Oxygen versus PAP for treatment of sleep apnea in chronic heart failure

描述(由申请人提供)： 慢性心力衰竭(HF)是一种与高死亡率相关的高度流行的疾病，尽管最近在药物治疗方面取得了进展，但这种疾病仍然存在。在退伍军人事务部，09财年因心力衰竭的门诊就诊人数达到90万人次，退伍军人事务部住院人数超过9.6万人次。中枢性睡眠呼吸暂停(CSA)是一种常见的并存疾病，约三分之一的慢性心力衰竭患者存在中度至重度CSA，并伴有射血分数降低。中枢性睡眠呼吸暂停与慢性心力衰竭的死亡率翻倍有关。一些小型治疗试验显示，在使用持续正压(CPAP)或适应性压力支持伺服呼吸机(ASV)治疗CsA后，左心室射血分数(LVEF)有所改善，尽管CPAP治疗心力衰竭的CsA在无移植存活率方面有所改善，但单一的长期结果研究发现，这种改善并不存在差异。此外，大多数患有CSA的心衰患者没有典型的睡眠呼吸暂停症状，因此通常不愿接受正压治疗带来的不适。因此，需要更好的耐受性和可能更有效的替代正压的方法来治疗慢性心力衰竭患者的CsA。睡眠期间补充氧气已被证明可以减轻一些慢性心力衰竭患者的CsA严重程度。此外，尽管CsA对心衰的不良影响可能是多因素的，但睡眠呼吸暂停的间歇性低氧特征似乎起着核心作用。低氧是睡眠呼吸暂停患者交感神经过度活动的主要原因，它可能通过直接作用于心肌和通过血压升高而导致心肌功能障碍的进展；它刺激活性氧的产生，这可能有助于心肌细胞的损伤和死亡；它还诱导促进全身炎症的转录因子。这表明，夜间低氧血症的预防可能会减轻睡眠呼吸暂停对心脏的不利影响，即使它本身并不能消除环孢素A。本研究是一项随机临床试验，旨在评价夜间补充氧(NSO)、CPAP和ASV治疗射血分数降低的慢性心力衰竭患者环孢素A的疗效。慢性心力衰竭患者的LVEF&lt；45%将在他们自己的家中通过通宵便携式睡眠监测仪进行CSA筛查。共有161名中到重度CSA患者，定义为呼吸暂停低通气指数&gt；15，其中50%的事件是中枢性呼吸暂停或低呼吸暂停，然后将以1：2：2：2的比例随机分配到3个月的治疗中，分别采用最佳医疗管理、最佳医疗管理加CPAP、最佳医疗管理加ASV或最佳医疗管理加夜间补充氧气。主要的结果测量将在基线和治疗期结束时进行，将通过超声心动图测量的LVEF的变化和通过心肺运动试验测量的峰值VO2的变化。次要观察指标将包括24小时动态血压、尿儿茶酚胺排泄量、尿异前列腺素排泄量(氧化应激标志物)、III型胶原氨基末端前肽(心室重塑标志物)、B型利钠肽以及几种炎症标志物的血浆水平。NSO、CPAP和ASV治疗的依从性也将进行比较。初步分析将比较每一个有效的治疗组和对照组。将使用非劣势设计来评估NSO和CPAP是否不逊于ASV。

DESCRIPTION (provided by applicant): Chronic heart failure (HF) is a highly prevalent disease associated with high rates of mortality, which have persisted despite recent advances in pharmacologic therapy. Within the VA, outpatient encounters for HF reached 900,000 in FY09 and VA hospitalizations were over 96,000. Central sleep apnea (CSA) is a common comorbid condition, with moderate to severe CSA present in approximately one-third of patients with chronic HF with reduced ejection fraction. Central sleep apnea is associated with a doubling of mortality in chronic HF. Several small treatment trials show improvement in left ventricular ejection fraction (LVEF) following treatment of CSA with continuous positive airway pressure (CPAP) or adaptive pressure-support servo-ventilation (ASV), although the single long-term outcome study of CPAP therapy for CSA in HF found no difference in transplant-free survival despite improved LVEF. Moreover, most HF patients with CSA do not experience typical sleep apnea symptoms and are therefore often unwilling to accept the discomfort of positive airway pressure therapy. Therefore, better tolerated and possibly more effective alternatives to positive airway pressure are needed for treating CSA in patients with chronic HF. Supplemental oxygen during sleep has been shown to reduce the severity of CSA in some patients with chronic HF. Moreover, although the adverse effects of CSA on HF are likely to be multifactorial, the intermittent hypoxia characteristic of sleep apnea appears to play a central role. Hypoxia is the major cause of sympathetic hyperactivity in sleep apnea, which may contribute to progression of myocardial dysfunction through both direct effects on the myocardium and through elevation of blood pressure; it stimulates the generation of reactive oxygen species, which may contribute to myocyte damage and death; and it induces transcription factors that promote systemic inflammation. This suggests that prevention of nocturnal hypoxemia might mitigate the adverse effects of sleep apnea on the heart, even if it does not eliminate CSA per se. This study is a randomized clinical trial to assess the effects of nocturnal supplemental oxygen (NSO), CPAP and ASV for the treatment of CSA in patients with chronic HF with reduced ejection fraction. Patients with chronic HF with LVEF <45% will be screened for CSA with overnight portable sleep monitoring in their own home. A total of 161 patients with moderate to severe CSA, defined as an apnea-hypopnea index >15 with >50% of events being central apneas or hypopneas, will then be randomized in a 1:2:2:2 ratio to 3 months of treatment with optimal medical management alone, optimal medical management plus CPAP, optimal medical management plus ASV, or optimal medical management plus nocturnal supplemental oxygen. The primary outcome measures, to be made at baseline and at the end of the treatment period, will be change in LVEF as measured by echocardiogram and change in peak VO2 as measured by cardiopulmonary exercise testing. Secondary outcome measures will include 24 hour ambulatory blood pressure profile, urinary catecholamine excretion, urinary excretion of isoprostanes (a marker of oxidative stress), aminoterminal propeptide of type III collagen (a marker of ventricular remodeling), B-type natriuretic peptide, and plasma levels of several markers of inflammation. Adherence to therapy with NSO, CPAP and ASV will also be compared. The primary analysis will compare each of the active treatment groups to control. A non-inferiority design will be used to assess whether NSO and CPAP are non-inferior to ASV.