Cardiopulmonary-bypass and Reno-protective Effect of Atorvastatin Trial (CREAT)

A Phase II Randomised, Double-blind, Placebo-controlled Study of the Effect of Atorvastatin on Postoperative Renal Function in Patients Undergoing Elective Cardiopulmonary Bypass.

Acute kidney dysfunction is common after cardiac surgery. While many patients suffer no long-term ill effects from post-operative kidney dysfunction, some require initiation of dialysis therapy that can contribute to long-term morbidity. Further, there is evidence to suggest that those patients requiring dialysis after cardiac surgery have a higher risk of death in hospital.

The exact reasons why some patients develop acute kidney dysfunction after cardiac surgery is not well understood. However, research evidence to date has suggested that the presence of co-morbid illnesses (i.e., diabetes mellitus) and exposure to cardiopulmonary bypass (heart-lung machine used during operation when heart is stopped). Cardiopulmonary bypass, in particular, has been shown to over-activate several aspect of the body's immune system. Such over-activity can induce oxidative stress and contribute to acute kidney dysfunction.

The investigators believe that the statin drug, atorvastatin, might reduce the oxidative stress that occurs during cardiopulmonary bypass, and thus, prevent or reduce the magnitude of acute kidney dysfunction in those patients at highest risk. The investigators hope to give atorvastatin (40 mg orally) to patients immediately prior to and for 3 days after cardiac surgery, and to compare the effects on kidney function with patients who have not had atorvastatin.

Atorvastatin is the most commonly prescribed medication in Australia and is used to reduce blood cholesterol levels and decrease the risk of heart attacks and stroke. Recently, however, it has been discovered that atorvastatin may be useful for prevention of inflammation and oxidative stress in other conditions, such as following cardiac surgery with cardiopulmonary bypass.

Thus, the investigators plan to examine whether atorvastatin can prevent acute kidney dysfunction. This trial as planned is a pilot study. If atorvastatin shows promising evidence of reduction in acute kidney dysfunction, further studies on a larger scale would be required to justify its general use.

The investigators plan to determine whether atorvastatin, a statin drug, possesses kidney protective effects in patients at risk for perioperative acute kidney dysfunction after cardiac surgery and exposure to cardiopulmonary bypass.

This is a pilot, randomized, blinded, placebo-controlled trial.

The investigators plan to administer atorvastatin (40 mg orally) or placebo to patients immediately prior to and for 3 days after cardiac surgery. The atorvastatin/placebo will be given orally either by orogastric tube after induction of anaesthesia or swallowed by the patients.

Whether a particular patient receives the atorvastatin or placebo will be decided at random, and neither the patient nor the investigators will be aware of the allocated treatment.

The investigators plan to measure kidney function before and after cardiac surgery using the standard blood tests. The investigators also plan to measure markers of inflammation and oxidative stress in the blood. This may give insight into the mechanisms whereby atorvastatin exerts its effects. The investigators will also take four 20 ml samples of blood, spaced before, and after the operation, from the arterial catheter routinely inserted in every patient undergoing cardiac surgery.

The investigators believe that there will be no significant additional risk to a patient who participates in the study, and no discomfort other than that normally associated with cardiac surgery. Informed consent will be obtained from the patient prior to the operation by one of the investigators or the ICU research nurse. The clinical care of a patient who does not consent for any reason will not be affected.

Study Overview

• Status: Completed
• Conditions: Acute Kidney Dysfunction
• Intervention / Treatment: Drug: Placebo; Drug: Atorvastatin

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3084
      • Austin Health

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:

• Cardiac surgical patients in whom the use of cardiopulmonary bypass was planned
• Written informed consent of patient
• Age > 18 years

• And having at least one ore more of the following risk factors for postoperative AKI:

  • Age =/> 70 years
  • Preoperative plasma creatinine >120 µmol/L, New York Heart Association class III/IV or LVEF <35%
  • Insulin dependent diabetes mellitus
  • Valve surgery (with or without coronary artery bypass graft)
  • Redo cardiac surgery

Exclusion Criteria:

• An emergency operation is indicated (within 24 hours after hospital admission or on intra-aortic balloon pump)
• Pregnancy is confirmed or breastfeeding is present
• A renal allograft is present
• Preoperative acute renal failure within 6 weeks (acute rise in serum creatinine > 50% from baseline) is present
• Pre-operative end stage renal disease (serum creatinine > 300 µmol/L) is present
• Chronic moderate to high dose corticosteroid therapy (>10 mg/d prednisone or equivalent) is present
• Known Allergy to Atorvastatin

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2	Drug: Placebo; Placebo tablet
Active Comparator: 1	Drug: Atorvastatin; Atorvastatin tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in serum creatinine from baseline to peak level	within first two-seven postoperative days

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in NGAL from baseline to peak	within first 24 postoperatively
Length of stay in Intensive care	from admission to discharge from Intensive care
Hospital-Mortality	during hospital stay
Proportion of patients developing an increase in serum creatinine > 25% or >44µmicromol/L from baseline to peak level	within first two-seven postoperative days
Proportion of patients developing any of the RIFLE criteria: R, I or F	within first seven postoperative days
Proportion of patients developing any of the AKI stages: 1, 2 or 3 (using network definition)	within first seven postoperative days
Requirement of renal replacement therapy	within hospital stay
Length of stay in Hospital	from admission to discharge from hospital

Collaborators and Investigators

• Sponsor: Austin Health

Publications and helpful links

General Publications

• Prowle JR, Calzavacca P, Licari E, Ligabo EV, Echeverri JE, Haase M, Haase-Fielitz A, Bagshaw SM, Devarajan P, Bellomo R. Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery. Nephrology (Carlton). 2012 Mar;17(3):215-24. doi: 10.1111/j.1440-1797.2011.01546.x.

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: May 28, 2009
• First Submitted That Met QC Criteria: May 28, 2009
• First Posted (Estimate): May 29, 2009

Study Record Updates

• Last Update Posted (Estimate): September 11, 2012
• Last Update Submitted That Met QC Criteria: September 9, 2012
• Last Verified: August 1, 2009

More Information

Terms related to this study

• Keywords: Oxidative stress; Atorvastatin; Cardiac surgery; Cardiopulmonary bypass; Acute renal dysfunction
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: H2007/02810