Angiotensin receptor-neprilysin inhibitors (ARNi) and sodium glucose co-transporter 2 inhibitors (SGLT2i) are backbone guideline-directed medical therapies for patients with heart failure with reduced ejection fraction (HFrEF). Expert documents suggest that ARNi and SGLT2i should both be started rapidly. However, to date, no studies have assessed the efficacy and safety of these therapies when started simultaneously or sequentially.The purpose of this study was to evaluate the efficacy and safety of simultaneous vs sequential initiation of ARNi and SGLT2i in HFrEF.Randomized noninferiority trial comparing 2 treatment strategies: 1) simultaneous ARNi/SGLT2i initiation (up to 5 days apart); vs 2) sequential initiation of one agent followed by the other (4-12 weeks later). The primary endpoint is a composite of hypotension, hyperkalemia, hypokalemia, estimated glomerular filtration rate drop ≥50% from baseline, emergency visit for HF, HF hospitalization, or cardiovascular death. The prespecified noninferiority margin for the absolute between-group difference is 20% with a two-sided 95% CI. Follow-up time was approximately 24 weeks.Sixty-two patients were randomized: 29 simultaneous vs 33 sequential. Baseline characteristics were overall well balanced between groups. The mean age was 68.1 ± 10.4 years, 65% were men, 48% were inpatients, 79% had a "de novo" HF diagnosis, 39% of patients had a prior treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, 61% with beta-blockers, and 27% with mineralocorticoid receptor antagonists. The mean left ventricular ejection fraction was 33% ± 9%, systolic blood pressure was 125.3 ± 17.4 mm Hg, estimated glomerular filtration rate was 78.1 ± 23.8 mL/min/1.73 m2, and serum potassium was 4.3 ± 0.5 mmol/L. Most patients in the sequential group (n = 27) were started on SGLT2i and 6 were started on ARNi.Initiation of ARNi and SGLT2i in Patients With HFrEF is a randomized trial to test whether a simultaneous initiation of ARNi and SGLT2i is noninferior to a sequential initiation of one agent followed by the other 4 to 12 weeks apart.