Statin Therapy In Atrial Refractoriness and Reperfusion Injury (STARR)

August 6, 2014 updated by: University of Oxford

Prevention of Atrial Oxidative Stress and Electrical Remodelling in Patients Undergoing Cardiac Surgery: Randomised Placebo-controlled Trial of Perioperative High-dose Atorvastatin

Patients with coronary artery disease are often prescribed drugs called statins because research has shown that, by lowering cholesterol, they reduce the risk of having a heart attack or other complications in the long-term. Experimental studies have suggested that statins may also have rapid anti-inflammatory, anti-oxidant and anti arrhythmic actions; however, whether these effects are of any benefit to patients remains to be proven. The purpose of STARR trial (Statin Therapy in Atrial Refractoriness and Reperfusion injury) is to evaluate whether a short course of a commonly used statin (atorvastatin, 80 mg once a day) decreases inflammation and stabilises electrical properties of the upper chamber of the heart in the post operative period of patients undergoing cardiac surgery on the heart-lung machine either for valve replacement and/or coronary artery bypass grafting. It will also examine whether this treatment can protect the heart from sustaining tissue damage when blood supply is restored after a period of ischaemia during the course of the surgery.In addition it will also explore the impact of this intervention on biology of the vessels used for bypass surgery and the fat tissue in the vicinity of the heart & blood vessels.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Evidence that pre- or perioperative statin treatment may reduce the occurrence of post-operative atrial fibrillation and improve clinical outcome in patients undergoing coronary artery bypass graft (CABG) or major vascular surgery has been largely generated by observational studies. In a recent meta-analysis of 6 randomized trials (of which only 2 had postoperative atrial fibrillation (AF) as a predefined outcome) evaluating the use of perioperative statin treatment in patients undergoing cardiac surgery (n=651 patients in total - study size between 40 and 200 patients), statin use was found to reduce the patients' relative risk of developing postoperative AF by 43% (RR 0.57, 95%CI 0.45,0.72) and their absolute risk by 14% (95% CI 8%,20%). Although these findings would be consistent with a rapid and, possibly, lipid-independent antiarrhythmic effect of statins, they have important limitations (e.g., single-centre, small size, lack of continuous ECG monitoring, mostly "ancillary" findings") and less bearing on current clinical practice, as they mostly included statin-naïve patients. For these reasons, the recent guidelines for the management of AF have not given a strong recommendation for the use of statins in the prevention of postoperative AF. Thus, whether intensive statin treatment in the perioperative period can confer cardio protection by reduction of atrial oxidative stress & improvement in atrial electrical remodelling remains to be demonstrated.As endothelial function is a strong determinant of clinical outcomes, improvement of vascular redox state & increase in nitric oxide bioavailability of arterial & venous grafts of patients undergoing cardiac surgery may improve post operative outcomes.However it is still unclear whether higher doses of atorvastatin could confer additional beneficial effects on human vessels. Adipose tissue (AT) by releasing vasoactive molecules & adipokines can affect myocardial and vascular biology. Recent evidence suggests that statins may favourably alter AT biosynthetic activity and increase the AT release of adiponectin (An adipokine that has been shown to have anti-inflammatory and anti-atherogenic effects) in turn improving the vascular & myocardial redox state. However there are only limited data on the effects of statins on human adipose tissue biology and most findings to date are based on cell lines and/or relevant mouse models.

Study Type

Interventional

Enrollment (Actual)

80

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Oxfordshire
      • Oxford, Oxfordshire, United Kingdom, OX3 9DU
        • Oxford University Hospitals NHS Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Participant is willing and able to give informed consent for participation in the study.
  • Male or Female, aged 18 years or above.
  • Requiring elective cardiac surgery.
  • Able (in the Investigators' opinion) and willing to comply with all study requirements.
  • Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study.

Exclusion Criteria:

