Therapeutic Efficacy And Clinical Analysis Of Bosentan In The Treatment Of Idiopathic Pulmonary Arterial Hypertension And Congenital Heart Disease Associated With Pulmonary Arterial Hypertension

Part 1:Therapeutic efficacy and clinical analysis of Bosentan in the treatment of idiopathic pulmonary arterial hypertension and congenital heart disease associated with pulmonary arterial hypertensionBackgroundPulmonary arterial hypertension (PAH) is a relatively rare disease involved with the pulmonary arterioles injury. The pathological mechanisms are increased pulmonary vascular resistance and compensatory increased pulmonary artery pressure, leading to heart failure, low blood pressure or sudden death.Bosentan is the first synthesized oral endothelin receptor antagonist. Several foreign clinical studies of bosentan had confirmed that it could raise the exercise endurance of IPAH, CTD-PAH (connective tissue diseases related to pulmonary hypertension), Eisenmenger physiology, CTEPH (chronic thromboembolic pulmonary hypertension), improve heart function classification of WHO, delay the time to clinical deterioration and improve survival rate and so on. But there were rare reports focused on the quality of life (QoL). It was reported that congenital heart disease associated with pulmonary hypertension (CHD-PAH) and idiopathic pulmonary arterial hypertension (IPAH) had similarities in the pathological mechanism-endothelial dysfunction, which had been correlated with disease severity and prognosis. The aim of this study was to observe the efficacy and safety of bosentan in the treatment of patients with idiopathic pulmonary hypertension and congenital heart disease associated with pulmonary hypertension, especially involving evaluation of the quality of life (QoL).Objective1.To analyze the clinical features in patients with moderate to severe pulmonary hypertension; and to evaluate whether differences exist between CHD-PAH and IPAH two subgroups.2. To evaluate the efficacy and safety of bosentan as first-line therapy for IPAH and CHD-PAH by a prospective short-term follow-up; and to discuss the clinical benefit.3. To evaluate the improvement of quality of life on CHD-PAH and IPAH patients.Methods1. This study was a single-center, prospective observational study.40 cases of severe patients diagnosed with IPAH or CHD-PAH in Zhongshan Hospital, Department of cardiology were enrolled from May 2012 to May 2013 (32 males and 8 females). Bosentan was prescribed in addition to common therapy.2. All patients admitted to hospital were evaluated 6MWD, Borg dyspnea index, the WHO heart function grade, Doppler echocardiography, blood related inspection check and right cardiac catheterization (RHC), and the baseline characteristics were collected. Patients were informed to finish 1 month and 3 months follow-up in outpatient. Adverse drug reactions and processing conditions were observed.1) Primary endpoints:6 minutes walking distance (6MWD), WHO heart function, quality of life questionnaire (SF-36 QoL).2) Secondary endpoints:Borg dyspnea index, echocardiographic index (SPAP, LVEF), clinical deterioration (including death, heart and lung transplantation, hospitalization).3. Patients’ database was established by ACCESS, summing up all the diagnosis and medication informations of patients with pulmonary hypertension. All statistical analyses were performed by SPSS16.0 software. Measurement data were expressed as mean±S.D. Qualitative data were analyzed by chi-square test. Continuous variable data between the two groups were compared using independent sample t test or Wilcoxon rank sum test. Paired t-test was used to compare the differences before and after treatment. Pearson or spearman analysis was used for correlation analysis. P<0.05 is statistical significance, P<0.01 for a quite statistical significance.ResultsThe results of the study were divided in three parts:1. Results suggested that bosentan may significantly lower the systolic pulmonary artery pressure, improve exercise capacity, cardiac function and ease the dyspnea, chest pain and other symptoms for moderate to severe CHD-PAH and IPAH patients whose WHO heart function classifications were Ⅱ～Ⅳ grade after short term treatment.1.1 Patients’ exercise capacity and WHO heart function were improved after bosentan treatment. Statistically