Statin Therapy In Atrial Refractoriness and Reperfusion Injury (STARR)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT01780740
First received: January 23, 2013
Last updated: May 14, 2013
Last verified: May 2013
  Purpose

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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by University of Oxford:

Primary Outcome Measures:
  • Post operative changes in the atrial effective refractory period [ Time Frame: Serial measurements over the first 4 post operative days ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • Atrial tissue biomarkers [ Time Frame: Right atrial appendage harvested at the time of venous cannulation and after separation from cardio-pulmonary bypass ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: January 2012
Estimated Study Completion Date: February 2014
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Sugar pill manufactured to mimic Atorvastatin 40mg tablet.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01780740

Locations
United Kingdom
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
  More Information

Publications:

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT01780740     History of Changes
Other Study ID Numbers: 10/H0505/35, 2009-013228-21
Study First Received: January 23, 2013
Last Updated: May 14, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Oxford:
Bypass Surgery, Coronary Artery
Atrial fibrillation
Ischaemia-reperfusion injury
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Statins, HMG-CoA

Additional relevant MeSH terms:
Atrial Fibrillation
Heart Failure
Ischemia
Reperfusion Injury
Wounds and Injuries
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Vascular Diseases
Postoperative Complications
Atorvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 22, 2014