Clinical Trial: Statin Therapy In Atrial Refractoriness and Reperfusion Injury

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

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 Summary: 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 biolog
Sponsor: University of Oxford

Current Primary Outcome:

• 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.
• 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

Original Primary Outcome: Post operative changes in the atrial effective refractory period [ Time Frame: Serial measurements over the first 4 post operative days ]

Current Secondary Outcome:

• 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 ]
• 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.
• 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.
• 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.
• 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.
• 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 ]

Original Secondary Outcome:

• 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 ]
• 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 production of reactive oxygen species,nitric oxide (NO)-redox balance and contribution of individual atrial oxidase systems.
• 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.
• 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.
• 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.
• 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 ]

Information By: University of Oxford

Dates:
Date Received: January 23, 2013
Date Started: January 2012
Date Completion:
Last Updated: August 6, 2014
Last Verified: August 2014