PAHTCH Pulmonary Arterial Hypertension Treatment With Carvedilol for Heart Failure (Carvedilol)

Pulmonary Hypertension Clinical Trial

— PAHTCH  

Official title:

Pulmonary Arterial Hypertension Treatment With Carvedilol for Heart Failure

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01586156
• Other study ID #: 11-1198
• Secondary ID: R01HL115008
• Status: Completed
• Phase: N/A
• Start date: December 2012
• Est. completion date: July 2016

Study information

• Verified date: November 2018
• Source: The Cleveland Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature leading to elevated pulmonary pressure and right ventricular (RV) dysfunction with heart failure. Measures of RV function are better predictors of mortality and long term outcomes than pulmonary vascular resistance. The interaction between RV function and the pulmonary circulation is not fully understood, but increased after load appears insufficient to explain right heart failure. Yet, all approved PAH therapies target vasodilation of the pulmonary vasculature to lower pressures

Description:

Pulmonary arterial hypertension (PAH) is a serious condition characterized by endothelial dysfunction leading to pulmonary vascular constriction, smooth muscle and endothelial proliferation, and progressive right-sided heart failure. The severity of pulmonary hypertension is mostly determined by the response of the right ventricle (RV) to the increased afterload or pulmonary pressures, and RV failure is the leading cause of death in PAH. Most accepted therapies for PAH have been aimed at vasodilation of the pulmonary vasculature, and there has been little thought that PAH patients would benefit from traditional left heart failure treatments. A cornerstone therapy in left heart failure is £]-adrenergic receptor blockade because of its ability to reverse cardiac remodeling and improve clinical outcomes, despite decades of concern regarding its propensity to exacerbate heart failure. It has been reported to reduce mortality by about 30% in patients, and while the precise mechanisms that contribute to its beneficial effects remain to be elucidated, there is evidence that patients with underlying contractile reserve (i.e., via recruitment of viable myocardium with £]-adrenergic receptor stimulation) may experience greater recovery of their cardiac function. In a study using rats with pulmonary hypertension treated with £] blocker, RV function improved, and maladaptive myocardial remodeling was prevented.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Men and women age 18 or older not greater than age 65 years

• Diagnosis of pulmonary arterial hypertension class 1, 3, 4, 5 (Dana Point 2008)

• NYHA (New York Health Association)/WHO (World Health Organization) Class I-III

• PAH medications must have been initiated according to the latest consensus statement recommendations and remained stable for the last 30 days

• Women of child-bearing age must use a double-barrier local contraception till completion of the study

• Subjects must demonstrate understanding of the study, sign the informed consent, and have a reliable method of communication for contact and ability to comply with the study requirements

Exclusion Criteria:

• Participation in any other treatment studies during enrollment

• Significant illness in the past 30 days requiring hospitalization

• Hepatic insufficiency (transaminase levels > 4 fold the upper limit of normal or bilirubin > 2 fold the upper limit of normal),

• History of HIV, Hepatitis B or C

• Serum creatinine > 2.8 mg/dl

• Pregnancy, breast-feeding, or lack of safe contraception

• Acute decompensated heart failure within past 30 days

• Known allergy or intolerance to carvedilol or other ß blockers

• Significant, persistent bradycardia (resting heart rate < 50 bpm) or hypotension (systolic blood pressure < 100 mmHg or mean blood pressure < 70 mmHg) at the time of enrollment

• Second or third-degree AV (Atrial Ventricular) block without pacemaker

• Use of CYP2D6 isoenzyme inhibitors (such as quinidine, fluoxetine, paroxetine, propafenone) which increase drug levels and result in greater vasodilating effects and hypotension

• Use of hypotensive drugs that deplete catecholamines (such as reserpine and monoamine oxidase inhibitors) which may lead to greater signs of hypotension or bradycardia

• Other medical and psychosocial conditions as determined by principal investigator deemed unsuitable for enrollment

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Heart Failure
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Carvedilol
Group 1 will receive 3.125mg carvedilol twice daily for six months.Group 2 will receive carvedilol in a dose escalation scheme.
• placebo
Placebo will be taken twice daily for 6 months

Locations

Country	Name	City	State
United States	Cleveland Clinic	Cleveland	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
The Cleveland Clinic	National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Farha S, Saygin D, Park MM, Cheong HI, Asosingh K, Comhair SA, Stephens OR, Roach EC, Sharp J, Highland KB, DiFilippo FP, Neumann DR, Tang WHW, Erzurum SC. Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlle — View Citation

Park JH, Park MM, Farha S, Sharp J, Lundgrin E, Comhair S, Tang WH, Erzurum SC, Thomas JD. Impaired Global Right Ventricular Longitudinal Strain Predicts Long-Term Adverse Outcomes in Patients with Pulmonary Arterial Hypertension. J Cardiovasc Ultrasound. — View Citation

Saygin D, Highland KB, Farha S, Park M, Sharp J, Roach EC, Tang WHW, Thomas JD, Erzurum SC, Neumann DR, DiFilippo FP. Metabolic and Functional Evaluation of the Heart and Lungs in Pulmonary Hypertension by Gated 2-[18F]-Fluoro-2-deoxy-D-glucose Positron E — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Echocardiogram Right Ventricular Systolic Pressure (RVSP)	We hypothesized that RVSP might decrease in participants on carvedilol.	6 months
Other	6 Minute Walk Test	We hypothesized that carvedilol would not worsen 6 minute walk distance.	6 months
Other	NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide)	We hypothesized that carvedilol would be safe and tolerable and thus that NT-BNP, a measure of heart failure, would not increase in participants on carvedilol.	6 months
Other	Echocardiogram Left Ventricular Cardiac Output	We hypothesized that carvedilol would be safe and tolerable and thus that Left ventricular cardiac output, a measure of heart function, would not decrease in participants on carvedilol.	6 months
Primary	Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography)	We hypothesize that use of carvedilol in patients with PAH (Pulmonary Arterial Hypertension) will decrease the cardiac glucose utilization, and this will be measurable as a drop in fasting FDG-PET standardized uptake values of the heart at 6 months as compared to baseline	6 months
Secondary	Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine	We hypothesize that use of carvedilol in patients with PAH will increase beta adrenergic receptor function and this will be measurable as an increase in cAMP measured in the urine at 6 months in participants in dose escalation carvedilol.	6 months
Secondary	Beta-Adrenergic Receptor (Alprenolol Binding Assay)	We hypothesize that use of carvedilol in patients with PAH will increase beta- adrenergic receptor availability, and this will be measurable as a increase in alprenolol binding over time of drug use.	6 months