重组人心钠肽治疗心力衰竭的Ⅲ期临床试验

发布时间：2018-11-13 13:40

【摘要】：目的：确证重组人心钠肽治疗急性心力衰竭或慢性心力衰竭急性发作的有效性和安全性。方法：本试验为随机、双盲、安慰剂对照临床研究,分为漂浮导管组(导管组)和非漂浮导管组。导管组采用Swan-Ganz导管监测血流动力学,观察指标：肺毛细血管楔压(PCWP)、肺动脉收缩压、肺动脉平均压、肺动脉舒张压、心输出量、每搏量、心脏指数、外周血管阻力。左室射血分数≤40%的心衰患者随机分入对照组和重组人心钠肽组(rhANP组),其中导管组要求PCWP≥13mmHg。在常规药物治疗的基础上,静脉泵入安慰剂或rhANP 1h,起始剂量为0.1μg/kg/min,半小时后若临床症状无明显改善,且收缩压≥100mmHg(漂浮导管组还要求PCWP≥15mmHg),则增至0.15μg/kg/min,在基线Omin,15min,30min,45min, 1h,3h,6h和12h时测定血流动力学参数。在基线Omin,30min, 1h,3h,6h,12h,24h,3天时评价呼吸困难、其他临床症状。主要疗效观察指标为用药开始1h后导管组的PCWP的下降情况和用药12h后非漂浮导管组的呼吸困难改善情况。基线和用药后3天检测血常规、血生化、尿常规、心电图等指标,并记录不良事件。1月电话随访。结果：2009年03月至2013年07月,全国12家中心共入组477例患者(导管组122例),以3：1的比例随机分配至rhANP组和对照组。由于对照组的导管组中1例患者给药前撤除知情同意,因此rhANP组358例(导管组93例),对照组118例(导管组28例)纳入统计分析。rhANP组和对照组患者的基线特征均衡,年龄为 54.52±13.70 vs.56.04±12.87岁(P=0.2888), 男性比例为76.3% vs.71.2%(P=0.2749), NYHA心功能分级Ⅲ或Ⅳ级的比例为98.9% vs.100.0%(P=0.9205),慢性心力衰竭急性恶化的比例为85.5% vs.88.1% (P=0.4617),心力衰竭病因主要是扩张型心肌病,为60.1% vs.51.7%(P=0.1118),左室射血分数为28.92±6.52% vs.29.86±6.65%(P=0.1781)。漂浮导管组中,rhANP组和对照组基线PCWP无统计学差异,分别是23.71±7.00和25.66±8.78mmHg (P=0.2263)。用药后两组PCWP即开始下降,半小时后,rhANP组的PCWP较基线下降幅度为-5.45mmHg,而对照组仅为-2.03mmHg, rhANP组均值明显低于对照组(18.26±7.80vs.23.63±8.04 mmHg,P=0.0023)。基线后1h, rhANP组PCWP下降幅度最大,为-7.74mmHg,而对照组下降值仅为-1.82mmHg, rhANP组均值明显低于对照组(15.97±7.70 vs.23.84±6.99mmHg,P0.0001).基线后3h,rhANP组的PCWP的改善程度仍优于对照组(19.52±6.55 vs.24.79 ±8.42mmHg,P=0.0007)。其他血流动力学指标,如肺动脉收缩压、肺动脉平均压、肺动脉舒张压、心输出量、每搏量、心脏指数和外周血管阻力,在rhANP组的改善也更为明显。在基线后6h时(停药5h),rhANP组和对照组的PCWP无统计学差异(21.43±6.51 vs.24.79±10.67 mmHg,P=0.1250)。非漂浮导管人群中,rhANP组和对照组基线时1级以上呼吸困难是95.1% vs.95.6%,2级以上呼吸困难是75.5% vs.73.3%,两组基线呼吸困难严重程度无统计学差异(P=0.9869)。rhANP组基线后12h的2级以上呼吸困难改善率显著高于对照组(41.4% vs.32.2%,P=0.0167)。总人群中,rhANP组和对照组的不良事件发生率无统计学差异,为221(61.7%) vs.63(53.4%)例(P=0.1108)；严重不良事件也无统计学差异,为15(4.2%)vs.4(3.4%)例(P=1.0000)。患者一月内的死亡率无统计学差异,为11(3.1%)vs.3(2.5%)例(死亡风险比为1.21；95%可信区间为0.34～4.26；P=1.0000)。结论：在常规治疗的基础上静脉使用rhANP治疗急性心力衰竭,可快速并且显著的改善血流动力学,降低肺毛细血管嵌压、肺动脉收缩压、舒张压、平均压和外周血管阻力,升高心脏每搏量、心输出量、心脏指数,显著改善患者呼吸困难,同时,安全性良好。
[Abstract]:Objective: To confirm the efficacy and safety of recombinant human natriuretic peptide in the treatment of acute heart failure or chronic heart failure. Methods: This test was a randomized, double-blind, placebo-controlled clinical study divided into a floating catheter group (catheter group) and a non-floating catheter group. Hemodynamics were monitored by the Swan-Ganz catheter in the group of catheters: pulmonary capillary wedge pressure (PCWP), pulmonary artery systolic pressure, pulmonary artery mean pressure, pulmonary arterial pressure, cardiac output, stroke volume, cardiac index, and peripheral vascular resistance. In the left chamber, 40% of the patients with heart failure were randomly divided into the control group and the recombinant human sodium peptide group (rhANP group), in which the group of catheters required PCWP-13mmHg. On the basis of routine drug treatment, the vein was pumped into the placebo or rhANP for 1 h with a starting dose of 0.1. m u.g/ kg/ min. After half an hour, the clinical symptoms were not significantly improved, and the systolic blood pressure was 100 mmHg (the floating catheter group also required PCWP-15mmHg) to increase to 0. 15. m u.g/ kg/ min, at baseline Omin, 15min, 30min, 45min, 1h, 3h, The hemodynamic parameters were determined at 6 h and 12 h. Dyspnoea and other clinical symptoms were evaluated at baseline Omin, 30min, 1h, 3h, 6h, 12h, 24h and 3 days. The primary efficacy observations were the decrease in the PCWP of the catheter group after the start of the medication and the improvement in the dyspnea of the non-floating catheter group after 12h. Blood routine, blood biochemistry, urine routine, electrocardiogram and other indexes were detected for 3 days after baseline and administration, and adverse events were recorded. The telephone follow-up was conducted in January. Results: From March 2009 to July 2013, 477 patients (122 cases of catheter group) were enrolled in 12 centers of the country, and were randomly assigned to the rhANP group and the control group at a ratio of 3: 1. As a result of the withdrawal of the informed consent prior to the administration of 1 patient in the control group, 358 patients (93 in the catheter group) and 118 in the control group (28 in the catheter group) were included in the statistical analysis. The baseline characteristics of the rhANP group and the control group were balanced, the age was 54. 52-13.70 vs.56. 04-12. 87 (P = 0.2888), the male ratio was 76.3% vs. 71.2% (P = 0.2749), the proportion of the NYHA functional grade III or IV was 98.9% vs. 100. 0% (P = 0.9205), and the proportion of the acute exacerbation of chronic heart failure was 85.5% vs. 80.1% (P = 0.4617). The main causes of heart failure were dilated cardiomyopathy, 60. 1% vs. 55.1% (P = 0.1118), and the left ventricular ejection fraction was 28. 92% 6.52% vs. 29. 86% 6.65% (P = 0.1781). There was no statistical difference between the baseline PCWP of the rhANP group and the control group in the floating catheter group, which was 23.71-7.00 and 25.66-8.78mmHg (P = 0.2263), respectively. After half an hour, the baseline of PCWP in the rhANP group was-5.45mmHg, while the mean of the control group was-2.03mmHg, and the mean of rhANP group was significantly lower than that of the control group (18. 26-7.80 vs. 23. 63-8.04 mmHg, P = 0. 0023). The mean value of PCWP in rhANP group was-7.74mmHg and the mean value of the control group was-1.82mmHg, and the mean of rhANP group was significantly lower than that of the control group (15.97% 7.70 vs. 23.84, 6.99mmHg, P. 0001). The improvement of PCWP in the rhANP group was still superior to that of the control group (19.52, 6.55 vs. 24.79, 8.42mmHg, P = 0.0007) after the baseline period of 3h. Other hemodynamic parameters, such as pulmonary arterial systolic pressure, mean pulmonary artery pressure, pulmonary arterial pressure, cardiac output, stroke volume, cardiac index, and peripheral vascular resistance, were also more evident in the rhANP group. There was no statistical difference in the PCWP between the rhANP group and the control group at 6 h after the baseline (21. 43, 6.51 vs. 24. 79, 10.67 mmHg, P = 0.1250). In the non-floating catheter population, the dyspnea in the rhANP group and the control group at baseline was 95.1% vs. 95.6%, and the 2-grade dyspnea was 75.5% vs. 73.3%. There was no statistical difference between the two groups of baseline dyspnea (P = 0.9869). The improvement rate of dyspnea was significantly higher than that of the control group (41.4% vs. 32. 2%, P = 0.0167). There was no statistical difference in the incidence of adverse events in the rhANP group and the control group in the total population, 221 (61.7%) vs. 63 (53.4%) (P = 0.1108), and no significant adverse events, 15 (4.2%) vs. 4 (3.4%) (P = 1.0000). There was no statistical difference in mortality in the first month of the patient, with 11 (3.1%) vs. 3 (2.5%) cases (death risk ratio of 1.21; 95% confidence interval of 0.34-4.26; P = 1.0000). Conclusion: On the basis of routine treatment, rhANP can be used to treat acute heart failure, and the blood flow dynamics can be improved rapidly and significantly, pulmonary capillary pressure, pulmonary artery systolic pressure, diastolic blood pressure, mean pressure and peripheral blood tube resistance can be reduced, and cardiac output and cardiac output can be increased. The heart index significantly improved the patient's dyspnea, while the safety was good.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R541.6

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