西地那非治疗肺动脉高压前瞻性多中心临床研究
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摘要
本研究为国家十一五科技支撑计划重大项目课题“提高肺动脉高压诊治水平研究”(项目编号：2006BAI01A07,资金来源：国家科技部)的子课题,包括三部分内容：①西地那非治疗肺动脉高压前瞻性多中心临床研究,②西地那非治疗先天性心脏病相关性肺动脉高压前瞻性多中心临床研究,③西地那非治疗肺动脉高压前瞻性多中心临床研究单中心数据分析。
第一部分：西地那非治疗肺动脉高压前瞻性多中心临床研究
目的：通过多中心临床研究探讨西地那非治疗中国肺动脉高压患者的临床疗效及耐受性,为西地那非治疗中国肺动脉高压患者提供循证医学证据。
方法：连续入选2007年5月-2009年4月中国医学科学院阜外心血管病医院等18个中心收治的肺动脉高压患者90例,研究经中国医学科学院阜外心血管病医院临床医学(／药物实验)伦理委员会审核通过。给予西地那非25mg一日三次口服,记录基线资料包括肺动脉高压诊断类型,病史(症状,主要临床症状出现的时间,基础病程时间,家族史,口服减肥药史,静脉血栓病史、静脉曲张史,口服避孕药史,流产史,)体格检查(颈静脉怒张,水肿,腹水),血常规(红细胞计数,血红蛋白,白细胞,血小板,)、凝血分析(INR)、生化指标(转氨酶,总胆红素,尿素氮,肌酐),WHO肺动脉高压功能分级,6分钟步行距离测试,Borg呼吸困难评分,完整的血流动力学资料(平均右房压、右室舒张末压、平均肺动脉压、心输出量、心指数、全肺阻力和肺静脉血氧饱和度)。观察治疗12周后患者NYHA心功能分级、WHO肺动脉高压功能分级、六分钟步行距离、Borg呼吸困难指数、血流动力学指标的变化以及临床恶化情况。同时观察患者血球分析及血生化指标及不良反应。
结果：肺动脉高压共90例；研究对象中,CHDPH为主要人群,60(66.67%)；其次为IPAH,比例为15(16.67%)；CTDPH为9(10%)；CTEPH为6(6.67%)。60例先心病相关性肺动脉高压中,以室间隔缺损(VSD)为主,24(40%)；房间隔缺损(ASD)和动脉导管未闭(PDA)均为：16(26.67%)。12周时,90例患者服药依从性好,均完成口服12周西地那非25mg一日三次。治疗12周后,患者NYHA心功能分级,WHO肺动脉高压功能分级较基线明显改善(P<0.01),其中4例Ⅳ级升高至Ⅲ级,2例升高到Ⅱ级；8例Ⅲ级升高为Ⅱ级,2例升高至工级；15例Ⅱ级升高至Ⅰ级。无NYHA心功能分级及WHO肺动脉高压功能分级恶化病例。治疗12周后六分钟步行距离较前明显增加,由基线341.85±93.16m增加至403.36±87.96m；差值61.51±79.12m,P<0.0001。12周与基线步行距离差值分段比较,IPAH及CTEPH中,60-90m及以上者比例较大；CHDPH中0-60m比例较大。Borg呼吸困难指数由基线2.93±2.59降低到2.37±2.0,差值为：-0.57±1.85,p=0.0046。右室舒张末压由基线11.53±12.43mmHg降低到9.38±10.87mmHg,差值为一2.05±10.98mmHg,P<0.05；肺动脉平均压由基线72.74±21.33mmHg降低到67.14±19.43mmHg,差值为-5.60±12.45mmHg,P<0.0001；心输出量由基线4.03±1.99L／min增加到4.97±2.49L／min,差值为0.86±1.76L／min,P<0.0001；心指数由基线2.58±1.26 L／min／m2增加到3.18±1.50 L／min／m2,差值为0.56±0.99L／min／ms,,P<0.0001；全肺阻力降低415.30±724.76 Dys.s.cm-5,P<0.0001；差异均有统计学意义。患者无临床恶化情况。患者耐受良好,无严重不良事件。
结论：西地那非治疗可显著改善肺动脉高压患者功能分级,活动耐力及血流动力学。西地那非治疗中国肺动脉高压患者是安全有效的,为西地那非治疗中国肺动脉高压患者提供了循证医学证据。
第二部分：西地那非治疗先天性心脏病相关性肺动脉高压前瞻性多中心临床研究
