Trial Outcomes & Findings for The RAS, Fibrinolysis and Cardiopulmonary Bypass (NCT NCT00607672)
NCT ID: NCT00607672
Last Updated: 2012-10-10
Results Overview
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
Recruitment status
COMPLETED
Study phase
PHASE4
Target enrollment
111 participants
Primary outcome timeframe
From the start of surgery until postoperative day 2
Results posted on
2012-10-10
Participant Flow
Adult patients scheduled for elective cardiac surgery requiring cardiopulmonary bypass were recruited from the Vanderbilt surgery clinic between 2006 and 2011.
Patients were excluded after enrollment if they met exclusion criteria, if surgery was canceled or if the patient changed his mind.
Participant milestones
| Measure |
Placebo
Patients are randomized to placebo prior to surgery
|
Ramipril (ACEI)
Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter
|
Candesartan (ARB)
Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
|
|---|---|---|---|
|
Overall Study
STARTED
|
32
|
27
|
27
|
|
Overall Study
COMPLETED
|
28
|
24
|
22
|
|
Overall Study
NOT COMPLETED
|
4
|
3
|
5
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
The RAS, Fibrinolysis and Cardiopulmonary Bypass
Baseline characteristics by cohort
| Measure |
Placebo
n=28 Participants
Patients are randomized to placebo prior to surgery
|
Ramipril (ACEI)
n=24 Participants
Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter
|
Candesartan (ARB)
n=22 Participants
Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.
|
Total
n=74 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
0 Participants
n=7 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
13 Participants
n=99 Participants
|
11 Participants
n=107 Participants
|
8 Participants
n=206 Participants
|
32 Participants
n=7 Participants
|
|
Age, Categorical
>=65 years
|
15 Participants
n=99 Participants
|
13 Participants
n=107 Participants
|
14 Participants
n=206 Participants
|
42 Participants
n=7 Participants
|
|
Age Continuous
|
66.14 years
STANDARD_DEVIATION 11.24 • n=99 Participants
|
64.38 years
STANDARD_DEVIATION 10.35 • n=107 Participants
|
67.05 years
STANDARD_DEVIATION 8.14 • n=206 Participants
|
65.84 years
STANDARD_DEVIATION 10.03 • n=7 Participants
|
|
Sex: Female, Male
Female
|
19 Participants
n=99 Participants
|
12 Participants
n=107 Participants
|
12 Participants
n=206 Participants
|
43 Participants
n=7 Participants
|
|
Sex: Female, Male
Male
|
9 Participants
n=99 Participants
|
12 Participants
n=107 Participants
|
10 Participants
n=206 Participants
|
31 Participants
n=7 Participants
|
|
Region of Enrollment
United States
|
28 participants
n=99 Participants
|
24 participants
n=107 Participants
|
22 participants
n=206 Participants
|
74 participants
n=7 Participants
|
PRIMARY outcome
Timeframe: From the start of surgery until postoperative day 2To 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
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Tissue-type Plasminogen Activator (t-PA) Antigen Response
Pre CPB
|
14.36 ng/mL
Standard Error 1.45
|
14.05 ng/mL
Standard Error 1.86
|
11.97 ng/mL
Standard Error 1.03
|
|
Tissue-type Plasminogen Activator (t-PA) Antigen Response
60min of CPB
|
27.65 ng/mL
Standard Error 3.39
|
36.67 ng/mL
Standard Error 7.26
|
24.89 ng/mL
Standard Error 2.96
|
|
Tissue-type Plasminogen Activator (t-PA) Antigen Response
Post surgery
|
34.56 ng/mL
Standard Error 3.35
|
41.11 ng/mL
Standard Error 3.37
|
31.47 ng/mL
Standard Error 2.61
|
|
Tissue-type Plasminogen Activator (t-PA) Antigen Response
Postoperative day 1
|
20.25 ng/mL
Standard Error 2.03
|
17.10 ng/mL
Standard Error 1.38
|
15.75 ng/mL
Standard Error 1.32
|
|
Tissue-type Plasminogen Activator (t-PA) Antigen Response
Postoperative day 2
|
16.56 ng/mL
Standard Error 1.87
|
12.49 ng/mL
Standard Error 0.93
|
12.89 ng/mL
Standard Error 1.01
|
PRIMARY outcome
Timeframe: From the start of surgery until postoperative day 2To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the fibrinolytic responses to CPB as measured by PAI-1 response
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Plasminogen Activator Inhibitor-1 (PAI-1) Response
Pre CPB
|
15.14 ng/mL
Standard Error 1.42
|
16.25 ng/mL
Standard Error 2.70
|
18.28 ng/mL
Standard Error 2.91
|
|
Plasminogen Activator Inhibitor-1 (PAI-1) Response
60min of CPB
|
20.43 ng/mL
Standard Error 1.63
|
19.41 ng/mL
Standard Error 1.98
|
24.19 ng/mL
Standard Error 3.84
|
|
Plasminogen Activator Inhibitor-1 (PAI-1) Response
Post surgery
|
39.69 ng/mL
Standard Error 3.78
|
41.62 ng/mL
Standard Error 5.89
|
49.10 ng/mL
Standard Error 7.32
|
|
Plasminogen Activator Inhibitor-1 (PAI-1) Response
Postoperative day 1
|
31.83 ng/mL
Standard Error 4.47
|
26.27 ng/mL
Standard Error 4.50
|
21.70 ng/mL
Standard Error 2.75
|
|
Plasminogen Activator Inhibitor-1 (PAI-1) Response
Postoperative day 2
|
21.59 ng/mL
Standard Error 3.77
|
17.33 ng/mL
Standard Error 3.77
|
13.4 ng/mL
Standard Error 1.55
|
PRIMARY outcome
Timeframe: From the start of surgery until postoperative day 2To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-6
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Interleukin-6 (IL-6) Response
Pre CPB
|
6.29 pg/mL
Standard Error 1.25
|
9.33 pg/mL
Standard Error 3.25
|
6.44 pg/mL
Standard Error 1.20
|
|
Interleukin-6 (IL-6) Response
Post surgery
|
116.04 pg/mL
Standard Error 28.19
|
167.51 pg/mL
Standard Error 35.64
|
144.76 pg/mL
Standard Error 29.52
|
|
Interleukin-6 (IL-6) Response
Postoperative day 1
|
224.96 pg/mL
Standard Error 63.26
|
172.65 pg/mL
Standard Error 68.93
|
218.16 pg/mL
Standard Error 68.47
|
|
Interleukin-6 (IL-6) Response
Postoperative day 2
|
166.96 pg/mL
Standard Error 28.79
|
144.67 pg/mL
Standard Error 46.41
|
243.72 pg/mL
Standard Error 117.65
|
PRIMARY outcome
Timeframe: From the start of surgery until postoperative day 2To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-8
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Interleukin-8 (IL-8) Response
Pre CPB
|
16.18 pg/mL
Standard Error 3.77
|
11.86 pg/mL
Standard Error 1.42
|
13.38 pg/mL
Standard Error 2.19
|
|
Interleukin-8 (IL-8) Response
Post surgery
|
66.44 pg/mL
Standard Error 15.06
|
80.07 pg/mL
Standard Error 20.28
|
76.76 pg/mL
Standard Error 18.90
|
|
Interleukin-8 (IL-8) Response
Postoperative day 1
|
46.18 pg/mL
Standard Error 8.90
|
37.39 pg/mL
Standard Error 6.04
|
37.11 pg/mL
Standard Error 4.44
|
|
Interleukin-8 (IL-8) Response
Postoperative day 2
|
34.39 pg/mL
Standard Error 5.55
|
28.06 pg/mL
Standard Error 5.28
|
37.77 pg/mL
Standard Error 5.43
|
PRIMARY outcome
Timeframe: From the start of surgery until postoperative day 2To 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
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Interleukin-10 (IL-10) Response
Pre CPB
|
4.45 pg/mL
Standard Error 0.47
|
5.36 pg/mL
Standard Error 0.80
|
4.21 pg/mL
Standard Error 0.61
|
|
Interleukin-10 (IL-10) Response
Post surgery
|
461.90 pg/mL
Standard Error 84.64
|
815.74 pg/mL
Standard Error 273.29
|
749.56 pg/mL
Standard Error 199.31
|
|
Interleukin-10 (IL-10) Response
Postoperative day 1
|
30.70 pg/mL
Standard Error 6.91
|
26.89 pg/mL
Standard Error 4.64
|
22.55 pg/mL
Standard Error 3.04
|
|
Interleukin-10 (IL-10) Response
Postoperative day 2
|
16.74 pg/mL
Standard Error 3.09
|
14.59 pg/mL
Standard Error 3.16
|
14.26 pg/mL
Standard Error 2.13
|
SECONDARY outcome
Timeframe: First 24 hours after arrival in the intensive care unitBlood loss over 24 hours as measured by chest tube output
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Blood Loss
|
437 mL
Standard Error 35
|
470 mL
Standard Error 59
|
511 mL
Standard Error 119
|
SECONDARY outcome
Timeframe: From arrival in intensive care unit until discharge from hospitalThe percentage of patients that were taken back to the operating room for re-exploration because of bleeding
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Re-exploration for Bleeding
|
3.6 percentage of patients
|
8.3 percentage of patients
|
4.5 percentage of patients
|
SECONDARY outcome
Timeframe: From the start of surgery until discharge from hospitalPercentage of patients that received blood product transfusion
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Blood Product Transfusion Requirement
Cryoprecipitate
|
7.1 percentage of patients
|
4.2 percentage of patients
|
4.5 percentage of patients
|
|
Blood Product Transfusion Requirement
Packed red blood cells
|
67.9 percentage of patients
|
62.5 percentage of patients
|
2.7 percentage of patients
|
|
Blood Product Transfusion Requirement
Plasma
|
60.7 percentage of patients
|
29.2 percentage of patients
|
31.8 percentage of patients
|
|
Blood Product Transfusion Requirement
Platelets
|
46.4 percentage of patients
|
29.2 percentage of patients
|
22.7 percentage of patients
|
SECONDARY outcome
Timeframe: From the end of cardiopulmonary bypass until arrival in intensive care unitOutcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Vasopressor Drug Use
Dobutamine
|
35.7 percentage of patients
|
29.2 percentage of patients
|
27.3 percentage of patients
|
|
Vasopressor Drug Use
Mlrinone
|
25.0 percentage of patients
|
25.0 percentage of patients
|
22.7 percentage of patients
|
|
Vasopressor Drug Use
Norepinephrine
|
85.7 percentage of patients
|
79.2 percentage of patients
|
95.5 percentage of patients
|
|
Vasopressor Drug Use
Epinephrine
|
7.1 percentage of patients
|
4.3 percentage of patients
|
13.6 percentage of patients
|
SECONDARY outcome
Timeframe: From arrival in intensive care unit until discharge from hospitalNew onset atrial fibrillation based on electrocardiogram (ECG) rhythm strips with a duration longer than 10 seconds
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
New Onset Atrial Fibrillation
|
17.9 percentage of patients
|
16.7 percentage of patients
|
27.3 percentage of patients
|
SECONDARY outcome
Timeframe: From the start of surgery until postoperative day 3Acute 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.
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Acute Kidney Injury
|
28.6 percentage of patients
|
23.8 percentage of patients
|
36.4 percentage of patients
|
SECONDARY outcome
Timeframe: From arrival in intensive care unit until discharge from hospitalNew onset neurological deficit with a duration of longer than 24 hours
Outcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Stroke
|
7.1 percentage of patients
|
4.2 percentage of patients
|
4.5 percentage of patients
|
SECONDARY outcome
Timeframe: From the start of surgery until discharge from hospitalOutcome measures
| Measure |
Placebo
n=28 Participants
Placebo group
|
Ramipril (ACEI)
n=24 Participants
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 Participants
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Length of Hospital Stay
|
7.7 days
Standard Error 0.5
|
6.3 days
Standard Error 0.6
|
8.1 days
Standard Error 1.0
|
Adverse Events
Placebo
Serious events: 2 serious events
Other events: 11 other events
Deaths: 0 deaths
Ramipril (ACEI)
Serious events: 1 serious events
Other events: 10 other events
Deaths: 0 deaths
Candesartan (ARB)
Serious events: 2 serious events
Other events: 12 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Placebo
n=28 participants at risk
Placebo group
|
Ramipril (ACEI)
n=24 participants at risk
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 participants at risk
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Nervous system disorders
Stroke
|
7.1%
2/28 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
4.2%
1/24 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
4.5%
1/22 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
|
General disorders
In-hospital mortality
|
0.00%
0/28 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
0.00%
0/24 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
4.5%
1/22 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
Other adverse events
| Measure |
Placebo
n=28 participants at risk
Placebo group
|
Ramipril (ACEI)
n=24 participants at risk
Angiotensin-converting enzyme group
|
Candesartan (ARB)
n=22 participants at risk
Angiotensin receptor blocker group
|
|---|---|---|---|
|
Renal and urinary disorders
Acute kidney injury
|
28.6%
8/28 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
20.8%
5/24 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
36.4%
8/22 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
|
Cardiac disorders
New onset atrial fibrillation
|
17.9%
5/28 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
16.7%
4/24 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
27.3%
6/22 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
|
General disorders
Re-exploration
|
3.6%
1/28 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
8.3%
2/24 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
4.5%
1/22 • The patients were followed from the day of surgery until discharge from hospital, an average of 8 days
|
Additional Information
Dr. Mias Pretorius
Vanderbilt University School of Medicine
Phone: 16153430665
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place