Coronary Artery Disease, Coronary Disease, Heart Diseases, Myocardial Ischemia, Valvular Heart Disease
Conditions
Keywords
Physiological Effects of Drugs, Cardiovascular Agents, Therapeutic Uses, Pharmacologic Actions, Mannitol, Cardiac Surgery, Cardioplegic Solutions, HTK solution, Myocardial protection, Coronary Artery Disease, Myocardial Ischemia, Coronary Disease, Heart Diseases
Brief summary
The purpose of the study is to demonstrate that Custodiol-HTK is not inferior to cold cardioplegic solution in patients undergoing cardiovascular surgery requiring cardioplegic arrest.
Detailed description
The objective of this study is to demonstrate that Custodiol is not inferior to cold cardioplegic solution for myocardial protection by comparing standard cold blood cardioplegia to Custodiol solution with respect to myocardial injury as measured by Creatine phosphokinase MB isoenzyme (CK-MB),troponin-I at 7 hours post surgery and changes in ejection fraction by trans-thoracic echocardiogram (TTE)or trans-esophageal echocardiogram (TEE) at 24 hours post surgery.
Interventions
DRUGCustodiol HTK
After cross-clamping of the aorta approximately 1-2 L of Custodiol-HTK was infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml were administered as needed. The cardioplegic solution was delivered at a temperature of 4°C - 10°C.
After cross-clamping the aorta, at least 1000 mL of a 4:1 mixture of cold blood: cold crystalloid was administered at a pressure of 300 mmHg or less via a twin roller pump. Every 20 minutes an additional \> 200 mL was administered in an antegrade/retrograde fashion throughout the remainder of the case. The cardioplegic solution was delivered at a temperature of 4°C - 8°C.
Sponsors
Essential Pharmaceuticals, LLC
Marc Sakwa, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients undergoing scheduled cardiac surgery requiring cardioplegic arrest with expected cross clamp time\>45 minutes * Patients age 18 and older
Exclusion criteria
* Pregnant women\* * Urgent or emergent cases * Repeat cardiovascular surgical procedures * Patients on dialysis * Any known allergies to components of either cardioplegia solution \*All women of child bearing potential must have a negative serum or urine pregnancy test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB) | Baseline and 7 hours post surgery | Creatine phosphokinase MB isoenzyme (CK-MB) difference from baseline 7 hours post surgery |
| Change in Troponin I | Baseline and 7 hours post surgery | Troponin I values, difference from baseline 7 hours post surgery |
| Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE) | Baseline and 24 hours post surgery | LV ejection fraction by TTE, difference from baseline at 24 hours post surgery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time on Mechanically Assisted Ventilation | up to 36 hours post procedure | time in hours from intubation to extubation, with intervening transport to the cardiac critical care unit. |
| Duration of Vasopressor / Inotropic Agent | up to 36 hours post procedure | Total time in minutes on any vasopressor or inotropic agent, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine |
| Postoperative Inotropic Infusion >20 Minutes | during operative procedure | Number of patients receiving vasopressor or inotropic infusion for greater than 20 minutes in the operating room, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine. |
| Cardiac Dysrhythmias | up to 36 hrs post surgery | Number of participants with new or worsening of cardiac dysrhythmias |
| Myocardial Infarction | up to 36 hours post procedure | Number or participants fulfilling at least two of the following 3 criteria: (1) CK-MB of 100 ug/L or more and/or troponin-I of 3.0 ug/L or more, (2) appearance of new postoperative Q waves on the EKG of more than 0.03 seconds, and (3) a new hypokinetic or akinetic area in the left or right ventricle by echocardiography. |
| Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | pre-operative | CK-MB measured pre-operatively |
| Cardiac Marker - Troponin-I | pre-operatively | Troponin-I measured pre-operatively |
| Intensive Care Unit (ICU) Length of Stay | up to 100 days after admission | Duration of stay in ICU, from ICU admission to ICU discharge |
| All Cause Mortality | 30 days post procedure | Number of participants with all-cause mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative |
| Cardiovascular Mortality | 30 days post procedure | Number of participants with cardiovascular-related mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Cold Blood Cardioplegia 55 participants were randomized to Standard cold blood cardioplegia. Cold Blood Cardioplegia: One liter of cold blood cardioplegic solution, mixed at a ratio of 4:1 per Beaumont standard of care (blood /cardioplegic solution), contains the following in a 500 cc bag of D5W (dextrose 5% in water): 50meq/L potassium chloride, 37.5 meq/L sodium bicarbonate and 7.5 meq/L magnesium sulfate.
