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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00141778
First received: August 30, 2005
Last updated: February 19, 2013
Last verified: February 2013

August 30, 2005
February 19, 2013
April 2005
July 2010   (final data collection date for primary outcome measure)
Postoperative Atrial Fibrillation [ Time Frame: Measured from admission to the ICU until discharge from hospital ] [ Designated as safety issue: No ]
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.
  • a. Test the hypothesis that angiotensin II induces oxidation and inflammation in humans through endogenous aldosterone
  • b. Test the hypothesis that exogenous aldosterone induces oxidation and inflammation in humans through a mineralocorticoid receptor-dependent mechanism
  • c. Test the hypothesis that exogenous aldosterone induces oxidation and inflammation in humans through an AT1 receptor-dependent mechanism
Complete list of historical versions of study NCT00141778 on ClinicalTrials.gov Archive Site
  • Acute Renal Failure [ Time Frame: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group. ] [ Designated as safety issue: Yes ]
    Percentage of patients with a creatinine concentrations >2.5mg/dl
  • Hypotension [ Time Frame: Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average. ] [ Designated as safety issue: Yes ]
    Percentage of patients with hypotension defined as a systolic blood pressure <90 mmHg and/or prolonged requirement for vasopressor use.
  • Hypokalemia [ Time Frame: Measured until the time of hospital discharge, which was an average of 5.7 to 6.8 days depending on the treatment arm. ] [ Designated as safety issue: Yes ]
    Percentage of patients who had a serum potassium concentrations <3.5 milliequivalents (mEq)/L
  • Time to Tracheal Extubation [ Time Frame: It is the time (in minutes) from admission to the ICU until tracheal extubation ] [ Designated as safety issue: Yes ]
    It is the time in minutes that it took to extubate the patient after surgery.
  • Length of Hospital Stay (Days) [ Time Frame: Measured from the day of surgery until the time of hospital discharge ] [ Designated as safety issue: No ]
  • Death [ Time Frame: Measured until the time of hospital discharge ] [ Designated as safety issue: Yes ]
    The percentage of patients in each study arm who died.
  • Stroke [ Time Frame: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm. ] [ Designated as safety issue: Yes ]
    Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT.
  • Perioperative Interleukin(IL)-6 Concentrations [ Time Frame: Perioperative period ] [ Designated as safety issue: No ]
    Interleukin-6 was measured at several time points (see time points in table) over the course of the study
  • Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations [ Time Frame: Perioperative period ] [ Designated as safety issue: No ]
    Plasminogen activator inhibitor-1 (PAI-1) was measured at several time points (see table) over the course of the study.
  • Perioperative C-reactive Protein (CRP) Concentrations [ Time Frame: Perioperative period ] [ Designated as safety issue: No ]
    C-reactive protein was measured at several time points (see table) over the course of the study.
Test the hypothesis that either angiotensin-converting enzyme inhibition or aldosterone receptor antagonism decreases the incidence of atrial fibrillation following cardiopulmonary bypass
Not Provided
Not Provided
 
Renin-angiotensin-aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation (AF)
RAAS, Inflammation, and Post-operative AF

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.

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.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Atrial Fibrillation
  • Drug: Placebo
    Matching placebo taken once a day
    Other Name: Placebo tablet
  • Drug: Ramipril
    Taken orally, once a day
    Other Name: Angiotensin-converting enzyme inhibitor
  • Drug: Spironolactone
    Taken orally, once a day
    Other Name: Mineralocorticoid Receptor Antagonist
  • Placebo Comparator: Placebo
    matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge
    Intervention: Drug: Placebo
  • Experimental: Ramipril
    Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge
    Intervention: Drug: Ramipril
  • Experimental: Spironolactone
    Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge
    Intervention: Drug: Spironolactone

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
455
August 2010
July 2010   (final data collection date for primary outcome measure)

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
Both
18 Years to 80 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00141778
040385, R01HL077389
Yes
Nancy J. Brown, Vanderbilt University
Vanderbilt University
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Nancy J. Brown, M.D. Vanderbilt University
Vanderbilt University
February 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP