Congestive Heart Failure
Conditions
Keywords
Left Ventricular Assist Device Implantation, Progressive Left Ventricular Failure
Brief summary
The purpose of this study is to assess the utility of nitric oxide for inhalation during left ventricular assist device (LVAD) implantation following cardiopulmonary bypass (CPB). This is to be assessed by the number of patients in each treatment group meeting failure criteria within 24 hours on study drug, as defined by two or more of the following: * Left ventricular flow rate index (LVFRI) ≤ 2.0 L/min/m\^2 * Administration of ≥ 20 inotropic equivalents (IE) * 10 µg/kg/min dopamine, dobutamine, enoximone or amrinone is equivalent to 10 IE * 0.1 µg/kg/min epinephrine or norepinephrine is equivalent to 10 IE * 1 µg/kg/min milrinone is equivalent to 15 IE * 0.1 U/min vasopressin is equivalent to 10 IE * Mean arterial pressure (MAP) ≤ 55 mmHg * Central venous pressure (CVP) ≥ 16 mmHg * Percent mixed venous oxygen saturation (SvO2) ≤ 55% Or at least one of the following criteria: * Failure to wean from cardiopulmonary bypass at least once due to hemodynamic failure. Re-initiation of cardiopulmonary bypass to correct bleeding or other technical issues will not be considere 'failure to wean' * Death
Detailed description
40 ppm of either nitric oxide for inhalation or N2 (placebo) will be continuously administered to the patient starting at least 5 minutes prior to initiating the first weaning attempt from CPB and continue until the patient is either extubated, has reached failure criteria, or has been treated with study drug for 48 hours following discontinuation of CPB, whichever come first. All patients will be monitored peri-operatively with a pulmonary arterial line, central venous line, and systemic arterial line. Baseline data collection by a designated clinical staff member will begin following induction of anesthesia and prior to skin incision. Following a successful wean from cardiopulmonary bypass, post-op data will be collected within 1 hour following end time of surgery. Data will then be collected at 6, 12, 18, 24, and 48 hours from post-op or until extubation, in which case weaning from study drug will begin. Open label investigational nitric oxide for inhalation may be administered once a patient meets a minimum of two of the failure criteria or fails to wean at least once due to hemodynamic failure from cardiopulmonary bypass.
Interventions
DRUGNitric Oxide
40 ppm of Nitric Oxide continuously administered for 48 hours
DRUGNitrogen
Nitrogen (N2) administered at 40 ppm for 48 hours
Sponsors
Mallinckrodt
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Scheduled to undergo their first LVAD implantation, (or at least 6 months after explanation of a previous LVAD). * Has a pulmonary vascular resistance of at least 2.5 Wood units (200 dynes/sec.) in the 30 days prior to LVAD placement. * Greater than 18 years of age. * Signed IRB approved informed consent.
Exclusion criteria
* Patients with congestive heart failure due to giant cell myocarditis or restrictive cardiomyopathy. * Elective Biventricular Assist Device (BiVAD) surgery, or current support with a temporary BiVad. * LVAD procedure expected to be done without cardiopulmonary bypass. * Pregnancy (a negative pregnancy test must be documented prior to enrollment). * Received nitric oxide by inhalation therapy within the past 24 hours. * Investigational drugs that are expected to change systemic or pulmonary vascular resistance are not allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Subjects With Left Ventricular Failure During Left Ventricular Assistance Device (LVAD) Placement After Cardio Pulmonary Bypass, as Determined by Failure Criteria, After Administration of Nitric Oxide. | 28 days | Failure criteria used to measure outcome includes: * Left ventricular flow rate index (LVFRI) ≤ 2.0 L/min/m\^2 * Administration of ≥ 20 inotropic equivalents (IE) * Mean arterial pressure (MAP) ≤ 55 mm Hg * Central venous pressure (CVP) ≥ 16 mm Hg * Percentage of mixed venous oxygen saturation (SvO2) of ≤ 55% OR failure to wean from cardio pulmonary bypass (CPB) at least once due to hemodynamic failure or death. |
Countries
Germany, United Kingdom, United States
Participant flow
Recruitment details
There were 8 study medical centers that participated and enrolled subjects; 6 centers in the United States and 2 centers in Germany. There were 150 subjects enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Nitric Oxide Inhaled Nitric Oxide (iNO) administered through the INOvent delivery system to subjects at 40 parts per million (ppm) for up to 48 hours | 73 |
| Nitrogen Nitrogen (N2) administered through the INOvent delivery system to subjects at 40 ppm for up to 48 hours. | 77 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Change in surgical plan | 2 | 6 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Subinvestigator unavailable | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Inhaled Nitric Oxide | Nitrogen | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 73 Participants | 77 Participants | 150 Participants |
| Age, Continuous | 57.6 years STANDARD_DEVIATION 9.75 | 54.0 years STANDARD_DEVIATION 11.95 | 55.8 years STANDARD_DEVIATION 11.04 |
| Region of Enrollment Germany | 35 participants | 35 participants | 70 participants |
| Region of Enrollment United States | 38 participants | 42 participants | 80 participants |
| Sex: Female, Male Female | 9 Participants | 12 Participants | 21 Participants |
| Sex: Female, Male Male | 64 Participants | 65 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 73 | 6 / 77 |
| serious Total, serious adverse events | 7 / 73 | 11 / 77 |
Outcome results
Primary
The Number of Subjects With Left Ventricular Failure During Left Ventricular Assistance Device (LVAD) Placement After Cardio Pulmonary Bypass, as Determined by Failure Criteria, After Administration of Nitric Oxide.
Failure criteria used to measure outcome includes: * Left ventricular flow rate index (LVFRI) ≤ 2.0 L/min/m\^2 * Administration of ≥ 20 inotropic equivalents (IE) * Mean arterial pressure (MAP) ≤ 55 mm Hg * Central venous pressure (CVP) ≥ 16 mm Hg * Percentage of mixed venous oxygen saturation (SvO2) of ≤ 55% OR failure to wean from cardio pulmonary bypass (CPB) at least once due to hemodynamic failure or death.
Time frame: 28 days
Population: The analysis was determined for intent-to-treat population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inhaled Nitric Oxide | The Number of Subjects With Left Ventricular Failure During Left Ventricular Assistance Device (LVAD) Placement After Cardio Pulmonary Bypass, as Determined by Failure Criteria, After Administration of Nitric Oxide. | 7 Participants |
| Nitrogen | The Number of Subjects With Left Ventricular Failure During Left Ventricular Assistance Device (LVAD) Placement After Cardio Pulmonary Bypass, as Determined by Failure Criteria, After Administration of Nitric Oxide. | 12 Participants |