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
  Purpose

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.


Condition Intervention Phase
Atrial Fibrillation
Drug: Placebo
Drug: Ramipril
Drug: Spironolactone
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: RAAS, Inflammation, and Post-operative AF

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 455
Study Start Date: April 2005
Study Completion Date: August 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge
Drug: Placebo
Matching placebo taken once a day
Other Name: Placebo tablet
Experimental: Ramipril
Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge
Drug: Ramipril
Taken orally, once a day
Other Name: Angiotensin-converting enzyme inhibitor
Experimental: Spironolactone
Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge
Drug: Spironolactone
Taken orally, once a day
Other Name: Mineralocorticoid Receptor Antagonist

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

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00141778

Locations
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Nancy J. Brown, M.D. Vanderbilt University
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Nancy J. Brown, Professor of Medicine and Pharmacology, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00141778     History of Changes
Obsolete Identifiers: NCT00134862
Other Study ID Numbers: 040385, R01HL077389
Study First Received: August 30, 2005
Results First Received: August 3, 2012
Last Updated: February 19, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
atrial fibrillation
cardiac surgery

Additional relevant MeSH terms:
Atrial Fibrillation
Inflammation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Angiotensin-Converting Enzyme Inhibitors
Ramipril
Enzyme Inhibitors
Mineralocorticoids
Spironolactone
Aldosterone Antagonists
Protease Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Hormone Antagonists
Diuretics
Natriuretic Agents
Cardiovascular Agents
Therapeutic Uses
Antihypertensive Agents

ClinicalTrials.gov processed this record on April 16, 2014