目的：探讨西地那非治疗先天性心脏病相关性肺动脉高压患者的临床疗效及耐受性,为西地那非治疗先天性心脏病相关性肺动脉高压患者提供循证医学证据。
方法：连续入选2007年5月-2009年4月中国医学科学院阜外心血管病医院等9个中心收治的肺动脉高压患者60例,研究经中国医学科学院阜外心血管病医院临床医学(／药物实验)伦理委员会审核通过。给予西地那非25mg一日三次口服,记录基线资料包括肺动脉高压诊断类型,病史(症状,主要临床症状出现的时间,基础病程时间,家族史,口服减肥药史,静脉血栓病史、静脉曲张史,口服避孕药史,流产史,)体格检查(颈静脉怒张,水肿,腹水),血常规(红细胞计数,血红蛋白,白细胞,血小板,)、凝血分析(INR)、生化指标(转氨酶,总胆红素,尿素氮,肌酐),WHO肺动脉高压功能分级,6分钟步行距离测试,Borg呼吸困难评分,完整的血流动力学资料(平均右房压、右室舒张末压、平均肺动脉压、心输出量、心指数、全肺阻力和肺静脉血氧饱和度)。观察治疗12周后患者NYHA心功能分级、WHO肺动脉高压功能分级、六分钟步行距离、Borg呼吸困难指数、血流动力学指标的变化以及临床恶化情况。同时观察患者血球分析及血生化指标及不良反应。
结果：治疗12周后,患者NYHA心功能分级,WHO肺动脉高压功能分级较基线明显改善(P<0.01),其中2例Ⅳ级升高至Ⅲ级,3例Ⅲ级升高为Ⅱ级,6例升高至Ⅰ级；7例Ⅱ级升高至Ⅰ级。无NYHA心功能分级及WHO肺动脉高压功能分级恶化病例。治疗12周后六分钟步行距离较前明显增加,由基线371.99±78.73m增加至12周422.94±76.9；差值50.94±66.86m,P<0.0001。Borg呼吸困难指数由基线2.57±1.42降低到2.10±1.32,p=0.03。右室舒张末压由基线12.05±14.04mmHg降低到9.81±12.0mmHg,差值为-2.09±11.84mmHg,P=0.0783；肺动脉平均压由基线80.19±20.76mmHg降低到73.77±18.24mmHg,差值为-6.42±13.36mmHg,P=0.0002；心输出量由基线4.38±2.18L／min增加到5.56±2.68L／min,差值为1.09±1.98L／min,P<0.0001；心指数由基线2.84±1.37L／min／m2增加到3.62±1.57L／min／m2,差值为0.74±1.07,P<0.0001；全肺阻力降低518.29±759.05Dys.s.cm-5,P<0.0001；差异均有统计学意义。患者无临床恶化情况。患者耐受良好,无严重不良事件。
结论：西地那非治疗可显著改善先心病相关性肺动脉高压患者功能分级,活动耐力及血流动力学。西地那非治疗先心病相关性肺动脉高压患者是安全有效的,为西地那非治疗先心病相关性肺动脉高压患者提供了循证医学证据,做了有益的探索尝试。
第三部分：西地那非治疗肺动脉高压前瞻性多中心临床研究单中心数据分析
目的：通过对多中心临床研究和单中心数据的比较分析,探讨西地那非治疗中国肺动脉高压患者多中心与单中心的异同点,为西地那非治疗中国肺动脉高压患者提供循证医学证据。
方法：连续入选2007年5月-2009年4月阜外心血管病医院收治的肺动脉高压患者56例,研究经中国医学科学院阜外心血管病医院临床医学(／药物实验)伦理委员会审核通过。给予西地那非25mg一日三次口服,记录基线资料包括肺动脉高压诊断类型,病史(症状,主要临床症状出现的时间,基础病程时间,家族史,口服减肥药史,静脉血栓病史、静脉曲张史,口服避孕药史,流产史,)体格检查(颈静脉怒张,水肿,腹水),血常规(红细胞计数,血红蛋白,白细胞,血小板,)、凝血分析(INR)、生化指标(转氨酶,总胆红素,尿素氮,肌酐),WHO肺动脉高压功能分级,6分钟步行距离测试,Borg呼吸困难评分,完整的血流动力学资料(平均右房压、右室舒张末压、平均肺动脉压、心输出量、心指数、全肺阻力和肺静脉血氧饱和度)。观察治疗12周后患者NYHA心功能分级、WHO肺动脉高压功能分级、六分钟步行距离、Borg呼吸困难指数、血流动力学指标的变化以及临床恶化情况。同时观察患者血球分析及血生化指标及不良反应。
