The RAS, Fibrinolysis and Cardiopulmonary Bypass

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00607672
• Collaborator: (none)
• Enrollment: 111
• Locations: 2
• Arms: 3
• Duration (Months): 64
• Patients Per Site: 55.5
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Each year over a million patients worldwide undergo cardiac surgery requiring cardiopulmonary bypass (CPB).1 CPB is associated with significant morbidity including hemodynamic instability, the transfusion of allogenic blood products, and inflammation. Blood product transfusion increases mortality after cardiac surgery. Enhanced fibrinolysis contributes to increased blood product transfusion requirements in the perioperative period. CPB activates the kallikrein-kinin system (KKS), leading to increased bradykinin concentrations. Bradykinin, acting through its B2 receptor, stimulates the release of nitric oxide, inflammatory cytokines and tissue-type plasminogen activator (t-PA). Based on data indicating that angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients with coronary artery disease, many patients undergoing CPB are taking ACE inhibitors. While interruption of the renin-angiotensin system (RAS) reduces inflammation in response to CPB, ACE inhibitors also potentiate the effects of bradykinin and may augment B2-mediated change in fibrinolytic balance and inflammation. In contrast, angiotensin II type 1 receptor antagonism does not potentiate bradykinin and does not inhibit bradykinin metabolism.

Studies in animals suggest that bradykinin receptor antagonism inhibits reperfusion-induced increases in vascular permeability and neutrophil recruitment.A randomized, placebo controlled clinical trial of a bradykinin B2 receptor antagonist demonstrated some effect on survival in patients with systemic inflammatory response syndrome and gram-negative sepsis. In addition, we and others have shown bradykinin B2 receptor antagonism reduces vascular t-PA release during ACE inhibition. The current proposal derives from data from our laboratory and others elucidating the role of the KKS in the inflammatory, hypotensive and fibrinolytic response to CPB. Specifically, we have found that CPB activates the KKS and that ACE inhibition and smoking further increases bradykinin concentrations. During CPB, bradykinin concentrations correlate inversely with mean arterial pressure and directly with t-PA. Moreover, we have found that bradykinin receptor antagonism attenuates protamine-related hypotension following CPB. The current proposal tests the central hypothesis that the fibrinolytic and inflammatory response to cardiopulmonary bypass differ during angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease; Angiotensin Converting Enzyme; Angiotensin Receptor Blockers; Cardiopulmonary Bypass; Fibrinolysis; Inflammation	Drug: Placebo; Drug: Ramipril; Drug: Candesartan	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 111 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The RAS, Fibrinolysis and Cardiopulmonary Bypass
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1 Patients are randomized to placebo prior to surgery	Drug: Placebo; Placebo
Active Comparator: 2 Patients are randomized to Ramipril prior to surgery	Drug: Ramipril; Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter
Active Comparator: 3 Patients are randomized to Candesartan (ARB) prior to surgery	Drug: Candesartan; Candesartan 16mg/d

Outcome Measures

Primary Outcome Measures

1. Tissue-type Plasminogen Activator (t-PA) Antigen Response [From the start of surgery until postoperative day 2]

   To compare the effects of angiotensin II type I (AT1) receptor antagonism or angiotensin-converting enzyme (ACE) inhibition versus placebo on the fibrinolytic responses to cardiopulmonary bypass (CPB) as measured by t-PA antigen response

2. Plasminogen Activator Inhibitor-1 (PAI-1) Response [From the start of surgery until postoperative day 2]

   To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the fibrinolytic responses to CPB as measured by PAI-1 response

3. Interleukin-6 (IL-6) Response [From the start of surgery until postoperative day 2]

   To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-6

4. Interleukin-8 (IL-8) Response [From the start of surgery until postoperative day 2]

   To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-8

5. Interleukin-10 (IL-10) Response [From the start of surgery until postoperative day 2]

   To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by the IL-10 response

Secondary Outcome Measures

1. Blood Loss [First 24 hours after arrival in the intensive care unit]

   Blood loss over 24 hours as measured by chest tube output

2. Re-exploration for Bleeding [From arrival in intensive care unit until discharge from hospital]

   The percentage of patients that were taken back to the operating room for re-exploration because of bleeding

