Sildenafil Pulmonary Hypertension, Prospective Multi-center Clinical Studies

Part I:Sildenafil therapy for PAH patients prospective, Multi-center studyObjective: To explore the safety and efficiency of oral sildenafil therapy for PAH patients, and provide evidence for sildenafil treatment for Chinese PAH patients.Methods: In this 12-week, prospective,open-label, uncontrolled study,90 patients with PAH from 18 medical centers such as Chinese Academy of Medical Sciences Fu Wai Hospital were given oral sildenafil.The study was approved by Chinese Academy of Medical Sciences Fu Wai Hospital research ethics committee. Collecting Baseline Data including PAH diagnosis type,history(symptom,the time of major clinical symptoms,the time of foundation course, family history, history of oral appetite suppressants, history of venous thrombosis, history of varicose veins, history of oral contraceptives, history of abortion), physical examination (jugular vein engorgement, edema, ascites),Blood cell analysis (Red blood cell count, Hemoglobin, Leukocyte, Blood platelet),Coagulation analysis (INR),Biochemical examanination (transaminase, total bilirubin, urea nitrogen, creatinine),WHO PH function class,six minutes walk test distance,Borg dyspnea score,complete hemodynamic data (mean right atrial pressure,right ventricular end diastolic pressure,mean pulmonary arterial pressure,cardiac output,Cardiac index,total pulmonary resistance and pulmonary venous oxygen saturation).The primary end point was the change from baseline to 12 weeks in exercise capacity assessed by the 6-min walk (6MW) test. Secondary end point included changes in world organization (WHO) class, cardiopulmonary hemodynamic. Clinical worsening (defined as death, transplantation, hospitalization for pulmonary arterial hypertension or initiation of additional therapies for pulmonary arterial hypertension, such as intravenous epoprostenol or oral bosentan).Results: PAH patients are total 90 cases. CHDPH patients are main groups,60 (66.67%); and then IPAH patients,15 (16.67%); CTDPH patients,9 (10%); CTEPH patients 6(6.67%).60 cases CHDPH patients, ventricular septal defect(VSD) are main groups,24(40%); atrial septal defect(ASD) and patent ductus arteriosus(PDA):16 (26.67%) After 12 weeks,90 patients are all good compliance, Significant improvement was seen in NYHA heart function calss and world health organization (WHO) class than baseline (P<0.01), four cases classⅣto classⅢ, two casese to classⅡ,8 cases classⅢimprove to classⅡ,2 cases to classⅠ,15 cases classⅡto classⅠ. No NYHA heart function class and WHO PH function class deterioration cases. Oral sidenafil increased 6MW distance (mean±SE) (p<0.01),from baseline 341.85±93.16m improving to 12 weeks 403.36±87.96m; change was 61.51±79.12m, P<0.0001. Difference of Six minutes walk test distances between 12 weeks and baseline, in IPAH and CTEPH patients, the percent of change with distances of 60-90m and more than 90 m are higher; in CHDPH patients, the percent of change with distances of 0-60m are higher. Borg dyspnea score change from baseline 2.93±2.59 to 12 weeks 2.37±2.0, change was:-0.57±1.85, p=0.0046. Significant improvement was seen in hemodynamics (mean pulmonary artery pressure, p<0.01; cardiac index, p<0.01; pulmonary vascular resistance, p<.0001) at week 12 compared with baseline. Mean right atrial pressure from baseline 11.53±12.43mmHg decrease to 9.38±10.87mmHg, change was-2.05±10.98mmHg, P<0.05; mean pulmonary arterial pressure from baseline 72.74±21.33mmHg decrease to 67.14±19.43mmHg, change was-5.60±12.45mmHg, P<.0001; cardiac output from baseline 4.03±1.99L/min increase to 4.97±2.49L/min, change was 0.86±1.76L/min, P<0.0001; cardiac index from baseline 2.58±1.26 L/min/m2 increase to 3.18±1.50 L/min/m2, change was 0.56±0.99L/min/m2, P<0.0001; total pulmonary resistance decrease 415.30±724.76 Dys-s-cm-5, P<0.0001; Side effects were mild and consistent with those reported with sildenafil treatment. No statistically significant clinical worsening was observed with sildenafil