结果：先天性心脏病相关性肺动脉高压为41(73.2%)；其次为特发病肺动脉高压,9(10.7%)；结缔组织相关性肺动脉高压为4(7.1%)；慢性血栓栓塞性肺动脉高压为2(3.6%)。12周时,56例患者服药依从性好,均完成口服12周西地那非25mg一日三次。治疗12周后,患者NYHA心功能分级,WHO肺动脉高压功能分级较基线明显改善(P<0.01),其中2例Ⅳ级升高至Ⅲ级；8例Ⅲ级改善为Ⅱ级,2例升高至Ⅰ级；5例Ⅱ级升高至Ⅰ级。无NYHA心功能分级及WHO肺动脉高压功能分级恶化病例。治疗12周后患者六分钟步行距离较前明显增加,由基线352.2±80.0m增加至396.5±78.1m；差值44.2±70.5m,差异有显著性,P<0.0001；右室舒张末压降低3.2±11.2mmHg,P<0.05；肺动脉平均压降低6.5±14.09mmHg,P<0.001；心输出量增加1.1±2.0 L／min,P<0.0001；心指数增加0.7±1.1L／min／m2,P<0.0001；全肺阻力降低489.8±831.7 Dys.s.cm-5,P<0.0001；差异均有统计学意义。患者无临床恶化情况。患者耐受良好,无严重不良事件。与多中心临床研究比较基线六分钟步行距离偏高,治疗12周后六分钟步行距离变化小于多中心研究,治疗12周心输出量改变0.86±1.76L／min,心指数基线差值为0.56±0.99L／min／m2；全肺阻力降低415.30±724.76 Dys.s.cm-5,与多中心研究比较,各指标改善趋势一致,但改善程度不同,差异无统计学意义。可能与纳入患者诊断类型比例不同及基线情况不同有关。
结论：本研究通过对多中心临床研究和单中心数据的分析比较,显示单中心数据分析中主要观察终点和次要观察终点的改善趋势与多中心研究一致,但六分钟步行及血流动力学指标的差异无显著性。
Part I:Sildenafil therapy for PAH patients prospective, Multi-center study
Objective: 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 disease
Objective: 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 study
Objective: 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.
第一部分：西地那非治疗肺动脉高压前瞻性多中心临床研究
目的：通过多中心临床研究探讨西地那非治疗中国肺动脉高压患者的临床疗效及耐受性,为西地那非治疗中国肺动脉高压患者提供循证医学证据。
方法：连续入选2007年5月-2009年4月中国医学科学院阜外心血管病医院等18个中心收治的肺动脉高压患者90例,研究经中国医学科学院阜外心血管病医院临床医学(／药物实验)伦理委员会审核通过。给予西地那非25mg一日三次口服,记录基线资料包括肺动脉高压诊断类型,病史(症状,主要临床症状出现的时间,基础病程时间,家族史,口服减肥药史,静脉血栓病史、静脉曲张史,口服避孕药史,流产史,)体格检查(颈静脉怒张,水肿,腹水),血常规(红细胞计数,血红蛋白,白细胞,血小板,)、凝血分析(INR)、生化指标(转氨酶,总胆红素,尿素氮,肌酐),WHO肺动脉高压功能分级,6分钟步行距离测试,Borg呼吸困难评分,完整的血流动力学资料(平均右房压、右室舒张末压、平均肺动脉压、心输出量、心指数、全肺阻力和肺静脉血氧饱和度)。观察治疗12周后患者NYHA心功能分级、WHO肺动脉高压功能分级、六分钟步行距离、Borg呼吸困难指数、血流动力学指标的变化以及临床恶化情况。同时观察患者血球分析及血生化指标及不良反应。
结果：肺动脉高压共90例；研究对象中,CHDPH为主要人群,60(66.67%)；其次为IPAH,比例为15(16.67%)；CTDPH为9(10%)；CTEPH为6(6.67%)。60例先心病相关性肺动脉高压中,以室间隔缺损(VSD)为主,24(40%)；房间隔缺损(ASD)和动脉导管未闭(PDA)均为：16(26.67%)。12周时,90例患者服药依从性好,均完成口服12周西地那非25mg一日三次。治疗12周后,患者NYHA心功能分级,WHO肺动脉高压功能分级较基线明显改善(P<0.01),其中4例Ⅳ级升高至Ⅲ级,2例升高到Ⅱ级；8例Ⅲ级升高为Ⅱ级,2例升高至工级；15例Ⅱ级升高至Ⅰ级。无NYHA心功能分级及WHO肺动脉高压功能分级恶化病例。治疗12周后六分钟步行距离较前明显增加,由基线341.85±93.16m增加至403.36±87.96m；差值61.51±79.12m,P<0.0001。12周与基线步行距离差值分段比较,IPAH及CTEPH中,60-90m及以上者比例较大；CHDPH中0-60m比例较大。Borg呼吸困难指数由基线2.93±2.59降低到2.37±2.0,差值为：-0.57±1.85,p=0.0046。右室舒张末压由基线11.53±12.43mmHg降低到9.38±10.87mmHg,差值为一2.05±10.98mmHg,P<0.05；肺动脉平均压由基线72.74±21.33mmHg降低到67.14±19.43mmHg,差值为-5.60±12.45mmHg,P<0.0001；心输出量由基线4.03±1.99L／min增加到4.97±2.49L／min,差值为0.86±1.76L／min,P<0.0001；心指数由基线2.58±1.26 L／min／m2增加到3.18±1.50 L／min／m2,差值为0.56±0.99L／min／ms,,P<0.0001；全肺阻力降低415.30±724.76 Dys.s.cm-5,P<0.0001；差异均有统计学意义。患者无临床恶化情况。患者耐受良好,无严重不良事件。
结论：西地那非治疗可显著改善肺动脉高压患者功能分级,活动耐力及血流动力学。西地那非治疗中国肺动脉高压患者是安全有效的,为西地那非治疗中国肺动脉高压患者提供了循证医学证据。
第二部分：西地那非治疗先天性心脏病相关性肺动脉高压前瞻性多中心临床研究
目的：探讨西地那非治疗先天性心脏病相关性肺动脉高压患者的临床疗效及耐受性,为西地那非治疗先天性心脏病相关性肺动脉高压患者提供循证医学证据。
方法：连续入选2007年5月-2009年4月中国医学科学院阜外心血管病医院等9个中心收治的肺动脉高压患者60例,研究经中国医学科学院阜外心血管病医院临床医学(／药物实验)伦理委员会审核通过。给予西地那非25mg一日三次口服,记录基线资料包括肺动脉高压诊断类型,病史(症状,主要临床症状出现的时间,基础病程时间,家族史,口服减肥药史,静脉血栓病史、静脉曲张史,口服避孕药史,流产史,)体格检查(颈静脉怒张,水肿,腹水),血常规(红细胞计数,血红蛋白,白细胞,血小板,)、凝血分析(INR)、生化指标(转氨酶,总胆红素,尿素氮,肌酐),WHO肺动脉高压功能分级,6分钟步行距离测试,Borg呼吸困难评分,完整的血流动力学资料(平均右房压、右室舒张末压、平均肺动脉压、心输出量、心指数、全肺阻力和肺静脉血氧饱和度)。观察治疗12周后患者NYHA心功能分级、WHO肺动脉高压功能分级、六分钟步行距离、Borg呼吸困难指数、血流动力学指标的变化以及临床恶化情况。同时观察患者血球分析及血生化指标及不良反应。
结果：治疗12周后,患者NYHA心功能分级,WHO肺动脉高压功能分级较基线明显改善(P<0.01),其中2例Ⅳ级升高至Ⅲ级,3例Ⅲ级升高为Ⅱ级,6例升高至Ⅰ级；7例Ⅱ级升高至Ⅰ级。无NYHA心功能分级及WHO肺动脉高压功能分级恶化病例。治疗12周后六分钟步行距离较前明显增加,由基线371.99±78.73m增加至12周422.94±76.9；差值50.94±66.86m,P<0.0001。Borg呼吸困难指数由基线2.57±1.42降低到2.10±1.32,p=0.03。右室舒张末压由基线12.05±14.04mmHg降低到9.81±12.0mmHg,差值为-2.09±11.84mmHg,P=0.0783；肺动脉平均压由基线80.19±20.76mmHg降低到73.77±18.24mmHg,差值为-6.42±13.36mmHg,P=0.0002；心输出量由基线4.38±2.18L／min增加到5.56±2.68L／min,差值为1.09±1.98L／min,P<0.0001；心指数由基线2.84±1.37L／min／m2增加到3.62±1.57L／min／m2,差值为0.74±1.07,P<0.0001；全肺阻力降低518.29±759.05Dys.s.cm-5,P<0.0001；差异均有统计学意义。患者无临床恶化情况。患者耐受良好,无严重不良事件。
