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

Phase 2

Completed

Conditions: Atrial Fibrillation

Interventions: Drug: Placebo
Drug: Ramipril
Drug: Spironolactone

Registration Number: NCT00141778

Lead Sponsor: Vanderbilt University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 455

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 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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge
Ramipril	Ramipril	Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge
Spironolactone	Spironolactone	Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge

Primary Outcome Measures

Name	Time	Method
Postoperative Atrial Fibrillation	Measured from admission to the ICU until discharge from hospital	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

Name	Time	Method
Acute Renal Failure	Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group.	Percentage of patients with a creatinine concentrations \>2.5mg/dl
Hypotension	Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average.	Percentage of patients with hypotension defined as a systolic blood pressure \<90 mmHg and/or prolonged requirement for vasopressor use.
Hypokalemia	Measured until the time of hospital discharge, which was an average of 5.7 to 6.8 days depending on the treatment arm.	Percentage of patients who had a serum potassium concentrations \<3.5 milliequivalents (mEq)/L
Time to Tracheal Extubation	It is the time (in minutes) from admission to the ICU until tracheal extubation	It is the time in minutes that it took to extubate the patient after surgery.
Length of Hospital Stay (Days)	Measured from the day of surgery until the time of hospital discharge
Death	Measured until the time of hospital discharge	The percentage of patients in each study arm who died.
Stroke	Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm.	Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT.
Perioperative Interleukin(IL)-6 Concentrations	Perioperative period	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	Perioperative period	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	Perioperative period	C-reactive protein was measured at several time points (see table) over the course of the study.