Trial Outcomes & Findings for Renin-angiotensin-aldosterone System (RAAS), Inflammation, and Post-Operative Atrial Fibrillation (AF) (NCT NCT00141778)

NCT ID: NCT00141778

Last Updated: 2013-03-22

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2/PHASE3
• Target enrollment: 455 participants
• Primary outcome timeframe: Measured from admission to the ICU until discharge from hospital
• Results posted on: 2013-03-22

Participant Flow

Patients were recruited between 2005 and 2010 from Vanderbilt University Medical Center and Brigham and Women's Hospital

One week to four days prior to surgery, patients were randomized to treatment with placebo, ramipril or spironolactone. Preexisting ACE inhibitor, angiotensin receptor blocker, or MR antagonist use was stopped at randomization. Four hundred and fifty-eight patients met inclusion and were randomized

Participant milestones

Measure	Placebo Placebo Group	Ramipril Angiotensin-Converting Enzyme Inhibitor Group. Ramipril was given as 2.5 mg the first 3 days followed by 5 mg/day, with the dose reduced to 2.5 mg/day on the first postoperative day only.	Spironolactone Mineralocorticoid Receptor (MR) Antagonist Group.Spironolactone was given as 25 mg/day.
Randomization Prior to Study Med STARTED	152	153	153
Randomization Prior to Study Med COMPLETED	147	151	147
Randomization Prior to Study Med NOT COMPLETED	5	2	6
Started Study Medication STARTED	147	151	147
Started Study Medication COMPLETED	145	144	143
Started Study Medication NOT COMPLETED	2	7	4

Reasons for withdrawal

Measure	Placebo Placebo Group	Ramipril Angiotensin-Converting Enzyme Inhibitor Group. Ramipril was given as 2.5 mg the first 3 days followed by 5 mg/day, with the dose reduced to 2.5 mg/day on the first postoperative day only.	Spironolactone Mineralocorticoid Receptor (MR) Antagonist Group.Spironolactone was given as 25 mg/day.
Randomization Prior to Study Med Withdrawal by Subject	5	2	6
Started Study Medication Met safety criteria for discontinuation	2	4	3
Started Study Medication Withdrawal by Subject	0	2	0
Started Study Medication Difficulty Swallowing	0	1	0
Started Study Medication Chest Discomfort	0	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group	Total n=445 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	94 Participants n=5 Participants	101 Participants n=7 Participants	99 Participants n=5 Participants	294 Participants n=4 Participants
Age, Categorical >=65 years	53 Participants n=5 Participants	50 Participants n=7 Participants	48 Participants n=5 Participants	151 Participants n=4 Participants
Age Continuous	60.0 years STANDARD_DEVIATION 12.0 • n=5 Participants	58.7 years STANDARD_DEVIATION 12.3 • n=7 Participants	59.2 years STANDARD_DEVIATION 12.3 • n=5 Participants	59.3 years STANDARD_DEVIATION 12.2 • n=4 Participants
Sex: Female, Male Female	53 Participants n=5 Participants	45 Participants n=7 Participants	51 Participants n=5 Participants	149 Participants n=4 Participants
Sex: Female, Male Male	94 Participants n=5 Participants	106 Participants n=7 Participants	96 Participants n=5 Participants	296 Participants n=4 Participants
Region of Enrollment United States	147 participants n=5 Participants	151 participants n=7 Participants	147 participants n=5 Participants	445 participants n=4 Participants

PRIMARY outcome

Timeframe: Measured from admission to the ICU until discharge from hospital

Population: Four hundred fifty-eight patients were randomized. Of these 445 took study medication and were included in the intention-to-treat analysis.

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.

Outcome measures

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group
Postoperative Atrial Fibrillation	27.2 percentage of patients	27.8 percentage of patients	25.9 percentage of patients

SECONDARY outcome

Timeframe: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average, depending on the study group.

Population: The intention-to-treat analysis included anyone who had received any study medication.

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

Outcome measures

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group
Acute Renal Failure	5.4 percentage of patients	0.7 percentage of patients	0.7 percentage of patients

SECONDARY outcome

Timeframe: Measured during and after surgery, until discharge, from 5.7 to 6.8 days on average.

Population: The intention-to-treat analysis included anyone who had received any medication.

Percentage of patients with hypotension defined as a systolic blood pressure <90 mmHg and/or prolonged requirement for vasopressor use.