结论：西地那非治疗可显著改善先心病相关性肺动脉高压患者功能分级,活动耐力及血流动力学。西地那非治疗先心病相关性肺动脉高压患者是安全有效的,为西地那非治疗先心病相关性肺动脉高压患者提供了循证医学证据,做了有益的探索尝试。
第三部分：西地那非治疗肺动脉高压前瞻性多中心临床研究单中心数据分析
目的：通过对多中心临床研究和单中心数据的比较分析,探讨西地那非治疗中国肺动脉高压患者多中心与单中心的异同点,为西地那非治疗中国肺动脉高压患者提供循证医学证据。
方法：连续入选2007年5月-2009年4月阜外心血管病医院收治的肺动脉高压患者56例,研究经中国医学科学院阜外心血管病医院临床医学(／药物实验)伦理委员会审核通过。给予西地那非25mg一日三次口服,记录基线资料包括肺动脉高压诊断类型,病史(症状,主要临床症状出现的时间,基础病程时间,家族史,口服减肥药史,静脉血栓病史、静脉曲张史,口服避孕药史,流产史,)体格检查(颈静脉怒张,水肿,腹水),血常规(红细胞计数,血红蛋白,白细胞,血小板,)、凝血分析(INR)、生化指标(转氨酶,总胆红素,尿素氮,肌酐),WHO肺动脉高压功能分级,6分钟步行距离测试,Borg呼吸困难评分,完整的血流动力学资料(平均右房压、右室舒张末压、平均肺动脉压、心输出量、心指数、全肺阻力和肺静脉血氧饱和度)。观察治疗12周后患者NYHA心功能分级、WHO肺动脉高压功能分级、六分钟步行距离、Borg呼吸困难指数、血流动力学指标的变化以及临床恶化情况。同时观察患者血球分析及血生化指标及不良反应。
结果：先天性心脏病相关性肺动脉高压为41(73.2%)；其次为特发病肺动脉高压,9(10.7%)；结缔组织相关性肺动脉高压为4(7.1%)；慢性血栓栓塞性肺动脉高压为2(3.6%)。12周时,56例患者服药依从性好,均完成口服12周西地那非25mg一日三次。治疗12周后,患者NYHA心功能分级,WHO肺动脉高压功能分级较基线明显改善(P<0.01),其中2例Ⅳ级升高至Ⅲ级；8例Ⅲ级改善为Ⅱ级,2例升高至Ⅰ级；5例Ⅱ级升高至Ⅰ级。无NYHA心功能分级及WHO肺动脉高压功能分级恶化病例。治疗12周后患者六分钟步行距离较前明显增加,由基线352.2±80.0m增加至396.5±78.1m；差值44.2±70.5m,差异有显著性,P<0.0001；右室舒张末压降低3.2±11.2mmHg,P<0.05；肺动脉平均压降低6.5±14.09mmHg,P<0.001；心输出量增加1.1±2.0 L／min,P<0.0001；心指数增加0.7±1.1L／min／m2,P<0.0001；全肺阻力降低489.8±831.7 Dys.s.cm-5,P<0.0001；差异均有统计学意义。患者无临床恶化情况。患者耐受良好,无严重不良事件。与多中心临床研究比较基线六分钟步行距离偏高,治疗12周后六分钟步行距离变化小于多中心研究,治疗12周心输出量改变0.86±1.76L／min,心指数基线差值为0.56±0.99L／min／m2；全肺阻力降低415.30±724.76 Dys.s.cm-5,与多中心研究比较,各指标改善趋势一致,但改善程度不同,差异无统计学意义。可能与纳入患者诊断类型比例不同及基线情况不同有关。
结论：本研究通过对多中心临床研究和单中心数据的分析比较,显示单中心数据分析中主要观察终点和次要观察终点的改善趋势与多中心研究一致,但六分钟步行及血流动力学指标的差异无显著性。
Part I:Sildenafil therapy for PAH patients prospective, Multi-center study
Objective: 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 disease
Objective: 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 study
Objective: 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.
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