CLINICAL TRIAL: AASK-ABPM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 1.具体目标：患有高血压肾病的非裔美国人夜间血压升高的发生率极高。在这一人群中，降低夜间血压是否能预防心血管-肾脏并发症是未知的，降低夜间血压的可行性也是未知的。这项先导性研究是一项长期研究计划的第一步，该计划将确定夜间降压作为高血压慢性肾脏疾病的治疗干预措施的作用。在这项初步研究中被确定为有效和安全的策略将被用于更大规模的试验，以评估它们对临床终点的影响。这项先导性研究的总体目标是确定两种基于雷米普利的降压方案的效果，每种方案都旨在降低夜间血压1一个特定的目标1确定每种策略相对于常规治疗对夜间血压的影响。具体目标2确定与常规治疗相关的每种策略对临床血压、日间血压、24小时血压和低血压状态的影响。 背景和原理在几项观察性研究中，夜间血压升高与不良的肾脏和心血管结局相关。例如，在Piuma的研究中，非勺型女性的心血管发病率是勺型女性的6倍(相对风险，6.79，p0.05)。1在SYST-EUR研究中，每增加10%的夜间/白天收缩压，心血管事件的风险就增加41%(p=0.03)。2在一项对糖尿病患者的小型但具有挑衅性的回顾分析中，SturRock等人证明，勺型糖尿病患者的死亡率低于非勺型糖尿病患者(8vs26%，3与传统的血压测量相比，动态血压监测与微量白蛋白尿的存在和/或程度更密切相关。4，5-7此外，夜间血压下降缓慢的患者更有可能出现微量白蛋白尿。一些小型研究前瞻性地评估了动态血压与肾功能下降和蛋白尿的关系。在一项为期3年的前瞻性研究中，Timio等人表明，非勺型患者的肌酐清除率下降速度比勺型患者快(0.37±0.2比0.27±0.09毫升/分/月)；在另一项研究中，在24个月内肌酐清除量的下降与夜间平均舒张压(r=0.52p=0.001)和夜间舒张压下降(r=0.61p=0.001)之间有显著的相关性。9在最近的一项前瞻性研究中，纳入了75名尿白蛋白排泄和血压正常的1型糖尿病患者，睡眠中收缩压的升高先于微量白蛋白尿的发展。在那些睡眠期间血压正常下降的人中，从正常白蛋白排泄到微量白蛋白尿的进展不太可能。10如随后所述，来自AASK队列研究的横断面数据证实并扩展了这些观察结果。这些观察性研究的结果提出了一个关键的研究问题，即降低夜间血压是否会降低肾脏和心血管疾病的风险？据我们所知，还没有试验解决这个问题，可能是因为关于可能降低夜间血压的干预措施的信息很少。两个试验，一个在欧洲，一个在日本，已经解决了这个可行性问题。在148名非勺型高血压患者中，Hermida等人证明，PM服用valsartan可使75%的患者转为勺型，同时与AM服药相比，24小时平均降压效果相似(AM服药为13/8.5 mm Hg，PM服药为14.7/10.3 mm Hg)。11类似地，黑田等人比较了37名患者服用AM和PM的曲度普利。24小时平均血压降低相似(AM为7.2 mm Hg，PM为5.2 mm Hg)，但PM服用曲多普利(11 Mm Hg)的平均夜间血压降低幅度高于AM(3.6 mm Hg)。还有12项研究在睡前服用多沙唑嗪、13-15尼索地平、地尔硫卓或维拉帕米。然而，这些研究没有包括非洲裔美国人、慢性肾脏疾病患者或服用多种药物方案的个人，即心血管-肾脏结果的高风险患者，他们在临床结果试验中逻辑上是研究人群。一项正在进行的临床试验研究，日本晨峰-1(JMS-1)，正在评估通过交感神经系统阻断在夜间使用阿尔法阻滞剂多沙唑嗪和必要时添加β阻滞剂来严格控制早晨的血压是否可以减少高血压靶器官的损害。 在心脏结局预防评估(HOPE)研究中，雷米普利作为方案的一部分在夜间服用。这项研究显示，与安慰剂相比，雷米普利组的心血管风险显著降低。20夜间血压降低是否有助于降低心血管风险尚不能证实，但这是一个合理的考虑。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 1. Specific Aims: African-Americans with hypertensive kidney disease have an extremely high prevalence of elevated nocturnal blood pressure (BP). Whether reducing nocturnal BP prevents cardiovascular-renal complications in this population is unknown, as is the feasibility of lowering nocturnal BP. This pilot study is the first step in a long-term research initiative that will determine the role of nocturnal blood pressure reduction as a therapeutic intervention in hypertensive chronic kidney disease. Strategies identified as effective and safe in this pilot study will be used in larger trials to evaluate their effect on clinical end points. The overall goal of this pilot study is to determine the effects of two ramipril based ntihypertensive regimen strategies, each designed to lower nocturnal BP a Specific Aim 1 Determine the effects of each strategy, relative to usual treatment, on nocturnal BP. Specific Aim 2 Determine the effects of each strategy, relative to usual treatment, on clinic BP, daytime BP, 24 hour BP, and dipping status. 2. Background and rationale Elevated nocturnal BP has been associated with adverse renal and cardiovascular outcomes in several observational studies. For example, in the PIUMA study, women who were non-dippers had six fold higher cardiovascular morbidity than dippers (relative risk, 6.79, p0.05).1 In the Syst-Eur study, for every 10% higher night/day ratio of systolic BP, the risk of cardiovascular events was increased by 41% (p=0.03).2 In a small, but provocative retrospective analysis of diabetics, Sturrock et al demonstrated that dippers had a lower mortality than non-dippers (8 vs 26%, p=0.04) and that non-dippers who developed renal insufficiency had the highest mortality (42%).3 Compared to conventional BP measurements, ABPM is more closely associated with the presence and/or magnitude of microalbuminuria. 