#CardsJC: EMPEROR-Preserved Trial

  • Post category: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:

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
  1. Ponikowski P et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016. 37:2129-2200.
  2. Cheng RK et al. Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population. Am Heart J 2014. 168:721-30.
  3. Srivastava PK et al. Heart Failure With Mid-range Ejection Fraction. Curr Heart Fail Rep 2020. 17:1-8.
  4. Redfield MM. Heart failure with preserved ejection fraction. New England Journal of Medicine. 2016;375(19):1868-1877.
  5. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
  6. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet. 2003;362(9386):777-781.
  7. Cleland JGF, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (Pep-chf) study. Eur Heart J. 2006;27(19):2338-2345.
  8. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. New England Journal of Medicine. 2008;359(23):2456-2467.
  9. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268.
  10. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392.
  11. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131(1):34-42. doi:10.1161/CIRCULATIONAHA.114.013255
  12. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. New England Journal of Medicine. 2015;373(24):2314-2324.
  13. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. The Lancet. 2012;380(9851):1387-1395.
  14. Yancy Clyde W., Jessup Mariell, Bozkurt Biykem, et al. 2017 acc/aha/hfsa focused update of the 2013 accf/aha guideline for the management of heart failure. Journal of the American College of Cardiology. 2017;70(6):776-803.
  15. O’Connor CM, deFilippi C. Paragon-hf — why we do randomized, controlled clinical trials. New England Journal of Medicine. 2019;381(17):1675-1676
  16. McMurray John J.V., Jackson Alice M., Lam Carolyn S.P., et al. Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction. Circulation. 2020;141(5):338-351.
  17. Anker SD, Filippatos BG, Ferreira JP, et al., on behalf of the EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure With a Preserved Ejection Fraction. N Engl J Med 2021; Aug 27.
  18. Packer M, Butler J, Zannad F, et al. Empagliflozin and Major Renal Outcomes in Heart Failure. N Engl J Med 2021; Aug 27.
  19. Drazner MH. SGLT2 Inhibition in Heart Failure With a Preserved Ejection Fraction — A Win Against a Formidable Foe. N Engl J Med 2021; Aug 27.

The published archive features curated twitter highlights from the journal club event.

SUMMARY:  

Dr. Juliette Power, @JuliettePower44, Cardiology Fellow at the University of Minnesota, Minneapolis, MN. 

VISUAL ABSTRACT:  

Dr. Isadora Sande Mathias, @IsaMathiasMD, Cardiology Fellow at the Houston Methodist, Houston, TX. 

JOURNAL CLUB PROMO GRAPHIC:  

Christian Faaborg-Andersen, @c_andersen_1, Medical Student at Emory School of Medicine, Atlanta, GA. 

HOUSE EINTHOVEN CHIEF FELLOW: 

Dr. Colin Blumenthal, @CBlumenthal2, Cardiology Fellow at the University of Pennsylvania, Philadelphia, PA. 

DIRECTOR of JOURNAL CLUB: 

Dr. Rick Ferraro, @RichardAFerraro, Cardiology Fellow at the Johns Hopkins Hospital, Baltimore, MD.

#CardsJC: EMPEROR-Preserved Trial