Phosphodiesterase-5 Inhibitor in Eisenmenger Syndrome

Clinical Efficacy of Phosphodiesterase-5 Inhibitor Tadalafil in Eisenmenger Syndrome - A Randomised, Placebo Controlled, Double Blind, Crossover Study

A preliminary observational study by the investigators has shown that tadalafil, a selective phosphodiesterase-5 inhibitor (PDE-5) decreases pulmonary vascular resistance(PVR) in patients of eisenmenger syndrome (ES) resulting in increase in pulmonary blood flow (Qp), systemic oxygen saturation (SaO2), functional class and exercise capacity. The aim of this placebo controlled trial was to assess the effect of the drug on exercise capacity and functional class compared to placebo.

Study Overview

• Status: Completed
• Conditions: Eisenmenger Syndrome
• Intervention / Treatment: Drug: Tadalafil, placebo

Detailed Description

Methods Patients of ES with age greater than or equal to 18 years and weight greater than or equal to 30 kgs in World Health Organisation (WHO) functional class II and III attending our congenital clinic were invited to participate in the study. Informed written consent was taken from all the patients before screening procedures were initiated for the study. A detailed clinical examination and non-invasive testing including electrocardiogram, chest X ray, pulmonary function tests (to exclude associated restrictive/obstructive lung disease) and echocardiography(including contrast echo if required for demonstrating right to left shunt) were conducted. Patients with simple congenital heart defects (atrial septal defect > 2cm, ventricular septal defect > 1cm and aortopulmonary communications > 0.4 cm) with echocardiographic evidence of right to left shunt were included. Medical therapy and clinical condition of the patients had to be stable for 3 months prior to screening. Patients on treatment with prostanoids, endothelial receptor antagonists (ERA), PDE-5 inhibitors or any other vasodilators with in 1month prior to screening were excluded. A systemic pulse oximetry (SpO2) between 70% and 90% at rest in room air and a baseline 6 minute walk test(6MWT) distance between 150 and 450 meters were required for inclusion. Eisenmenger physiology was confirmed by cardiac catheterization as mean pulmonary artery pressure > 40mmHg, pulmonary capillary wedge pressure < 15mmHg and pulmonary vascular resistance >10 wood units/m2. Oxygen study was also done in selected patients to diagnose reversible pulmonary arterial hypertension(PAH) and such patients were excluded. Patients were also excluded if they were in WHO class IV, were in congestive heart failure or had PCWP > 15mmHg,had left ventricular ejection fraction <40%, atrial fibrillation, patent ductus arteriosus, complex congenital heart defects, restrictive lung disease(total lung capacity < 70% of predicted), obstructive lung disease ( forced expiratory volume in 1 second [FEV1] < 70% of predicted with FEV1/ Forced vital capacity [FVC] < 60%), previously diagnosed coronary artery disease requiring nitrate therapy, abnormal biochemical profile and hypersensitivity to PDE- 5 inhibitors. Left and right heart catheterization was done in eligible patients as described in our preliminary observational study. Calculation of pulmonary and systemic blood flow(Qs), PVR and SVR was performed using the Ficks equation and assumed values of oxygen consumption according to age and gender of patient. The study was conducted according to the most recent amendments to the Declaration of Helsinki and in adherence to good clinical practice guidelines. The trial was approved by the National Drug Regulatory Authority (DCG) and the ethical committee of our institution.

