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May 3, 2022 Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 e934 CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. In a large-scale trial that compared the vasodilator combination with placebo, the use of hydralazine and isosorbide dinitrate reduced mortality in patients with HF treated with digoxin and diuretics but not an ACEi or beta blocker.4 However, in 2 other trials that compared the vasodilator combination with an ACEi, the ACEi produced more favorable effects on survival.6,7 A post hoc retrospective analysis of these vasodilator trials showed particular efficacy of isosorbide dinitrate and hydralazine in the African American cohort.1 In a subsequent trial, which was limited to patients self-identified as African American, the addition of a fixed-dose combination of hydralazine and isosorbide dinitrate to standard therapy with an ACEi or ARB, a beta blocker, and MRA offered significant benefit.2 Thus, the combination of hydralazine and isosorbide dinitrate is appropriate for African Americans with HFrEF who remain symptomatic despite concomitant use of ACEi (or ARB), beta blockers, and MRA. There are insufficient data for concomitant use with ARNi. 2. The economic value of hydralazine and isosorbide nitrate therapy was assessed by the A-HeFT trial.3 This analysis found hydralazine and isosorbide dinitrate increased survival and reduced health care costs over the 12.8-month trial. Extrapolating beyond the trial, the analysis found hydralazine and isosorbide dinitrate remained high value over a lifetime with a cost per life-year <$60 000 despite conservative assumptions regarding the durability of therapy effectiveness and previously higher hydralazine and isosorbide dinitrate costs. 3. It is unclear if a benefit of hydralazine-isosorbide dinitrate (suggested in a trial before the use of ACEi)4 exists for non–African Americans with HFrEF. Despite the lack of data with the vasodilator combination in patients who are intolerant of ACEi or ARB, especially those with renal insufficiency, the combined use of hydralazine and isosorbide dinitrate might be considered as a therapeutic option in such patients. Although the potential benefit is unknown and has not been shown in recent observational datasets,5 in V-HeFT I, the use of hydralazine and isosorbide dinitrate reduced mortality in patients with HF treated with digoxin and diuretics, compared with placebo.4 If patients are unable to tolerate firstline agents, such as ARNi, ACEi, or ARB, because of drug intolerance, hypotension, or renal insufficiency, referral to a HF specialist can provide guidance for further management, and the use of hydralazine and isosorbide dinitrate in these patients might be considered. 7.3.6 Other Drug Treatment Recommendations for Other Drug Treatment Referenced studies that support the recommendations are summarized in the Online Data Supplements. COR LOE Recommendations 2b B-R 1. In patients with HF class II to IV symptoms, omega-3 polyunsaturated fatty acid (PUFA) supplementation may be reasonable to use as adjunctive therapy to reduce mortality and cardiovascular hospitalizations.1–4 2b B-R 2. In patients with HF who experience hyperkalemia (serum potassium level ≥5.5 mEq/L) while taking a renin-angiotensin-aldosterone system inhibitor (RAASi), the effectiveness of potassium binders (patiromer, sodium zirconium cyclosilicate) to improve outcomes by facilitating continuation of RAASi therapy is uncertain.5,6 3: No Benefit B-R 3. In patients with chronic HFrEF without a specific indication (eg, venous thromboembolism [VTE], AF, a previous thromboembolic event, or a cardioembolic source), anticoagulation is not recommended.7–9 Synopsis Trials in prevention of CVD, including HF, showed that omega-3 PUFA supplementation results in a 10% to 20% risk reduction in fatal and nonfatal cardiovascular events when used with other evidence-based therapies.2,3,10 Hyperkalemia is common in HF and can lead to arrhythmias and underuse of GDMT.11,12 Two newer gastrointestinal potassium-binding agents—patiromer and sodium zirconium cyclosilicate—have been shown to lower potassium levels and enable treatment with a RAASi in patients with HF.5,6,13 Recommendation-Specific Supportive Text 1. Supplementation with omega-3 PUFA has been evaluated as an adjunctive therapy for CVD and HF.14 The GISSI-HF (Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure) trial showed a reduction in death among post-MI patients taking 1 g of omega-3 PUFA (850–882 mg of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters in the ratio of 1:1.2).10 A post hoc subgroup analysis revealed that this reduction in mortality and SCD was concentrated in the approximately 2000 patients with reduced LVEF.10 The GISSI-HF investigators randomized symptomatic patients with HF to 1 g daily of omega-3 PUFA (850–882 mg of EPA-DHA) or placebo. Death from any cause was reduced from 29% with placebo to 27% in those treated with omega-3 PUFA.2 The outcome of death or admission to hospital for a cardiovascular event was also significantly reduced. The REDUCE-IT trial randomized patients with established CVD Downloaded from http://ahajournals.org by on October 7, 2026