Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure
Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure
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DOI：
10.1016/j.jchf.2018.02.007
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发表时间：
2018-07-01
影响因子：
13
通讯作者：
Solomon, Scott D.
中科院分区：
文献类型：
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作者：
Vaduganathan, Muthiah;Claggett, Brian;Solomon, Scott D.
目的：本研究旨在确定在心力衰竭（HF）临床试验中，利钠肽（NPs）的治疗相关变化是否能预测长期治疗效果。
背景：心力衰竭治疗中药物和器械疗效缺乏可靠的预测指标，这对新疗法的开发和评估构成了重大障碍。
方法：该研究对1987年至2013年间完成的16项Ⅲ期慢性心力衰竭试验进行了试验层面的分析，研究了48844名患者中的18种治疗比较。计算了NPs的平均对照或安慰剂校正变化与临床终点的长期治疗效果（以对数转换的风险比表示）之间的加权皮尔逊相关系数。
结果：临床终点的中位随访时间为28个月（第25至75百分位范围：18至36个月）。NPs数据在中位748名患者（第25至75百分位范围：270至1868名）中可获得，且在随机分组后中位4个月（第25至75百分位范围：3至6个月）进行测量。NPs的治疗相关变化与全因死亡率的长期治疗效果无关（r = 0.12；p = 0.63），但与心力衰竭住院相关（r = 0.63；p = 0.008）。当分析仅限于过去十年（>2010年）完成的试验、使用N末端B型利钠肽前体检测（r = 0.65；p = 0.06）以及评估肾素 - 血管紧张素 - 醛固酮系统抑制剂（r = 0.97；p = 0.0002）时，与心力衰竭住院的相关性提高。
结论：在研究广泛的干预措施时，NPs的治疗相关变化似乎与心力衰竭住院的长期治疗效果有适度相关性，但与全因死亡率的影响无关。这些观察结果对在Ⅱ期试验中使用NPs以决定Ⅲ期试验提出了重要的警示。（C）2018年美国心脏病学会基金会
OBJECTIVES This study sought to determine whether treatment-related changes in natriuretic peptides (NPs) predict longer-term therapeutic effects in clinical trials of heart failure (HF).BACKGROUND The lack of reliable predictors of efficacy of drugs and devices in HF has presented a major hurdle to the development and evaluation of novel therapies.METHODS The study conducted a trial-level analysis of 16 phase III chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. Weighted Pearson correlation coefficients were calculated between average control-or placebo-corrected changes in NPs and longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios).RESULTS Median follow-up for clinical endpoints was 28 (25th to 75th percentile range: 18 to 36) months. NPs were available in a median of 748 (25th to 75th percentile range: 270 to 1,868) patients and measured at a median of 4 (25th to 75th percentile range: 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r = 0.12; p = 0.63), but were correlated with HF hospitalization (r = 0.63; p = 0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r = 0.92; p = 0.0095), using N-terminal pro-B-type NP assays (r = 0.65; p = 0.06), and evaluating inhibitors of the renin-angiotensin-aldosterone system (r = 0.97; p = 0.0002).CONCLUSIONS When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision making regarding phase III trials. (C) 2018 by the American College of Cardiology Foundation.