Direct comparison of simultaneous and sequential ARNI/SGLT2i initiation in HFrEF

In the randomized INITIATE-HFrEF trial among 62 HFrEF patients, simultaneous initiation of an ARNI and SGLT2 inhibitor (≤5 days apart) was noninferior to a sequential strategy (4–12 weeks apart).

This summary is based on the publication of Ferreira JP, Oliveira AC, Saraiva F, et al. - Simultaneous or Sequential Initiation of ARNI and SGLT2I in Patients With HFrEF: The INITIATE-HFrEF Trial. J Am Coll Cardiol. 2026 Jan 16:S0735-1097(25)10604-9 [Online ahead of print]. doi: 10.1016/j.jacc.2025.12.070

Introduction and methods

Background

ARNIs and SGLT2 inhibitors are core components of GDMT for patients with HFrEF [1-3]. These therapies have distinct and complementary mechanisms of action and show early benefits in this population [4,5]. However, the optimal timing for initiating these medications is not well defined, and randomized data directly comparing simultaneous and sequential initiation are lacking.

Aim of the study

The authors investigated the efficacy and safety of simultaneous versus sequential initiation of an ARNI and SGLT2 inhibitor in HFrEF patients.

Methods

The INITIATE-HFrEF (Initiation of ARNi and SGLT2i in Patients With HFrEF) trial was a prospective, pragmatic, investigator-initiated, open-label, phase 4, noninferiority RCT conducted in Portugal in which 62 adult patients with symptomatic HFrEF (LVEF <50%), eGFR ≥25 mL/min/1.73 m², serum potassium ≤5.4 mmol/L, and systolic blood pressure (SBP) ≥100 mmHg were included [6]. Patients treated with an ARNI or SGLT2 inhibitor within the preceding 30 days were excluded.

Participants were randomized to one of the following strategies: (1) simultaneous ARNI and SGLT2 inhibitor initiation (≤5 days apart); or (2) sequential initiation of either an ARNI or SGLT2 inhibitor, followed by the other agent 4–12 weeks later. The ARNI was sacubitril/valsartan (dose range: 24 mg/26 mg twice daily to 97 mg/103 mg twice daily). The SGLT2 inhibitor was empagliflozin or dapagliflozin (10 mg daily).

Outcomes

The primary endpoint was a composite outcome of time to first event of hypotension (SBP <100 mmHg with signs or symptoms), hyperkalemia (serum potassium >6.0 mmol/L), hypokalemia (serum potassium <3.0 mmol/L), investigator-reported worsening kidney function (eGFR decline ≥50% from baseline, eGFR <15 mL/min/1.73 m², renal transplantation, or dialysis), outpatient worsening HF, emergency room visit due to worsening HF requiring intravenous diuretics, HF hospitalization, or CV death. The modified primary endpoint incorporated investigator-reported events, in addition to the composite outcome.

Secondary endpoints included the individual components of the primary endpoint and longitudinal changes from baseline in SBP, eGFR, serum potassium levels, and LVEF.

Main results

• At 24 weeks, the primary endpoint had occurred in 10 of the 29 patients (34.5%) in the group assigned to simultaneous ARNI/SGLT2 inhibitor initiation and 15 of the 33 patients (45.5%) in the group with sequential initiation (HR: 0.82; 95%CI: 0.37–1.84). The absolute between-group difference in the primary endpoint rate was –10.9% (95%CI: –34.8% to 12.9%), which met the prespecified noninferiority margin for the upper limit of the 2-sided 95%CI of 20%.
• The incidence of the modified primary endpoint was 44.8% in the simultaneous group and 60.6% in the sequential group at 24 weeks (HR: 0.88; 0.43–1.79; absolute between-group difference: –15.5%; 95%CI: –38.8% to 7.8%).
• At 24 weeks, a larger mean SBP reduction from baseline was observed in the sequential group compared with the simultaneous group (–13.3 mmHg; 95%CI: –19.3 to –7.4 vs. –4.1 mmHg; 95%CI: –10.4 to 2.1; P<0.05).
• There were no between-group differences in changes from baseline in eGFR and serum potassium levels.
• At baseline, the mean LVEF was 33% ± 9%. In both treatment groups, it increased by 11% at 24 weeks.
• By week 24, 64% of the participants were being treated with ≥50% of the recommended ARNI dose.

Conclusion

The randomized open-label INITIATE-HFrEF trial demonstrated that a strategy of simultaneous ARNI/SGLT2 inhibitor initiation (≤5 days apart) was noninferior to a sequential strategy (4–12 weeks apart) in 62 HFrEF patients. The authors concluded that their “findings, together with existing randomized data and current practice standards, support simultaneous initiation of ARNI and SGLT2 inhibitors to accelerate GDMT implementation in HFrEF.”

Find this article online at J Am Coll Cardiol.

References

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6. Ferreira JP, Oliveira AC, Saraiva F, et al. Design, rationale, and methods of the INITIATE-HFrEF trial: ARNI and SGLT2 inhibitors sequencing in HFrEF. JACC Adv. https://doi.org/10.1016/j.jacadv.2026.102589