波生坦起始联合与序贯联合治疗肺动脉高压患者的长期疗效及预后

Bosentan up-front or sequential add-on combination treatment for pulmonary arterial hypertension:long-term effects and prognosis

目的评估波生坦起始联合治疗或序贯治疗肺动脉高压患者的长期疗效、安全性及生存预后情况。方法入选自2007年7月至2013年1月在上海市肺科医院心肺循环科住院,明确诊断为第一大类肺动脉高压的患者104例,给予波生坦标准剂量2次/d口服,进行开放性、观察性研究。根据治疗方案分成起始联合治疗组和序贯治疗组,并进行长期随访,截止至2013年6月。评估并比较服药前后病情改善情况及生存率情况。结果波生坦平均治疗(22.6±15.8)个月,68.1%患者WHO肺动脉高压功能分级无明显恶化(明显改善6例,稳定56例)。N末端-脑钠肽前体的对数值(lgNT-proBNP)由2.8±0.8下降至2.5±0.2,但差异无统计学意义(P=0.15)。超声心动图测得肺动脉收缩压(PASP)由(95.2±21.3)mmHg(1mmHg=0.133kPa)下降至(88.6±24.4)mmHg(P=0.009);射血分数(EF)由(73.6±9.3)%升至(77.4±9.0)%(P=0.02);右房横径大小和右室横径大小无明显改变。右心导管检查测得肺动脉平均压和右房平均压无明显改变;肺血管阻力由(16.4±8.4)Wood U/m2降至(13.9±8.0)Wood U/m2,但差异无统计学意义(P=0.06);心排量(CO)由(3.8±2.0)L/min升至(4.8±2.3)L/min(P=0.04)。Kaplan-Meier生存分析显示1、2、3、4和5年生存率分别为92.5%、83.7%、71.7%、67.2%和57.6%。起始联合组1、2、3和4年生存率分别为95.1%、88.9%、84.2%和77.7%;序贯治疗组1、2、3和4年生存率分别为92.3%、79.4%、53.3%和26.6%,两组生存率差异有统计学意义(P=0.038)。仅有1例患者因颜面部水肿明显而停用波生坦。结论长期联合使用波生坦可使患者的心功能无明显恶化,心排出量增加且安全性良好,同时起始联合治疗较序贯治疗对患者预后更有益。

Objective To investigate the long-term effects and safety of bosentan combination treatment （up-front combination and sequential add-on combination） for pulmonary arterial hypertension （PAH） patients and the prognosis of the patients. Methods In this open and observational study, a total of 104 patients who were diagnosed as having PAH in the Department of Pulmonary Circulation and Cardiology, Shanghai Pulmonary Hospital, were given bosentan （twice a day） before treatment from Jul. 2007 to Jan. 2013. According to the treatment regimen, the patients were divided into up-front combination group or sequential add-on combination group, and the patients were followed up till Jun. 2013. Then the improvements and the survival rates of the patients were evaluated and compared before and after treatment. Results The median treatment time with bosentan was （22.6 ± 15.8） months. The WHO functional class had no obvious worsening in 68.1% of patients with bosentan treatment, with the situation improved in 6 patients and steady in 56. The lgNT-proBNP value was decreased from 2.8±0.8 to 2.5 ±0.2, but showing no significant difference （P = 0. 15）. Echocardiogram examination found that the pulmonary arterial systolic pressure （PASP） decreased from （95.2±21.3）mmHg （1 mmHg = 0. 133 kPa） to （88.6±24.4）mmHg （P=0. 009） ejection fraction （EF） increased from （73.6±9.3）% to （77.4±9.0）% （P=0.02）; transverse size of right artial （RA-T size） and transverse size of right ventricular （RV-T size） showed no changes. Hemodynamic observations found that the mean PAP （mPAP） and mean right arterial pressure （mRAP） showed no change; pulmonary vascular resistance （PVR） decreased from （16.4± 8.4）Wood U/m^2 to （13. 9 ± 8.0） Wood U/m^2 , but showing no significant difference （P = 0.06） ; and cardiac output （CO） increased from （3.8±2.0） L/min to （4.8±2.3） L/min （P=0.04）. The results of Kaplan-Meier survival estimates for 1, 2, 3 , 4 and 5 years were 92.5%, 83.7%, 71.7% , 67.2% and 57.6%, respectively. The 1, 2, 3 and 4 years survival rates of patients were 95.1%, 88.9%, 84.2% and 77.7% in the up-front combination group, and 92.3%, 79.4%, 53.3% and 26.6 % in the sequential add-on combination group, respectively, with significant difference found between the two groups （P= 0. 038）. Only one patient in our study stopped bosentan due to severe facial edema. Conclusion Long-term bosentan combination treatment can prevent cardiac function worsening in PAH patients, increasing cardiac output and with satisfactory safety. Moreover, up-front combination therapy with bosentan has a better prognosis than sequential add-on combination therapy for PAH patients.