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，但其仍然存在。在退伍军人管理局，2009财年HF门诊患者达到90万人，退伍军人管理局住院患者超过96000人。中枢性睡眠呼吸暂停（CSA）是一种常见的共病，约三分之一的慢性心力衰竭伴射血分数降低患者存在中度至重度CSA。中枢性睡眠呼吸暂停与慢性心力衰竭患者死亡率加倍相关。几项小型治疗试验显示，采用持续气道正压通气（CPAP）或自适应压力支持伺服通气（ASV）治疗CSA后，左心室射血分数（LVEF）有所改善，尽管CPAP治疗CSA治疗HF的单一长期结局研究发现，尽管LVEF有所改善，但无移植生存率无差异。此外，大多数患有CSA的HF患者不会经历典型的睡眠呼吸暂停症状，因此通常不愿意接受气道正压通气治疗的不适。因此，需要更好的耐受性和可能更有效的替代气道正压通气治疗慢性HF患者的CSA。睡眠期间补充氧气已被证明可以降低某些慢性HF患者的CSA严重程度。此外，尽管CSA对HF的不良影响可能是多因素的，但睡眠呼吸暂停的间歇性缺氧特征似乎起着核心作用。缺氧是睡眠呼吸暂停中交感神经过度活跃的主要原因，这可能通过对心肌的直接影响和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，这可能导致心肌细胞损伤和死亡;它诱导转录因子，促进全身炎症。这表明，预防夜间低氧血症可能会减轻睡眠呼吸暂停对心脏的不良影响，即使它本身不能消除CSA。 本研究是一项随机临床试验，旨在评估夜间补充供氧（NSO）、CPAP和ASV治疗射血分数降低的慢性HF患者CSA的效果。 LVEF <45%的慢性HF患者将在自己家中通过夜间便携式睡眠监测进行CSA筛查。共161例中度至重度CSA患者（定义为呼吸暂停低通气指数>15，>50%的事件为中枢性呼吸暂停或呼吸不足）将以1：2：2：2的比例随机分配至3个月的治疗组，分别接受仅最佳药物管理、最佳药物管理加CPAP、最佳药物管理加ASV或最佳药物管理加夜间补充供氧。在基线和治疗期结束时进行的主要结局指标将是通过超声心动图测量的LVEF变化和通过心肺运动试验测量的峰值VO 2变化。次要结局指标将包括24小时动态血压曲线、尿儿茶酚胺排泄、异前列腺素（氧化应激的标志物）的尿排泄、III型胶原的氨基末端前肽（心室重塑的标志物）、B型利钠肽和几种炎症标志物的血浆水平。还将比较NSO、CPAP和ASV治疗的依从性。主要分析将比较每个活性治疗组与对照组。将采用非劣效性设计评估NSO和CPAP是否非劣效于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.