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/valsartanLiterature - Yang M, Butt JH, Kondo T, et al. - Eur J Heart Fail. 2022 Nov 7. doi: 10.1002/ejhf.2722
Introduction and methods
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% . 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.
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.
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).
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.
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.