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

Atrial Fibrillation Clinical Trial

Official title:

RAAS, Inflammation, and Post-operative AF

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00141778
• Other study ID #: 040385
• Secondary ID: R01HL077389
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: August 30, 2005
• Last updated: February 19, 2013
• Start date: April 2005
• Est. completion date: August 2010

Study information

• Verified date: February 2013
• Source: Vanderbilt University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00134862

Recruitment information / eligibility

• Status: Completed
• Enrollment: 455
• Est. completion date: August 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• Placebo
Matching placebo taken once a day
• Ramipril
Taken orally, once a day
• Spironolactone
Taken orally, once a day

Locations

Country	Name	City	State
United States	Vanderbilt University	Nashville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
Vanderbilt University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Billings FT 4th, Pretorius M, Siew ED, Yu C, Brown NJ. Early postoperative statin therapy is associated with a lower incidence of acute kidney injury after cardiac surgery. J Cardiothorac Vasc Anesth. 2010 Dec;24(6):913-20. doi: 10.1053/j.jvca.2010.03.024 — View Citation

Fleming GA, Murray KT, Yu C, Byrne JG, Greelish JP, Petracek MR, Hoff SJ, Ball SK, Brown NJ, Pretorius M. Milrinone use is associated with postoperative atrial fibrillation after cardiac surgery. Circulation. 2008 Oct 14;118(16):1619-25. doi: 10.1161/CIRC — View Citation

Pretorius M, Murray KT, Yu C, Byrne JG, Billings FT 4th, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Mishra V, Body SC, Brown NJ. Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillati — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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.	Yes
Secondary	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.	Yes
Secondary	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.	Yes
Secondary	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	Yes
Secondary	Length of Hospital Stay (Days)		Measured from the day of surgery until the time of hospital discharge	No
Secondary	Death	The percentage of patients in each study arm who died.	Measured until the time of hospital discharge	Yes
Secondary	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.	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No