially detrimental. Two retrospective analyses of large-scale clinical trials have shown a linear relationship between mortality and digoxin serum concentration in patients with AF and at risk for stroke, including those with HF, and in patients with HF. The risk of death was independently associated with serum digoxin concentration, with a significantly higher risk observed in those with concentrations ≥1.2 ng/mL and ≥1.6 ng/mL.8,9 The benefit of digoxin in patients with HF remains controversial. GDMT is expected to be optimized before considering the addition of digoxin. Clinical worsening after withdrawal of digoxin has been shown.10 Therapy with digoxin may either be continued in the absence of a contraindication or discontinued with caution.11 Therapy with digoxin is commonly initiated and maintained at a dose of 0.125 to 0.25 mg daily. Low doses (0.125 mg daily or every other day) should be used initially if the patient is >70 years of

Figure 7. Additional Medical Therapies for Patients With HFrEF. Colors correspond to COR in Table 2. Recommendations for additional medical therapies that may be considered for patients with HF are shown. GDMT indicates guideline-directed medical therapy; HF, heart failure; HFH, heart failure hospitalization; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic dimension; MV, mitral valve; MR, mitral regurgitation; NP, natriuretic peptide; NSR, normal sinus rhythm; NYHA, New York Heart Association; and RAASi, renin-angiotensin-aldosterone system inhibitors.

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