SGLT2i efficacious and safe regardless of baseline ARNI treatment in HFrEF
Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial
Introduction and methods
Sacubitril/valsartan treatment reduced CV death or HF hospitalization in HFrEF patients compared with enalapril in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial . In the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF) trial, dapagliflozin (10 mg) reduced the composite of CV death or worsening HF in HFrEF patients with or without diabetes [2, 3]. Here, dapagliflozin had a beneficial effect in a subset of patients receiving sacubitril/valsartan at baseline. However, the safety of combined therapy with dapagliflozin and sacubitril/valsartan was unknown.
This study evaluated in detail the efficacy and safety of dapagliflozin in HFrEF patients (n=4744) who were on sacubitril/valsartan (n=508) and in patients who were not on this treatment (n=4236) at baseline in the DAPA-HF trial. Primary outcome was a composite of worsening HF, defined as either an unplanned HF hospitalization or an urgent HF visit that required intravenous diuretic therapy, or CV death. Secondary outcomes included a composite of CV death or HF hospitalization, the total number of hospitalizations for HF and CV death, change in the Kansas City Cardiomyopathy Questionnaire Clinical Total Symptom Score (KCCQ-TSS), worsening renal function, and death from any cause. The prespecified safety analyses included occurrence of AEs. AEs included serious AEs, AEs associated with discontinuation of study treatment, and AEs of interest (i.e., volume depletion, renal events, major hypoglycemia, bone fractures, diabetic ketoacidosis, amputations, Fournier’s gangrene, and laboratory findings of note).
- Patients who were on sacubitril/valsartan were more likely to be from North America or Europe, and were more likely to have lower ejection fractions and systolic and diastolic BPs than patients who were not on sacubitril/valsartan. However, both of these groups were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies.
- Benefit of dapagliflozin compared to placebo was similar in patients taking sacubitril/valsartan (unadjusted HR 0.75, 95%CI 0.50-1.13) and in patients not taking sacubitril/valsartan (unadjusted HR 0.74, 95%CI 0.65-0.86) for primary endpoint of worsening HF or CV death (P-interaction=1.00). Similar findings were observed for secondary endpoints.
- Among patients randomized to dapagliflozin or placebo, there were no differences between those taking sacubitril/valsartan or those not taking sacubitril/valsartan in percentage of patients who discontinued study therapy for any reason or for an AE. There were also no differences between both groups in percentage of patients with AEs of interest.
- There were no differences in magnitude of systolic BP lowering, change in serum creatinine, or change in serum potassium due to dapagliflozin between those taking or those not taking sacubitril/valsartan.
Benefit and safety of dapagliflozin compared to placebo was similar between those taking sacubitril/valsartan and those not taking sacubitril/valsartan at baseline in HFrEF patients in the DAPA-HF trial. According to the authors, the findings suggest that use of both agents together could further lower morbidity and mortality in patients with HFrEF.