Nitric Oxide for Patients with Sickle Cell Anemia and Pulmonary Hypertension

一氧化氮治疗镰状细胞性贫血和肺动脉高压患者

• 批准号: 8344827
• 负责人: Gregory Kato
• 金额: $ 11.91万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8344827
• 关键词: Accounting; Acute; Adult; Adverse event; Anemia; Arginine; Blood Vessels; Breathing; Cardiac; Cardiac Output; Clinical; Clinical Trials; Collaborations; Confidence Intervals; Control Groups; Data; Development; Enrollment; Exercise Tolerance; FDA approved; Hemolysis; Intravenous; Laboratories; Link; Lung; Manuscripts; Monitor; Nature; Nitric Oxide; Normal Statistical Distribution; Oral; Oxygen; Patients; Pharmaceutical Preparations; Population; Preparation; Process; Prostaglandins I; Protocols documentation; Publications; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Radiology Specialty; Relative (related person); Resistance; Right Ventricular Function; Sampling; Secondary to; Sickle Cell; Sickle Cell Anemia; Staging; Symptoms; Testing; Transfusion; Universities; Vasodilator Agents; Ventricular; Walking; bosentan; design; digital; hemodynamics; hydroxyurea; inhaled nitric oxide; mortality; patient population; pressure; pulmonary function; response; sildenafil; statistics

Our studies suggest that secondary pulmonary hypertension is common in adult patients with sickle cell disease, appears to be resistant to hydroxyurea therapy, is linked to hemolysis and is associated with a high mortality. This study evaluated (1) the pathophysiologic processes that are associated with and potentially contribute to secondary pulmonary hypertension in adult patients with sickle cell anemia. (2) the relative acute vasodilatory effects of oxygen, intravenous prostacyclin, and inhaled nitric oxide on pulmonary artery pressures and other hemodynamic parameters in patients with secondary pulmonary hypertension and sickle cell disease. (3) the effects of two months of inhaled nitric oxide on pulmonary artery pressures, other hemodynamic parameters, exercise tolerance and symptoms in this patient population and (4) the effects of three months of exchange transfusion on pulmonary artery pressures, other hemodynamic parameters, exercise tolerance, and symptoms in patients who do not receive or fail to respond to NO therapy. We enrolled 60 subjects in the clinical trial with 50 completing stage I, 16 completing stage II and 7 completing stage III. Due to the availability of FDA approved oral medications, such as Prostacyclin, Bosentan, Sildenafil and L-Arginine, etc, Stage II of this protocol was only offered if the oral medications failed or were not tolerated. There were no adverse events related to the inhalation of nitric oxide and approximately 80% of patients responded with decreases in pulmonary pressures. The efficacy data accrued to date are currently under analysis for publication. Conclusions: The use of six-minute walk distance to evaluate the effects of therapies such as hydroxyurea, transfusion, and selective pulmonary vasodilator and remodeling agents has the potential to accelerate the development of specific therapies for this population. These results suggest that increased pulmonary vascular resistance is poorly tolerated in patients with severe anemia, potentially explaining the increased mortality associated with its development in this population. This protocol is now closed for accrual and is only open for data and sample analysis. We planned to continue analysis for the coming year, which includes: The analysis of Stage I of the protocol consists of descriptive statistics proportions, means, standard deviations, etc. We are comparing these studies to the control group of sickle cell patients that do not have pulmonary hypertension. Protocol hemodynamic, pulmonary function, clinical laboratory and other data are being analyzed in relationship to mortality in preparation for publication. These data are also being analyzed to determine relationships to 1) radiology data obtained during the study, in collaboration with CC Radiology Department collaborators led by D. Daniel Mollura; 2) planned analysis of hemodynamic Witt monitor digital files by calculating right ventricular flow-volume loops, a promising way to determine right ventricular function, in collaboration with University of Pittsburgh cardiologist Hunter Champion. The primary endpoint in Stage II of the protocol is response or no response to study medications, with response defined as a decrease of at least 10% in systolic pulmonary artery pressure. The proportion of responders on each medication (i.e NO, prostacyclin, and oxygen) will be estimated (point estimate and 95% confidence intervals). In addition, point estimates and 95% confidence intervals will be determined for differences between proportions responding to different medications, taking the paired nature of the data into account. We are noting the proportions of patients with every possible combination of responses i.e., response to all three medications, response to NO and oxygen but not to prostacyclin, etc. In particular, we are noting the association between response to NO and response to prostacyclin. Mean absolute changes in systolic pulmonary artery pressure are also being compared among the medications. Change in vascular and cardiac pressure and in cardiac output are also being summarized and compared among medications. For Stage III of the protocol we are analyzing mean pulmonary artery pressure (MPAP) in the completed population by a paired t-test, on the change from baseline (i.e., MPAP at eight weeks vs. MPAP at baseline). The statistical null hypothesis tested is that there is either no change or an increase in mean change of MPAP. It is not expected that the assumption of a normal distribution of the changes will be seriously violated. If it is, however, perhaps because of an extremely skewed distribution of the changes, the baseline and eight-week values may be transformed (probably logarithmically) before calculating the change. A manuscript has been prepared and submitted.

