Drug Therapy and Surgery in Congenital Heart Disease With Pulmonary Hypertension

Combined Clinical and Surgical Approaches to Congenital Heart Disease Associated With Pulmonary Arterial Hypertension (PAH-CHD)

The purpose of this study is to test the hypothesis that treating PAH-CHD patients preoperatively with PAH drugs and keeping them on treatment for six months after surgery reduces the risk of immediate postoperative death and the risk of residual PAH at six months following operation to <10%.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension; Congenital Heart Disease
• Intervention / Treatment: Drug: Sildenafil singly or in association with Bosentan

Detailed Description

Pulmonary arterial hypertension (PAH) is a complicating factor in the management of congenital heart disease (CHD) with intracardiac or extracardiac communications. In children with moderate to severe PAH, the risk of serious complications following the surgical repair of shunts (including right cardiac failure and death) is 15-20% or even higher, and the risk of late, postoperative residual PAH is ~25%. We therefore intend to conduct a study aimed at reducing the risk of severe immediate postoperative complications and the risk of residual PAH at six months following surgery to less than 10% in children with moderate PAH (primary objective). The study is also aimed at promoting a statistically significant reduction in pulmonary artery pressure and pulmonary vascular resistance at six month after surgery, compared with baseline in children with moderate or severe PAH (secondary objective). We hypothesized that these goals could be achieved by treating patients preoperatively and for six months postoperatively with sildenafil, either singly or combined with bosentan. Both drugs have been approved for treatment of PAH on the basis of randomized clinical trials. Preoperative and postoperative (on treatment) hemodynamic evaluation will be based on noninvasive and invasive diagnostic procedures. As an additional objective, we intend to analyze possible abnormalities in genes that have been shown to be associated with PAH-CHD, and inflammatory mediators as well. The idea is to investigate whether changes in these markers correlate with the clinical profile and response to treatments.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 05403-900
    • Instituto do Coração (InCor) HCFMUSP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Potentially operable patients with congenital cardiac septal defects (bi-ventricular physiology) and PAH, must have at least three of the following severity criteria: age > 18 months; absence of congestive heart failure (pulmonary congestion); Down syndrome; bidirectional shunting across the septal defect; periods of systemic (peripheral) oxygen saturation < 90%.

Exclusion Criteria:

• Patients with complex cardiac anomalies for whom there are no possibilities of complete repair. Patients with uni-ventricular physiology.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Single-arm study; Preoperatively, sildenafil until development of pulmonary congestion (1-4 weeks). On treatment pulmonary congestion (dyspnea and need for increasing diuretics) occurs when there is a substantial decrease in pulmonary vascular resistance, which may be confirmed noninvasively by Doppler-echocardiography. At that moment, patient will be assigned to surgery. If pulmonary congestion is not observed, bosentan will be added on top of sildenafil, and the patient will be kept on treatment for 10-12 months. In this case, a new cardiac catheterization will be performed before surgery. In both cases (short-term and medium-term treatment) patients will be kept on treatment for six months following surgery, and then re-catheterized.

Drug: Sildenafil singly or in association with Bosentan; Sildenafil, 1-4 mg/Kg/day (6-hour intervals) preoperatively, until development of pulmonary congestion (generally 1-4 weeks) or preoperatively, for 10-12 months, in association with bosentan (15.6-62.5 mg b.i.d.) if pulmonary congestion does not develop. Surgery will be performed at 1-4 weeks (short-term treatment) or at 10-12 months (medium-term treatment) if operability criteria are met (catheterization). In both cases (short and medium-term treatments), the drug or drugs will be kept for 6 months postoperatively, when final catheterization will be performed for efficacy testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immediate postoperative right cardiac failure and mortality, and prevalence of residual PAH six months after surgery.	Drug treatment must reduce the prevalence of immediate postoperative right cardiac failure / death to <10%, and the prevalence of residual PAH six months after cardiac surgery to <10%. Residual PAH is defined as an elevation of mean pulmonary artery pressure above 25 mmHg, and elevation of pulmonary vascular resistance above 3.0 Wood units x squared meters (body surface area).	Six months following surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary vascular resistance six months after surgical repair of congenital cardiac shunts with PAH	Drug treatment before surgery and maintained for six months following repair of congenital cardiac shunts must promote a statistically significant reduction in pulmonary vascular resistance (at six months) compared with baseline (preoperative) level.	Six months following surgery

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo; Instituto do Coracao
• Investigators: Principal Investigator: Antonio Augusto Lopes, M.D., Instituto do Coração (InCor) - HCFMUSP - São Paulo - Brazil

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): March 1, 2020

Study Registration Dates

• First Submitted: March 5, 2012
• First Submitted That Met QC Criteria: March 5, 2012
• First Posted (Estimate): March 8, 2012

Study Record Updates

• Last Update Posted (Actual): March 30, 2020
• Last Update Submitted That Met QC Criteria: March 26, 2020
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Bosentan; Pulmonary arterial hypertension; Sildenafil; Congenital heart disease; Pediatric cardiac surgery
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Hypertension, Pulmonary; Cardiovascular Abnormalities; Heart Diseases; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Endothelin Receptor Antagonists; Sildenafil Citrate; Bosentan
• Other Study ID Numbers: CAPPesq 0502/11