Statin Therapy In Atrial Refractoriness and Reperfusion Injury

NCT01780740 | Completed Phase 4

• 2 other identifiers: 10/H0505/352009-013228-21
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Bypass Surgery, Coronary Artery; Atrial fibrillation; Ischaemia-reperfusion injury; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Statins, HMG-CoA

Outcome Measures

Primary Outcomes (2)

• Post operative changes in the atrial effective refractory period

  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

  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 Outcomes (6)

• 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

• Adipose tissue biomarkers

  Epicardial,perivascular, mesothoracic and subcutaneous adipose tissue samples collected at the time of surgery

• Vascular tissue biomarkers

  Surplus vessels from saphenous venous and internal mammary artery grafts collected at the time of surgery

• Biomarkers in peripheral blood

  Peripheral blood samples processed to separate plasma/serum before surgery, on post operative day 3 and 5

Study Arms (2)

Atorvastatin

EXPERIMENTAL

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

Drug: Atorvastatin

Sugar pill

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Atorvastatin DRUG

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

Also known as: Lipitor

Atorvastatin

Placebo DRUG

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

Also known as: Sugar pill manufactured to mimic Atorvastatin 40mg tablet.

Sugar pill

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (1)

Oxford University Hospitals NHS trust

Oxford, Oxfordshire, OX3 9DU, United Kingdom

Location

Related Publications (12)

• Antoniades C, Demosthenous M, Reilly S, Margaritis M, Zhang MH, Antonopoulos A, Marinou K, Nahar K, Jayaram R, Tousoulis D, Bakogiannis C, Sayeed R, Triantafyllou C, Koumallos N, Psarros C, Miliou A, Stefanadis C, Channon KM, Casadei B. Myocardial redox state predicts in-hospital clinical outcome after cardiac surgery effects of short-term pre-operative statin treatment. J Am Coll Cardiol. 2012 Jan 3;59(1):60-70. doi: 10.1016/j.jacc.2011.08.062.

  PMID: 22192670 BACKGROUND

• Antoniades C, Bakogiannis C, Leeson P, Guzik TJ, Zhang MH, Tousoulis D, Antonopoulos AS, Demosthenous M, Marinou K, Hale A, Paschalis A, Psarros C, Triantafyllou C, Bendall J, Casadei B, Stefanadis C, Channon KM. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation. 2011 Jul 19;124(3):335-45. doi: 10.1161/CIRCULATIONAHA.110.985150. Epub 2011 Jul 5.

  PMID: 21730307 BACKGROUND

• Reilly SN, Jayaram R, Nahar K, Antoniades C, Verheule S, Channon KM, Alp NJ, Schotten U, Casadei B. Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins. Circulation. 2011 Sep 6;124(10):1107-17. doi: 10.1161/CIRCULATIONAHA.111.029223. Epub 2011 Aug 15.

  PMID: 21844076 BACKGROUND

• Chen WT, Krishnan GM, Sood N, Kluger J, Coleman CI. Effect of statins on atrial fibrillation after cardiac surgery: a duration- and dose-response meta-analysis. J Thorac Cardiovasc Surg. 2010 Aug;140(2):364-72. doi: 10.1016/j.jtcvs.2010.02.042. Epub 2010 Apr 9.

  PMID: 20381820 BACKGROUND

• European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery; Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010 Oct;31(19):2369-429. doi: 10.1093/eurheartj/ehq278. Epub 2010 Aug 29. No abstract available.

  PMID: 20802247 BACKGROUND

• Kim YM, Kattach H, Ratnatunga C, Pillai R, Channon KM, Casadei B. Association of atrial nicotinamide adenine dinucleotide phosphate oxidase activity with the development of atrial fibrillation after cardiac surgery. J Am Coll Cardiol. 2008 Jan 1;51(1):68-74. doi: 10.1016/j.jacc.2007.07.085.

  PMID: 18174039 BACKGROUND

• Kim YM, Guzik TJ, Zhang YH, Zhang MH, Kattach H, Ratnatunga C, Pillai R, Channon KM, Casadei B. A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res. 2005 Sep 30;97(7):629-36. doi: 10.1161/01.RES.0000183735.09871.61. Epub 2005 Aug 25.

  PMID: 16123335 BACKGROUND

• Maack C, Kartes T, Kilter H, Schafers HJ, Nickenig G, Bohm M, Laufs U. Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment. Circulation. 2003 Sep 30;108(13):1567-74. doi: 10.1161/01.CIR.0000091084.46500.BB. Epub 2003 Sep 8.

  PMID: 12963641 BACKGROUND

• Laufs U, Kilter H, Konkol C, Wassmann S, Bohm M, Nickenig G. Impact of HMG CoA reductase inhibition on small GTPases in the heart. Cardiovasc Res. 2002 Mar;53(4):911-20. doi: 10.1016/s0008-6363(01)00540-5.

  PMID: 11922901 BACKGROUND

• Antoniades C, Bakogiannis C, Tousoulis D, Reilly S, Zhang MH, Paschalis A, Antonopoulos AS, Demosthenous M, Miliou A, Psarros C, Marinou K, Sfyras N, Economopoulos G, Casadei B, Channon KM, Stefanadis C. Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity. Circulation. 2010 Sep 14;122(11 Suppl):S66-73. doi: 10.1161/CIRCULATIONAHA.109.927376.

  PMID: 20837928 BACKGROUND

• Wojcicka G, Jamroz-Wisniewska A, Atanasova P, Chaldakov GN, Chylinska-Kula B, Beltowski J. Differential effects of statins on endogenous H2S formation in perivascular adipose tissue. Pharmacol Res. 2011 Jan;63(1):68-76. doi: 10.1016/j.phrs.2010.10.011. Epub 2010 Oct 20.

  PMID: 20969959 BACKGROUND

• Jayaram R, Jones M, Reilly S, Crabtree MJ, Pal N, Goodfellow N, Nahar K, Simon J, Carnicer R, DeSilva R, Ratnatunga C, Petrou M, Sayeed R, Roalfe A, Channon KM, Bashir Y, Betts T, Hill M, Casadei B. Atrial nitroso-redox balance and refractoriness following on-pump cardiac surgery: a randomized trial of atorvastatin. Cardiovasc Res. 2022 Jan 7;118(1):184-195. doi: 10.1093/cvr/cvaa302.

  PMID: 33098411 DERIVED

MeSH Terms

Conditions

Atrial Fibrillation; Reperfusion Injury

Interventions

Atorvastatin; Sugars; Tablets

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Postoperative Complications

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Carbohydrates; Dosage Forms; Pharmaceutical Preparations

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2013
• First Posted: January 31, 2013
• Study Start: January 1, 2012
• Primary Completion: August 1, 2014
• Study Completion: August 1, 2014
• Last Updated: August 7, 2014

Record last verified: 2014-08

Locations

GB (1)