Clinical trial NCT00141778: Renin-angiotensin-aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation (AF)
Official title: RAAS, Inflammation, and Post-operative AF
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Atrial Fibrillation
Keywords: atrial fibrillation
cardiac surgery
Lead sponsor: Vanderbilt University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2005-09-01
Enrollment: 455
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Atrial fibrillation (AF) is the most prevalent, sustained type of irregular heartbeat and affects over 2 million Americans. Post-operative AF, which leads to significant morbidity and a prolonged hospital stay, complicates 20% to 40% of cardiopulmonary bypass (CPB) surgical procedures. While recent studies indicate that interruption of the renin-angiotensin-aldosterone system by either angiotensin-converting enzyme (ACE) inhibition or AT1 receptor antagonism decreases the incidence of AF following a heart attack or cardioversion (electric shock to the heart), its effect on the incidence of post-operative AF has not been throughly studied. Studies in both animals and humans suggest that inflammation-induced atrial remodeling plays an important role in the cause of AF. Recent studies also provide evidence that activation of the renin-angiotensin-aldosterone system induces inflammation, myocyte injury, proarrhythmic electrical remodeling, and fibrosis through aldosterone.

Detailed description: AF is the most prevalent, sustained type of irregular heartbeat and affects over 2 million Americans. Post-operative atrial fibrillation(AF), which leads to significant morbidity and a prolonged hospital stay, complicates 20% to 40% of CPB surgical procedures. While recent studies indicate that interruption of the renin-angiotensin-aldosterone system by either angiotensin-converting enzyme(ACE) inhibition or angiotensin II subtype 1 (AT1) receptor antagonism decreases the incidence of AF following a heart attack or cardioversion (electric shock to the heart), its effect on the incidence of post-operative AF has not been throughly studied. Studies in both animals and humans suggest that inflammation-induced atrial remodeling plays an important role in the cause of AF. Recent studies also provide evidence that activation of the renin-angiotensin-aldosterone system induces inflammation, myocyte injury, proarrhythmic electrical remodeling, and fibrosis through aldosterone.

This study will evaluate the effectiveness of ACE inhibition and aldosterone receptor antagonism at decreasing inflammation and AF following cardiopulmonary bypass (CPB) surgery.

Eligibility criteria: Inclusion Criteria:

1. Undergoing elective valvular heart surgery, coronary artery bypass grafting
2. If female, must be postmenopausal for at least 1 year, status-post surgical sterilization, or if of childbearing potential, utilizing adequate birth control and willing to undergo urine beta-hcg testing prior to drug treatment and throughout the study

Exclusion Criteria

1. History of AF other than remote paroxysmal AF
2. Ejection fraction less than 30%
3. Evidence of coagulopathy (INR greater than 1.7 without warfarin therapy)
4. Emergency surgery
5. History of ACE inhibitor-induced angioedema
6. Low blood pressure (systolic blood pressure less than 100 mmHg and evidence of hypoperfusion)
7. Hyperkalemia (potassium level greater than 5.0 milliequivalents (mEq)/L at study entry)
8. Impaired kidney function (serum creatinine level greater than 1.6 mg/dl)
9. Any underlying or acute disease requiring regular medication that could possibly cause complications or make implementation of the study or interpretation of the study results difficult
10. Inability to discontinue current ACE inhibitor, AT1 receptor antagonist, or aldosterone receptor antagonist therapy
11. History of alcohol or drug abuse
12. Treatment with any investigational drug in the month prior to study entry
13. Mental condition that makes it impossible to understand the nature, scope and possible consequences of the study
14. Inability to comply with the study procedures (e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study)
15. Pregnant or breastfeeding

Primary outcomes:
measure: Postoperative Atrial Fibrillation
timeFrame: Measured from admission to the ICU until discharge from hospital
Secondary outcomes:
measure: Acute Renal Failure
timeFrame: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group.
measure: Hypotension
timeFrame: Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average.
measure: Hypokalemia
timeFrame: Measured until the time of hospital discharge, which was an average of 5.7 to 6.8 days depending on the treatment arm.
measure: Time to Tracheal Extubation
timeFrame: It is the time (in minutes) from admission to the ICU until tracheal extubation
measure: Length of Hospital Stay (Days)
timeFrame: Measured from the day of surgery until the time of hospital discharge
measure: Death
timeFrame: Measured until the time of hospital discharge
measure: Stroke
timeFrame: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm.
measure: Perioperative Interleukin(IL)-6 Concentrations
timeFrame: Perioperative period
measure: Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations
timeFrame: Perioperative period
measure: Perioperative C-reactive Protein (CRP) Concentrations
timeFrame: Perioperative period
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
Study officials:
affiliation: Vanderbilt University
name: Nancy J. Brown, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Billings FT 4th, Pretorius M, Siew ED, Yu C, Brown NJ. Early postoperative statin therapy is associated with a lower incidence of acute kidney injury after cardiac surgery. J Cardiothorac Vasc Anesth. 2010 Dec;24(6):913-20. doi: 10.1053/j.jvca.2010.03.024.
citation: Fleming GA, Murray KT, Yu C, Byrne JG, Greelish JP, Petracek MR, Hoff SJ, Ball SK, Brown NJ, Pretorius M. Milrinone use is associated with postoperative atrial fibrillation after cardiac surgery. Circulation. 2008 Oct 14;118(16):1619-25. doi: 10.1161/CIRCULATIONAHA.108.790162. Epub 2008 Sep 29.
citation: Pretorius M, Murray KT, Yu C, Byrne JG, Billings FT 4th, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Mishra V, Body SC, Brown NJ. Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery. Crit Care Med. 2012 Oct;40(10):2805-12. doi: 10.1097/CCM.0b013e31825b8be2.
citation: Sidorova TN, Mace LC, Wells KS, Yermalitskaya LV, Su PF, Shyr Y, Atkinson JB, Fogo AB, Prinsen JK, Byrne JG, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Glabe CG, Brown NJ, Barnett JV, Murray KT. Hypertension is associated with preamyloid oligomers in human atrium: a missing link in atrial pathophysiology? J Am Heart Assoc. 2014 Dec 2;3(6):e001384. doi: 10.1161/JAHA.114.001384.
citation: Billings FT 4th, Pretorius M, Schildcrout JS, Mercaldo ND, Byrne JG, Ikizler TA, Brown NJ. Obesity and oxidative stress predict AKI after cardiac surgery. J Am Soc Nephrol. 2012 Jul;23(7):1221-8. doi: 10.1681/ASN.2011090940. Epub 2012 May 24.