Pulmonary Hypertension
Conditions
Keywords
pulmonary hypertension, vasodilator challenge, echocardiography, outcomes, iloprost, inhaled nitric oxide
Brief summary
This study will compare the clinical efficacy of inhaled iloprost as an invasive, selective vasodilator in the cardiac catheterization laboratory in patients with pulmonary hypertension to the gold standard of inhaled nitric oxide. It will also examine whether echocardiographic estimates of response to inhaled iloprost can predict responsiveness to invasive vasodilator testing in patients with pulmonary hypertension.
Detailed description
Iloprost was the first inhaled prostacyclin analogue to be FDA-approved for the treatment of pulmonary arterial hypertension. Iloprost aerosol has been shown to significantly improve pulmonary hemodynamics in patients with idiopathic pulmonary hypertension (PH), with an effect greater than nitric oxide and sildenafil. It has also been shown to be more effective than nitric oxide at reducing pulmonary arterial pressure (PAP) than prostacyclin infusion when used in the cardiac catheterization laboratory. Because of its administration through inhalational means, iloprost has the advantage of selective action on the pulmonary vasculature with avoidance of the systemic side effects that plague many of the other treatments for PH. The investigators intend to compare the efficacy of inhaled iloprost in reducing pulmonary artery pressure to the gold standard of nitric oxide in patients with pulmonary hypertension. Without an established noninvasive algorithm to identify beneficial hemodynamic response to vasodilators, patients with pulmonary hypertension (PH) are routinely subjected to expensive and invasive testing. Echocardiography is routinely used to facilitate a diagnosis of PH and a few echocardiographically-derived estimates have even been shown to correlate with vasodilator responsiveness and survival. Dynamic, real time changes in echocardiographic parameters have not been previously evaluated as a predictor of vasodilator responsiveness or of clinical outcome. The investigators will examine whether echocardiographic changes in response to inhaled iloprost can predict invasively derived vasodilator responsiveness and help assess prognosis in patients with pulmonary hypertension, possibly even obviating the need for invasive testing.
Interventions
DRUGIloprost and nitric oxide administration
Iloprost will be administered by the I-neb ultrasonic nebulizer (Respironics, Cedar Grove, New Jersey) with a disposable attachment that allows for administration to a supine patient at a concentration of 10 µg/ml with a 10 minute dose of 2.5 µg and then repeated to a cumulative dose of 5.0 µg if tolerated.
Sponsors
Actelion
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients no younger than 18 years of age * Recently diagnosed pulmonary hypertension (defined by RV systolic pressure of ≥ 40 mmHg as measured by echocardiography), going for invasive hemodynamic assessment for pulmonary hypertension * Normal left ventricular function defined as a left ventricular ejection fraction (LVEF) greater than or equal to 50%
Exclusion criteria
* Heart failure (LVEF \< 50%, diastolic dysfunction \> stage 1, history or symptoms of left heart failure) - Group II pulmonary hypertension * 2+ or higher MR or AI * Inadequate echocardiographic windows * Pregnancy * Systolic blood pressure ≤ 90 mmHg
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Invasively Measured Pulmonary Artery Pressures After Challenge With iNO (Inhaled Nitrous Oxide) and Iloprost | Baseline and approximately 30 minutes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Systolic Pulmonary Arterial Pressure After Vasodilator Challenge | Baseline and during vasodilator inhalation, approximately 30 minutes | — |
| Number of Participants Who Respond After Vasodilator Challenge | Baseline and during vasodilator inhalation, approximately 30 minutes | Dichotomize the vasodilator response into responders and nonresponders, based on a 10 mmHg drop in PA pressure and a mean pressure \<40mmHg determined invasively. Receiver operating characteristic (ROC) curves will evaluate the echocardiographic parameters for prediction of vasodilator response. |
| Number of Participants With Clinical Response to Vasodilator Challenge by Echo | Baseline, approximately 30 minutes, 3 months, and 12 months | Measure the clinical response to vasodilator challenge during echocardiography, by tracking the changes of echo parameters (such as RVSP) before and after iloprost challenge, as well as through the 3 and 12 month follow-up visits. |
| Association of Change in Pressures After Vasodilator Challenge With Clinical Outcomes | 3 months and 12 months | Observe the association of the percent change of echocardiographically estimated pressures after iloprost challenge with mid-term clinical outcomes (all cause mortality and all cause mortality +/- hospitalization). These data will be collected at 3 months and at 12 months. Data from all hospitalizations will be collected though we will make special note of those related to pulmonary hypertension. |
Countries
United States
Participant flow
Recruitment details
Patients were identified from pulmonary hypertension clinic as well as those referred to the catheterization lab for their initial diagnostic right heart catheterization for evaluation of pulmonary hypertension.
Participants by arm
| Arm | Count |
|---|---|
| Nitric Oxide and Iloprost Administration Each patient will receive 40 ppm inhaled nitric oxide and 2.5-5 mcg inhaled iloprost in the catheterization laboratory with assessment of hemodynamic response. Patients will also receive 2.5-5 mcg iloprost during echocardiographic assessment.
Iloprost and nitric oxide administration: Iloprost will be administered by the I-neb ultrasonic nebulizer (Respironics, Cedar Grove, New Jersey) with a disposable attachment that allows for administration to a supine patient at a concentration of 10 µg/ml with a 10 minute dose of 2.5 µg and then repeated to a cumulative dose of 5.0 µg if tolerated. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Connector tubing not available | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Nitric Oxide and Iloprost Administration |
|---|---|
| Age, Continuous | 54.9 years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 23 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 27 |
| other Total, other adverse events | 0 / 27 |
| serious Total, serious adverse events | 0 / 27 |
Outcome results
Primary
Change in Invasively Measured Pulmonary Artery Pressures After Challenge With iNO (Inhaled Nitrous Oxide) and Iloprost
Time frame: Baseline and approximately 30 minutes
Population: Participants who completed the study. Each participant was analyzed after challenge with iNO and after challenge with iloprost.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide | Change in Invasively Measured Pulmonary Artery Pressures After Challenge With iNO (Inhaled Nitrous Oxide) and Iloprost | 10.7 percent change | Standard Deviation 7.1 |
| Iloprost | Change in Invasively Measured Pulmonary Artery Pressures After Challenge With iNO (Inhaled Nitrous Oxide) and Iloprost | 13.3 percent change | Standard Deviation 12.5 |
Comparison: Null hypothesis: inhalation with iNO (the gold standard) would provide greater response than the comparator (iloprost).p-value: 0.148t-test, 2 sided
Secondary
Association of Change in Pressures After Vasodilator Challenge With Clinical Outcomes
Observe the association of the percent change of echocardiographically estimated pressures after iloprost challenge with mid-term clinical outcomes (all cause mortality and all cause mortality +/- hospitalization). These data will be collected at 3 months and at 12 months. Data from all hospitalizations will be collected though we will make special note of those related to pulmonary hypertension.
Time frame: 3 months and 12 months
Population: 0 participants had a change of echocardiographically estimated pressures, as indicated in outcome #4
Secondary
Number of Participants Who Respond After Vasodilator Challenge
Dichotomize the vasodilator response into responders and nonresponders, based on a 10 mmHg drop in PA pressure and a mean pressure \<40mmHg determined invasively. Receiver operating characteristic (ROC) curves will evaluate the echocardiographic parameters for prediction of vasodilator response.
Time frame: Baseline and during vasodilator inhalation, approximately 30 minutes
Population: Participants who completed the study. Each participant was analyzed after challenge with iNO and after challenge with iloprost.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide | Number of Participants Who Respond After Vasodilator Challenge | 1 Participants |
| Iloprost | Number of Participants Who Respond After Vasodilator Challenge | 4 Participants |
Comparison: Null hypothesis was that fewer patients receiving iloprost (new agent) would respond compared to iNO (the gold standard).p-value: 0.346Fisher Exact
Secondary
Number of Participants With Clinical Response to Vasodilator Challenge by Echo
Measure the clinical response to vasodilator challenge during echocardiography, by tracking the changes of echo parameters (such as RVSP) before and after iloprost challenge, as well as through the 3 and 12 month follow-up visits.
Time frame: Baseline, approximately 30 minutes, 3 months, and 12 months
Population: Participants who completed the study. Two patients refused to undergo echocardiography and repeat inhalation of iloprost.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inhaled Nitric Oxide | Number of Participants With Clinical Response to Vasodilator Challenge by Echo | Baseline | 0 Participants |
| Inhaled Nitric Oxide | Number of Participants With Clinical Response to Vasodilator Challenge by Echo | 30 minutes | 0 Participants |
| Inhaled Nitric Oxide | Number of Participants With Clinical Response to Vasodilator Challenge by Echo | 3 months | 0 Participants |
| Inhaled Nitric Oxide | Number of Participants With Clinical Response to Vasodilator Challenge by Echo | 12 months | 0 Participants |
Secondary
Percent Change in Systolic Pulmonary Arterial Pressure After Vasodilator Challenge
Time frame: Baseline and during vasodilator inhalation, approximately 30 minutes
Population: Participants who completed the study. Two patients refused to undergo echocardiography and repeat inhalation of iloprost.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide | Percent Change in Systolic Pulmonary Arterial Pressure After Vasodilator Challenge | 0 percentage of change | Standard Deviation 0 |