3. Blood Product Transfusion Requirement [From the start of surgery until discharge from hospital]

   Percentage of patients that received blood product transfusion

4. Vasopressor Drug Use [From the end of cardiopulmonary bypass until arrival in intensive care unit]

5. New Onset Atrial Fibrillation [From arrival in intensive care unit until discharge from hospital]

   New onset atrial fibrillation based on electrocardiogram (ECG) rhythm strips with a duration longer than 10 seconds

6. Acute Kidney Injury [From the start of surgery until postoperative day 3]

   Acute kidney injury (AKI) was defined according to Acute Kidney Injury Network (AKIN) criteria,specifically any increase in subject serum creatinine concentration of 50% or 0.3 mg/dL (26.5 umol/L) within 72 hours of surgery.

7. Stroke [From arrival in intensive care unit until discharge from hospital]

   New onset neurological deficit with a duration of longer than 24 hours

8. Length of Hospital Stay [From the start of surgery until discharge from hospital]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Inclusion Criteria

1. Subjects, 18 to 80 years of age, scheduled for elective cardiac surgery requiring CPB

2. For female subjects, the following conditions must be met:

postmenopausal for at least 1 year, or 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 on every study day

Exclusion Criteria:

1. Left ventricle ejection fraction less than 30%

2. History of ACE inhibitor-induced angioedema

3. Hypotension (systolic blood pressure <100 mmHg and evidence of hypoperfusion)

4. Hyperkalemia (baseline potassium >5.0 mEq/L)

5. Inability to discontinue current ACE inhibitor or AT1 receptor antagonist.

6. Emergency surgery

7. Impaired renal function (serum creatinine >1.6 mg/dl)

8. Pregnancy

9. Breast-feeding

10. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult

11. History of alcohol or drug abuse

12. Treatment with any investigational drug in the 1 month preceding the study

13. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study

14. Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	TN Valley Healthcare System	Nashville	Tennessee	United States	37212
2	Vanderbilt University	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University

Investigators

• Principal Investigator: Mias Pretorius, MBChB, MSc, Vanderbilt University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mias Pretorius, Associate Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00607672
• Other Study ID Numbers: 051170; HL 085740-01
• First Posted: Feb 6, 2008
• Last Update Posted: Oct 10, 2012
• Last Verified: Sep 1, 2012

• Keywords provided by Mias Pretorius, Associate Professor, Vanderbilt University: Angiotensin Converting Enzyme; Angiotensin Receptor Blockers; Cardiopulmonary Bypass; Fibrinolysis; Inflammation
• Additional relevant MeSH terms: Coronary Artery Disease; Inflammation; Candesartan; Ramipril

Study Results

Participant Flow

Recruitment Details	Adult patients scheduled for elective cardiac surgery requiring cardiopulmonary bypass were recruited from the Vanderbilt surgery clinic between 2006 and 2011.
Pre-assignment Detail	Patients were excluded after enrollment if they met exclusion criteria, if surgery was canceled or if the patient changed his mind.

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Period Title: Overall Study
STARTED	32	27	27
COMPLETED	28	24	22
NOT COMPLETED	4	3	5

Baseline Characteristics

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)	Total
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	Total of all reporting groups
Overall Participants	28	24	22	74
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	13 46.4%	11 45.8%	8 36.4%	32 43.2%
>=65 years	15 53.6%	13 54.2%	14 63.6%	42 56.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.14 (11.24)	64.38 (10.35)	67.05 (8.14)	65.84 (10.03)
Sex: Female, Male (Count of Participants)
Female	19 67.9%	12 50%	12 54.5%	43 58.1%
Male	9 32.1%	12 50%	10 45.5%	31 41.9%
Region of Enrollment (participants) [Number]
United States	28 100%	24 100%	22 100%	74 100%

