Short-term Atorvastatin's Effect on Acute Kidney Injury Following Cardiac Surgery

Aim1a: Statin naive patient's scheduled for cardiac surgery will be randomized to 80mg atorvastatin or placebo on the day prior to surgery and then 40mg daily thereafter until hospital discharge to test the hypothesis that short-term atorvastatin use decreases:

1. acute kidney injury following cardiac surgery.
2. postoperative delirium following cardiac surgery.

Aim1b: Patients using statins preoperatively will be randomized to atorvastatin 80mg or placebo on day of surgery and 40mg or placebo on postop day 1 with resumption of preoperative statin therapy on postop day 2 to test the hypothesis that short-term atorvastatin use decreases:

1. acute kidney injury following cardiac surgery.
2. postoperative delirium following cardiac surgery.

Endpoints include glomerular filtration, urine and plasma markers of renal dysfunction, markers of oxidative stress, mitochondrial function, systemic inflammatory markers, delirium, dialysis, stroke, myocardial infarction, time to extubation, ICU length of stay, and death.

Study Overview

• Status: Completed
• Conditions: Delirium; Acute Kidney Injury; Acute Renal Failure; Post-Operative Delirium; Icu Delirium
• Intervention / Treatment: Drug: atorvastatin; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 653
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• open heart surgery

Exclusion Criteria:

• acute coronary syndrome with troponin leak or unrelenting angina
• liver dysfunction (transaminases 2x normal)
• history of myopathy or liver dysfunction on prior statin therapy
• use of potent CYP3A4 inhibitors such as antifungal azoles, macrolide antibiotics, HIV protease inhibitors, and nefazodone.
• pregnancy or breast feeding
• cyclosporine use
• dialysis
• history of kidney transplant
• fibrate users who cannot stop fibrate use.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: statin; Aim1 intervention: atorvastatin 80mg 1 day prior to open heart surgery and 40mg daily thereafter until hospital discharge. Aim2 intervention: atorvastatin 80mg the day of cardiac surgery and 40mg on postop day 1.	Drug: atorvastatin; Aim1 intervention: atorvastatin 80mg 1 day prior to open heart surgery and 40mg daily thereafter until hospital discharge. Aim2 intervention: atorvastatin 80mg the day of cardiac surgery and 40mg on postop day 1.; Other Names: Lipitor
Placebo Comparator: placebo; Aim 1 control: placebo one day prior to cardiac surgery and daily thereafter until hospital discharge. Aim 2 control: placebo the day of cardiac surgery and postop day 1.	Drug: placebo; Aim 1 control: placebo one day prior to cardiac surgery and daily thereafter until hospital discharge. Aim 2 control: placebo the day of cardiac surgery and postop day 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Acute Kidney Injury	postoperative day 2
Number of Participants With Delirium	while in ICU (about 2 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Requiring Dialysis		while in ICU (about 2 days)
Liver Enzyme: Aspartate Aminotransferase Level		postoperative day 1
Number of Participants With Stroke		while in ICU (about 2 days)
Number of Participants That Died		until postoperative hospital discharge (about 7 days)
Mitochondrial Function--mtDNA Copy Number	mtDNA copy number	anesthesia induction and POD 1
Mitochondrial Function--lactate / Pyruvate Ratio	lactate / pyruvate ratio	anesthesia induction, after CPB, and POD 1
Mitochondrial Function--PGC-1alpha RNA Expression	PGC-1alpha RNA expression	anesthesia induction and POD 1
Urine Markers of Renal Injury	tissue inhibitor metaloproteinase-2 x insulin-like growth factor binding protein-7	anesthesia induction, 30 minutes into cardiopulm bypass (CPB), after CPB, ICU admission, 6 hours postop, and Post op Day (POD) 1, 2, 3
Plasma Markers of Oxidative Stress: f2-Isoprostanes		anesthesia induction, 30 minutes into cardiopulmonary bypass (CPB), after CPB, ICU admission, 6 hours postop, and POD 1, 2, 3.
Plasma Markers of Oxidative Stress: Isofurans		anesthesia induction, 30 minutes into cardiopulmonary bypass (CPB), after CPB, ICU admission, 6 hours postop, and POD 1, 2, 3.
Urine Markers of Oxidative Stress: f2-Isoprostanes		anesthesia induction, 30 minutes into cardiopulmonary bypass (CPB), after CPB, ICU admission, 6 hours postop, and POD 1, 2, 3.
Urine Markers of Oxidative Stress: Isofurans		anesthesia induction, 30 minutes into cardiopulmonary bypass (CPB), after CPB, ICU admission, 6 hours postop, and POD 1, 2, 3.
Plasma Markers of Inflammation: Measurements of Neuronal Injury (Ubiquitin C-terminal Hydrolase-1)	measurements of neuronal injury (ubiquitin C-terminal hydrolase-1)	anesthesia induction, ICU admission, and POD 1
Plasma Markers of Inflammation: Blood Brain Barrier Disruption (S100 Calcium-binding Protein B)	measurements of blood brain barrier disruption (S100 calcium-binding protein B)	anesthesia induction, ICU admission, and POD 1

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Frederic T. Billings, IV, MD, Vanderbilt University

Publications and helpful links

General Publications

• Smith LE, Smith DK, Blume JD, Linton MF, Billings FT 4th. High-Density Lipoprotein Cholesterol Concentration and Acute Kidney Injury After Cardiac Surgery. J Am Heart Assoc. 2017 Dec 9;6(12):e006975. doi: 10.1161/JAHA.117.006975.
• Billings FT 4th, Hendricks PA, Schildcrout JS, Shi Y, Petracek MR, Byrne JG, Brown NJ. High-Dose Perioperative Atorvastatin and Acute Kidney Injury Following Cardiac Surgery: A Randomized Clinical Trial. JAMA. 2016 Mar 1;315(9):877-88. doi: 10.1001/jama.2016.0548.
• Billings FT 4th, Ball SK, Roberts LJ 2nd, Pretorius M. Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response. Free Radic Biol Med. 2011 Jun 1;50(11):1480-7. doi: 10.1016/j.freeradbiomed.2011.02.011. Epub 2011 Feb 18.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: November 12, 2008
• First Submitted That Met QC Criteria: November 13, 2008
• First Posted (Estimate): November 14, 2008

Study Record Updates

• Last Update Posted (Actual): September 16, 2019
• Last Update Submitted That Met QC Criteria: August 29, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: delirium; cardiac; short-term; statin; aki
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Kidney Diseases; Urologic Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Renal Insufficiency; Delirium; Wounds and Injuries; Acute Kidney Injury; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: 081238

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All study data that are necessary to assess the study hypotheses regarding the primary and secondary outcomes are available for sharing in a manner that protects the privacy of study participants.
• IPD Sharing Time Frame: Data will become available within 6 weeks of request and will be available indefinitely.
• IPD Sharing Access Criteria: These data will be made available upon reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR