發(fā)布時(shí)間：2018-11-13 13:40

【摘要】：目的：確證重組人心鈉肽治療急性心力衰竭或慢性心力衰竭急性發(fā)作的有效性和安全性。方法：本試驗(yàn)為隨機(jī)、雙盲、安慰劑對(duì)照臨床研究,分為漂浮導(dǎo)管組(導(dǎo)管組)和非漂浮導(dǎo)管組。導(dǎo)管組采用Swan-Ganz導(dǎo)管監(jiān)測(cè)血流動(dòng)力學(xué),觀察指標(biāo)：肺毛細(xì)血管楔壓(PCWP)、肺動(dòng)脈收縮壓、肺動(dòng)脈平均壓、肺動(dòng)脈舒張壓、心輸出量、每搏量、心臟指數(shù)、外周血管阻力。左室射血分?jǐn)?shù)≤40%的心衰患者隨機(jī)分入對(duì)照組和重組人心鈉肽組(rhANP組),其中導(dǎo)管組要求PCWP≥13mmHg。在常規(guī)藥物治療的基礎(chǔ)上,靜脈泵入安慰劑或rhANP 1h,起始劑量為0.1μg/kg/min,半小時(shí)后若臨床癥狀無明顯改善,且收縮壓≥100mmHg(漂浮導(dǎo)管組還要求PCWP≥15mmHg),則增至0.15μg/kg/min,在基線Omin,15min,30min,45min, 1h,3h,6h和12h時(shí)測(cè)定血流動(dòng)力學(xué)參數(shù)。在基線Omin,30min, 1h,3h,6h,12h,24h,3天時(shí)評(píng)價(jià)呼吸困難、其他臨床癥狀。主要療效觀察指標(biāo)為用藥開始1h后導(dǎo)管組的PCWP的下降情況和用藥12h后非漂浮導(dǎo)管組的呼吸困難改善情況�；�和用藥后3天檢測(cè)血常規(guī)、血生化、尿常規(guī)、心電圖等指標(biāo),并記錄不良事件。1月電話隨訪。結(jié)果：2009年03月至2013年07月,全國12家中心共入組477例患者(導(dǎo)管組122例),以3：1的比例隨機(jī)分配至rhANP組和對(duì)照組。由于對(duì)照組的導(dǎo)管組中1例患者給藥前撤除知情同意,因此rhANP組358例(導(dǎo)管組93例),對(duì)照組118例(導(dǎo)管組28例)納入統(tǒng)計(jì)分析。rhANP組和對(duì)照組患者的基線特征均衡,年齡為 54.52±13.70 vs.56.04±12.87歲(P=0.2888), 男性比例為76.3% vs.71.2%(P=0.2749), NYHA心功能分級(jí)Ⅲ或Ⅳ級(jí)的比例為98.9% vs.100.0%(P=0.9205),慢性心力衰竭急性惡化的比例為85.5% vs.88.1% (P=0.4617),心力衰竭病因主要是擴(kuò)張型心肌病,為60.1% vs.51.7%(P=0.1118),左室射血分?jǐn)?shù)為28.92±6.52% vs.29.86±6.65%(P=0.1781)。漂浮導(dǎo)管組中,rhANP組和對(duì)照組基線PCWP無統(tǒng)計(jì)學(xué)差異,分別是23.71±7.00和25.66±8.78mmHg (P=0.2263)。用藥后兩組PCWP即開始下降,半小時(shí)后,rhANP組的PCWP較基線下降幅度為-5.45mmHg,而對(duì)照組僅為-2.03mmHg, rhANP組均值明顯低于對(duì)照組(18.26±7.80vs.23.63±8.04 mmHg,P=0.0023)�；�后1h, rhANP組PCWP下降幅度最大,為-7.74mmHg,而對(duì)照組下降值僅為-1.82mmHg, rhANP組均值明顯低于對(duì)照組(15.97±7.70 vs.23.84±6.99mmHg,P0.0001).基線后3h,rhANP組的PCWP的改善程度仍優(yōu)于對(duì)照組(19.52±6.55 vs.24.79 ±8.42mmHg,P=0.0007)。其他血流動(dòng)力學(xué)指標(biāo),如肺動(dòng)脈收縮壓、肺動(dòng)脈平均壓、肺動(dòng)脈舒張壓、心輸出量、每搏量、心臟指數(shù)和外周血管阻力,在rhANP組的改善也更為明顯。在基線后6h時(shí)(停藥5h),rhANP組和對(duì)照組的PCWP無統(tǒng)計(jì)學(xué)差異(21.43±6.51 vs.24.79±10.67 mmHg,P=0.1250)。非漂浮導(dǎo)管人群中,rhANP組和對(duì)照組基線時(shí)1級(jí)以上呼吸困難是95.1% vs.95.6%,2級(jí)以上呼吸困難是75.5% vs.73.3%,兩組基線呼吸困難嚴(yán)重程度無統(tǒng)計(jì)學(xué)差異(P=0.9869)。rhANP組基線后12h的2級(jí)以上呼吸困難改善率顯著高于對(duì)照組(41.4% vs.32.2%,P=0.0167)�？�?cè)巳褐?rhANP組和對(duì)照組的不良事件發(fā)生率無統(tǒng)計(jì)學(xué)差異,為221(61.7%) vs.63(53.4%)例(P=0.1108)；嚴(yán)重不良事件也無統(tǒng)計(jì)學(xué)差異,為15(4.2%)vs.4(3.4%)例(P=1.0000)�；颊咭辉聝�(nèi)的死亡率無統(tǒng)計(jì)學(xué)差異,為11(3.1%)vs.3(2.5%)例(死亡風(fēng)險(xiǎn)比為1.21；95%可信區(qū)間為0.34～4.26；P=1.0000)。結(jié)論：在常規(guī)治療的基礎(chǔ)上靜脈使用rhANP治療急性心力衰竭,可快速并且顯著的改善血流動(dòng)力學(xué),降低肺毛細(xì)血管嵌壓、肺動(dòng)脈收縮壓、舒張壓、平均壓和外周血管阻力,升高心臟每搏量、心輸出量、心臟指數(shù),顯著改善患者呼吸困難,同時(shí),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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R541.6

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