Renin-angiotensin-aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation (AF)

NCT00141778 | Completed Phase 2 Results DMC

• 2 other identifiers: 040385R01HL077389
• Study Type: interventional
• Target: 455
• Locations: 1 country
• Sites: 1

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.

Conditions

Atrial Fibrillation

Keywords

atrial fibrillation; cardiac surgery

Outcome Measures

Primary Outcomes (1)

• Postoperative Atrial Fibrillation

  The primary endpoint of the study was the percentage of patients with electrocardiographically confirmed AF of at least 10 secs duration at any time following the end of surgery until hospital discharge, an average from 5.7 days in the ramipril group to 6.8 days in the placebo group. Patients were monitored continuously on telemetry throughout the postoperative period until discharge. Electrocardiograms were obtained for any rhythm changes detected on telemetry monitoring, and in addition, electrocardiograms were performed preoperatively, at admission to the intensive care unit, and daily starting on postoperative day 1. All electrocardiograms and rhythm strips were reviewed in a blinded fashion by a single cardiac electrophysiologist.

  Measured from admission to the ICU until discharge from hospital

Secondary Outcomes (10)

• Acute Renal Failure

  Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group.

• Hypotension

  Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average.

• Hypokalemia

  Measured until the time of hospital discharge, which was an average of 5.7 to 6.8 days depending on the treatment arm.

• Time to Tracheal Extubation

  It is the time (in minutes) from admission to the ICU until tracheal extubation

• Length of Hospital Stay (Days)

  Measured from the day of surgery until the time of hospital discharge

Study Arms (3)

Placebo

PLACEBO COMPARATOR

matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge

Drug: Placebo

Ramipril

EXPERIMENTAL

Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge

Drug: Ramipril

Spironolactone

EXPERIMENTAL

Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge

Drug: Spironolactone

Interventions

Placebo DRUG

Matching placebo taken once a day

Also known as: Placebo tablet

Placebo

Ramipril DRUG

Taken orally, once a day

Also known as: Angiotensin-converting enzyme inhibitor

Ramipril

Spironolactone DRUG

Taken orally, once a day

Also known as: Mineralocorticoid Receptor Antagonist

Spironolactone

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 milliequivalents (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

Sponsors & Collaborators

• Vanderbilt University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (6)

• 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.

  PMID: 20599398 RESULT

• 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.

  PMID: 18824641 RESULT

• 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.

  PMID: 22824930 RESULT

• Hashimoto H, Yamada H, Murata M, Watanabe N. Diuretics for preventing and treating acute kidney injury. Cochrane Database Syst Rev. 2025 Jan 29;1(1):CD014937. doi: 10.1002/14651858.CD014937.pub2.

  PMID: 39878152 DERIVED

• 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.

  PMID: 25468655 DERIVED

• 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.

  PMID: 22626819 DERIVED

MeSH Terms

Conditions

Atrial Fibrillation

Interventions

Ramipril; Angiotensin-Converting Enzyme Inhibitors; Spironolactone; Mineralocorticoid Receptor Antagonists

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Diuretics, Potassium Sparing; Diuretics; Natriuretic Agents

Limitations and Caveats

We excluded patients with an ejection fraction less than 30% or a creatinine above 1.6 and therefore the results are not applicable to patients with left ventricular dysfunction or more severe chronic kidney disease.

Results Point of Contact

• Title: Dr. Mias Pretorius
• Organization: Vanderbilt University School of Medicine

mias.pretorius@vanderbilt.edu

16153430665

Study Officials

• Nancy J. Brown, M.D.

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and Pharmacology

Study Record Dates

• First Submitted: August 30, 2005
• First Posted: September 1, 2005
• Study Start: April 1, 2005
• Primary Completion: July 1, 2010
• Study Completion: August 1, 2010
• Last Updated: March 22, 2013
• Results First Posted: March 22, 2013

Record last verified: 2013-02

Locations

US (1)