STARR: Statin Therapy In Atrial Refractoriness and Reperfusion Injury

Sponsor

University of Oxford (Other)

Overall Status

Completed

CT.gov ID

NCT01780740

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

2.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Disorder; Heart, Functional, Postoperative, Cardiac Surgery Cardiac Insufficiency Following Cardiac Surgery Atrial Fibrillation Ischaemia-reperfusion Injury	Drug: Atorvastatin Drug: Placebo	Phase 4

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 Design

Study Type:

Interventional

Actual Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

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

Study Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Aug 1, 2014

Actual Study Completion Date :

Aug 1, 2014

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Post operative changes in the atrial effective refractory period [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.
Atrial tissue biomarkers [Right atrial appendage harvested at the time of venous cannulation and after separation from cardio-pulmonary bypass]
Evaluation of production of reactive oxygen species

Secondary Outcome Measures

Post-operative recovery of left ventricular systolic and diastolic function [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 [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.
Adipose tissue biomarkers [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.
Vascular tissue biomarkers [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.
Biomarkers in peripheral blood [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.
Post operative atrial fibrillation detected by continuous ECG monitoring. [Monitoring will commence soon after surgery and will be continued until the end of post operative day 5]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oxford University Hospitals NHS trust	Oxford	Oxfordshire	United Kingdom	OX3 9DU

Sponsors and Collaborators

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