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

NHLBI申办的PITCH-HF试验（#U01HL 105562）将于2013年第1季度开始入组。PITCH-HF是第一个 一项对照良好、随机、大规模（n= 2，012）试验，研究他达拉非（FDA批准的 选择性磷酸二酯酶5型抑制剂（PDE 5i），对心血管（CV）死亡和心力衰竭（HF）的影响 左心室收缩功能障碍和继发性肺动脉高压患者的住院治疗。 PDE 5i的生物学强烈提示潜在的肾保护作用，但PITCH-HF目前缺乏肾保护作用。 端点。慢性肾脏疾病（CKD）（反映为蛋白尿和肾小球滤过率降低） [GFR]）和急性肾损伤（阿基）显著导致CV患者的发病率和死亡率 疾病和HF。我们预计PITCH-HF中30%的参与者将出现一个或多个这些终点 在研究期间。改变HF患者肾脏疾病病程的治疗方法非常缺乏。 这项申请要求为PITCH-ER提供适度的资金，这是一项辅助研究，旨在解决两个主要的患者- 定向问题：（1）长期他达拉非治疗是否减缓GFR下降的速率和/或改变 与安慰剂相比，白蛋白尿发生/进展？我们将检查eGFR的纵向测量（利用 最先进的公式，包括血清肌酐和半胱氨酸蛋白酶抑制剂C）和点尿白蛋白对 （2）PDE 5i治疗是否降低阿基频率和/或尿生物标志物的大小 反映亚临床肾损伤与安慰剂相比的变化？通过阿基裁定委员会，我们将监测 阿基事件的发生率及其严重程度，使用最新的KDIGO阿基共识标准。我们还将 使用经验证的尿液生物标志物检测亚临床肾损伤：中性粒细胞明胶酶相关脂质运载蛋白 和肾损伤标志物1。我们预计30%的PITCH-HF人群将患有糖尿病， 放大了HF患者肾损伤的风险，因此，我们在本提案中纳入了重复分析的计划 按照基线糖尿病状态分层为子目标1和2，如果治疗效果在以下患者之间存在差异， 没有糖尿病。母研究缺乏尿液收集和GFR的现代测量，如血清 半胱氨酸蛋白酶抑制剂C，并且在研究期间将不检查GFR的下降或阿基发作的频率。因此，在本发明中， 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、经济和有效的方法来确定 PDE 5抑制的潜在肾保护作用。我们的合作团队拥有高绩效的经验， 肾脏终点的质量辅助研究，以及此类研究的生物样本采集和检测 利用最先进的肾功能和生物学指标。我们的目标是强大的，并专注于良好的- 定义的终点，使我们能够以最小的负担回答重要的临床和科学问题， 受试者和母体研究。PITCH-HF执行委员会和NHLBI评审员同意这一点 该提案可能从根本上改变CKD、阿基和CHF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.