Outcome Measures

1. Primary Outcome

Title	Tissue-type Plasminogen Activator (t-PA) Antigen Response
Description	To compare the effects of angiotensin II type I (AT1) receptor antagonism or angiotensin-converting enzyme (ACE) inhibition versus placebo on the fibrinolytic responses to cardiopulmonary bypass (CPB) as measured by t-PA antigen response
Time Frame	From the start of surgery until postoperative day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Placebo group	Angiotensin-converting enzyme group	Angiotensin receptor blocker group
Measure Participants	28	24	22
Pre CPB	14.36 (1.45)	14.05 (1.86)	11.97 (1.03)
60min of CPB	27.65 (3.39)	36.67 (7.26)	24.89 (2.96)
Post surgery	34.56 (3.35)	41.11 (3.37)	31.47 (2.61)
Postoperative day 1	20.25 (2.03)	17.10 (1.38)	15.75 (1.32)
Postoperative day 2	16.56 (1.87)	12.49 (0.93)	12.89 (1.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Mixed Models Analysis
	Comments

2. Primary Outcome

Title	Plasminogen Activator Inhibitor-1 (PAI-1) Response
Description	To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the fibrinolytic responses to CPB as measured by PAI-1 response
Time Frame	From the start of surgery until postoperative day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Placebo group	Angiotensin-converting enzyme group	Angiotensin receptor blocker group
Measure Participants	28	24	22
Pre CPB	15.14 (1.42)	16.25 (2.70)	18.28 (2.91)
60min of CPB	20.43 (1.63)	19.41 (1.98)	24.19 (3.84)
Post surgery	39.69 (3.78)	41.62 (5.89)	49.10 (7.32)
Postoperative day 1	31.83 (4.47)	26.27 (4.50)	21.70 (2.75)
Postoperative day 2	21.59 (3.77)	17.33 (3.77)	13.4 (1.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Blood Loss
Description	Blood loss over 24 hours as measured by chest tube output
Time Frame	First 24 hours after arrival in the intensive care unit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Measure Participants	28	24	22
Mean (Standard Error) [mL]	437 (35)	470 (59)	511 (119)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	Kruskal-Wallis
	Comments

4. Secondary Outcome

Title	Re-exploration for Bleeding
Description	The percentage of patients that were taken back to the operating room for re-exploration because of bleeding
Time Frame	From arrival in intensive care unit until discharge from hospital

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Measure Participants	28	24	22
Number [percentage of patients]	3.6	8.3	4.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.73
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Blood Product Transfusion Requirement
Description	Percentage of patients that received blood product transfusion
Time Frame	From the start of surgery until discharge from hospital

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Measure Participants	28	24	22
Packed red blood cells	67.9	62.5	2.7
Plasma	60.7	29.2	31.8
Platelets	46.4	29.2	22.7
Cryoprecipitate	7.1	4.2	4.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments	For plasma transfusion comparison. Ramipril and Candesartan versus placebo
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Vasopressor Drug Use
Time Frame	From the end of cardiopulmonary bypass until arrival in intensive care unit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Measure Participants	28	24	22
Dobutamine	35.7	29.2	27.3
Mlrinone	25.0	25.0	22.7
Norepinephrine	85.7	79.2	95.5
Epinephrine	7.1	4.3	13.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments	Comparison for norepinephrine use
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	New Onset Atrial Fibrillation
Description	New onset atrial fibrillation based on electrocardiogram (ECG) rhythm strips with a duration longer than 10 seconds
Time Frame	From arrival in intensive care unit until discharge from hospital

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Measure Participants	28	24	22
Number [percentage of patients]	17.9	16.7	27.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.62
	Comments
	Method	Chi-squared
	Comments

8. Secondary Outcome

Title	Acute Kidney Injury
Description	Acute kidney injury (AKI) was defined according to Acute Kidney Injury Network (AKIN) criteria,specifically any increase in subject serum creatinine concentration of 50% or 0.3 mg/dL (26.5 umol/L) within 72 hours of surgery.
Time Frame	From the start of surgery until postoperative day 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Measure Participants	28	24	22
Number [percentage of patients]	28.6	23.8	36.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	Chi-squared
	Comments

