p.34 抽出テキスト

6.1.4.3 Beta-blockers

Beta-blockers have been shown to reduce morbidity and mortality in patients with HFrEF in addition to treatment with an ACE-I and diuretics.36,287–292 Bisoprolol, sustained-release metoprolol (succinate), and carvedilol have been shown to reduce the risk of death in patients with HFrEF, whereas nebivolol only reduced the combined endpoint of all-cause mortality and CV hospitalization. An individual patient meta-analysis of RCTs of beta-blockers suggested similar reductions in CV and allcause mortality for patients in sinus rhythm with HFrEF who had LVEF <40% and LVEF 40%–50%.36 Beta-blockers should be initiated early in clinically stable patients, at low doses and gradually uptitrated to the highest tolerated dose. In patients admitted with DHF, beta-blockers should be cautiously initiated in hospital, once the patient is haemodynamically stabilized. Every effort should be made to achieve the target doses of the beta-blockers shown to be effective in major clinical trials (Table 11). Even if symptoms do not improve, long-term treatment should be maintained to reduce the risk of major CV events. The effect of beta-blockers in patients with HFrEF and AF remains uncertain. A retrospective subgroup individual-patient data meta-analysis of all major beta-blocker trials in HFrEF showed no benefit on hospital admissions and mortality in the subgroup of patients with HFrEF with AF.36,293 However, to date no RCT has ever been conducted investigating the effect of beta-blockers specifically in patients with AF and HFrEF, despite beta-blockers being potentially useful for rate control of AF.

6.1.5 Additional medical therapy for heart failure with

reduced ejection fraction 6.1.5.1. If-channel inhibitor (ivabradine) Ivabradine should be considered in patients with symptomatic HFrEF who at rest are in sinus rhythm with heart rate ≥70 b.p.m., LVEF ≤35%, and recent HFH, despite stable FMT including optimized beta-blocker therapy.294 Ivabradine slows heart rate by inhibition of the If current. In the SHIFT trial, the primary composite endpoint of CV death or HFH was reduced, mainly driven by a reduction in HFH.294 Importantly, only 25% of patients studied in the trial were on optimal doses of betablockers.294 As beta-blockers have well-proven morbidity and mortality benefits, they should be initiated and uptitrated to target doses first, before assessing the resting heart rate for consideration of adding ivabradine.

6.1.5.2 Vericiguat

The oral soluble guanylate cyclase stimulator vericiguat may be considered in patients with symptomatic HFrEF and LVEF <45% despite optimal FMT. The VICTORIA study assessed the efficacy and safety of vericiguat in patients with LVEF <45% and with recent episodes of WHF, who were already on the highest tolerated FMT. The incidence of the primary endpoint of CV death or HFH was lower among those who received vericiguat than among those who received placebo.295 There was no reduction in either all-cause or CV death. The much higher event rate in VICTORIA compared with other RCTs in patients with HFrEF was associated with a shorter median follow-up to acquire the total number of events needed, which may explain why HFH were reduced, but CV mortality was not significantly reduced.296 There was also heterogeneity in a subgroup analysis, with less benefit in patients with the highest NT-proBNP levels. The VICTOR study evaluated vericiguat in ambulatory patients with HFrEF (LVEF ≤40%) who did not have a recent WHF event and who were on contemporary FMT. VICTOR was neutral for the primary composite endpoint of time to CV death or HFH (HR 0.93; 95% CI 0.83–1.04; P = .22).297 Over a median follow-up of ∼18.5 months, CV death was numerically lower with vericiguat (9.6% vs 11.3%; HR 0.83; 95% CI 0.71–0.97), whereas HFH was similar between groups (11.4% vs 11.9%; HR 0.95; 95% CI 0.82– 1.10). The trial therefore did not confirm a primary composite benefit in a stable, well-treated ambulatory HFrEF population, although pooled analyses combining VICTOR and VICTORIA suggest benefit across the broader HFrEF spectrum. Also, there was a reduction in all-cause mortality, a secondary endpoint in the trials.298,299

6.1.5.3 Hydralazine and isosorbide dinitrate

There is no clear evidence to recommend the use of hydralazine and isosorbide dinitrate in all patients with HFrEF. In a small RCT conducted in self-identified black patients the addition of the combination of hydralazine and isosorbide dinitrate to conventional therapy at that time (an ACE-I, a beta-blocker, and an MRA) reduced mortality and HFH, and improved QoL in patients with symptomatic HFrEF.300 It is unclear if a benefit of hydralazine and isosorbide dinitrate exists for non-black patients with HFrEF. Additionally, a combination of hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who cannot tolerate any of an ACE-I, an ARNI, or an ARB (or if they are contraindicated) to potentially reduce HFH and mortality. This recommendation is based on the results of the Veterans Administration Cooperative Study, which included only male patients with symptomatic HFrEF who were treated with only digoxin and diuretics.301

6.1.5.4 Cardiac glycosides

Cardiac glycosides, digoxin or digitoxin, should be considered in patients with HFrEF to reduce the risk of HFH.302–304 In the DIG trial, the overall effect on mortality with digoxin was neutral but there was a reduction in HFH.303 Moreover, the effects of digoxin in patients with HFrEF and AF have not been studied in RCTs, but digoxin may be useful for the treatment of AF with rapid ventricular rate when other therapies cannot be used.305–307 A serum digoxin concentration <1.2 ng/mL should be used as a target during ongoing therapy.308 The DIGIT-HF trial examined whether low-dose digitoxin added to contemporary FMT improves outcomes in patients with chronic symptomatic HFrEF (LVEF ≤40% and NYHA class III/IV or LVEF ≤30% and NYHA class II).304 The trial included most patients in NYHA class III and, contrary to the DIG trial, also included patients with AF. They were randomized to digitoxin [starting 0.07 mg daily, then titrated to target serum concentrations (10.5–23.6 nmol/L)] vs placebo. Over a median follow-up of 36 months, the primary composite endpoint—death from any cause or HFH— occurred in 39.5% of the digitoxin group vs 44.1% of the placebo group (HR 0.82; 95% CI 0.69–0.98; P = .03). There was no significant reduction in all-cause mortality alone (27.2% vs 29.5%; HR 0.86; 95% CI 0.69–1.07) or in HFH alone (28.1% vs 30.4%; Downloaded from academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehag100/8766302 by guest on 31 August 2026