Dapagliflozin to Prevent the Incidence of Contrast Induced Nephropathy After Heart Catheterization and Percutaneous Coronary Intervention

Left heart catheterization and percutaneous coronary intervention (PCI) has become a useful tool in interventional cardiology, in which iodinated contrast media is used. Although the use of iodinated contrast media (CM) is considered to be safe in patients with normal renal function, it is risky in patients with known chronic renal insufficiency (CKD) and diabetes mellitus. Contrast induced nephropathy (CIN) remains one of the most leading causes of in hospital acute kidney injury (AKI), affecting morbidity and mortality. There are various mechanisms through which CM develop their nephrotoxic effects, including renal vasoconstriction and medullary hypoxia, tubular cell toxicity and reactive oxygen species formation.

Inhibitors of type 2 sodium- glucose co-transporter (SGLT2i) is a relatively recent addition to the array of anti-diabetic agents, becoming part of everyday clinical practice. However, although SGLT2i were first used solely as antidiabetics because of their glycosuric effect, further research demonstrated that these drugs may independently reduce cardiovascular events, especially in patients with heart failure, a benefit that was consistent among diabetic and non-diabetic patients. Moreover, pleiotropic effects have been observed, including a reno-protective action. In addition to the effects mediated by intrarenal hemodynamic changes, SGLT2-i also have direct anti-inflammatory and antifibrotic nephroprotective effects. Indeed, SGLT2-i suppress the production of reactive oxygen species, lessening glomerulosclerosis and tubulo-interstitial fibrosis.

These findings suggest that the use of SGLT2i could offer benefit by reducing/ preventing the nephrotoxic effects of contrast media leading to the assumption that the use of these drugs could prevent the incidence nephropathy after cardiac catheterization and percutaneous coronary intervention.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Kidney Injury; Percutaneous Coronary Intervention; Left Cardiac Catheterization; Sodium-glucose Co-transporter 2 Inhibitors
• Intervention / Treatment: Drug: Dapagliflozin 5mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 1722
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Spyridon Deftereos, Prof.; Email: spdeftereos@gmail.com
• Study Contact Backup: Name: Georgios Giannopoulos, Prof.; Phone Number: +302107768132; Email: georgios.giannopolous@yale.edu

Study Locations

• Greece
  • Athens, Greece, 11527
    • Cardiology Department, Athens General Hospital "G. Gennimatas"
  • Athens, Greece, 12462
    • 2nd Department of Cardiology, National and Kapodistrian University of Athens, Faculty of Medicine, Athens, Greece.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age>18 years
• Written informed consent
• Glomerular Filtration Rate (GFR)≥ 30 ml/min/1.73m2 [CKD stage G1-G3]
• Percutaneous coronary intervention in patients with NSTEMI, UA, STCD and asymptomatic patients

Exclusion Criteria:

• Active malignancy
• Participation in other intervention study
• Class I or equivalent indication for treatment with a SGLT2 inhibitor
• Pregnancy or willing of pregnancy during the follow up period
• Active urogenital infection
• Diabetes mellitus type 1
• History of diabetic ketoacidosis
• Cardiogenic shock

• eGFR < 29 ml/min/1.73m2

  • Patients with an indication for SGLT2 inhibitor will be included in a prospective registry. Their treatment will be determined by their attending physicians.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Dapagliflozin; Patients who will be randomized to receive dapagliflozin following cardiac catheterization and PCI	Drug: Dapagliflozin 5mg; Patients randomized in this arm will receive dapagliflozin at a dose of 5mg once daily.
PLACEBO_COMPARATOR: Placebo; Patients who will be randomized to receive placebo following cardiac catheterization and PCI	Drug: Placebo; Patients randomized in this arm will receive placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of incidence of acute kidney injury (AKI) between the two study arms	AKI is defined defined as an absolute creatinine level increase of at least 0.3 mg/dL (≥26.5 μmol/L) or at least 1.5-fold from baseline.	1 month

Secondary Outcome Measures

Outcome Measure	Time Frame
Development of at least Stage 2 AKI (according to the KDIGO criteria), i.e. Increase in sCR>2.0-fold from baseline.	1 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence (cases per 100 patient-years) of hypoglycemia in both arms Any episode of hypoglycemia defined as serum glucose 60< mg/dl associated with symptoms of hypoglycemia.		1 month
Incidence (cases per 100 patient-years)of diabetic ketoacidosis.	Any episode of metabolic acidosis (pH<7.3) with decreased serum bicarbonate (<18mEq/ml) and	1 month
Incidence (cases per 100 patient-years)of lower urinary tract infections		1 month
Comparison of all cause mortality between the two groups		1 month

Collaborators and Investigators

• Sponsor: G.Gennimatas General Hospital
• Collaborators: 2nd Department of Cardiology, "Attikon" University Hospital, National and Kapodistrian University of Athens
• Investigators: Principal Investigator: Spyridon Deftereos, Prof., 2nd Department of Cardiology, National and Kapodistrian University of Athens, Faculty of Medicine, Athens, Greece

Publications and helpful links

General Publications

• Aurelio A, Durante A. Contrast-induced nephropathy in percutaneous coronary interventions: pathogenesis, risk factors, outcome, prevention and treatment. Cardiology. 2014;128(1):62-72. doi: 10.1159/000358042. Epub 2014 Feb 18.
• Garofalo C, Borrelli S, Liberti ME, Andreucci M, Conte G, Minutolo R, Provenzano M, De Nicola L. SGLT2 Inhibitors: Nephroprotective Efficacy and Side Effects. Medicina (Kaunas). 2019 Jun 11;55(6):268. doi: 10.3390/medicina55060268.
• McCullough PA, Choi JP, Feghali GA, Schussler JM, Stoler RM, Vallabahn RC, Mehta A. Contrast-Induced Acute Kidney Injury. J Am Coll Cardiol. 2016 Sep 27;68(13):1465-1473. doi: 10.1016/j.jacc.2016.05.099.
• Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005 Nov;16(11):3365-70. doi: 10.1681/ASN.2004090740. Epub 2005 Sep 21.
• Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.
• Ishibashi Y, Matsui T, Yamagishi S. Tofogliflozin, A Highly Selective Inhibitor of SGLT2 Blocks Proinflammatory and Proapoptotic Effects of Glucose Overload on Proximal Tubular Cells Partly by Suppressing Oxidative Stress Generation. Horm Metab Res. 2016 Mar;48(3):191-5. doi: 10.1055/s-0035-1555791. Epub 2015 Jul 9.
• Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 Inhibitors and the Diabetic Kidney. Diabetes Care. 2016 Aug;39 Suppl 2:S165-71. doi: 10.2337/dcS15-3006.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): April 1, 2021
• Primary Completion (ANTICIPATED): September 1, 2023
• Study Completion (ANTICIPATED): December 1, 2023

Study Registration Dates

• First Submitted: March 17, 2021
• First Submitted That Met QC Criteria: March 18, 2021
• First Posted (ACTUAL): March 19, 2021

Study Record Updates

• Last Update Posted (ACTUAL): March 19, 2021
• Last Update Submitted That Met QC Criteria: March 18, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Acute Kidney Injury; iodinated contrast media; dapaglifozin; Sodium-glucose Co-transporter 2 Inhibitors
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 2663

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No