Background MRA or ARNI does not alter efficacy and safety of SGLT2i in HFmrEF/HFpEF

Dapagliflozin in patients with heart failure with mildly reduced and preserved ejection fraction treated with a mineralocorticoid receptor antagonist or sacubitril/valsartan

Literature - Yang M, Butt JH, Kondo T, et al. - Eur J Heart Fail. 2022 Nov 7. doi: 10.1002/ejhf.2722

Introduction and methods

Background

The DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial recently showed an 18%-reduction in the risk of worsening HF or CV death with the SGLT2i dapagliflozin versus placebo in HF patients with LVEF >40% [6]. However, the efficacy and tolerability/safety of adding a SGLT2i to an MRA or ARNI in patients with HFmrEF or HFpEF are unclear [3-5].

Aim of the study

In a prespecified analysis of the DELIVER trial, the efficacy and safety of treatment with dapagliflozin compared with placebo were evaluated in patients with HFmrEF or HFpEF who were or were not receiving background therapy with an MRA, ARNI, or both.

Methods

The DELIVER trial was a global, double-blind, placebo-controlled, event-driven RCT in which the efficacy and safety of dapagliflozin 10 mg daily were compared with those of placebo in 6263 patients with HFmrEF or HFpEF during a median follow-up duration of 2.3 years. At baseline, 2667 patients (42.6%) were treated with an MRA, 301 (4.8%) with an ARNI, and 197 (3.1%) with both drugs. Patients taking an MRA or ARNI were younger, had a lower mean systolic blood pressure and lower mean LVEF, and were more likely to have been previously hospitalized for HF than those not on an MRA or ARNI, respectively.

Outcomes

The primary endpoint of the DELIVER trial was a composite outcome of worsening HF or CV death. Secondary endpoints included total (first and recurrent) HF events and CV death; CV death; all-cause mortality; and change in the Kansas City Cardiomyopathy Questionnaire total symptom score from baseline to 8 months. For the current study, changes in systolic blood pressure, body weight, and serum creatinine level from baseline to 1 year, and eGFR change from baseline to 2 years were assessed.

The prespecified safety analyses included serious adverse events, adverse events leading to discontinuation of randomized treatment, and selected adverse events (including volume depletion, renal adverse events, amputation, major hypoglycemia, and diabetic ketoacidosis).

Main results

Efficacy of dapagliflozin by background MRA or ARNI therapy

  • The effect of dapagliflozin compared with placebo on the primary endpoint was similar for MRA non-users (hazard ratio (HR):0.86; 95%CI: 0.74–1.01) and MRA users (HR: 0.76; 95%CI: 0.64–0.91; P for interaction=0.30).
  • There were also no differences in the effect of dapagliflozin compared with placebo on any of the secondary outcomes between MRA users and non-users.
  • MRA users and non-users showed a similar eGFR “dip” during the first month of dapagliflozin treatment and a similar slowing of the eGFR decline by dapagliflozin, compared with placebo, from month 1 to 24.
  • The effect of dapagliflozin compared with placebo on the primary endpoint was comparable for ARNI non-users (HR: 0.82; 95%CI: 0.73–0.92) and ARNI users (HR: 0.74; 95%CI: 0.45–1.22; P for interaction=0.75).
  • Once more, the effect of dapagliflozin compared with placebo on any of the secondary outcomes did not differ between ARNI users and non-users. Due to the small number of patients in the ARNI subgroup, eGFR slopes could not be calculated.

Effect of dapagliflozin on physiological parameters by background MRA or ARNI therapy

  • The difference in systolic blood pressure from baseline to 1 year between the dapagliflozin and placebo groups did not differ between patients who took an MRA at baseline and non-MRA users (−0.64 vs. −1.29  mmHg; P for interaction=0.42) and patients who were on an ARNI and non-ARNI users (0.79 vs. −1.11 mmHg ; P for interaction=0.27).
  • The modest differences in placebo-corrected body weight and creatinine level from baseline to 1 year with dapagliflozin were also not influenced by background MRA or ARNI therapy.

Safety of dapagliflozin by background MRA or ARNI therapy

  • The frequency of none of the adverse events examined differed between the dapagliflozin and placebo groups, overall or according to background MRA or ARNI therapy.

Conclusion

This prespecified analysis of the DELIVER trial showed that the efficacy and safety of dapagliflozin were not influenced by background treatment with an MRA or ARNI in patients with HFmrEF or HFpEF. The authors therefore believe that the decision to start SGLT2i treatment in these patients should not depend on the background use of an MRA or ARNI.

References

1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022;24:4–131.

2. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e895–e1032.

3. Ferreira JP, Butler J, Zannad F, Filippatos G, Schueler E, Steubl D, et al. Mineralocorticoid receptor antagonists and empagliflozin in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol. 2022;79:1129–37.

4. Gevaert AB, Kataria R, Zannad F, Sauer AJ, Damman K, Sharma K, et al. Heart failure with preserved ejection fraction: recent concepts in diagnosis, mechanisms and management. Heart. 2022;108:1342–50.

5. Maeda D, Matsue Y, Minamino T. Is combination therapy the key for treatment of heart failure with mid-range or preserved ejection fraction? Circ J. 2022;86:1559–61.

6. Solomon SD, McMurray JJV, Claggett B, de Boer RA, De Mets D, Hernandez AF, et al.; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387:1089–98.

Find this article online at Eur J Heart Fail.

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