Renin-Angiotensin-Aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation - Full Text View

Sponsor:	Vanderbilt University
Collaborator:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	Vanderbilt University
ClinicalTrials.gov Identifier:	NCT00141778

Purpose

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 CPB surgical procedures. While recent studies indicate that interruption of the renin-angiotensin-aldosterone system by either 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.

Condition	Intervention	Phase
Atrial Fibrillation	Drug: Placebo Drug: Ramipril Drug: Spironolactone	Phase II Phase III

Study Type:	Interventional
Study Design:	Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study
Official Title:	RAAS, Inflammation, and Post-Operative AF

Resource links provided by NLM:

Genetics Home Reference related topics: Brugada syndrome familial atrial fibrillation short QT syndrome

MedlinePlus related topics: Atrial Fibrillation

Drug Information available for: Spironolactone Aldosterone Ramipril

U.S. FDA Resources

Further study details as provided by Vanderbilt University:

Primary Outcome Measures:

Occurrence of electrocardiographically confirmed AF or flutter at any time following neutralization of heparin at the end of CPB. [ Time Frame: Measured at time of hospital discharge. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Intra-operative MAP [ Time Frame: Measured during surgery ] [ Designated as safety issue: Yes ]
Intra-operative and post-operative requirements for pressors. [ Time Frame: Measured until the time of hospital discharge ] [ Designated as safety issue: Yes ]
Death [ Time Frame: Measured until the time of hospital discharge ] [ Designated as safety issue: Yes ]
Length of hospital stay [ Time Frame: Measured until the time of hospital discharge ] [ Designated as safety issue: No ]
Post-operative IL-6, PAI-1, t-PA and CRP concentrations and other biomarkers [ Time Frame: Measured until the time of hospital discharge ] [ Designated as safety issue: No ]
Serum potassium concentrations [ Time Frame: Measured until the time of hospital discharge ] [ Designated as safety issue: Yes ]
Creatinine concentrations(measured throughout the patient's hospital stay) [ Time Frame: Measured until the time of hospital discharge ] [ Designated as safety issue: Yes ]
Stroke [ Time Frame: Measured until the time of hospital discharge ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	777
Study Start Date:	April 2005
Estimated Study Completion Date:	April 2010
Estimated Primary Completion Date:	April 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Placebo Comparator	Drug: Placebo Matching placebo taken once a day
2: Experimental ACE inhibitor	Drug: Ramipril Taken orally, once a day
3: Experimental MR antagonist	Drug: Spironolactone Taken orally, once a day

Detailed Description:

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 CPB surgical procedures. While recent studies indicate that interruption of the renin-angiotensin-aldosterone system by either 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.

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

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Undergoing elective valvular heart surgery, coronary artery bypass grafting
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

History of AF other than remote paroxysmal AF
Ejection fraction less than 30%
Evidence of coagulopathy (INR greater than 1.7 without warfarin therapy)
Emergency surgery
History of ACE inhibitor-induced angioedema
Low blood pressure (systolic blood pressure less than 100 mmHg and evidence of hypoperfusion)
Hyperkalemia (potassium level greater than 5.0 mEq/L at study entry)
Impaired kidney function (serum creatinine level greater than 1.6 mg/dl)
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
Inability to discontinue current ACE inhibitor, AT1 receptor antagonist, or aldosterone receptor antagonist therapy
History of alcohol or drug abuse
Treatment with any investigational drug in the month prior to study entry
Mental condition that makes it impossible to understand the nature, scope and possible consequences of the study
Inability to comply with the study procedures (e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study)
Pregnant or breastfeeding

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00141778

Contacts

Contact: Nancy J Brown, M.D.

(615) 343-8701

nancy.j.brown@vanderbilt.edu

Locations

United States, Tennessee
Vanderbilt University	Recruiting
Nashville, Tennessee, United States, 37232
Contact: Nancy J Brown, M.D. 615-343-8701 nancy.j.brown@vanderbilt.edu
Principal Investigator: Nancy J. Brown, M.D.

Sponsors and Collaborators

Vanderbilt University

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:

Nancy J. Brown, M.D.

Vanderbilt University

More Information

No publications provided by Vanderbilt University

Additional publications automatically indexed to this study by National Clinical Trials Identifier (NCT ID):

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. Epub 2008 Sep 29.

Responsible Party:	Vanderbilt University Medical Center ( Nancy J. Brown M.D. )
Study ID Numbers:	040385, HL077389
Study First Received:	August 30, 2005
Last Updated:	June 23, 2009
ClinicalTrials.gov Identifier:	NCT00141778 History of Changes
Health Authority:	United States: Institutional Review Board

Additional relevant MeSH terms:

Heart Diseases
Hormone Antagonists
Diuretics
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Cardiovascular Agents
Pharmacologic Actions
Inflammation

Spironolactone
Pathologic Processes
Aldosterone Antagonists
Natriuretic Agents
Therapeutic Uses
Cardiovascular Diseases
Atrial Fibrillation
Arrhythmias, Cardiac

ClinicalTrials.gov processed this record on November 27, 2009