Spironolactone Combined With Captopril and Carvedilol for the Treatment of Pulmonary Arterial Hypertension

Official Title: Spironolactone Combined With Captopril and Carvedilol for the Treatment of Patients With Pulmonary Arterial Hypertension Associated With Congenital Heart Disease-Focus on Pulmonary Artery Remodeling

The purpose of this study is to determine whether a larger dose of the aldosterone antagonist spironolactone combined with an ACE inhibitor (captopril) and a beta-blocker (carvedilol) is effective in reverse pulmonary artery remodeling in patients with pulmonary arterial hypertension (PAH)secondary to congenital heart disease

Study Overview

• Status: Completed
• Conditions: Hypertension, Pulmonary
• Intervention / Treatment: Drug: spironolactone captopril carvedilol

Detailed Description

The pathogenesis of PAH involves multiple mechanisms. However, three common factors are thought to cause the increased pulmonary vascular resistance that characterizes this devastating disease: vasoconstriction, pulmonary vascular proliferation and remodeling, and thrombosis in situ. Advances in our knowledge of the molecular mechanisms involved in PAH suggest that endothelial dysfunction with chronic impaired production of vasoactive mediators plays a key role. Reduced production of vasoactive mediators, such as nitric oxide (NO) and prostacyclin, along with prolonged overexpression of vasoconstrictors such as endothelin-1 (ET-1), not only affect vascular tone but also promote vascular remodeling. Thus, these substances represent logical pharmacological targets. Animal studies showed ET-1 could stimulate aldosterone secretion in different species, both in vivo and in vitro. This stimulation involves the ET-B alone and both ET-A and ET-B receptor subtypes in rats and humans. Animal studies also showed spironolactone combined with ACE inhibitor could normalize blood pressure, prevents upregulation of vascular ET-1, restore nitric oxide (NO)-mediated endothelial dysfunction. Beta-blockers have ability to reduce dp/dt in pulmonary artery, as well as left ventricle, thus prevent further damage to the dysfunctional endothelium. Furthermore, we observed from our practice that the aforementioned therapy could lower pulmonary artery pressure in patents with pulmonary hypertension secondary to left ventricular dysfunction. Thus, we hypothesize spironolactone combined with ACE inhibitor and beta-blocker has the ability to reverse remodeling of pulmonary artery in PAH patients.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Hebei
    • Shijiazhuang, Hebei, China, 050031
      • The First Hospital of Hebei Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• A mean pulmonary artery pressure higher than 25 mm Hg or, when estimated by echocardiography, pulmonary artery pressure more than half the systemic artery pressure
• Congenital systemic-to-pulmonary shunts

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Dyspnoea score
Exercise capacity (six-minute walk)
NYHA/WHO functional class
Change of acropachy
Blood gas test
Pulmonary artery pressure (measured by echocardiogram or catheter)

Secondary Outcome Measures

Outcome Measure
Blood gas test
Other echocardiographic changes:
Systolic pulmonary arterial pressure
Change of right to left shunt expressed by time-velocity integral (TVI) from the defect
Change of left to right shunt expressed by TVI from the defect
Right ventricular (RV) acceleration time (ms)
RV ejection time (ms)
Ratio of RV ejection time/RV acceleration time
Pulmonary arterial valve TVI
Change of diameters of both left and right ventricles
Change of diameters of both left and right atrium
Doppler mitral valve (MV) TVI

Collaborators and Investigators

• Sponsor: Hebei Medical University
• Investigators: Study Chair: Kunshen Liu, M.D., The First Hospital of Hebei Medical University

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Study Completion: May 1, 2006

Study Registration Dates

• First Submitted: October 17, 2005
• First Submitted That Met QC Criteria: October 17, 2005
• First Posted (Estimate): October 18, 2005

Study Record Updates

• Last Update Posted (Estimate): June 30, 2008
• Last Update Submitted That Met QC Criteria: June 27, 2008
• Last Verified: October 1, 2005

More Information

Terms related to this study

• Keywords: aldosterone antagonists, spironolactone, captopril carvedilol
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Protective Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Angiotensin-Converting Enzyme Inhibitors; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Spironolactone; Carvedilol; Captopril
• Other Study ID Numbers: 0510-A