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

Vanderbilt University455 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: Measured from admission to the ICU until discharge from hospital

Secondary Outcomes

Acute Renal Failure

Percentage of patients with a creatinine concentrations \>2.5mg/dl

Time frame: 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.

Time frame: 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

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.

Time to Tracheal Extubation

It is the time in minutes that it took to extubate the patient after surgery.

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

Length of Hospital Stay (Days)

Time frame: Measured from the day of surgery until the time of hospital discharge

Death

The percentage of patients in each study arm who died.

Time frame: Measured until the time of hospital discharge

Stroke

Percentage of patients in each study group who experience a cerebrovascular event, confirmed by CT.

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: Perioperative period

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes