| Aims:This study was designed to confirm the efficacy and safety of infusion of recombinant human atrial natriuretic peptide (rhANP) in patients with acute decompensated heart failure, including new-onset acute heart failure and acute exacerbation of chronic heart failure.Methods:This was a randomized, double-blind, placebo-controlled, multicenter study, including the non-catheterized group and the catheterized group. Swan-Ganz catheter was applied in the catheterized group to measure hemodynamic parameters, such as pulmonary capillary wedge pressure(PCWP), pulmonary artery systolic(PAPs), pulmonary arterydiastolic pressure(PAPd) and pulmonary artery mean pressure(PAPm), stroke volume(SV), cardiac output(CO),cardiac index(CI) and systemic vascular resistance(SVR).Patients with left ventricular ejection fraction(LVEF) less than 40% were randomly assigned to receive rhANP or placebo (initiated at a rate of 0.1μg/kg/min, adjusted to 0.15μg/kg/min half an hour later if the systolic blood pressure was more than 100mmHg, and stopped one hour later from the initiation). In the catheterized group, PCWP was required to be more than 13 mmHg at baseline and 15mmHg or higher when the dose was adjusted. Hemodynamic parameters were measured at Omin,15min,30min, 45min, 1h,3h,6h and 12h after the start of study drug. Dyspnea and other symptoms were assessed at Omin,30min, 1h,3h,6h,12h,24h and 3 days. The coprimary end point was the decrease of pulmonary capillary wedge pressure (PCWP) at one hour among catheterized patients and dyspnoea improvement at 12 hours among non-catheterized patients. Blood was drawn for chemical and haematological analysis,urine sample was collected for urine routine analysis, and electrocardiogram was performed at baseline andwithin 3 days after the initiation of the study drug.Adverse events were monitored through study day 3,and mortality was assessed through a month by telephone.Results:From March 2009 to July 2013, a total of 477 patients were underwent randomization at a ratio of 3:1 at 12 centers in China. One catheterized patient randomized in theplacebo group withdrew consent and did not receive the study drug. Therefore,358 patients received rhANP (93 catheterized) and 118 (28 catheterized) received placebo. The baseline characteristics were well balanced between rhANP group and placebo group. The patients were 54.52±13.70 vs.56.04±12.87 (P=0.2888), with males 76.3% vs.71.2%(P=0.2749), NYHA Ⅲ or Ⅳ grades 98.9% vs. 100.0%(P=0.9205), acute exacerbation of chronic heart failure 85.5% vs. 88.1%(P=0.4617), dilated cardiomyopathy 60.1% vs.51.7%(P=0.1118), LVEF 28.92 ±6.52% vs.29.86±6.65%(P=0.1781). In the catheterized patients, the baseline PCWP values were similar between therhANP and theplacebo groups (23.71±7.0 vs.25.66±8.78 mmHg, P=0.2263), both of which were decreased after initiation of the study drug. At 0.5 h, the mean reduction of PCWP was greater with rhANP than placebo (-5.45 vs.-2.03mmHg, P=0.0023).At 1 h, the maximum reduction of PCWP was observed in rhANP group, which was significantly greater than that in placebo group (-7.74±.95vs.-1.82±.47mmHg,P<0.0001).At 3h, PWCP was sustainably lower in therhANP group than in theplacebo group (19.52±6.55v.s.24.79±8.42mmHg, P=0.0007). Other hemodynamic parameters, such as PAPs, PAPd, PAPm, SV,CO, CI and SVR, also improved more significantly in the rhANP group.However, no significant differences were found between the two groups for PCWP at 6 hours (21.43±6.51vs.24.79±10.67 mmHg, P=0.1250) and afterwards.In the non-catheterized group, there was no difference for patients’ dyspnea severity between the rhANP and placebo group (P=0.9869), with 95.1% vs.95.6% patient more than one grade and 75.5% vs.73.3% more than two grades. However,the proportion of patients withdyspnea improvement of two grades at least at 12 hours was more in the rhANP group than that in the placebo group (41.4% vs. 32.2%,P=0.0167).There were no significantdifferences in the frequency of adverse events between the rhANP group and placebo group,221 (61.7%) vs.63 (53.4%) (P=0.1108).And the severe adverse events were also balanced,15 (4.2%) vs.4 (3.4%) (P=1.0000).Mortality at one month was 11(3.1%) in the rhANP group versus 3(2.5%) in the placebo group (hazard ratio:1.21; 95% confidence interval [CI]:0.34 to 4.26; P =1.0000).Conclusion:For patients with ADHF, in addition to stand therapy, theinfusion of rhANP had prompt and evident haemodynamic improvement involving the decrease of PCWP, PAPs, PAPd, PAPm, SVR and the increase of SV, CO and CI, as well as an evident effect on dyspnoea, with safety.
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