After cross-clamping the aorta, at least 1000 mL of a 4:1 mixture of cold blood: cold crystalloid was administered at a pressure of 300 mmHg or less via a twin roller pump. Every 20 minutes an additional \> 200 mL was administered as needed. The cardioplegic solution was delivered at a temperature of 4°C - 8°C. | 55 |
| Custiodiol HTK 55 participants were randomized to Custodiol HTK. Custodiol HTK (histidine-tryptophan-ketoglutarate) cardioplegia: One liter of HTK solution (Custodiol; Koehler Chemi, Alsbach-Haenlien, Germany) contains the following components: 15 mmol/L sodium chloride, 9 mmol/L potassium chloride, 4 mmol/L magnesium chloride, 18 mmol/L histidine hydrochloride, 180 mmol/L histidine, 2 mmol/L tryptophan, 30 mmol/L mannitol, 0.015 mmol/L calcium chloride, 1 mmol/L potassium hydrogen 2-ketoglutarate, osmolarity 310 mOsm/kg, pH 7.02-7.20.
Custodiol-HTK was delivered to establish and maintain cardiac arrest. After cross-clamping of the aorta approximately 1-2 L of Custodiol-HTK was infused into the ascending aorta over 6-8 minutes. Additional doses of 100-200 ml were administered as needed. Custodiol-HTK was delivered at a temperature of 4°C - 10°C. | 55 |
| Total | 110 |
Baseline characteristics
| Characteristic | Custiodiol HTK | Standard Cold Blood Cardioplegia | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 32 Participants | 32 Participants | 64 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 23 Participants | 46 Participants |
| Age, Continuous | 63 years STANDARD_DEVIATION 13 | 70 years STANDARD_DEVIATION 11 | 66 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 55 participants | 55 participants | 110 participants |
| Sex: Female, Male Female | 26 Participants | 20 Participants | 46 Participants |
| Sex: Female, Male Male | 29 Participants | 35 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 55 | 34 / 55 |
| serious Total, serious adverse events | 3 / 55 | 9 / 55 |
Outcome results
Primary
Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB)
Creatine phosphokinase MB isoenzyme (CK-MB) difference from baseline 7 hours post surgery
Time frame: Baseline and 7 hours post surgery
Population: Patients for which both baseline and 7 hours post surgery values were available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB) | 18.8 ng/mL |
| Cold Blood Cardioplegia | Change in Creatine Phosphokinase-MB Isoenzyme (CK-MB) | 22.2 ng/mL |
Primary
Change in Troponin I
Troponin I values, difference from baseline 7 hours post surgery
Time frame: Baseline and 7 hours post surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Change in Troponin I | 9.65 ng/mL |
| Cold Blood Cardioplegia | Change in Troponin I | 10.15 ng/mL |
Primary
Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE)
LV ejection fraction by TTE, difference from baseline at 24 hours post surgery
Time frame: Baseline and 24 hours post surgery
Population: patients for whom both preoperative and 24 hour LV ejection fractions were obtained
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE) | -0.06 % LV volume | Standard Deviation 11 |
| Cold Blood Cardioplegia | Changes in Left Ventricular (LV) Ejection Fraction (EF) by Transthoracic Echocardiogram (TTE) | 1.9 % LV volume | Standard Deviation 10 |
Secondary
All Cause Mortality
Number of participants with all-cause mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative
Time frame: 30 days post procedure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | All Cause Mortality | 0 participants |
| Cold Blood Cardioplegia | All Cause Mortality | 0 participants |
Secondary
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
CK-MB measured 24 hours post-operatively
Time frame: 24 hours post procedure
Population: Only patients for whom 24 hour CK-MB values were available were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | 20 ng/mL | Standard Deviation 14 |
| Cold Blood Cardioplegia | Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | 24 ng/mL | Standard Deviation 25 |
Secondary
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
CK-MB measured pre-operatively
Time frame: pre-operative
Population: Only patients for whom preoperative CK-MB levels were available were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | 1.9 ng/mL | Standard Deviation 1.2 |
| Cold Blood Cardioplegia | Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | 2.6 ng/mL | Standard Deviation 2 |
Secondary
Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB)
CK-MB measured 48 hours post-operatively
Time frame: 48 hours post procedure
