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

Summary

Background

It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies.

Methods

We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II–IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977.

Findings

In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65–0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69–1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52–0·88]; p_interaction=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54–0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66–1·00]; p_interaction=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61–0·88]; not given combination HR 0·76 [0·62–0·94]; p_interaction=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups.

Interpretation

Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy.

Funding

Boehringer Ingelheim and Eli Lilly and Company.

Introduction

A common scenario in the medical treatment of heart failure with reduced ejection fraction (HFrEF) is the inability to achieve target doses of guideline-directed medical therapy,1, 2 which results in therapeutic regimens of varying doses of each life-saving therapy. As each trial assessing treatments thus far has focused on optimising their doses to the target, ambiguity remains about the benefit of prescribing new therapies to individuals not receiving target doses of the background treatments.³ In the EMPEROR-Reduced trial, empagliflozin reduced the incidence of cardiovascular death or heart failure hospitalisation in patients with HFrEF compared with placebo.⁴ In addition, empagliflozin reduced total hospitalisation for heart failure and serious adverse renal outcomes, while improving functional class and health status, effects that were seen in patients with and without diabetes.4, 5, 6, 7

Research in context

Evidence before this study

It is important to evaluate whether a new therapy for heart failure with reduced ejection fraction (HFrEF) affords clinically meaningful benefits in addition to established disease-modifying therapies. We searched MEDLINE from database inception up until July 12, 2021, using a string of key words including “sodium-glucose transporter 2 inhibitors”, “heart failure”, and “HFrEF” to identify articles that assessed cardiovascular outcomes with SGLT2 inhibitors stratified by background therapy, using data from randomised trials. The search was not limited to articles in English. We identified one such analysis from the DAPA-HF trial, showing dapagliflozin's efficacy, and none regarding empagliflozin. In the EMPEROR-Reduced trial, empagliflozin reduced the incidence of cardiovascular death or heart failure hospitalisations in patients with HFrEF compared with placebo. The trial did not mandate specific doses or specific drugs of background heart failure therapies and hence there is an opportunity to determine if the benefits of empagliflozin are influenced by established disease-modifying therapies, when used in combination and when prescribed at target or sub-target doses.

Added value of this study

The present study extends similar analyses previously conducted on dapagliflozin in DAPA-HF through the inclusion of additional clinically relevant subgroups, and the evaluation of the key secondary and extended composite outcomes. In particular, we studied the efficacy of empagliflozin versus placebo in patients given less than 50% and 50% or more of target doses of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, β blockers, and mineralocorticoid receptor antagonists. In addition, the treatment effect was evaluated according to whether or not patients were receiving one of five therapeutic combinations at baseline. We found that empagliflozin reduced the primary outcome regardless of background therapy or its target doses, and irrespective of background use of dual and triple therapy combinations. Similar patterns of benefit were observed for the secondary and extended composite outcomes.

Implications of all the available evidence

These data indicate that empagliflozin provides clinically important benefits in HFrEF in addition to existing disease-modifying therapies, regardless of breadth or intensity of use. This observation points to a complementary mechanism of action in HFrEF and suggests that four-drug treatment is associated with benefit, even if sub-target doses of each therapy are used.

The EMPEROR-Reduced trial required patients to be treated for heart failure, but did not mandate specific doses or specific drugs. Consequently, the trial provided an opportunity to determine if the benefits of empagliflozin are influenced by established disease-modifying therapies when used in combination and when prescribed at target or sub-target doses, as similarly evaluated with dapagliflozin in the DAPA-HF trial.8, 9 Conventional inhibitors of the renin–angiotensin system (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], angiotensin receptor neprilysin inhibitors [ARNIs]), β blockers, and mineralocorticoid receptor antagonists (MRAs) are established treatments for HFrEF. As such, in this post-hoc analysis, we aimed to evaluate the efficacy and safety of empagliflozin in patients given these foundational drug classes, used alone or in combination or prescribed at 50% or greater or at less than 50% of target dose.