therapy for PAH patients.Conclusions: Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with pulmonary arterial hypertension, sildenafil is safe and appears to be effective for the treatment of patients with pulmonary arterial hypertension.PartⅡ:Impact of Sildenafil therapy on pulmonary arterial hypertension in adults with congenital heart diseaseObjective: To explore the safety and efficiency of oral sildenafil therapy for PAH patients, and provide evidence for sildenafil treatment for Chinese PAH patients. Methods: In this 12-week, prospective, open-label, uncontrolled study,60 patients with PAH from 9 medical centers such as Chinese Academy of Medical Sciences Fu Wai Hospital were given oral sildenafil.The study was approved by Chinese Academy of Medical Sciences Fu Wai Hospital research ethics committee. Collecting Baseline Data including PAH diagnosis type, history(symptom, the time of major clinical symptoms, the time of foundation course, family history, history of oral appetite suppressants, history of venous thrombosis, history of varicose veins, history of oral contraceptives, history of abortion), physical examination (jugular vein engorgement, edema, ascites),Blood cell analysis (Red blood cell count, Hemoglobin, Leukocyte, Blood platelet), Coagulation analysis (INR), Biochemical examanination (transaminase, total bilirubin, urea nitrogen, creatinine), WHO PH function class, six minutes walk test distance, Borg dyspnea score, complete hemodynamic data (mean right atrial pressure, right ventricular end diastolic pressure, mean pulmonary arterial pressure, cardiac output, Cardiac index, total pulmonary resistance and pulmonary venous oxygen saturation). The primary end point was change from baseline to 12 weeks in exercise capacity assessed by the 6-min walk (6MW) test. Secondary end point included changes in world organization (WHO) class, cardiopulmonary hemodynamic. Clinical worsening (defined as death, transplantation, hospitalization for pulmonary arterial hypertension, or initiation of additional therapies for pulmonary arterial hypertension, such as intravenous epoprostenol or oral bosentan).Results:PAH patients are total 60 cases.60 cases CHDPH patients, ventricular septal defect (VSD) are main groups,24 (40%); atrial septal defect (ASD) and patent ductus arteriosus (PDA):16 (26.67%). After 12 weeks,60 patients are all good compliance, Significant improvement was seen in NYHA heart function calss and world health organization (WHO) class than baseline (P<0.01),2 cases class IV to class III, 3 casese to classⅡ; 6 cases class III improve to classⅡ; 6 cases to class I; 7 cases class II to class I. No NYHA heart function class and WHO PH function class deterioration cases。oral sidenafil increased 6MW distance (mean±SE) (p<0.01),from baseline 371.99±78.73m improving to 12 weeks 422.94±76.95; change was 50.94±66.86m, P<0.0001. Borg dyspnea score change from baseline 2.57±1.42 to 12 weeks 2.10±1.32, p=0.03. Significant improvement was seen in hemodynamics (mean pulmonary artery pressure, p<0.01; cardiac index, p<0.01; pulmonary vascular resistance, p<0.0001) at week 12 compared with baseline. Mean right atrial pressure from baseline 12.05±14.04mmHg decrease to 9.81±12.0 mmHg, change was-2.09±11.84mmHg, P=0.0783; mean pulmonary arterial pressure from baseline 80.19±20.76mmHg decrease to 73.77±18.24mmHg, change was-6.42±13.36mmHg, P=0.0002; cardiac output from baseline 4.38±2.18 L/min increase to 5.56±2.68L/min,change was 1.09±1.98L/min, P<0.0001; cardiac index from baseline 2.84±1.37 L/min/m2 increase to 5.56±2.68 L/min/m2,change was 0.74±1.07L/min/m2, P<0.0001; total pulmonary resistance decrease 518.29±759.05 Dys-s-cm-5, P<0.0001; Side effects were mild and consistent with those reported with sildenafil treatment. No statistically significant clinical worsening was observed with sildenafil therapy for PAH patients.Conclusions: Our study confirmed and extended previous studies, and suggested that oral sildenafil was safe and effective for the treatment of patients