PDE5i with Tadalafil Changes the Extent of Renal Damage (PITCH_ER)

NHLBI赞助的Pitch-HF试验(#U01HL105562)将于2013年第1季度开始注册。Pitch-HF是第一个 FDA批准的研究他达拉非疗效的良好对照、随机、大规模(n=2,012)试验 选择性磷酸二酯酶5型抑制剂(PDE5I)对心血管(CV)死亡和心力衰竭(HF)的影响 左心室收缩功能不全和继发性肺动脉高压患者的住院情况。 PDE5i的生物学特性强烈表明具有潜在的肾脏保护作用，但Pitch-HF目前缺乏肾脏 终端。慢性肾脏疾病(CKD)(表现为蛋白尿和肾小球滤过率降低 [GFR])和急性肾损伤(AKI)对心血管疾病患者的发病率和死亡率有显著影响 疾病和心力衰竭。我们预计E30%的Pitch-HF参与者会出现一个或多个这样的终点 在研究期间。严重缺乏改变心力衰竭患者肾脏疾病进程的治疗方法。 这项申请要求为Pitch-ER提供适度的资金，这是一项辅助研究，旨在解决两名主要患者- 导向性问题：(1)慢性他达拉非治疗是否延缓GFR下降和/或改变 蛋白尿与安慰剂的发展/进展？我们将检查EGFR的纵向措施(利用 包括血清肌酐和胱抑素C)和现场尿白蛋白的最新方程 (2)PDE5i治疗是否降低AKI频率和/或尿生物标志物的大小 与安慰剂相比，反映亚临床肾损伤的变化？利用AKI裁决委员会，我们将监督 使用KDIGO最新的AKI共识标准来评估AKI事件的发生率及其严重程度。我们还将 应用尿生物标志物：中性粒细胞明胶酶相关脂钙蛋白检测亚临床肾损伤 和肾脏损伤标记物1。我们预计30%的Pitch-HF人群将患有糖尿病，这 放大肾功能衰竭患者的肾损伤风险，因此，我们在该提案中包括重复我们的分析的计划 根据基线糖尿病状态分层作为子目标1和2，治疗效果应该在有以下情况的患者中有所不同 而且没有糖尿病。母公司的研究缺乏尿液收集和现代的GFR测量方法，如血清 半胱氨酸氨基转移酶C，不会在研究期间检查GFR的下降或AKI发作的频率。因此， 这项建议对时间特别敏感。通过利用Pitch-HF基础设施和 随机化，这项辅助研究提供了一种有效、经济和强大的方法来识别 PDE5抑制的潜在肾脏保护作用。我们的协作团队在高性能方面有经验 肾脏终点的高质量辅助研究，以及此类研究生物样本的收集和检测 利用最先进的肾功能和生物学测量方法。我们的目标是强有力的，并专注于 定义的端点，使我们能够以最小的负担回答重要的临床和科学问题 受试者和家长的研究。Pitch-HF执行委员会和NHLBI审查员同意这一点 建议可能从根本上改变慢性肾脏病、急性心肌梗死和充血性心力衰竭患者的临床护理模式。

The NHLBI-sponsored PITCH-HF trial (#U01HL105562) will begin enrollment in Q1 2013. PITCH-HF is the first well-controlled, randomized, large-scale (n=2,012) trial studying the effect of tadalafil, an FDA-approved selective phosphodiesterase type 5 inhibitor (PDE5i), on cardiovascular (CV) deaths and heart failure (HF) hospitalizations in patients with left ventricular systolic dysfunction and secondary pulmonary hypertension. The biology of PDE5i strongly suggests a potential renoprotective effect, but PITCH-HF currently lacks renal endpoints. Both chronic kidney disease (CKD) (reflected by albuminuria and reduced glomerular filtration rate [GFR]) and acute kidney injury (AKI) significantly contribute to morbidity and mortality in patients with CV disease and HF. We expect e30% of participants in PITCH-HF will develop one or more of these endpoints over the study period. Therapies that alter the course of renal disease in patients with HF are sorely lacking. This application requests modest funding for PITCH-ER, an ancillary study to address two major patient- oriented questions: (1) Does chronic tadalafil treatment slow the rate of GFR decline and/or modify the development/progression of albuminuria vs placebo? We will examine longitudinal measures of eGFR (utilizing state-of-the-art equations that incorporate serum creatinine and cystatin C) and spot urine albumin-to- creatinine ratios; (2) Does PDE5i treatment reduce AKI frequency and/or the magnitude of urinary biomarker changes reflecting subclinical renal injury vs placebo? Using an AKI adjudication committee, we will monitor the incidence of AKI events and their severity using the latest KDIGO consensus criteria for AKI. We will also detect subclinical renal injury using the validated urinary biomarkers: neutrophil gelatinase-associated lipocalin and kidney injury marker 1. We expect that 30% of the overall PITCH-HF population will have diabetes, which amplifies the risk for renal injury in HF patients, thus, we include in this proposal a plan to repeat our analyses stratified by baseline diabetes status as Sub-Aims 1 and 2 should treatment effects differ between those with and without diabetes. The parent study lacks urine collection and modern measures of GFR such as serum cystatin C, and will not examine decline in GFR or frequency of AKI episodes during the study period. Thus, this proposal is particularly time-sensitive. By taking advantage of the PITCH-HF infrastructure and randomization, this ancillary study provides an efficient, economical, and well-powered approach to identify potential renoprotective effects of PDE5 inhibition. Our collaborative team has experience in performing high quality ancillary studies with renal endpoints, and collection and testing of biological samples from such studies utilizing state-of-the-art measures of renal function and biology. Our aims are well-powered and focus on well- defined endpoints, allowing us to answer important clinical and scientific questions with minimal burden to subjects and the parent study. The PITCH-HF Executive Committee and the NHLBI reviewers agree this proposal may radically shift the clinical care paradigm for patients with CKD, AKI, and CHF.