9. Secondary Outcome

Title	Stroke
Description	New onset neurological deficit with a duration of longer than 24 hours
Time Frame	From arrival in intensive care unit until discharge from hospital

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Measure Participants	28	24	22
Number [percentage of patients]	7.1	4.2	4.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	Chi-squared
	Comments

10. Secondary Outcome

Title	Length of Hospital Stay
Time Frame	From the start of surgery until discharge from hospital

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Patients are randomized to placebo prior to surgery	Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter	Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
Measure Participants	28	24	22
Mean (Standard Error) [days]	7.7 (0.5)	6.3 (0.6)	8.1 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Kruskal-Wallis
	Comments

11. Primary Outcome

Title	Interleukin-6 (IL-6) Response
Description	To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-6
Time Frame	From the start of surgery until postoperative day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Placebo group	Angiotensin-converting enzyme group	Angiotensin receptor blocker group
Measure Participants	28	24	22
Pre CPB	6.29 (1.25)	9.33 (3.25)	6.44 (1.20)
Post surgery	116.04 (28.19)	167.51 (35.64)	144.76 (29.52)
Postoperative day 1	224.96 (63.26)	172.65 (68.93)	218.16 (68.47)
Postoperative day 2	166.96 (28.79)	144.67 (46.41)	243.72 (117.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Mixed Models Analysis
	Comments

12. Primary Outcome

Title	Interleukin-8 (IL-8) Response
Description	To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-8
Time Frame	From the start of surgery until postoperative day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Placebo group	Angiotensin-converting enzyme group	Angiotensin receptor blocker group
Measure Participants	28	24	22
Pre CPB	16.18 (3.77)	11.86 (1.42)	13.38 (2.19)
Post surgery	66.44 (15.06)	80.07 (20.28)	76.76 (18.90)
Postoperative day 1	46.18 (8.90)	37.39 (6.04)	37.11 (4.44)
Postoperative day 2	34.39 (5.55)	28.06 (5.28)	37.77 (5.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	Mixed Models Analysis
	Comments

13. Primary Outcome

Title	Interleukin-10 (IL-10) Response
Description	To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by the IL-10 response
Time Frame	From the start of surgery until postoperative day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ramipril (ACEI)	Candesartan (ARB)
Arm/Group Description	Placebo group	Angiotensin-converting enzyme group	Angiotensin receptor blocker group
Measure Participants	28	24	22
Pre CPB	4.45 (0.47)	5.36 (0.80)	4.21 (0.61)
Post surgery	461.90 (84.64)	815.74 (273.29)	749.56 (199.31)
Postoperative day 1	30.70 (6.91)	26.89 (4.64)	22.55 (3.04)
Postoperative day 2	16.74 (3.09)	14.59 (3.16)	14.26 (2.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ramipril (ACEI), Candesartan (ARB)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
Arm/Group Title	Placebo		Ramipril (ACEI)		Candesartan (ARB)
Arm/Group Description	Placebo group		Angiotensin-converting enzyme group		Angiotensin receptor blocker group
All Cause Mortality
	Placebo		Ramipril (ACEI)		Candesartan (ARB)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Ramipril (ACEI)		Candesartan (ARB)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/28 (7.1%)		1/24 (4.2%)		2/22 (9.1%)
General disorders
In-hospital mortality	0/28 (0%)		0/24 (0%)		1/22 (4.5%)
Nervous system disorders
Stroke	2/28 (7.1%)		1/24 (4.2%)		1/22 (4.5%)
Other (Not Including Serious) Adverse Events
	Placebo		Ramipril (ACEI)		Candesartan (ARB)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/28 (39.3%)		10/24 (41.7%)		12/22 (54.5%)
Cardiac disorders
New onset atrial fibrillation	5/28 (17.9%)		4/24 (16.7%)		6/22 (27.3%)
General disorders
Re-exploration	1/28 (3.6%)		2/24 (8.3%)		1/22 (4.5%)
Renal and urinary disorders
Acute kidney injury	8/28 (28.6%)		5/24 (20.8%)		8/22 (36.4%)

Limitations/Caveats

We cannot exclude the possibility that our results may have been different if we studied a homogenous surgery population.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.