The reduce trial

The aim of the study is to investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction. Drug Information available for: Empagliflozin.

FDA Resources. Arms and Interventions. Outcome Measures. Number of all-cause hospitalizations first and recurrent. Eligibility Criteria. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials. San Martin S. Louis C. Jan Hubac, s. Nysa, Poland, Medicome Sp. Oswiecim, Poland, Specialized Practice Dr. More Information. Additional Information: Related Info. Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations EMPEROR-Reduced : a post-hoc analysis of a randomised, double-blind trial.

Lancet Diabetes Endocrinol. Epub Nov Is the impact of add on heart failure therapy influenced by background therapy? J Am Coll Cardiol. Epub Aug Eur Heart J. Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Epub Oct Erratum in: Circulation. N Engl J Med. Nassif ME, Kosiborod M. Effects of sodium glucose cotransporter type 2 inhibitors on heart failure. Diabetes Obes Metab. National Library of Medicine U.

National Institutes of Health U. Department of Health and Human Services. Conclusions and Relevance In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure.

These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD. Trial Registration isrctn. Acute exacerbations of chronic obstructive pulmonary disease COPD are a risk factor for disease deterioration, 1 and patients with frequent exacerbations have increased mortality. Observational data suggest that low-dose oral regimens are not associated with worse outcomes than high-dose intravenous treatment.

Long-term use of systemic glucocorticoids is an independent risk factor for increased mortality in COPD. Although it has become quite common clinical practice to administer glucocorticoids in COPD exacerbations for shorter periods, an adequately powered randomized clinical trial comparing reduced with recommended treatment duration has not been published.

The REDUCE trial tested the hypothesis that in patients presenting to the emergency department with acute exacerbation of COPD, a 5-day course of systemic glucocorticoid treatment would not result in an inferior clinical outcome compared with conventional day treatment, but would significantly decrease glucocorticoid exposure and reduce untoward effects.

The trial was approved by the institutional review boards of participating hospitals. All patients provided written informed consent. This study report adheres to the consolidated standards for the reporting of noninferiority trials. Inclusion criteria were exacerbation of COPD as defined by the presence of at least 2 of the following: change in baseline dyspnea, cough, or sputum quantity or purulence, 15 , 16 age older than 40 years, and a smoking history of 20 pack-years or more. Eligible patients were randomly assigned either 5 or 14 days of systemic glucocorticoids using a centralized, secured study website in order to ensure allocation concealment Figure 1.

Allocation according to a computer-generated randomization list nQuery Advisor, version 6. All patients received 40 mg of intravenous methylprednisolone on day 1, followed by 40 mg of oral prednisone daily from day 2 through 5.

Patients received study glucocorticoid dose irrespective of possible pretreatment. The first dose was given intravenously to facilitate administration to patients in distress. From day 6 through 14, patients received 40 mg of oral prednisone or matching placebo once daily. Patients, caregivers, outcome assessors, data collectors, the biostatistician, and all other investigators remained blinded to group allocation until the primary analysis was completed.

In addition to the study medication, all patients received a broad-spectrum antibiotic for 7 days and an inhaled, nebulized, short-acting bronchodilator 4 to 6 times daily as needed while hospitalized. End points were assessed daily during hospitalization, as well as on days 6, 15, 30, 90, and On days 15 and 90, assessment was by telephone interview only. The primary end point of this trial was time to next COPD exacerbation during a follow-up of 6 months, defined as an acute clinical deterioration beyond usual day-to-day variation, requiring interaction with a clinician.

Secondary end points were all-cause mortality, change in FEV 1 , cumulative glucocorticoid dose, and clinical performance assessed using questionnaires for the Medical Research Council dyspnea scale, 20 a bronchitis-associated quality-of-life score, 21 and patient-reported overall performance using a visual analog scale , all assessed at the index exacerbation and during 6 months of follow-up.

We assessed duration of hospital stay, time to open-label glucocorticoid therapy, and need for mechanical ventilation intubation or noninvasive ventilation during the index exacerbation. We used a modified Delphi technique to define noninferiority regarding the primary end point. Categorical variables are summarized by absolute numbers and percentages of total.

