Statin Therapy In Atrial Refractoriness and Reperfusion Injury

NCT ID: NCT01780740

Last Updated: 2014-08-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-01-31
• Study Completion Date: 2014-08-31

Brief Summary

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.

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.

Conditions

Disorder; Heart, Functional, Postoperative, Cardiac Surgery; Cardiac Insufficiency Following Cardiac Surgery; Atrial Fibrillation; Ischaemia-reperfusion Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Atorvastatin

Atorvastatin (80 mg od) started not earlier than 6 days before surgery and continued until the 5th post-operative day included;

Group Type: EXPERIMENTAL

Atorvastatin

Intervention Type: DRUG

Atorvastatin (80 mg od) started not earlier than 6 days before surgery and continued until the 5th post-operative day included;

Sugar pill

Placebo started not earlier than 6 days before surgery and continued until the 5th post-operative day included.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo started not earlier than 6 days before surgery and continued until the 5th post-operative day included;

Interventions

Atorvastatin

Atorvastatin (80 mg od) started not earlier than 6 days before surgery and continued until the 5th post-operative day included;

Intervention Type: DRUG

Placebo

Placebo started not earlier than 6 days before surgery and continued until the 5th post-operative day included;

Intervention Type: DRUG

Other Intervention Names

Lipitor; Sugar pill manufactured to mimic Atorvastatin 40mg tablet.

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Oxford

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Prof.Barbara Casadei, MD.DPhil.FRCP

Role: PRINCIPAL_INVESTIGATOR

Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford

Dr.Raja Jayaram, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford

Locations

Oxford University Hospitals NHS trust

Oxford, Oxfordshire, United Kingdom

Countries

United Kingdom

References

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Other Identifiers

2009-013228-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

10/H0505/35

Identifier Type: -

Identifier Source: org_study_id