significant differences were found on the 6MWD from (351.9± 70.9) m to (393.1±63.4) m (P<0.01) after 1 month and increased to (425.6±68.9) m (P<0.01) after 3 months. Borg dyspnea index was 3.39±1.25 before treatment,2.56± 0.83 after 1 month, and 1.92±0.81 after 3 months(P<0.01).10 patients remained the original WHO heart function grade.26 (65%) patients lowered I level,17 of which changed from Ⅲ to Ⅱ,9 of which changed from Ⅱ to 1.4 (10%) patients lowered Ⅱ levels.1.2 The influence on Doppler echocardiography after 3 months’ bosentan treatment. No change in heart function and left ventricular ejection fraction (LVEF) of patients were observed, while the left atrial diameter (mm) increased slightly, from 34.2±7.1 mm to 35.7±5.9 mm,95% CI was (3.02,0.00) with significant difference (P<0.05). In subgroup analyses, CHD-PAH group’s left atrial diameter changed from 34.75±6.83 mm to 36.95±6.70 mm (P<0.05), while IPAH group’s changed from 33.08±8.12 mm to 33.85±4.71 mm (P>0.05). Systolic pulmonary artery pressure (SPAP) measured by echocardiographic significantly improved from 110.6±24.1mmHg to 99.5±26.3 mmHg (P=0.011) after 3 months, and only IPAH group had significant difference (P< 0.05). After treatment, the ratio for pericardial effusion fell from 37.5% to 20.0%.2. After 3 months’ treatment, both CHD-PAH and IPAH group showed significant improvement for seven out of eight SF-36 domains with good safety and tolerance.2.1 After 3 months’ treatment, the patients’ quality of life had improved significantly. We evaluated the QoL from eight domains, including physiological functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health; all domains were improved significantly except the social functioning (P <0.01). It was the same for CHD-PAH and IPAH two subgroups’ analyses(P<0.01). It could be referred from relatively improved QoL change rate that physiological functioning, general health and self-evaluation 3 domains were improved significantly, 130%,82% and 51% respectively.2.2 Two groups of patients were not found serious adverse events during treatment. Only 1 (2.5%) female patient with CHD-PAH occured transaminase lifts; 2 cases were found eleations edema (5.0%, each 1 case for CHD-PAH and IPAH group).3. Results of correlation analysis show the relevance of SPAP determined by echocardiography and main parameters of right heart catheterization. Several domains of QoL showed correlation with 6MWD.ConclusionBosentan may significantly lower the systolic pulmonary artery pressure, improve WHO heart function and exercise capacity for CHD-PAH and IPAH patients whose WHO heart function classifications are Ⅱ～Ⅳ grade after 3 months’ treatment; 7 out of eight SF-36 domains were improved after treatment; no serious adverse event was observed during treatment.Part 2:Clinical Characteristics and Therapeutic Drug Analysis of Congenital Heart Disease Associated with Pulmonary Arterial HypertensionObjectiveTo investigate the correlation between clinical characteristics and therapeutic drug of congenital heart disease associated pulmonary arterial hypertension (CHD-PAH) in our hospital.MethodsThe clinical data and treatment of 98 patients with CHD-PAH were retrospectively analyzed in the department of cardiology in our hospital from 2009.1 to 2011.12 according to the 2009 European guidelines for pulmonary arterial hypertension.Results59 cases out of 98 were given endothelin receptor antagonist.14 cases were given phosphodiesterase type 5 inhibitors.11 cases were given the inhaled iloprost.7 cases were given endothelin receptor antagonist combined with phosphodiesterase type 5 inhibitors and 7 cases were given inhaled iloprost combined with phosphodiesterase type 5 inhibitors. The percentage of using phosphodiesterase type 5 inhibitors in patients with WHO heart function level Ⅱ (33.3%) was significantly higher than patients with level Ⅲ(7.4%). All kinds of specific pulmonary drug distributed equally in diverse subgroups of pulmonary vascular resistance and pulmonary artery systolic pressure with no statistically significant differences.ConclusionThere is relationship between selecting specific pulmonary treatment and cardiac function level for patients with CHD-PAH, however, no correlation are found between drug treatment and pulmonary vascular resistance or pulmonary artery systolic pressure.