Differences in time to next exacerbation or time to death were assessed using the Kaplan-Meier method in combination with the log-rank test and Cox proportional hazards models. The proportional hazard assumption was tested using Schoenfeld residuals. Because differences between the 2 survival curves might appear mainly at the beginning of follow-up which would be in contradiction to the proportional hazard assumption , we also estimated the difference in average event-free survival time over days between short-term and conventional therapy by first determining the area under each of the 2 survival curves up to days and then taking their difference.

Patients lost to follow-up were censored at the time of last contact. Differences in cumulative dose of steroids were analyzed with the Mann-Whitney U test and bootstrap t tests. To compare length of hospital stay, we used the log-rank test, excluding individuals who were discharged from the emergency department, died, or withdrew consent during hospitalization.

The time course of clinical parameters FEV 1 , dyspnea scale, quality-of-life score, self-assessed performance was analyzed using mixed linear models. Time andgroup were treated as categorical variables. Their interaction was also included in the model and served to test the null hypothesis of parallel time course patterns.

An unstructured covariance matrix was used to model correlations of residuals within participants. Conventional null hypotheses on single parameters were tested using 2-tailed tests. For the main outcome, noninferiority was additionally assessed by a 1-tailed Wald test of the difference between the observed HR and 1. Potential interactions between treatment and other factors, also used to assess heterogeneity of results across subgroups, were tested using likelihood ratio tests for time-to-event outcomes and F tests for quantitative outcomes.

After approximately half of the intended number of patients had completed the study, an independent data and safety monitoring board performed a preplanned interim safety analysis.

Based on their findings, they advocated completion of the study without safety concerns. Baseline characteristics of participants are summarized in Table 1 , and results for the primary and secondary end points in Table 2 and Table 3. Of patients evaluated for eligibility, underwent randomization Figure 1. Three patients were excluded after randomization in a blinded fashion because of erroneous initial COPD diagnoses. The data from the remaining patients were used for all intention-to-treat analyses.

A total of patients completed the day treatment period according to study protocol and were included in the per-protocol analysis. Twelve patients 7. The 2 treatment groups were well balanced in terms of age, severity of airway obstruction, and pretreatment with glucocorticoids Table 1. There were more women in the conventional group than in the short-term treatment group The median number of days of follow-up in the conventional group was 10th percentile, ; 90th percentile, days and in the short-term group 10th percentile, ; 90th percentile, days.

A total of 56 patients Time to reexacerbation did not differ between groups as demonstrated in the Kaplan-Meier plots Figure 2. In a Cox regression analysis, the HR of reexacerbation between the short-term and conventional treatment group was 0.

Among patients who experienced a reexacerbation during follow-up, the median time to event was Estimates of reexacerbation rates were Sensitivity analyses adjusting for baseline variables, including sex, provided similar results eTable 2. In a prespecified subgroup analysis, we also investigated differences in the primary outcome between patients with and without previous systemic glucocorticoid use and with different severities of COPD according to GOLD grade.

We calculated the areas under the survival curves AUC to quantify the difference in average event-free survival. In the intention-to-treat analysis, estimates of AUC were If analyzed per protocol, the AUCs were Overall survival did not differ between the treatment groups, as evidenced by Kaplan-Meier plots Figure 3. The HRs for death for short-term compared with standard treatment were 0. During hospital stay, there was no increase in the requirement for mechanical ventilation with the short-term treatment regimen.

In a longitudinal analysis, there were almost no differences between groups. Similarly, significant amelioration of dyspnea eFigure 1A , bronchitis-associated quality of life eFigure 1B , and patient-assessed overall performance eFigure 1C occurred during the first 5 days of the study; respective scores did not change significantly thereafter. Additionally, there was no difference in the use of open-label glucocorticoids.

The 5-day group received less than half of the dose of glucocorticoids than the day group. While there was no difference in glucocorticoid-related adverse events, the 5-day treatment was associated with a shorter hospitalization.

Of note, the question of corticosteroid dosing for COPD exacerbations in ICU patients was addressed in retrospective trial by Kiser and colleagues. Comparisons are day vs. Outcomes are at 6 months unless otherwise stated.

Defined as an acute clinical deterioration beyond usual day-to-day variation requiring interaction with a clinician.