Outcome measures

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group
Hypotension	5.4 percentage of patients	10.6 percentage of patients	10.2 percentage of patients

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group
Hypokalemia	11.6 percentage of patients	13.8 percentage of patients	6.8 percentage of patients

SECONDARY outcome

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

Population: The intention-to-treat analysis included all patients who received any study medication.

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

Outcome measures

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group
Time to Tracheal Extubation	1091.3 minutes Standard Deviation 3067.3	970.1 minutes Standard Deviation 3548.1	576.4 minutes Standard Deviation 761.5

SECONDARY outcome

Timeframe: Measured from the day of surgery until the time of hospital discharge

Population: The intention-to-treat analysis included anyone who had received any study medication.

Outcome measures

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group
Length of Hospital Stay (Days)	6.8 days Standard Deviation 8.2	5.7 days Standard Deviation 3.2	5.8 days Standard Deviation 3.4

SECONDARY outcome

Timeframe: Measured until the time of hospital discharge

Population: The intention-to-treat analysis included all patients who received any study medication.

The percentage of patients in each study arm who died.

Outcome measures

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group
Death	1.4 percentage of patients	2.0 percentage of patients	0 percentage of patients

SECONDARY outcome

Timeframe: Measured until the time of hospital discharge, from 5.7 to 6.8 days on average depending on the study arm.

Population: The intention-to-treat analysis included all those who received any study drug.

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

Outcome measures

Measure	Placebo n=147 Participants Placebo Group	Ramipril n=151 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 Participants Mineralocorticoid Receptor (MR) Antagonist group
Stroke	2.7 percentage of patients	1.3 percentage of patients	2.0 percentage of patients

SECONDARY outcome

Timeframe: Perioperative period

Population: All participants included in the intention-to-treat analysis who had available plasma samples.

Interleukin-6 was measured at several time points (see time points in table) over the course of the study

Outcome measures

Measure	Placebo n=136 Participants Placebo Group	Ramipril n=136 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=140 Participants Mineralocorticoid Receptor (MR) Antagonist group
Perioperative Interleukin(IL)-6 Concentrations Initiation of surgery	4.7 pg/ml Standard Deviation 6.7	4.6 pg/ml Standard Deviation 7.1	6.6 pg/ml Standard Deviation 10.2
Perioperative Interleukin(IL)-6 Concentrations 30min intraop	12.0 pg/ml Standard Deviation 18.4	20.5 pg/ml Standard Deviation 72.6	11.3 pg/ml Standard Deviation 20.2
Perioperative Interleukin(IL)-6 Concentrations 60min intraop	15.6 pg/ml Standard Deviation 20.1	28.8 pg/ml Standard Deviation 100.9	17.4 pg/ml Standard Deviation 29.4
Perioperative Interleukin(IL)-6 Concentrations Postop	130.0 pg/ml Standard Deviation 213.7	202.1 pg/ml Standard Deviation 668.7	145.7 pg/ml Standard Deviation 427.1
Perioperative Interleukin(IL)-6 Concentrations Postoperative day 1	119.0 pg/ml Standard Deviation 143.1	171.0 pg/ml Standard Deviation 208.6	164.9 pg/ml Standard Deviation 200.2
Perioperative Interleukin(IL)-6 Concentrations Postoperative day 2	100.3 pg/ml Standard Deviation 106.8	95.5 pg/ml Standard Deviation 90.8	109.6 pg/ml Standard Deviation 116.9

SECONDARY outcome

Timeframe: Perioperative period

Population: PAI-1 was measured in all subjects in the intention-to-treat analysis for which plasma was available.

Plasminogen activator inhibitor-1 (PAI-1) was measured at several time points (see table) over the course of the study.

Outcome measures

Measure	Placebo n=135 Participants Placebo Group	Ramipril n=133 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=136 Participants Mineralocorticoid Receptor (MR) Antagonist group
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Initiation of surgery	19.6 ng/mL Standard Deviation 16.6	16.2 ng/mL Standard Deviation 11.9	17.3 ng/mL Standard Deviation 12.0
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations 30min intraop	19.2 ng/mL Standard Deviation 10.7	19.7 ng/mL Standard Deviation 12.5	17.3 ng/mL Standard Deviation 10.9
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations 60min intraop	21.0 ng/mL Standard Deviation 10.9	22.0 ng/mL Standard Deviation 13.7	20.1 ng/mL Standard Deviation 11.7
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Postop	36.4 ng/mL Standard Deviation 24.6	38.9 ng/mL Standard Deviation 28.0	34.0 ng/mL Standard Deviation 22.3
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Postoperative day 1	55.2 ng/mL Standard Deviation 43.8	47.9 ng/mL Standard Deviation 31.4	48.9 ng/mL Standard Deviation 35.0
Perioperative Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Postoperative day 2	28.1 ng/mL Standard Deviation 20.4	25.7 ng/mL Standard Deviation 17.9	31.0 ng/mL Standard Deviation 30.5

