Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts.
Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts.
J Am Coll Cardiol. 2017 Mar 21;69(11):1409-1419. doi: 10.1016/j.jacc.2016.12.035.
In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments.
It was hypothesized that the addition of tolvaptan to a background diuretic improved dyspnea early in patients selected for an enhanced vasopressin antagonism response.
In a double-blind trial, patients were randomized to tolvaptan 30 mg/day or placebo. Study entry required hospitalization within the previous 36 h, active dyspnea, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m; 2) hyponatremia; or 3) diuretic resistance (urine output ≤125 ml/h following intravenous furosemide ≥40 mg). The primary endpoint was a 7-point change in self-assessed dyspnea at 8 and 16 h, using a novel standardized approach.
We randomized 250 patients. There was no difference in the primary endpoint of day 1 dyspnea reduction, despite significantly greater weight reduction with tolvaptan (-2.4 ± 2.1 kg vs. -0.9 ± 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01). There were 2 significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure and those without ascites showed directional favorability of tolvaptan over placebo for the primary endpoint compared with patients with these findings.
Despite rapid and persistent weight loss with tolvaptan compared with placebo, in patients with AHF who were selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in dyspnea. Apparent subsequent differences in dyspnea warrant further exploration of the temporal relationship between diuresis and dyspnea relief and a possible clinical role for tolvaptan. (Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management [SECRET of CHF]; NCT01584557).
在急性心力衰竭（AHF）患者中，呼吸困难缓解是最直接的目标。肾功能障碍、利尿剂抵抗和低钠血症是治疗的障碍。
假设在选择增强血管加压素拮抗反应的患者中，加用托伐普坦可改善早期呼吸困难。
在一项双盲试验中，患者随机分为托伐普坦 30mg/天或安慰剂。研究入选标准为：过去 36 小时内住院、有活动后呼吸困难以及以下任何一种情况：1）估算肾小球滤过率<60ml/min/1.73m；2）低钠血症；3）利尿剂抵抗（静脉注射呋塞米≥40mg 后 125ml/h 的尿量≤）。主要终点是使用新的标准化方法在 8 小时和 16 小时时自我评估呼吸困难的 7 分变化。
我们随机分配了 250 名患者。尽管托伐普坦组体重减轻更为明显（-2.4±2.1kg 与-0.9±1.8kg；p<0.001），但第 1 天呼吸困难减轻的主要终点没有差异。第 3 天，托伐普坦组呼吸困难减轻更为明显（p=0.01）。存在 2 个显著的治疗-亚组相互作用：颈静脉压不升高和无腹水的患者与有这些发现的患者相比，托伐普坦对主要终点的治疗效果优于安慰剂。
尽管与安慰剂相比，托伐普坦迅速且持续地减轻体重，但在因血管加压素受体抑制而更有可能获益的 AHF 患者中，托伐普坦并未导致呼吸困难的早期改善更大。呼吸困难的后续差异明显，需要进一步探讨利尿与呼吸困难缓解之间的时间关系，以及托伐普坦可能的临床作用。（随机、双盲、安慰剂对照研究托伐普坦短期治疗对因容量管理困难而恶化的心力衰竭住院患者的临床影响[心衰秘密（SECRET）]；NCT01584557）。