Population: Only patients for whom 48 hour CK-MB values are available are included in analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | 6.0 ng/mL | Standard Deviation 5.1 |
| Cold Blood Cardioplegia | Biochemical Marker - Creatine Kinase MB Isoenzyme (CK-MB) | 7.8 ng/mL | Standard Deviation 7 |
Secondary
Cardiac Dysrhythmias
Number of participants with new or worsening of cardiac dysrhythmias
Time frame: up to 36 hrs post surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Cardiac Dysrhythmias | 24 participants |
| Cold Blood Cardioplegia | Cardiac Dysrhythmias | 30 participants |
Secondary
Cardiac Marker - Troponin-I
Troponin-I measured 48 hours post-operative
Time frame: 48 hours post procedure
Population: Only patients for whom 48-hour Troponin-I values were available were included in analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Cardiac Marker - Troponin-I | 3.0 ng/mL | Standard Deviation 3.3 |
| Cold Blood Cardioplegia | Cardiac Marker - Troponin-I | 4.8 ng/mL | Standard Deviation 6.5 |
Secondary
Cardiac Marker - Troponin-I
Troponin-I measured pre-operatively
Time frame: pre-operatively
Population: Only patients for whom preoperative Troponin-I values were available were included in analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Cardiac Marker - Troponin-I | .03 ng/mL | Standard Deviation 0.01 |
| Cold Blood Cardioplegia | Cardiac Marker - Troponin-I | .03 ng/mL | Standard Deviation 0.01 |
Secondary
Cardiac Marker - Troponin-I
Troponin-I measured 24 hours post-operative
Time frame: 24 hours post procedure
Population: Only patients for whom 24-hour Troponin-I values were available were included in analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Cardiac Marker - Troponin-I | 5.7 ng/mL | Standard Deviation 5.4 |
| Cold Blood Cardioplegia | Cardiac Marker - Troponin-I | 7.8 ng/mL | Standard Deviation 8.1 |
Secondary
Cardiovascular Mortality
Number of participants with cardiovascular-related mortality AS reported in the Society of Thoracic Surgeons (STS) database after 30 days postoperative
Time frame: 30 days post procedure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Cardiovascular Mortality | 0 participants |
| Cold Blood Cardioplegia | Cardiovascular Mortality | 0 participants |
Secondary
Duration of Vasopressor / Inotropic Agent
Total time in minutes on any vasopressor or inotropic agent, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine
Time frame: up to 36 hours post procedure
Population: Patients not receiving any vasopressors are excluded from this analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Duration of Vasopressor / Inotropic Agent | 340 minutes |
| Cold Blood Cardioplegia | Duration of Vasopressor / Inotropic Agent | 582 minutes |
Secondary
Intensive Care Unit (ICU) Length of Stay
Duration of stay in ICU, from ICU admission to ICU discharge
Time frame: up to 100 days after admission
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Intensive Care Unit (ICU) Length of Stay | 3 days |
| Cold Blood Cardioplegia | Intensive Care Unit (ICU) Length of Stay | 3 days |
Secondary
Myocardial Infarction
Number or participants fulfilling at least two of the following 3 criteria: (1) CK-MB of 100 ug/L or more and/or troponin-I of 3.0 ug/L or more, (2) appearance of new postoperative Q waves on the EKG of more than 0.03 seconds, and (3) a new hypokinetic or akinetic area in the left or right ventricle by echocardiography.
Time frame: up to 36 hours post procedure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Myocardial Infarction | 0 participants |
| Cold Blood Cardioplegia | Myocardial Infarction | 0 participants |
Secondary
Postoperative Inotropic Infusion >20 Minutes
Number of patients receiving vasopressor or inotropic infusion for greater than 20 minutes in the operating room, including norepinephrine, epinephrine, vasopressin, milrinone, dobutamine, dopamine and/or neo-synephrine.
Time frame: during operative procedure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Postoperative Inotropic Infusion >20 Minutes | 47 participants |
| Cold Blood Cardioplegia | Postoperative Inotropic Infusion >20 Minutes | 43 participants |
Secondary
Time on Mechanically Assisted Ventilation
time in hours from intubation to extubation, with intervening transport to the cardiac critical care unit.
Time frame: up to 36 hours post procedure
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cardioplegia: Custodiol HTK Solution | Time on Mechanically Assisted Ventilation | 10.5 hours |
| Cold Blood Cardioplegia | Time on Mechanically Assisted Ventilation | 11.4 hours |