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Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 May 3, 2022 e933 CLINICAL STATEMENTS AND GUIDELINES

months).1,2 Patients enrolled had symptomatic chronic HFrEF (LVEF ≤40%, NYHA class II to IV, and elevated natriuretic peptides) and were already on GDMT. Important exclusions were eGFR <20 (EMPEROR-Reduced) or <30 mL/min/1.73 m2 (DAPA-HF), type 1 diabetes, or lower SBP <95 to 100 mm Hg.

Recommendation-Specific Supportive Text

1.	 In the DAPA-HF and EMPEROR-Reduced trials, SGLT2i compared with placebo reduced the composite of cardiovascular death or HF hospitalization by approximately 25%.1,2,9 The benefit in reduction of HF hospitalization was greater (30%) in both trials.9 Risk of cardiovascular death was significantly lowered (18%) with dapagliflozin, as was risk of all-cause mortality (17%). Although no significant cardiovascular mortality benefit was observed with empagliflozin in a meta-analysis of DAPA-HF and EMPEROR-Reduced trials, SGLT2i therapy was associated with a reduction in all-cause mortality and cardiovascular death.9 The benefits in both trials were seen irrespective of baseline diabetes status. Furthermore, serious renal outcomes were less frequent, and the rate of decline in eGFR was slower in patients treated with SGLT2i.1,2,9 In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes And Worsening Heart Failure) trial, patients with diabetes and HF hospitalization (79%: LVEF, <50%) were enrolled before discharge or within 3 days of discharge. Sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2, reduced the combined endpoint of cardiovascular death, HF hospitalization, or urgent HF visits by 33%10 but has not been approved by the US Food and Drug Administration (FDA) as of 2021. Although SGLT2i increased risk for genital infections, they were otherwise well tolerated in the trials. As the use of SGLT2i is translated into clinical practice, caution is warranted for euglycemic ketoacidosis, genital and soft tissue infections, and adjustment of diuretics, if needed, to prevent volume depletion.11 2.	 Two model-based analyses evaluated the economic value of dapagliflozin therapy compared with usual care based on the results of the DAPA-HF trial.3,4 Both analyses found costs per QALY between $60 000 and $90 000, which is consistent with intermediate value according to the benchmarks adopted for the current guideline. The results were most sensitive to the magnitude of cardiovascular mortality reduction, with a ≥8% reduction in cardiovascular mortality necessary for a cost per QALY below $150 000 in 1 study.3 There are a wide range of costs currently seen with dapagliflozin. These 2 analyses estimated a cost per QALY below $50 000 with annual dapagliflozin costs of $3240 (43% reduction from main analysis) and $2500 (40% reduction from main analysis), respectively.3,4 A smaller reduction in drug cost would lead to a cost per QALY of under $60 000, the threshold for high value in this guideline.

7.3.5 Hydralazine and Isosorbide Dinitrate

Recommendations for Hydralazine and Isosorbide Dinitrate Referenced studies that support the recommendations are summarized in the Online Data Supplements.

COR LOE Recommendations

1 A 1.	 For patients self-identified as African American with NYHA class III-IV HFrEF who are receiving optimal medical therapy, the combination of hydralazine and isosorbide dinitrate is recommended to improve symptoms and reduce morbidity and mortality.1,2

Value Statement: High Value (B-NR) 2.	 For patients self-identified as African American with NYHA class III to IV HFrEF who are receiving optimal medical therapy with ACEi or ARB, beta blockers, and MRA, the combination of hydralazine and isosorbide dinitrate provides high economic value.3

2b C-LD 3.	 In patients with current or previous symptomatic HFrEF who cannot be given first-line agents, such as ARNi, ACEi, or ARB, because of drug intolerance or renal insufficiency, a combination of hydralazine and isosorbide dinitrate might be considered to reduce morbidity and mortality.4,5

Synopsis Two RCTs, V-HeFT I (Vasodilator Heart Failure Trial) and A-HeFT (African-American Heart Failure Trial), established benefit of the combination of hydralazine-isosorbide dinitrate in self-identified African Americans.2,4 A-HeFT was terminated early because of evidence of remarkable benefit, but the result is vulnerable to a small number of events and the exigencies of early cessation of RCTs.2 The benefit in both trials was seen only at doses achieved in those trials that are higher than doses typically used in clinical practice and with short-acting nitrate therapy.2,4 Uptake of this regimen has been modest as a result of the complexity of the medical regimen and the array of drug-related adverse effects.5 Even when prescribed, there is marked underusage based on very low prescription refill rates. Race-based medical therapy remains a challenging issue, as well, with ongoing research now focused on biological hypotheses, particularly absence of European ancestry, which may be associated with responsiveness to this combination. There are insufficient data to guide the use of hydralazine-isosorbide dinitrate with ARNi. In patients with HFrEF who cannot receive first-line agents such as ARNi, ACEi, or ARB, referral to a HF specialist can provide guidance for further management because the use of hydralazine and isosorbide dinitrate in these patients is uncertain.

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