SECONDARY outcome

Timeframe: Perioperative period

Population: CRP was measured in all subjects from the intention-to-treat analysis for which plasma was available at those time points.

C-reactive protein was measured at several time points (see table) over the course of the study.

Outcome measures

Measure	Placebo n=127 Participants Placebo Group	Ramipril n=129 Participants Angiotensin-converting enzyme inhibitor group	Spironolactone n=126 Participants Mineralocorticoid Receptor (MR) Antagonist group
Perioperative C-reactive Protein (CRP) Concentrations Initiation of surgery	4.1 ug/mL Standard Deviation 6.8	4.3 ug/mL Standard Deviation 10.8	3.9 ug/mL Standard Deviation 7.3
Perioperative C-reactive Protein (CRP) Concentrations Postoperative day 1	51.4 ug/mL Standard Deviation 40.0	49.9 ug/mL Standard Deviation 38.5	64.3 ug/mL Standard Deviation 115
Perioperative C-reactive Protein (CRP) Concentrations Postoperative day 2	134.8 ug/mL Standard Deviation 137.4	131.0 ug/mL Standard Deviation 281.5	127.8 ug/mL Standard Deviation 84.8
Perioperative C-reactive Protein (CRP) Concentrations Postoperative day 3	128.3 ug/mL Standard Deviation 88.7	164.8 ug/mL Standard Deviation 416.5	189.4 ug/mL Standard Deviation 476.0
Perioperative C-reactive Protein (CRP) Concentrations Postoperative day 4	94.1 ug/mL Standard Deviation 67.3	105.2 ug/mL Standard Deviation 96.6	126.5 ug/mL Standard Deviation 95.4

Adverse Events

Placebo

Serious events: 8 serious events

Other events: 17 other events

Deaths: 0 deaths

Ramipril

Serious events: 6 serious events

Other events: 21 other events

Deaths: 0 deaths

Spironolactone

Serious events: 5 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=147 participants at risk Placebo Group	Ramipril n=151 participants at risk Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 participants at risk Mineralocorticoid Receptor (MR) Antagonist group
General disorders Death	1.4% 2/147 • Number of events 2 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	2.0% 3/151 • Number of events 3 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	0.00% 0/147 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.
Renal and urinary disorders Acute renal failure	5.4% 8/147 • Number of events 8 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	0.66% 1/151 • Number of events 1 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	0.68% 1/147 • Number of events 1 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.
Nervous system disorders Stroke	2.7% 4/147 • Number of events 4 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	1.3% 2/151 • Number of events 2 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	2.0% 3/147 • Number of events 4 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.
Respiratory, thoracic and mediastinal disorders Pneumonia	4.1% 6/147 • Number of events 6 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	2.6% 4/151 • Number of events 4 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	1.4% 2/147 • Number of events 2 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.

Other adverse events

Measure	Placebo n=147 participants at risk Placebo Group	Ramipril n=151 participants at risk Angiotensin-converting enzyme inhibitor group	Spironolactone n=147 participants at risk Mineralocorticoid Receptor (MR) Antagonist group
Cardiac disorders Hypotension	5.4% 8/147 • Number of events 8 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	10.6% 16/151 • Number of events 16 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	10.2% 15/147 • Number of events 15 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.
General disorders Hypokalemia	11.6% 17/147 • Number of events 17 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	13.9% 21/151 • Number of events 21 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	6.8% 10/147 • Number of events 10 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.
General disorders Hyperkalemia	0.68% 1/147 • Number of events 1 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	0.66% 1/151 • Number of events 1 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.	0.68% 1/147 • Number of events 1 • Duration of hospital stay, which averaged from 5.7 to 6.8 days depending on the study arm. The intention-to-treat analysis included all subjects who received any study drug.

Additional Information

Dr. Mias Pretorius

Vanderbilt University School of Medicine

Phone: 16153430665

Email: mias.pretorius@vanderbilt.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place