4,5-7 In addition, patients with a blunted nocturnal decline in BP are more likely to have microalbuminuria. A few small studies have prospectively evaluated the relationship between ABPM and decline in renal function and proteinuria. In a 3 year prospective study, Timio etal demonstrated that the non-dippers had a faster rate of creatinine clearance decline than the dippers (0.37¿ 0.2 vs. 0.27¿ 0.09 ml/min/month; p = 0.002).8 In another study, a significant association was reported between the decline in creatinine clearance over a 24-month period and average nighttime diastolic BP (r = 0.52, p = 0.001) and nocturnal diastolic fall (r = 0.61, p 0.001).9 In a recent prospective study that enrolled 75 young adults with type 1 diabetes with normal urinary albumin excretion and blood pressure, an increase in systolic blood pressure during sleep preceded the development of microalbuminuria. In those whose blood pressure during sleep decreased normally, the progression from normal albumin excretion to microalbuminuria was less likely.10 As described subsequently, cross-sectional data from the AASK cohort study corroborates and extends these observations. The results of these observational studies raise a critical research question, namely, does lowering nocturnal BP reduce the risk of renal and cardiovascular disease? To our knowledge, no trial has addressed this issue, perhaps because there is scant information about interventions that might lower nocturnal BPs. Two trials, one in Europe and one in Japan, have addressed this feasibility issue. In 148 non-dipper hypertensive patients, Hermida et al demonstrated that PM administration of valsartan resulted in the conversion to a dipper profile in 75% of patients while achieving similar 24 hour mean BP reduction compared to AM administration (13/8.5 mmHg in AM vs 14.7/10.3 mmHg in PM).11 Similarly, Kuroda et al compared AM versus PM administration of trandalopril in 37 patients. Reduction in 24 hour mean BP was similar (7.2 mmHg in AM, 5.2 mmHg in PM), but reduction of mean night time BP was higher with the PM administration of trandolapril (11 mm Hg) compared to the AM administration (3.6 mm Hg).12 Other studies have used doxazosin,13-15 nisoldipine, diltiazem or verapamiladministered at bed time. 161718However, these studies did not include African-Americans, patients with chronic kidney disease, or individuals on multiple drug regimens, that is, patients at high risk for cardiovascular-renal outcomes who would be logically the study population in a clinical outcome trial. An ongoing clinical trial study in progress, the Japan Morning Surge-1 (JMS-1), is evaluating whether strict morning blood pressure control by sympathetic nervous system blockade using an alpha-blocker, doxazosin at night time and with the addition of a beta-blocker if needed, can reduce hypertensive target organ damage.19 In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril was administered at night time as a part of the protocol. This study showed significant reduction in cardiovascular risk in the ramipril group compared to placebo.20 Whether night time blood pressure reduction contributed to reduction in cardiovascular risk cannot be confirmed, but is a reasonable consideration.