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

• ClinicalTrials.gov Identifier: NCT00791648
• Recruitment Status: Completed
• First Posted: November 14, 2008
• Results First Posted: March 6, 2017
• Last Update Posted: September 16, 2019
• Sponsor: Vanderbilt University Medical Center
• Information provided by (Responsible Party): Frederic T Billings IV, Vanderbilt University Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Kidney Injury; Post-Operative Delirium; Icu Delirium; Acute Renal Failure; Delirium	Drug: atorvastatin; Drug: placebo	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 653 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Short-term Atorvastatin's Effect on Acute Kidney Injury Following Cardiac Surgery
• Study Start Date: July 2009
• Actual Primary Completion Date: October 2014
• Actual Study Completion Date: December 2014

Arms and Interventions

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Acute Kidney Injury [ Time Frame: postoperative day 2 ]
2. Number of Participants With Delirium [ Time Frame: while in ICU (about 2 days) ]

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37212

Sponsors and Collaborators

Vanderbilt University Medical Center

Investigators

• Principal Investigator: Frederic T. Billings, IV, MD; Vanderbilt University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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). pii: 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.

• Responsible Party: Frederic T Billings IV, Assistant Professor of Anesthesiology and Critical Care Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT00791648
• Other Study ID Numbers: 081238
• First Posted: November 14, 2008
• Results First Posted: March 6, 2017
• Last Update Posted: September 16, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: Data will become available within 6 weeks of request and will be available indefinitely.
• Access Criteria: These data will be made available upon reasonable request.

Keywords provided by Frederic T Billings IV, Vanderbilt University Medical Center:

aki; delirium; statin; short-term; cardiac

Additional relevant MeSH terms:

Delirium; Acute Kidney Injury; Wounds and Injuries; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Atorvastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors