Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. RESULTS: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).

Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial.

BACKGROUND: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. METHODS: This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31-0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33-0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups. INTERPRETATION: In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings. FUNDING: Eli Lilly and Company.

LB3. Baricitinib plus Standard of Care for Hospitalized Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomized, Placebo-Controlled Trial

Background: The oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated

Baricitinib plus Standard of Care for Hospitalized Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomized, Placebo-Controlled Trial

Background Interventions to reduce mortality in critically ill patients with COVID-19 are a crucial unmet medical need. Baricitinib (BARI) is an oral, selective Janus kinase (JAK)1/JAK2 inhibitor with efficacy in hospitalized adults with COVID-19. Treatment with BARI 4-mg was evaluated in critically ill adult patients with COVID-19 with baseline need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Methods COV-BARRIER (NCT04421027) was a randomized double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection and elevation of ≥ 1 serum inflammatory marker. In this newly completed substudy, enrolled participants (not previously reported) from 4 countries on IMV or ECMO at study entry were randomly assigned 1:1 to once-daily BARI 4-mg or placebo (PBO) for up to 14 days plus standard of care (SOC), which included baseline systemic corticosteroid use in 86% of patients. The prespecified exploratory endpoints included all-cause mortality and number of ventilator-free days (VFDs) through Day 28. Results Characteristics for 101 participants are shown in Table 1. Treatment with BARI significantly reduced all-cause mortality by Day 28 compared to PBO [39.2% vs 58.0%, respectively;hazard ratio (HR) = 0.54 (95%CI 0.31, 0.96), p=0.030, relative risk (RR) = 0.68 (95%CI 0.45, 1.02);Figure 1A]. One additional death was prevented for every six BARI-treated patients. Significant reduction in mortality was also observed by Day 60 [45.1% vs 62.0%;HR = 0.56 (95%CI 0.33, 0.97), p=0.027, RR = 0.73 (95%CI 0.50, 1.06);Figure 1B]. Patients treated with BARI showed a numerical reduction in the duration of IMV and duration of hospitalization vs PBO and more BARI treated patients recovered (Table 2). No new safety findings were observed (Table 2). Conclusion Treatment with BARI+SOC (corticosteroids) resulted in an absolute risk reduction in mortality of 19% at Day 28 and 17% at Day 60 in patients with COVID-19 who were on IMV or ECMO at enrollment. These results are consistent with the reduction in mortality observed in the less severely ill hospitalized patients in the primary COV-BARRIER study population. Disclosures E. Wesley Ely, MD, CDC (Grant/Research Support)Eli Lilly (Other Financial or Material Support, Unpaid consultant)NIH (Grant/Research Support)VA (Grant/Research Support) Athimalaipet V. Ramanan, FRCP, AbbVie (Consultant, Speaker’s Bureau)Eli Lilly and Company (Consultant, Grant/Research Support, Speaker’s Bureau)Novartis (Consultant, Speaker’s Bureau)Pfizer (Consultant, Speaker’s Bureau)Roche (Consultant, Speaker’s Bureau)Sobi (Consultant, Speaker’s Bureau)UCB (Consultant, Speaker’s Bureau) Cynthia E. Kartman, RN BSN, Eli Lilly and Company (Employee, Shareholder) Stephanie de Bono, MD PhD, Eli Lilly and Company (Employee, Shareholder) Ran Liao, PhD, Eli Lilly and Company (Employee, Shareholder) Maria Lucia B Piruzeli, MD, Eli Lilly and Company (Employee, Shareholder) Sujatro Chakladar, PhD, Eli Lilly and Company (Employee, Shareholder) Vincent Marconi, MD, Bayer (Consultant, Scientific Research Study Investigator)Eli Lilly (Consultant, Scientific Research Study Investigator)Gilead Sciences (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator)