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=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	13 Participants n=5 Participants	11 Participants n=7 Participants	8 Participants n=5 Participants	32 Participants n=4 Participants
Age, Categorical >=65 years	15 Participants n=5 Participants	13 Participants n=7 Participants	14 Participants n=5 Participants	42 Participants n=4 Participants
Age Continuous	66.14 years STANDARD_DEVIATION 11.24 • n=5 Participants	64.38 years STANDARD_DEVIATION 10.35 • n=7 Participants	67.05 years STANDARD_DEVIATION 8.14 • n=5 Participants	65.84 years STANDARD_DEVIATION 10.03 • n=4 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	12 Participants n=7 Participants	12 Participants n=5 Participants	43 Participants n=4 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	12 Participants n=7 Participants	10 Participants n=5 Participants	31 Participants n=4 Participants
Region of Enrollment United States	28 participants n=5 Participants	24 participants n=7 Participants	22 participants n=5 Participants	74 participants n=4 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Tissue-type Plasminogen Activator (t-PA) Antigen Response Pre CPB	11.97 ng/mL Standard Error 1.03	14.36 ng/mL Standard Error 1.45	14.05 ng/mL Standard Error 1.86
Tissue-type Plasminogen Activator (t-PA) Antigen Response 60min of CPB	24.89 ng/mL Standard Error 2.96	27.65 ng/mL Standard Error 3.39	36.67 ng/mL Standard Error 7.26
Tissue-type Plasminogen Activator (t-PA) Antigen Response Post surgery	31.47 ng/mL Standard Error 2.61	34.56 ng/mL Standard Error 3.35	41.11 ng/mL Standard Error 3.37
Tissue-type Plasminogen Activator (t-PA) Antigen Response Postoperative day 1	15.75 ng/mL Standard Error 1.32	20.25 ng/mL Standard Error 2.03	17.10 ng/mL Standard Error 1.38
Tissue-type Plasminogen Activator (t-PA) Antigen Response Postoperative day 2	12.89 ng/mL Standard Error 1.01	16.56 ng/mL Standard Error 1.87	12.49 ng/mL Standard Error 0.93

PRIMARY outcome

Timeframe: 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

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Plasminogen Activator Inhibitor-1 (PAI-1) Response Pre CPB	18.28 ng/mL Standard Error 2.91	15.14 ng/mL Standard Error 1.42	16.25 ng/mL Standard Error 2.70
Plasminogen Activator Inhibitor-1 (PAI-1) Response 60min of CPB	24.19 ng/mL Standard Error 3.84	20.43 ng/mL Standard Error 1.63	19.41 ng/mL Standard Error 1.98
Plasminogen Activator Inhibitor-1 (PAI-1) Response Post surgery	49.10 ng/mL Standard Error 7.32	39.69 ng/mL Standard Error 3.78	41.62 ng/mL Standard Error 5.89
Plasminogen Activator Inhibitor-1 (PAI-1) Response Postoperative day 1	21.70 ng/mL Standard Error 2.75	31.83 ng/mL Standard Error 4.47	26.27 ng/mL Standard Error 4.50
Plasminogen Activator Inhibitor-1 (PAI-1) Response Postoperative day 2	13.4 ng/mL Standard Error 1.55	21.59 ng/mL Standard Error 3.77	17.33 ng/mL Standard Error 3.77

PRIMARY outcome

Timeframe: 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

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Interleukin-6 (IL-6) Response Pre CPB	6.44 pg/mL Standard Error 1.20	6.29 pg/mL Standard Error 1.25	9.33 pg/mL Standard Error 3.25
Interleukin-6 (IL-6) Response Post surgery	144.76 pg/mL Standard Error 29.52	116.04 pg/mL Standard Error 28.19	167.51 pg/mL Standard Error 35.64
Interleukin-6 (IL-6) Response Postoperative day 1	218.16 pg/mL Standard Error 68.47	224.96 pg/mL Standard Error 63.26	172.65 pg/mL Standard Error 68.93
Interleukin-6 (IL-6) Response Postoperative day 2	243.72 pg/mL Standard Error 117.65	166.96 pg/mL Standard Error 28.79	144.67 pg/mL Standard Error 46.41

PRIMARY outcome

Timeframe: 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

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Interleukin-8 (IL-8) Response Pre CPB	13.38 pg/mL Standard Error 2.19	16.18 pg/mL Standard Error 3.77	11.86 pg/mL Standard Error 1.42
Interleukin-8 (IL-8) Response Post surgery	76.76 pg/mL Standard Error 18.90	66.44 pg/mL Standard Error 15.06	80.07 pg/mL Standard Error 20.28
Interleukin-8 (IL-8) Response Postoperative day 1	37.11 pg/mL Standard Error 4.44	46.18 pg/mL Standard Error 8.90	37.39 pg/mL Standard Error 6.04
Interleukin-8 (IL-8) Response Postoperative day 2	37.77 pg/mL Standard Error 5.43	34.39 pg/mL Standard Error 5.55	28.06 pg/mL Standard Error 5.28

PRIMARY outcome

Timeframe: 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

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Interleukin-10 (IL-10) Response Pre CPB	4.21 pg/mL Standard Error 0.61	4.45 pg/mL Standard Error 0.47	5.36 pg/mL Standard Error 0.80
Interleukin-10 (IL-10) Response Post surgery	749.56 pg/mL Standard Error 199.31	461.90 pg/mL Standard Error 84.64	815.74 pg/mL Standard Error 273.29
Interleukin-10 (IL-10) Response Postoperative day 1	22.55 pg/mL Standard Error 3.04	30.70 pg/mL Standard Error 6.91	26.89 pg/mL Standard Error 4.64
Interleukin-10 (IL-10) Response Postoperative day 2	14.26 pg/mL Standard Error 2.13	16.74 pg/mL Standard Error 3.09	14.59 pg/mL Standard Error 3.16

SECONDARY outcome

Timeframe: First 24 hours after arrival in the intensive care unit

Blood loss over 24 hours as measured by chest tube output

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Blood Loss	511 mL Standard Error 119	437 mL Standard Error 35	470 mL Standard Error 59

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Re-exploration for Bleeding	4.5 percentage of patients	3.6 percentage of patients	8.3 percentage of patients

SECONDARY outcome

Timeframe: From the start of surgery until discharge from hospital

Percentage of patients that received blood product transfusion

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Blood Product Transfusion Requirement Packed red blood cells	2.7 percentage of patients	67.9 percentage of patients	62.5 percentage of patients
Blood Product Transfusion Requirement Plasma	31.8 percentage of patients	60.7 percentage of patients	29.2 percentage of patients
Blood Product Transfusion Requirement Platelets	22.7 percentage of patients	46.4 percentage of patients	29.2 percentage of patients
Blood Product Transfusion Requirement Cryoprecipitate	4.5 percentage of patients	7.1 percentage of patients	4.2 percentage of patients

SECONDARY outcome

Timeframe: From the end of cardiopulmonary bypass until arrival in intensive care unit

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Vasopressor Drug Use Mlrinone	22.7 percentage of patients	25.0 percentage of patients	25.0 percentage of patients
Vasopressor Drug Use Dobutamine	27.3 percentage of patients	35.7 percentage of patients	29.2 percentage of patients
Vasopressor Drug Use Norepinephrine	95.5 percentage of patients	85.7 percentage of patients	79.2 percentage of patients
Vasopressor Drug Use Epinephrine	13.6 percentage of patients	7.1 percentage of patients	4.3 percentage of patients

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
New Onset Atrial Fibrillation	27.3 percentage of patients	17.9 percentage of patients	16.7 percentage of patients

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Acute Kidney Injury	36.4 percentage of patients	28.6 percentage of patients	23.8 percentage of patients

SECONDARY outcome

Timeframe: From arrival in intensive care unit until discharge from hospital

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

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Stroke	4.5 percentage of patients	7.1 percentage of patients	4.2 percentage of patients

SECONDARY outcome

Timeframe: From the start of surgery until discharge from hospital

Outcome measures

Measure	Candesartan (ARB) n=22 Participants Patients are randomized to Candesartan 16mg/d (ARB) prior to surgery.	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
Length of Hospital Stay	8.1 days Standard Error 1.0	7.7 days Standard Error 0.5	6.3 days Standard Error 0.6

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: mias.pretorius@vanderbilt.edu

Results disclosure agreements

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