The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study programme: Design and exposure accrual for an evaluation of empagliflozin in routine clinical care

Abstract

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: The EMPA-REG OUTCOME trial showed that empagliflozin reduced the risk of cardiovascular death and hospitalization for heart failure (HHF) in diabetic patients with cardiovascular disease. EMPRISE is a study programme on the effectiveness, safety and healthcare utilization of empagliflozin in routine care, leveraging real-world data from two commercial and one federal US data sources from 2014 to 2019.Objectives: To describe rationale and design of EMPRISE, assess ability to minimize confounding and evaluate the time to reach sufficient statistical power for a key study outcome, HHF, using baseline information from the first year of EMPRISE. Methods:In 3 claims data sets, we identified a 1:1 propensity score (PS)-matched cohort of diabetic patients ≥18 years initiating empagliflozin or a dipeptidyl peptidase-4 inhibitor (DPP4i), resulting in 6643 total pairs. The PS model included >140 baseline covariates. We measured covariate balance via standardized differences (SD) and postmatching c-statistic. We computed the incidence rate (IR) of HHF, predicted exposure accrual over time and calculated expected power.Results: After PS matching, patient characteristics were balanced with SD <0.1 and cstatistic between 0.54 and 0.59. The population IR of HHF was 4.4 per 1000 personyears using a specific HHF definition and 14.8 using a broader HHF definition. In our projection, 80%-powered analyses would require a minimum of 169 HHF events, expected to accumulate by year 3 (specific definition) or year 2 (broader definition). Conclusion:Baseline information from EMPRISE provided evidence of solid confounding control and adequate exposure accrual with expected powered analyses for the primary outcomes. K E Y W O R D Scomparative effectiveness, confounding (epidemiology), empagliflozin, heart failure, realworld data, study validity, type 2 diabetes

Cardiovascular and renal effectiveness of empagliflozin in routine care in East Asia: Results from the EMPRISE East Asia study

“…However, effects on all‐cause mortality in CVD‐REAL were lower than observed in this study and CV outcome trials of SGLT2 inhibitors such as the EMPA‐REG OUTCOME trial, 6 CANVAS programme 27 and DECLARE‐TIMI 28 . The potential difference observed with EMPRISE East Asia could be due to the new user, active comparator design of EMPRISE, which minimizes biases such as immortal time bias by avoiding switching between SGLT2 inhibitors and DPP‐4 inhibitors, thereby avoiding an overestimate of the mortality rate in the comparator group 9 …”

“…28 The potential difference observed with EMPRISE East Asia could be due to the new user, active comparator design of EMPRISE, which minimizes biases such as immortal time bias by avoiding switching between SGLT2 inhibitors and DPP-4 inhibitors, thereby avoiding an overestimate of the mortality rate in the comparator group. 9 A significant reduction in the risk of ESRD was observed with empagliflozin compared to DPP-4 inhibitors, although the number of events is low. This is particularly important given the high prevalence of ESRD in East Asia.…”

“…EMPRISE was designed to enhance balance across treatment groups and minimize chances of confounding and time-related biases. 9,30,31 This study has a number of additional strengths.…”

“…The EMPagliflozin CompaRative EffectIveness and SafEty (EMPRISE) study programme includes noninterventional studies of the effectiveness, safety, healthcare utilization and cost of care of empagliflozin in routine clinical practice in T2D patients across the CV risk continuum in East Asia, Europe and the US using comparable methodology. 9 In the interim analysis of EMPRISE US (EUPAS20677, NCT03363464), empagliflozin was associated with a ~ 50% reduction in the risk of HHF compared with sitagliptin 10 and lower risk of HHF 11 and combined CV outcomes compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of glucose-lowering agents that are used at a similar stage in the treatment pathway as empagliflozin and have neutral effects on CV outcomes. 12 Here, we present the first analysis of data from EMPRISE East Asia (EUPAS27606, NCT03817463), evaluating the effectiveness of empagliflozin on CV and renal outcomes in routine clinical practice using data collected in Japan, South Korea and Taiwan.…”

The effect of sodium‐glucose transport protein 2 inhibitors on mortality and heart failure in randomized trials versus observational studies

“…Thus, the observational studies may have an inherent risk of producing inflated effect sizes for populations not tested in RCTs which could lead to drugs being prescribed based on unrealistic expectations of treatment effects. The discussion and observation of the inflated effect sizes reported in observational studies is not new, 14,15 however, with the large interest of the pharmaceutical industry 16–18 and regulatory agencies 19 to use observational studies to support clinical decision making, a critical appraisal and review of the existing literature is warranted.…”