  • Age>85yrs
  • Female participant who is pregnant, lactating or planning pregnancy during the course of the study.
  • Women of child-bearing potential without appropriate contraceptive measures. These include oral contraceptive pills, Intrauterine contraceptive devices etc
  • History of obstructive hepatobiliary disease or other serious hepatic disease or pre-operative ALT >2-fold the upper limit of normal or alcohol abuse
  • Creatinine >200 umol/L
  • Untreated hypothyroidism
  • Family history of hereditary muscle disorders
  • Known intolerance to statins or history of muscle toxicity with fibrates or statins.
  • Ongoing use of fibrates, niacin or of agents that are strong inhibitors of cytochrome P-450 or the P-glycoprotein within a month preceding randomization (cyclosporine, azole antifungals, such as itraconazole and ketoconazole, macrolide antibiotics, such as erythromycin and clarithromycin, protease inhibitors, nefazodone, verapamil, amiodarone or large quantity of grapefruit juice (≥ 1L/day) Patients on treatment with anti arrhythmic agents, other than beta-adrenergic receptor blockers.
  • Participant who is terminally ill or is inappropriate for placebo medication.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Atorvastatin
Atorvastatin (80 mg od) started not earlier than 6 days before surgery and continued until the 5th post-operative day included;
Drug: Atorvastatin
Atorvastatin (80 mg od) started not earlier than 6 days before surgery and continued until the 5th post-operative day included;
Other Names:
  • Lipitor
Placebo Comparator: Sugar pill
Placebo started not earlier than 6 days before surgery and continued until the 5th post-operative day included.
Drug: Placebo
Placebo started not earlier than 6 days before surgery and continued until the 5th post-operative day included;
Other Names:
  • Sugar pill manufactured to mimic Atorvastatin 40mg tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Post operative changes in the atrial effective refractory period
Time Frame: Serial measurements over the first 4 post operative days
The atrial effective refractory period (ERP) will be measured daily after surgery (up to post-operative day 4) based on a programmed stimulation protocol delivered by Medtronic Pacing system analyser 2090 via a Medtronic pacemaker connected serially to the atrial epicardial pacing wires.
Serial measurements over the first 4 post operative days
Atrial tissue biomarkers
Time Frame: Right atrial appendage harvested at the time of venous cannulation and after separation from cardio-pulmonary bypass
Evaluation of production of reactive oxygen species
Right atrial appendage harvested at the time of venous cannulation and after separation from cardio-pulmonary bypass

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Post-operative recovery of left ventricular systolic and diastolic function
Time Frame: Assessed by transthoracic echocardiography before surgery as well as before the day of first hospital discharge with an average of 5 days after surgery
Assessed by transthoracic echocardiography before surgery as well as before the day of first hospital discharge with an average of 5 days after surgery
Atrial tissue biomarkers
Time Frame: Right atrial appendage harvested at the time of venous cannulation and after separation from cardio-pulmonary bypass
Biomarkers of inflammation and oxidant stress. Evaluation of nitric oxide (NO)-redox balance and contribution of individual atrial oxidase systems.
Right atrial appendage harvested at the time of venous cannulation and after separation from cardio-pulmonary bypass
Adipose tissue biomarkers
Time Frame: Epicardial,perivascular, mesothoracic and subcutaneous adipose tissue samples collected at the time of surgery
Biomarkers of inflammation and oxidant stress. Evaluation of production of reactive oxygen species,Nitric oxide (NO)-redox balance and contribution of individual atrial oxidase systems.
Epicardial,perivascular, mesothoracic and subcutaneous adipose tissue samples collected at the time of surgery
Vascular tissue biomarkers
Time Frame: Surplus vessels from saphenous venous and internal mammary artery grafts collected at the time of surgery
Biomarkers of inflammation and oxidant stress. Evaluation of production of reactive oxygen species,Nitric oxide (NO)-redox balance and contribution of individual atrial oxidase systems.
Surplus vessels from saphenous venous and internal mammary artery grafts collected at the time of surgery
Biomarkers in peripheral blood
Time Frame: Peripheral blood samples processed to separate plasma/serum before surgery, on post operative day 3 and 5
Biomarkers of inflammation,oxidant stress and heart failure.
Peripheral blood samples processed to separate plasma/serum before surgery, on post operative day 3 and 5
Post operative atrial fibrillation detected by continuous ECG monitoring.
Time Frame: Monitoring will commence soon after surgery and will be continued until the end of post operative day 5
Monitoring will commence soon after surgery and will be continued until the end of post operative day 5

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oxford

Investigators

  • Principal Investigator: Prof.Barbara Casadei, MD.DPhil.FRCP, Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford
  • Principal Investigator: Dr.Raja Jayaram, MD, Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2012

Primary Completion (Actual)

August 1, 2014

Study Completion (Actual)

August 1, 2014

Study Registration Dates

First Submitted

January 23, 2013

First Submitted That Met QC Criteria

January 28, 2013

First Posted (Estimate)

January 31, 2013

Study Record Updates

Last Update Posted (Estimate)

August 7, 2014

Last Update Submitted That Met QC Criteria

August 6, 2014

Last Verified

August 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 10/H0505/35
  • 2009-013228-21 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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