EMPEROR-Preserved Trial - Cardionerds Twitter Journal Club

CardioNerds Journal Club is a monthly forum for Cardionerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the EMPEROR-Preserved Trial.

Table of contents for the EMPEROR-Preserved Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

EMPEROR-Preserved Trial Visual Abstract – CardioNerds

October 14, 2021

Empagliflozin in Heart Failure with a Preserved Ejection Fraction

The EMPEROR-Preserved Trial

Stefan D. Anker, M.D., Ph.D., Javed Butler, M.D., Gerasimos Filippatos, M.D., Ph.D., João P. Ferreira, M.D., Edimar Bocchi, M.D., Michael Böhm, M.D., Ph.D., Hans-Peter Brunner–La Rocca, M.D., Dong-Ju Choi, M.D., Vijay Chopra, M.D., Eduardo Chuquiure-Valenzuela, M.D., Nadia Giannetti, M.D., Juan Esteban Gomez-Mesa, M.D., Stefan Janssens, M.D., Ph.D., James L. Januzzi, M.D., Jose R. Gonzalez-Juanatey, M.D., Bela Merkely, M.D., Stephen J. Nicholls, M.D., Sergio V. Perrone, M.D., Ileana L. Piña, M.D., Piotr Ponikowski, M.D., Michele Senni, M.D., David Sim, M.D., Jindrich Spinar, M.D., Iain Squire, M.D., Stefano Taddei, M.D., Hiroyuki Tsutsui, M.D., Subodh Verma, M.D., Dragos Vinereanu, M.D., Jian Zhang, M.D., Ph.D., Peter Carson, M.D., Carolyn Su Ping Lam, M.D., Nikolaus Marx, M.D., Cordula Zeller, Dipl.Math., Naveed Sattar, M.D., Waheed Jamal, M.D., Sven Schnaidt, M.Sc., Janet M. Schnee, M.D., Martina Brueckmann, M.D., Stuart J. Pocock, Ph.D., Faiez Zannad, M.D., Ph.D., and Milton Packer, M.D. for the EMPEROR-Preserved Trial Investigators^*

Link to article

Chronic heart failure (HF) has 3 major subtypes defined by LVEF:
- HFpEF (LVEF ≥50%)
- HFmrEF (LVEF 40-<50%)
- HFrEF (LVEF <40%)

HFpEF = 50% of chronic HF patients
There are few therapies that improve HFpEF endpoints, underscoring the need to identify effective therapies in this population.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) inhibit renal glucose reabsorption and were initially marketed as oral diabetes medications.
EMPA-REG OUTCOME and CANVAS trials showed lower CKD risk and CVD events among adults with diabetes with SGLT2i.
EMPEROR-Reduced showed benefit of SGLT2i in reducing HF events among patients with HFrEF regardless of diagnosis of diabetes.
The role of this SGLT2i among adults with HFpEF is unclear.

Relevant Guidelines for the EMPEROR-Preserved Trial

From the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure:

Study Rational

Prior trials have shown benefit of SGLT2i in reducing HF events among patients with HFrEF regardless of diagnosis of diabetes; however, the role of this SGLT2i among adults with HFpEF is unclear.

Objective

To determine if empagliflozin reduces the risk of the composite of cardiovascular death or hospitalization for heart failure in adults with heart failure with mid-range or preserved ejection fraction.

EMPEROR-Preserved Trial:
Randomized, double-blind, multicenter (622 centers in 23 countries, N=5988), parallel-group, controlled trial. Enrollment: 2017-2020, Follow-up: median 26.2 months.

Intervention

Randomized to empagliflozin 10 mg daily or placebo
Stratified by geographic region, diabetes status, eGFR of 50, and LVEF

Enrollment criteria

Inclusion Criteria

NYHA class II-IV with LVEF >40% while clinically stable (and no prior LVEF ≤40 while clinically stable)
NT-proBNP >300 pg/mL if no AF or >900 pg/mL if AF
Aged ≥18 years
Evidence of hypertensive heart failure or structural heart disease characterized by LAE or LVH
Stable diuretic use
BMI <45 kg/m2
HF hospitalization within 12 months

