Efficacy and safety of dapagliflozin in patients hospitalized with COVID-19 with and without type 2 diabetes: a prespecified analysis of the DARE-19 randomized trial.

Background: Although several previous studies tested SGLT2 inhibitors in the setting of an acute, non-cardiovascular illness, detailed information on their efficacy and safety among participants with and without type 2 diabetes (T2D) from double-blind randomized trials is lacking. In this secondary prespecified analysis of the Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial, we sought to evaluate the safety and efficacy of initiating dapagliflozin during acute illness with COVID-19 in patients with and without T2D.

Methods: The DARE-19 trial randomized 1250 patients hospitalized with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo.

Contribution of the glomerular filtration rate slope to the kidney hierarchical composite endpoint.

Introduction: A recent chronic kidney disease (CKD) progression hierarchical composite endpoint (HCE) utilizes the glomerular filtration rate (GFR) slope for participants without a dichotomous event. Here, we evaluated clinical interpretations when HCE analyses are driven by GFR slope comparisons.

Methods: Using CKD trial data, we calculated win odds using only GFR slope; dichotomous kidney events and GFR slope; all-cause mortality, dichotomous kidney events, and GFR slope; and all-cause mortality with dichotomous kidney events.

Sodium-glucose co-transporter-2 inhibitors for hospitalised patients with COVID-19: a prospective meta-analysis of randomised trials.

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19.

Clinical trial designs to assess treatment effects on glomerular filtration rate decline.

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects.

Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b MIRACLE trial.

Aims: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study.

Methods And Results: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.

A hierarchical kidney outcome using win statistics in patients with heart failure from the DAPA-HF and DELIVER trials.

Win statistics offer a new approach to the analysis of outcomes in clinical trials, allowing the combination of time-to-event and longitudinal measurements and taking into account the clinical importance of the components of composite outcomes, as well as their relative timing. We examined this approach in a post hoc analysis of two trials that compared dapagliflozin to placebo in patients with heart failure and reduced ejection fraction (DAPA-HF) and mildly reduced or preserved ejection fraction (DELIVER). The effect of dapagliflozin on a hierarchical composite kidney outcome was assessed, including the following: (1) all-cause mortality; (2) end-stage kidney disease; (3) a decline in estimated glomerular filtration rate (eGFR) of ≥57%; (4) a decline in eGFR of ≥50%; (5) a decline in eGFR of ≥40%; and (6) participant-level eGFR slope.

Dapagliflozin and Days of Full Health Lost in the DAPA-HF Trial.

Background: Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome.

Objectives: To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being.

Methods: The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%.

Use of Win Statistics to Analyze Outcomes in the DAPA-HF and DELIVER Trials.

BACKGROUND: The primary end point in most heart failure (HF) trials is a composite of time to a first worsening HF event or cardiovascular death. Prevention of recurrent events and improvements in symptoms/quality of life are also important for patients but are usually analyzed separately. Win statistics can integrate all these outcomes into a single composite end point, which is analyzed in hierarchical order, reflecting the clinical importance of each component.

Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression.

Significance Statement: The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR but does not weigh the relative clinical importance of the end point components. By contrast, a hierarchical composite end point (HCE) accounts for the clinical importance of the end point components. The authors developed and validated a kidney HCE that combines clinical kidney outcomes with longitudinal GFR changes (GFR slope).

Validity and Utility of a Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression: A Review.

Clinical trials in nephrology often use composite end points comprising clinical events, such as onset of ESKD and initiation of kidney function replacement therapy, along with a sustained large ( e.g. , ≥50%) decrease in GFR.

Effect of Dapagliflozin on Total Heart Failure Events in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Trial.

Importance: In the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, dapagliflozin reduced the risk of time to first worsening heart failure (HF) event or cardiovascular death in patients with HF with mildly reduced or preserved ejection fraction (EF).

Objective: To evaluate the effect of dapagliflozin on total (ie, first and recurrent) HF events and cardiovascular death in this population.

Design, Setting, And Participants: In this prespecified analysis of the DELIVER trial, the proportional rates approach of Lin, Wei, Yang, and Ying (LWYY) and a joint frailty model were used to examine the effect of dapagliflozin on total HF events and cardiovascular death.

The maraca plot: A novel visualization of hierarchical composite endpoints.

Background: Hierarchical composite endpoints are complex endpoints combining outcomes of different types and different clinical importance into an ordinal outcome that prioritizes the clinically most important (e.g. most severe) event of a patient.

Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER.

Whether the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction (≤40% and >40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)).

Design and Analysis of Studies Based on Hierarchical Composite Endpoints: Insights from the DARE-19 Trial.

Background/aim: DARE-19 (NCT04350593) was a randomized trial studying the effects of dapagliflozin, an SGLT2 inhibitor, in hospitalized patients with COVID-19 pneumonia and cardiometabolic risk factors. The conduct of DARE-19 offered the opportunity to define an innovative and clinically meaningful endpoint in a new disease that would best reflect the known profile of dapagliflozin, accompanied by the statistical challenges of analysis and interpretation of such a novel endpoint.

Methods: Hierarchical composite endpoints (HCEs) are based on clinical outcomes which, unlike traditional composite endpoints incorporate ranking of components according to clinical importance.

Dapagliflozin and Kidney Outcomes in Hospitalized Patients with COVID-19 Infection: An Analysis of the DARE-19 Randomized Controlled Trial.

Background And Objectives: Patients who were hospitalized with coronavirus disease 2019 (COVID-19) infection are at high risk of AKI and KRT, especially in the presence of CKD. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial showed that in patients hospitalized with COVID-19, treatment with dapagliflozin versus placebo resulted in numerically fewer participants who experienced organ failure or death, although these differences were not statistically significant. We performed a secondary analysis of the DARE-19 trial to determine the efficacy and safety of dapagliflozin on kidney outcomes in the overall population and in prespecified subgroups of participants defined by baseline eGFR.

Power and sample size calculation for the win odds test: application to an ordinal endpoint in COVID-19 trials.

The win odds is a distribution-free method of comparing locations of distributions of two independent random variables. Introduced as a method for analyzing hierarchical composite endpoints, it is well suited to be used in the analysis of ordinal scale endpoints in COVID-19 clinical trials. For a single outcome, we provide power and sample size calculation formulas for the win odds test.

Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.

Background: COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness.

Dapagliflozin and Recurrent Heart Failure Hospitalizations in Heart Failure With Reduced Ejection Fraction: An Analysis of DAPA-HF.

Background: Patients with heart failure (HF) and reduced ejection fraction will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (ie, first and repeat) hospitalizations for heart failure in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure).

Methods: The total number of HF hospitalizations and cardiovascular deaths was examined by using the proportional-rates approach of Lei-Wei-Yang-Ying and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death.

Effects of dapagliflozin on prevention of major clinical events and recovery in patients with respiratory failure because of COVID-19: Design and rationale for the DARE-19 study.

Aims: Coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown significant cardio- and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high-risk patients with COVID-19.

Adjusted win ratio with stratification: Calculation methods and interpretation.

The win ratio is a general method of comparing locations of distributions of two independent, ordinal random variables, and it can be estimated without distributional assumptions. In this paper we provide a unified theory of win ratio estimation in the presence of stratification and adjustment by a numeric variable. Building step by step on the estimate of the crude win ratio we compare corresponding tests with well known non-parametric tests of group difference (Wilcoxon rank-sum test, Fligner-Policello test, van Elteren test, test based on the regression on ranks, and the rank analysis of covariance test).