Study design and procedure:

A double blind randomised placebo controlled crossover trial was carried out to study the efficacy and safety of oral tadalafil. Eligible patients were randomised to receive either oral tadalafil or matching placebo after baseline assessment of WHO functional class, exercise capacity by 6MWT and hemodynamic study by cardiac catheterization. Randomisation, blinding and drug/placebo administration was done by two pharmacists of the hospital. Patients received tadalafil 40mg once daily or matching placebo for 6 weeks which was followed by a 2 week washout before crossing over to the other drug for another 6 weeks. Routine medications for PAH like digoxin and diuretics was continued through out the study. Compliance was assessed by the pill count method at 3 weekly intervals. Safety of the drug or placebo was assessed by noting adverse effects, vital signs and (SaO2) by pulse oximetry at 3 week intervals. Clinical assessments (WHO functional class), 6 MWT and hemodynamic parameters by cardiac catheterization were reassessed after 6 weeks and again at the end of the study.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• India
  • New Delhi, India, 110002
    • Govind Ballabh Pant Hospital(GB Pant Hospital)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients of ES with age greater than or equal to 14 years and weight greater than or equal to 30 kgs in World Health Organisation (WHO) functional class II and III attending our congenital clinic were invited to participate in the study

Exclusion Criteria:

• WHO class IV,
• congestive heart failure or had PCWP > 15mmHg,
• left ventricular ejection fraction <40%,
• atrial fibrillation,
• patent ductus arteriosus,
• complex congenital heart defects,
• restrictive lung disease(total lung capacity < 70% of predicted), obstructive lung disease ( forced expiratory volume in 1 second [FEV1] < 70% of predicted with FEV1/ Forced vital capacity [FVC] < 60%),
• previously diagnosed coronary artery disease requiring nitrate therapy,
• abnormal biochemical profile and
• hypersensitivity to PDE- 5 inhibitors.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: placebo	Drug: Tadalafil, placebo; 20mg tablets, 2 tablets Once daily(i.e 40mg once daily) 20mg placebo 2 tablets once daily
ACTIVE_COMPARATOR: Tadalafil	Drug: Tadalafil, placebo; 20mg tablets, 2 tablets Once daily(i.e 40mg once daily) 20mg placebo 2 tablets once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary end point of efficacy was improvement in exercise tolerance as assessed by the un-encouraged 6 minute walk test (6MWT) compared to baseline after 6 weeks of treatment	6 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
The secondary endpoints were effect of the drug on systemic oxygen saturation (SaO2)	6 weeks
The secondary endpoints were effect of the drug on effective pulmonary blood flow(EPBF)	6 weeks
The secondary endpoints were effect of the drug on pulmonary vascular resistance (PVR).	6 weeks
The secondary endpoints were effect of the drug on systemic vascular resistance (SVR)	6 weeks
The secondary endpoints were effect of the drug on WHO functional class	6 weeks

Collaborators and Investigators

• Sponsor: Govind Ballabh Pant Hospital
• Investigators: Principal Investigator: Saibal Mukhopadhyay, M.D;D.M, GBPant Hospital; Study Director: Sanjay Tyagi, M.D;D.M, GBPant Hospital

Publications and helpful links

General Publications

• Mukhopadhyay S, Sharma M, Ramakrishnan S, Yusuf J, Gupta MD, Bhamri N, Trehan V, Tyagi S. Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: a preliminary observational study. Circulation. 2006 Oct 24;114(17):1807-10. doi: 10.1161/CIRCULATIONAHA.105.603001. Epub 2006 Oct 9.
• Mukhopadhyay S, Nathani S, Yusuf J, Shrimal D, Tyagi S. Clinical efficacy of phosphodiesterase-5 inhibitor tadalafil in Eisenmenger syndrome--a randomized, placebo-controlled, double-blind crossover study. Congenit Heart Dis. 2011 Sep-Oct;6(5):424-31. doi: 10.1111/j.1747-0803.2011.00561.x.

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (ACTUAL): July 1, 2010
• Study Completion (ACTUAL): July 1, 2010

Study Registration Dates

• First Submitted: September 8, 2010
• First Submitted That Met QC Criteria: September 13, 2010
• First Posted (ESTIMATE): September 14, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): September 14, 2010
• Last Update Submitted That Met QC Criteria: September 13, 2010
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Keywords: Tadalafil; phosphodiesterase-5 inhibitor; Eisenmenger syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Disease; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Syndrome; Eisenmenger Complex; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: ES/F.501(134)/EC/07/MC