我们的研究表明，在成年患有镰状细胞疾病的成年患者中，继发性肺高血压很常见，似乎对羟基脲疗法具有抗性，与溶血有关，并且与高死亡率有关。 这项研究评估了（1）与镰状细胞贫血患者相关并有助于造成继发性肺动脉高压的病理生理过程。 （2）氧气，静脉注射前列环蛋白和一氧化氮对肺动脉压和其他血液动力学参数的相对急性血管舒张作用对继发性肺动脉高压和镰状细胞病的患者的相对急性血管舒张作用。 （3）两个月吸入一氧化氮对该患者人群中肺动脉压力，其他血流动力学参数，运动耐受性和症状的影响，以及（4）三个月交换输血对肺动脉压力的影响，对其他不接受或未接受症状的患者的肺动脉压力，其他血液动力学参数，运动耐受性。 我们在临床试验中招募了60名受试者，其中有50阶段I，16阶段完成II期和7阶段完成III期。 由于获得了FDA批准的口服药物的可用性，例如前列环素，波森坦，西地那非和L-精氨酸等，仅当口服药物失败或不容忍时才能提供该方案的II阶段。 没有与一氧化氮吸入有关的不良事件，大约80％的患者随着肺部压力的减少反应。 迄今为止累积的功效数据目前正在分析中以进行发布。 结论：使用六分钟步行距离来评估疗法的影响，例如羟基脲，输血和选择性的肺血管扩张剂和重塑剂，有可能加速该人群的特定疗法。 这些结果表明，严重贫血患者的肺血管耐药性较差，有可能解释与该人群发育相关的死亡率增加。 该协议现已关闭以进行应计，仅用于数据和样本分析。 我们计划继续在来年进行分析，其中包括： 该方案的I期分析包括描述性统计比例，均值，标准偏差等。我们将这些研究与没有肺部高血压的对照组的对照组进行了比较。 方案血液动力学，肺功能，临床实验室和其他数据正在与死亡率有关，以准备出版。 还分析了这些数据以确定与1）研究期间获得的放射学数据，并与D. Daniel Mollura领导的CC放射学系合作者合作； 2）与匹兹堡大学心脏病专家亨特·冠军（Hunter Champion）合作，通过计算右心室流量循环来计算右心室流量循环的计划分析。 该方案的II阶段的主要终点是对研究药物的反应或无反应，其反应定义为收缩期肺动脉压力至少降低10％。 将估算每种药物的响应者在每种药物上的比例（即前列环蛋白和氧气）（点估计值和95％的置信区间）。 此外，将点估计值和95％的置信区间用于响应不同药物的比例之间的差异，考虑到数据的配对性质。 我们注意到患者的比例与反应的各种可能组合，即对所有三种药物的反应，对NO和氧气的反应，但对前列环蛋白的反应等。 在药物中，还比较了收缩压动脉压的平均绝对变化。 血管和心脏压力以及心输出量的变化也被总结并在药物中进行比较。 对于该方案的第三阶段，我们正在分析完整人群中的平均肺动脉压力（MPAP），这是对基线的变化（即八周的MPAP，而基线时MPAP的MPAP）。测试的统计零假设是，MPAP的平均变化没有变化或增加。 预计将严重违反变更正态分布的假设。 但是，如果是因为变化的分布极为偏斜，那么在计算变化之前，基线和八周的值可能会转换（可能是对数）。 手稿已准备好并提交。