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Background Introduction of guideline-directed medical therapy (GDMT) has transformed the care of heart failure (HF) with reduced ejection fraction, establishing four foundational drug classes. Yet, in clinical practice, many patients cannot initiate or maintain all four, and clinicians must pragmatically prioritise agents such as angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 inhibitor, whose comparative impacts are still explored. Moreover, the optimal loop diuretic to pair with modern GDMT, which enhances natriuresis, remains uncertain.Methods Between January 2022 and February 2024, we conducted a multicentre, open-label, randomised, 2×2 factorial design trial for ambulatory patients with symptomatic HF, elevated natriuretic peptide levels and left ventricular ejection fraction (LVEF) <50%, despite conventional therapies (eg, renin-angiotensin-aldosterone system inhibitors and beta-blockers). The patients were assigned to receive either sacubitril/valsartan or dapagliflozin, and torsemide or furosemide. The primary endpoint was the change in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) over 6 months; a prespecified secondary endpoint was a hierarchical clinical outcome.Results Of 231 randomised patients (median age 73 years; median LVEF 36%; 84.0% New York Heart Association class II), changes in KCCQ-OSS did not differ between sacubitril/valsartan and dapagliflozin (adjusted mean difference 2.53 points; 95% confidence interval (CI) −1.81 to 6.88; p=0.25) or between torsemide and furosemide (0.25 points; 95% CI −4.10 to 4.59; p=0.91). Hierarchical composite outcome analyses also showed no significant differences between sacubitril/valsartan and dapagliflozin (win ratio, 1.15; 95% CI 0.71 to 1.88), or between torsemide and furosemide (win ratio, 1.15; 95% CI 0.70 to 1.85).Conclusions This trial found no evidence of benefit of one treatment over another for health status over 6 months. Given the sample size and predefined power, modest differences between treatments cannot be excluded.Trial registration number UMIN000045229.