Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Division of Cardiology, Duke University Medical Center, Durham, North Carolina.
JAMA. 2015 Dec 1;314(21):2251-62. doi: 10.1001/jama.2015.15734.
Worsening chronic heart failure (HF) is a major public health problem.
To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF).
DESIGN, SETTING, AND PARTICIPANTS: Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic.
Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks.
The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point.
Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively.
Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF.
clinicaltrials.gov Identifier: NCT01951625.
重要性：慢性心力衰竭（HF）恶化是一个主要的公共卫生问题。
目的：确定可溶性鸟苷酸环化酶刺激剂维立西呱在左心室射血分数（LVEF）降低的慢性 HF 恶化患者中的最佳剂量和耐受性。
设计、地点和参与者：这是一项在 2013 年 11 月至 2015 年 1 月期间在欧洲、北美和亚洲进行的剂量发现 2 期研究，共纳入了 456 例患者，随访于 2015 年 6 月结束。患者在慢性 HF 恶化事件后 4 周内具有临床稳定性，LVEF 低于 45%，定义为充血和升高的利钠肽水平的恶化迹象和症状需要住院或门诊静脉利尿剂治疗。
干预措施：安慰剂（n=92）或口服维立西呱 4 种每日目标剂量之一（1.25 mg[n=91]、2.5 mg[n=91]、5 mg[n=91]、10 mg[n=91]），治疗 12 周。
主要结果和测量：主要终点是从基线到第 12 周时 N 端前 B 型利钠肽（NT-proBNP）的对数转换水平的变化。主要分析指定了与安慰剂相比，最高 3 个维立西呱组的 pooled 比较，并且次要分析评估了维立西呱和主要终点的剂量反应关系。
结果：总体而言，351 例（77.0%）患者完成了研究药物治疗，具有有效的 12 周 NT-proBNP 水平，且无主要方案偏差，有资格进行主要终点评估。在主要分析中，从基线到第 12 周时，pooled 维立西呱组（对数转换：基线，7.969；12 周，7.567；差异，-0.402；几何平均值：基线，2890 pg/mL；12 周，1932 pg/mL）和安慰剂组（对数转换：基线，8.283；12 周，8.002；差异，-0.280；几何平均值：基线，3955 pg/mL；12 周，2988 pg/mL）之间的 NT-proBNP 水平变化没有显著差异（均值差，-0.122；90%CI，-0.32 至 0.07；几何均数比，0.885，90%CI，0.73-1.08；P=0.15）。探索性的次要分析表明，存在剂量反应关系，较高的维立西呱剂量与 NT-proBNP 水平的更大降低相关（P<0.02）。安慰剂组和 10-mg 维立西呱组的任何不良事件发生率分别为 77.2%和 71.4%。
结论和相关性：在慢性 HF 恶化且 LVEF 降低的患者中，与安慰剂相比，维立西呱在 12 周时对 NT-proBNP 水平的变化没有统计学显著影响，但具有良好的耐受性。基于该研究中剂量反应关系的维立西呱进一步临床试验，对于慢性 HF 恶化的患者，需要确定这种药物的潜在作用。
试验注册：clinicaltrials.gov 标识符：NCT01951625。
