Empagliflozin in Heart Failure with Reduced Ejection Fraction and End Stage Renal Disease

Official title

The Safety and Efficacy of Empagliflozin in Patients with End-stage Renal Disease and Heart Failure with Reduced Ejection Fraction - a Randomized Controlled Trial

Overview

In patients with ESRD, up to 20% of patients suffer from HFrEF, leading to significant CV morbidity and mortality. Several drug classes that provide survival benefits for patients with HFrEF, including SGLT2i, lack data regarding their efficacy and safety in patients under chronic hemodialysis. As the primary target of SGLT2i is expressed mostly in the kidneys, the efficacy of SGLT2i in patients with ESRD may be limited. On the other hand, patients with ESRD are at higher risks of experiencing cardiovascular events and may still benefit from treatment. Several mechanistic studies have demonstrated direct actions of SGLT2i on the myocardium, thus it is possible that the benefits of SGLT2i on heart failure are independent of their glycosuric actions and may still be present in anuric subjects. Furthermore, pharmacokinetics and pharmacodynamics studies on empagliflozin demonstrated that peak plasma levels of empagliflozin in subjects with renal failure/ESRD were similar to those in subjects with normal renal function. The use of empagliflozin in patients with ESRD seemed safe in terms of pharmacokinetics and pharmacodynamics, yet its efficacy remains to be explored.

Interventions

• Drug Empagliflozin 25 MG
  The medication will be packed in a customized sealed jar and labeled on the exterior of the jar.
• Drug Placebo
  The placebo tablet is manufactured by Prince Pharmaceutical Co., Ltd, a leading manufacturer of nutritional supplements with certifications including cGMP, GMP, ISO, and HACCP. The Prince Pharmaceutical also provides Original Equipment Manufacturing (OEM)/Original Design Manufacturing (ODM) services for a wide array of tablet shapes, and post-processing techniques such as film coating and sugar coating.

Primary outcome measures

• Left ventricular mass [Time frame: 24 weeks of treatment]

Secondary outcome measures (12)

• Left ventricular mass index [Time frame: 24 weeks of treatment]
• LV end-systolic volume index [Time frame: 24 weeks of treatment]
• LV end-diastolic volume index [Time frame: 24 weeks of treatment]
• LA volume index [Time frame: 24 weeks of treatment]
• LV ejection fraction [Time frame: 24 weeks of treatment]
• Global longitudinal strain [Time frame: 24 weeks of treatment]
• LV end-systolic volume index [Time frame: 12 weeks and 24 weeks of treatment]
• LV end-diastolic volume index [Time frame: 12 weeks and 24 weeks of treatment]
• LA volume index [Time frame: 12 weeks and 24 weeks of treatment]
• LV ejection fraction [Time frame: 12 weeks and 24 weeks of treatment]
• Left ventricular mass index [Time frame: 12 weeks and 24 weeks of treatment]
• Global longitudinal strain [Time frame: 12 weeks and 24 weeks of treatment]

Eligibility criteria

Inclusion criteria

• Age ≥20 years old
• ESRD under chronic, maintenance hemodialysis with stable dry weight for the past 6 months
• Documented left ventricular ejection fraction <50% by any imaging modality within 1 month of screening

Exclusion criteria

• Age <20 years old
• Ongoing pregnancy
• NYHA class IV heart failure
• Any hospitalization for heart failure within the past month
• Ongoing acute urinary tract infection at the time of screening
• Known acute genital infection
• Severe peripheral artery disease (Rutherford category 4-6)
• Acute coronary syndrome, stroke or transient ischemic attack within the past month
• Recent initiation of chronic maintenance hemodialysis within 6 months
• Adjustment of dry weight with changes greater than 5% of body weight within the past month
• Documented left ventricular ejection fraction ≥50% by any imaging modality within 1 month of screening
• Refused informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Taiwan · 2 centers

• National Taiwan University Hospital Hsinchu Branch — Hsinchu
• Shin Kong Wu Ho-Su Memorial Hospital — Taipei

Publications

• Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008 Nov 4;52(19):1527-39. doi: 10.1016/j.jacc.2008.07.051. PMID 19007588
• Bansal N, Zelnick L, Bhat Z, Dobre M, He J, Lash J, Jaar B, Mehta R, Raj D, Rincon-Choles H, Saunders M, Schrauben S, Weir M, Wright J, Go AS; CRIC Study Investigators. Burden and Outcomes of Heart Failure Hospitalizations in Adults With Chronic Kidney Disease. J Am Coll Cardiol. 2019 Jun 4;73(21):2691-2700. doi: 10.1016/j.jacc.2019.02.071. PMID 31146814
• Kotecha D, Gill SK, Flather MD, Holmes J, Packer M, Rosano G, Bohm M, McMurray JJV, Wikstrand J, Anker SD, van Veldhuisen DJ, Manzano L, von Lueder TG, Rigby AS, Andersson B, Kjekshus J, Wedel H, Ruschitzka F, Cleland JGF, Damman K, Redon J, Coats AJS; Beta-Blockers in Heart Failure Collaborative Group. Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure. J Am Coll C PMID 31806133
• Ferro CJ, Mark PB, Kanbay M, Sarafidis P, Heine GH, Rossignol P, Massy ZA, Mallamaci F, Valdivielso JM, Malyszko J, Verhaar MC, Ekart R, Vanholder R, London G, Ortiz A, Zoccali C. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol. 2018 Dec;14(12):727-749. doi: 10.1038/s41581-018-0072-9. PMID 30361677
• Roehm B, Gulati G, Weiner DE. Heart failure management in dialysis patients: Many treatment options with no clear evidence. Semin Dial. 2020 May;33(3):198-208. doi: 10.1111/sdi.12878. Epub 2020 Apr 13. PMID 32282987
• Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Bohm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I PMID 32865377
• McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O PMID 31535829
• Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H, Zuo F, Quan A, Farkouh ME, Fitchett DH, Goodman SG, Goldenberg RM, Al-Omran M, Gilbert RE, Bhatt DL, Leiter LA, Juni P, Zinman B, Connelly KA. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation. 2019 Nov 19;140(2 PMID 31434508

Identifiers

NCT: NCT06249932 · 202301140MINC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