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

Study Overview
=================
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.

Official Title
-----------------
RAAS, Inflammation, and Post-operative AF

Conditions
-----------------
Atrial Fibrillation

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Ramipril
* Drug: Spironolactone


Participation Criteria
=================
Eligibility 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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>matched placebo pills daily beginning 4-7 days before surgery and continuing through discharge | Drug: Placebo<br>* Matching placebo taken once a day<br>* Other names: Placebo tablet;|
| Experimental: Ramipril<br>Ramipril daily (2.5mg, increased to 5mg) beginning 4 to 7 days before surgery and continuing through discharge | Drug: Ramipril<br>* Taken orally, once a day<br>* Other names: Angiotensin-converting enzyme inhibitor;|
| Experimental: Spironolactone<br>Spironolactone 25mg daily beginning 4 to 7 days before surgery and continuing through discharge | Drug: Spironolactone<br>* Taken orally, once a day<br>* Other names: Mineralocorticoid Receptor Antagonist;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Renal Failure | Percentage of patients with a creatinine concentrations >2.5mg/dl | Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group. | 
| Hypotension | Percentage of patients with hypotension defined as a systolic blood pressure <90 mmHg and/or prolonged requirement for vasopressor use. | Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average. | 
| Hypokalemia | Percentage of patients who had a serum potassium concentrations <3.5 milliequivalents (mEq)/L | 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 that it took to extubate the patient after surgery. | 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 | 
| Death | The percentage of patients in each study arm who died. | Measured until the time of hospital discharge | 
| Stroke | Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT. | Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm. | 
| Perioperative Interleukin(IL)-6 Concentrations | Interleukin-6 was measured at several time points (see time points in table) over the course of the study | Perioperative period | 
| Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations | Plasminogen activator inhibitor-1 (PAI-1) was measured at several time points (see table) over the course of the study. | Perioperative period | 
| Perioperative C-reactive Protein (CRP) Concentrations | C-reactive protein was measured at several time points (see table) over the course of the study. | Perioperative period | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
atrial fibrillation, cardiac surgery