Pulmonary Arterial Hypertension
Conditions
Brief summary
The purpose of this study is to determine whether carvedilol treatment of patients with pulmonary arterial hypertension and associated right heart failure is safe and results in an improved function of the right heart.
Detailed description
Patients with pulmonary arterial hypertension (PAH) will be treated with carvedilol for 24 weeks. During this time, carvedilol will be titrated from an initial dose of 3.125mg BID to a maximal dose of 25mg BID. At the start and end of the study, we will obtain cardiac MRI, 6 minute walk distance, brain natriuretic peptide (serum), echocardiogram, and functional class assessment. Our primary outcome is a change in right ventricular ejection fraction with cardiac MRI.
Interventions
DRUGCarvedilol
twice daily oral treatment in escalating dose
Sponsors
GlaxoSmithKline
Virginia Commonwealth University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* idiopathic, familial or associated PAH, WHO group 1 * NYHA class II or III * clinically stable with optimized PAH treatment for at least 3 months * no or minimal evidence of fluid overload or volume depletion, with or without diuretic treatment * age \> 18 years * mean pulmonary artery pressure (mPAP) \> 25 mmHg * 6 minute walk distance (6MWD) over 100m
Exclusion criteria
* Structural heart disease unrelated to PAH * Recent (\<3 months) treatment with an intravenous positive inotropic agent * current use of β-blockers * history of reactive airways disease * history of adverse reaction to β-blockers * heart block on ECG or resting heart rate \< 60 bpm * cardiac index \< 1.8 l/min/m2 * systemic hypotension (systolic pressure \< 90 mmHg) * pulmonary capillary wedge pressure \> 15 mmHg * inability to give informed consent * contraindications to CT and/or PET scanning * coagulopathy (INR\>1.5 or platelet count\<50000/mm3) * severe renal insufficiency (creatinine clearance \<30 ml/min/m2) * malignancy or any co-morbidity limiting survival or conditions predicting inability to complete the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Right Ventricular Ejection Fraction | baseline, 6 months | Change in right ventricular ejection fraction is measured by cardiac magnetic resonance imaging, using the method of disks with the reading radiologist being blinded to before and after images. Cardiac magnetic resonance imaging was done at baseline and 6 months only |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Right Ventricular End Systolic Volume | baseline and 6 months | right ventricular end systolic volume determined by MRI |
| Change in 6 Minute Walk Distance | baseline and 6 months | — |
| Change in Tricuspid Annular Plane Systolic Excursion | baseline and 6 months | Higher values indicate a better outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carvedilol Carvedilol is titrated from a dose of 3.125mg twice daily to a maximal dose of 25mg twice daily over 24 weeks. Patients are evaluated to their response with 6 minute walk testing, echocardiography, and cardiac MRI
Carvedilol: twice daily oral treatment in escalating dose | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 4 |
Baseline characteristics
| Characteristic | Carvedilol |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 60.6 years |
| Region of Enrollment United States | 6 participants |
| Right ventricular ejection fraction of blood | 38 % of ejected ventricular vol of blood |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 Participants |
| Six minute walk distance | 321 meters |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Absolute Change in Right Ventricular Ejection Fraction
Change in right ventricular ejection fraction is measured by cardiac magnetic resonance imaging, using the method of disks with the reading radiologist being blinded to before and after images. Cardiac magnetic resonance imaging was done at baseline and 6 months only
Time frame: baseline, 6 months
Population: Patients with right heart catheterization confirmed pulmonary arterial hypertension, already on pulmonary vasodilator therapy
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Carvedilol | Absolute Change in Right Ventricular Ejection Fraction | 10.4 % RVEF |
p-value: 0.028ANOVA
Secondary
Change in 6 Minute Walk Distance
Time frame: baseline and 6 months
Population: The patient who was excluded from analysis developed an orthopedic injury during the study and was unable to complete the walking test at conclusion of the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carvedilol | Change in 6 Minute Walk Distance | Participant 1 | 45 feet |
| Carvedilol | Change in 6 Minute Walk Distance | Participant 2 | 160 feet |
| Carvedilol | Change in 6 Minute Walk Distance | Participant 3 | 35 feet |
| Carvedilol | Change in 6 Minute Walk Distance | Participant 5 | 5 feet |
| Carvedilol | Change in 6 Minute Walk Distance | Participant 6 | 96 feet |
p-value: >0.05ANOVA
Secondary
Change in Right Ventricular End Systolic Volume
right ventricular end systolic volume determined by MRI
Time frame: baseline and 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carvedilol | Change in Right Ventricular End Systolic Volume | Participant 1 | 3 mL |
| Carvedilol | Change in Right Ventricular End Systolic Volume | Participant 2 | 14 mL |
| Carvedilol | Change in Right Ventricular End Systolic Volume | Participant 3 | 56 mL |
| Carvedilol | Change in Right Ventricular End Systolic Volume | Participant 4 | 11 mL |
| Carvedilol | Change in Right Ventricular End Systolic Volume | Participant 5 | 27 mL |
| Carvedilol | Change in Right Ventricular End Systolic Volume | Participant 6 | 25 mL |
p-value: 0.028ANOVA
Secondary
Change in Tricuspid Annular Plane Systolic Excursion
Higher values indicate a better outcome.
Time frame: baseline and 6 months
Population: The patient excluded from the analysis was unable to be present for the final echo-cardiogram due to lack of transportation and distance from the hospital. Multiple attempts to schedule the study test were made through phone and email.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carvedilol | Change in Tricuspid Annular Plane Systolic Excursion | Participant 1 | 0.4 centimeters |
| Carvedilol | Change in Tricuspid Annular Plane Systolic Excursion | Participant 2 | -0.08 centimeters |
| Carvedilol | Change in Tricuspid Annular Plane Systolic Excursion | Participant 4 | -0.12 centimeters |
| Carvedilol | Change in Tricuspid Annular Plane Systolic Excursion | Participant 5 | 0.45 centimeters |
| Carvedilol | Change in Tricuspid Annular Plane Systolic Excursion | Participant 6 | 0.08 centimeters |
p-value: >0.05ANOVA