Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction

Abstract

Background: In the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and HF hospitalization. We examined the frequency and significance of episodes of outpatient heart failure-worsening, requiring augmentation of oral therapy, and the effects of dapagliflozin on these additional events. Methods: Patients in New York Heart Association (NYHA) functional class II-IV, with a left ventricular ejection fraction ≤40%, and elevation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. The primary outcome was the composite of an episode of worsening heart failure (HF hospitalization or urgent HF visit requiring intravenous [IV] therapy) or cardiovascular (CV) death, whichever occurred first. An additional prespecified exploratory outcome was the primary outcome plus worsening HF symptoms/signs leading to initiation of new, or augmentation of existing, oral treatment. Results: Overall, 36% more patients experienced the expanded, compared with the primary, composite outcome. In the placebo group, 684/2371 (28.8%) patients, and 527/2373 (22.2%) participants in the dapagliflozin group, experienced the expanded outcome (HR 0.73, 0.65-0.82; P<0.0001); each component of the composite was reduced significantly by dapagliflozin. Over the median follow-up of 18.2 months, the number of patients needed to treat (NNT) with dapagliflozin to prevent one experiencing an episode of fatal or non-fatal worsening was 16. Among the 4744 randomized patients, the first episode of worsening was outpatient augmentation of treatment in 407 participants (8.6%), an urgent HF visit with IV therapy in 20 (0.4%), HF hospitalization in 489 (10.3%) and CV death in 295 (6.2%) patients. The adjusted risk of death from any cause (compared with no event) following an outpatient worsening was HR 2.67 (95%CI 2.03-3.52), after an urgent HF visit 3.00 (1.39-6.48) and after a HF hospitalization 6.21 (5.07-7.62). Conclusions: In DAPA-HF, outpatient episodes of HF worsening were common, of prognostic importance and reduced by dapagliflozin. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03036124.

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction

“…A similar risk reduction in urgent outpatient worsening heart failure events was also seen with dapagliflozin in a large-scale trial in patients with heart failure and a reduced ejection fraction (DAPA-HF [Dapagliflozin on Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure]). 23 Importantly, the lower risk of hospital admissions was not counterbalanced by a longer length of stay when patients in the empagliflozin group were hospitalized for heart failure.…”

“…18 – 21 Several treatments that reduce the risk of hospitalizations for heart failure in patients with heart failure and a reduced ejection fraction also favorably impact outpatient metrics of clinical instability. 21 – 23 …”

Sodium–glucose transporter-2 inhibitors for prevention and treatment of cardiorenal complications of type 2 diabetes

“…The cardiorenal benefits demonstrated by SGLT-2i are not only limited to patients with T2D, as a mounting evidence indicates that they can also be extended to patients without T2D who have CVD, HF, or CKD [36][37][38]48]. Intuitively, the use of these agents will presumably be extended to other medical figures that cooperate in the management of T2D, including cardiologists and nephrologists, within the frame of a multidisciplinary approach, with the paramount aim to improve glycemic control and reduce the risk of cardiorenal events.…”

“…Hospitalization for HF was significantly reduced by 31–32% with SGLT-2i [ 27 , 28 ], whether the meta-analyses included three (EMPA-REG, CANVAS, DECLARE) or four (+CREDENCE) trials. Since then, other outcome trials have been published: specifically, the VERTIS-CV trial [ 35 ] with ertugliflozin (8246 patients with T2D randomized to ertugliflozin or placebo and followed for a mean of 3.5 years), the DAPA-HF trial [ 36 , 37 ] with dapagliflozin (4744 patients with or without T2D and with HF randomized to dapagliflozin or placebo and followed for a median of 18.2 months), the EMPEROR-Reduced trial [ 38 ] with empagliflozin (3730 patients with or without T2D and with HF randomized to empagliflozin or placebo and followed for a median of 16 months), the SCORED trial [ 34 ] with sotagliflozin (10 584 patients with T2D and DKD randomized to sotagliflozin or placebo and followed for 16 months) and the SOLOIST-WHF trials [ 39 ] with sotagliflozin (1222 patients with T2D recently hospitalized for worsening HF randomized to sotagliflozin or placebo and followed for 9 months). The primary outcome varied across trials: MACE (EMPA-REG, CANVAS, DECLARE, VERTIS-CV), composite of end-stage kidney disease, doubling of the serum creatinine level, or death from renal or cardiovascular causes (CREDENCE), composite of worsening heart failure or cardiovascular death (DAPA-HF, EMPEROR-Reduced), deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure (SCORED, SOLOIST-WHF).…”

Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST‐WHF in perspective

“…In two recently completed studies—DAPA‐HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and EMPEROR‐Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction)—dapagliflozin and empagliflozin, respectively, reduced the risk of cardiovascular death and HHF by 26% in patients with HFrEF 20–22 . Importantly, these benefits were observed consistently in those with and without type 2 diabetes, were in addition to excellent background heart failure therapies, and resulted in an improvement in patient reported quality of life indices 20–32 . Because both trials recruited patients with chronic ambulatory HFrEF [and excluded patients with hospitalization due to decompensated heart failure less than 4 weeks prior to enrolment (DAPA‐HF)], it can be argued that the question of in‐hospital initiation of SGLT2 inhibitors during a WHF event has remained unanswered.…”