Exclusion Criteria

MI, CABG or other major CV surgery, or stroke/TIA in prior 90 days
Listed for orthotopic heart transplantation (OHT) or OHT recipient
Cardiomyopathy based on infiltrative diseases, muscular dystrophies, hypertrophic obstructive cardiomyopathy, or pericardial constriction
Severe valvular heart disease
Acute decompensated heart failure requiring intravenous diuretics, vasodilators, inotropic agents, or mechanical support within 1 week of screening
Atrial fibrillation or atrial flutter with resting HR >110 at screening
SBP ≥180 or <100 mm Hg or symptomatic hypotension
ICD in prior 3 months
Prior receipt of cardiac resynchronization therapy
Liver or kidney disease (eGFR <20 ml/min/1.73 m²)
Current use or prior use of a sodium-glucose co-transporter (SGLT)-2 inhibitor or combined SGLT-1 and -2 inhibitor

Outcomes

Primary Outcome: Composite CV death or hospitalization for heart failure

Secondary Outcomes:

Heart failure hospitalizations
Total hospitalizations
All-cause mortality
eGFR change from baseline
Composite renal outcome
New-onset type 2 diabetes among patients with prediabetes
Change in KCCQ score

Statistical Analysis
Intention-to-treat analysis. Differences between the placebo and empagliflozin groups for the primary outcome were assessed for statistical significance at an alpha level of 0.0497. Estimates of hazard ratios and 95% CI were calculated with cox proportional hazards models.

Notable Baseline Characteristics

From the empagliflozin group:

NYHA class II: 81%
Age: 71.8 years
Women 44.6%
HFmrEF (LVEF 41 to <50%): 33%
NICM: 64%
T2DM: 49%

Primary and Secondary Outcomes

Primary Outcomes

Death from cardiovascular causes or hospitalization for heart failure: 13.8% vs 17.1% (HR 0.79; 95% CI 0.69-0.90; P<0.001; NNT=30)
Hospitalization for heart failure: 8.6% vs 11.8% (HR 0.71; 95% CI 0.60-0.83; NNT=31)
(NS) Death from cardiovascular causes: 7.3% vs 8.2% (HR 0.91; 95% CI 0.76-1.09)

For the primary outcomes, benefit appeared somewhat attenuated among patients with EF ≥60%.

Secondary Outcomes

Total hospitalizations: 407 vs. 541 (p < 0.001)
Change in mean eGFR slope/year: -1.25 vs. -2.62 (p < 0.001)
(NS) Composite renal outcome 3.6% vs. 3.7% (p > 0.05)
(NS) All-cause mortality: 13.4% vs. 14.2% (HR 0.92, 95% CI 0.77-1.10, p > 0.05)
(NS) New-onset type 2 diabetes among patients with prediabetes: 12.0% vs. 14.0% (p > 0.05)

NS: Non-significant

Subgroup Analysis

A difference in effect was noted across LVEF groups (LVEF 40 to <50% (HFmrEF), 50 to <60%, and ≥60%) with the largest benefit among patients with HFmrEF.

Adverse events

Patients with any serious adverse event: 47.9% vs 51.6%
Urinary tract infections: 9.9% vs 8.1%
Genital infections: 2.2% vs 0.7%
Hypotension: 10.4% vs 8.6%
Hypoglycemic events: 2.4% vs 2.6%

Uncomplicated genital and urinary tract infections and hypotension were more common in patients treated with empagliflozin.

EMPEROR-Preserved Trial Conclusions

The EMPEROR-Preserved Trial is the first HFpEF trial to meet its primary end point: empagliflozin prevents hospitalizations due to heart failure with mid-range or preserved ejection fraction, irrespective of diabetes status. However, empagliflozin does not improve CV deaths or all-cause mortality.

Of note, trial participants with HFmrEF (33%) appear to derive the greatest benefit. There was trend toward benefit among patients with traditionally-considered HFpEF, though this was notably not statistically significant.

Limitations & Considerations

The trial combined HFpEF and HFmrEF making it unclear if the primary outcome would have reached statistical significance in a purely traditional HFpEF cohort
Heterogeneity of HFpEF makes studies difficult to interpret.
Boehringer Ingelheim (the pharmaceutical company that makes empagliflozin) participated in designing the protocol and statistical analysis plan as well as supervised the statistical analysis.
Cohort had very poor recruitment of Black patients and was ~75% white
Cohort baseline characteristics could limit extrapolation to many HFpEF clinic cohorts (average BMI ~30, average systolic blood pressure ~132), though this could argue benefit was achieved even in less sick patients
Hospitalizations for heart failure went down with empagliflozin, but KCCQ score did not, which could argue that reduction in hospitalization was not driven by improvement in volume status
Unlike SGLT2i trials in HFpEF, there was no improvement in the composite renal outcome
Lower overall adoption of MRA at baseline in this cohort and benefits only seen in patients not already on an MRA