Division of Cardiology, Department of Pediatrics, Riley Hospital for Children, Indiana Univ. School of Medicine, Indianapolis, IN 46202.
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892.
Am Heart J. 2019 Nov;217:52-63. doi: 10.1016/j.ahj.2019.08.002. Epub 2019 Aug 9.
Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials.
儿童抗凝存在诸多问题。目前使用的抗凝剂存在明显的弊端，可能会对生活质量（QOL）产生负面影响。本文描述了一项直接口服抗凝剂（DOAC）阿哌沙班在先天性和后天性心脏病儿童和婴儿中进行的前瞻性、随机、开放标签 II 期多国临床试验的设计、原理和方法。该试验旨在收集初步的安全性和药代动力学（PK）数据，并生成与标准治疗（SOC）抗凝剂维生素 K 拮抗剂（VKA）或低分子肝素（LMWH）相比，使用阿哌沙班的个体的 QOL 数据。该试验旨在解决的一个关键问题是，在没有充分的儿科安全性或疗效数据的情况下，将在成人试验中测试的治疗方法用于儿科人群的做法。儿科心脏病并不常见，具体诊断通常符合罕见病的标准；因此，统计学疗效可能难以实现。该试验将提供有价值的 PK 和安全性数据，旨在为儿科心脏病的抗凝治疗提供临床实践依据，在这种情况下，进行完全有效的 III 期临床试验是不可行的。该试验还解决了一个考虑因素，即除了疗效之外的指标，例如 QOL，在受监管的抗凝研究中尚未传统用作终点，但可能会在使用 DOAC 替代 VKA 或 LMWH 的临床决策中增加实质性权重。该研究检查了随机分配至 SOC 或阿哌沙班的儿童的心脏病和抗凝相关 QOL。通过行业-学术合作在儿科罕见病人群中进行临床试验具有相当大的优势和益处。SAXOPHONE 研究代表了 Bristol-Myers Squibb（BMS）/Pfizer 联盟与美国国立心肺血液研究所（NHLBI）儿科心脏网络（PHN）之间的合作，并且可能是未来儿科药物试验的一个有吸引力的模型。