with CHD-related PAH in adults.PartⅢ: Single center analysis of Sildenafil therapy for PAH patients prospective studyObjective: To compare the single center and multi-center study of oral sildenafil therapy for PAH patients, and provide evidence for sildenafil treatment for PAH patients.Methods: In this 12-week, prospective, open-label, uncontrolled study,56 patients with PAH from Chinese Academy of Medical Sciences Fu Wai Hospital were given oral sildenafil. The study was approved by Chinese Academy of Medical Sciences Fu Wai Hospital research ethics committee. Collecting Baseline Data including PAH diagnosis type, history(symptom, the time of major clinical symptoms, the time of foundation course, family history, history of oral appetite suppressants, history of venous thrombosis, history of varicose veins, history of oral contraceptives, history of abortion), physical examination (jugular vein engorgement, edema, ascites),Blood cell analysis (Red blood cell count, Hemoglobin, Leukocyte, Blood platelet),Coagulation analysis (INR),Biochemical examanination (transaminase, total bilirubin, urea nitrogen, creatinine), WHO PH function class, six minutes walk test distance, Borg dyspnea score, complete hemodynamic data (mean right atrial pressure, right ventricular end diastolic pressure, mean pulmonary arterial pressure, cardiac output, Cardiac index, total pulmonary resistance and pulmonary venous oxygen saturation). The primary end point was change from baseline to 12 weeks in exercise capacity assessed by the 6-min walk (6MW) test. Secondary end point included changes in world organization (WHO) class, cardiopulmonary hemodynamic. Clinical worsening (defined as death, transplantation, hospitalization for pulmonary arterial hypertension, or initiation of additional therapies for pulmonary arterial hypertension, such as intravenous epoprostenol or oral bosentan).Results:PAH patients are total 56 cases. CHDPH patients are main groups,41 (73.2%); and then IPAH patients,9 (10.7%); CTDPH patients,4 (7.1%); CTEPH patients 2 (3.6%). After 12 weeks,56 patients are all good compliance, Significant improvement was seen in NYHA heart function calss and world health organization (WHO) class than baseline(P<0.01),2 cases class IV to class III; 8 cases class III improve to class II; 2 cases to classⅠ; 5 cases class II to class I. No NYHA heart function class and WHO PH function class deterioration cases. Oral sidenafil increased 6MW distance (mean±SE) (p<0.01),from baseline 352.2±80.0m improving to 12 weeks 396.5±78.1m; change was 44.2±70.5m, P<0.0001. Significant improvement was seen in hemodynamics (mean pulmonary artery pressure, p<0.01; cardiac index, p<0.01; pulmonary vascular resistance, p<0.0001) at week 12 compared with baseline. Mean right atrial pressure decrease 3.2±11.2mmHg, P<0.05; mean pulmonary arterial pressure decrease 6.5±14.09 mmHg, P<.0001; cardiac output increase 1.1±2.0 L/min, P<0.0001; cardiac index increase 0.7±1.1L/min/m2, P<0.0001; total pulmonary resistance decrease 489.8±831.7 Dys·s·cm-5, P<0.0001; Side effects were mild and consistent with those reported with sildenafil treatment. No statistically significant clinical worsening was observed with sildenafil therapy for PAH patients. The different point is the single center analysis shows the change of six minutes walk test distance and hemodynamics are lower than multi-center study, maybe it is associated with the dignosis type and the different baseline condition.Conclusions:Comparing the single center and multi-center study of oral sildenafil therapy for PAH patients,in both studies sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with pulmonary arterial hypertension and is safe and appears to be effective for the treatment of patients with pulmonary arterial hypertension.The different point is the single center analysis shows the change of six minutes walk test distance and hemodynamic are lower than that in multi-center study, maybe it is associated with the diagnosis type and the different baseline condition.