Background

Treatment options for patients with chronic thromboembolic pulmonary hypertension ineligible for pulmonary endarterectomy (inoperable CTEPH) include balloon pulmonary angioplasty (BPA) and riociguat. However, these two treatment options have not been compared prospectively. We aimed to compare the safety and efficacy of BPA and riociguat in patients with inoperable CTEPH.

Methods

This open-label, randomised controlled trial was conducted at four high-volume CTEPH centres in Japan. Patients aged 20–80 years with inoperable CTEPH (mean pulmonary arterial pressure ≥25 to <60 mm Hg and pulmonary artery wedge pressure ≤15 mm Hg) and WHO functional class II or III were randomly assigned (1:1) to BPA or riociguat via a computer program located at the registration centre using a minimisation method with biased-coin assignment. In the BPA group, the aim was for BPA to be completed within 4 months of the initial date of the first procedure. BPA was repeated until mean pulmonary arterial pressure decreased to less than 25 mm Hg. The frequency of BPA procedures depended on the difficulty and number of the lesions. In the riociguat group, 1·0 mg riociguat was administered orally thrice daily. When the systolic blood pressure was maintained at 95 mm Hg or higher, the dose was increased by 0·5 mg every 2 weeks up to a maximum of 2·5 mg thrice daily; dose adjustment was completed within 4 months of the date of the first dose. The primary endpoint was change in mean pulmonary arterial pressure from baseline to 12 months, measured in the full analysis set (patients who were enrolled and randomly assigned to one of the study treatments, and had at least one assessment after randomisation). BPA-related complications and indices related to clinical worsening were recorded throughout the study period. Adverse events were recorded throughout the study period and evaluated in the safety analysis set (patients who were enrolled and randomely assigned to one of the study treatments, and had received part of or all the study treatments). This trial is registered in the Japan Registry of Clinical Trials (jRCT; jRCTs031180239) and is completed.

Findings

Between Jan 8, 2016, and Oct 31, 2019, 61 patients with inoperable CTEPH were enrolled and randomly assigned to BPA (n=32) or riociguat (n=29). Patients in the BPA group underwent an average of 4·7 (SD 1·6) BPA procedures. In the riociguat group, the mean maintenance dose was 7·0 (SD 1·0) mg/day at 12 months. At 12 months, mean pulmonary arterial pressure had improved by −16·3 (SE 1·6) mm Hg in the BPA group and −7·0 (1·5) mm Hg in the riociguat group (group difference −9·3 mm Hg [95% CI −12·7 to −5·9]; p<0·0001). A case of clinical worsening of pulmonary hypertension occurred in the riociguat group, whereas none occurred in the BPA group. The most common adverse event was haemosputum, haemoptysis, or pulmonary haemorrhage, affecting 14 patients (44%) in the BPA group and one (4%) in the riociguat group. In 147 BPA procedures done in 31 patients, BPA-related complications were observed in 17 procedures (12%) in eight patients (26%).

Interpretation

Compared with riociguat, BPA was associated with a greater improvement in mean pulmonary arterial pressure in patients with inoperable CTEPH at 12 months, although procedure-related complications were reported. These findings support BPA as a reasonable option for inoperable CTEPH in centres with experienced BPA operators, with attention to procedure-related complications.

Funding

Bayer Yakuhin.

Translation

For the Japanese translation of the abstract see Supplementary Materials section.

中文翻译：

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球囊肺血管成形术与利奥西呱治疗不能手术的慢性血栓栓塞性肺动脉高压 (MR BPA)：一项开放标签、随机对照试验

背景

不适合肺动脉内膜切除术（无法手术的 CTEPH）的慢性血栓栓塞性肺动脉高压患者的治疗选择包括球囊肺血管成形术 (BPA) 和利奥西呱。然而，这两种治疗方案尚未进行前瞻性比较。我们旨在比较 BPA 和利奥西呱对无法手术的 CTEPH 患者的安全性和有效性。

方法

这项开放标签、随机对照试验是在日本的四个大容量 CTEPH 中心进行的。20-80 岁不能手术的 CTEPH（平均肺动脉压≥25 至 <60 毫米汞柱和肺动脉楔压≤15 毫米汞柱）和 WHO 功能分级为 II 级或 III 级的患者被随机分配 (1:1) 至 BPA 或利奥西呱通过位于注册中心的计算机程序，使用带有偏差硬币分配的最小化方法。在 BPA 组中，目标是在第一次手术开始后的 4 个月内完成 BPA。重复 BPA 直至平均肺动脉压降至 25 mm Hg 以下。BPA 程序的频率取决于病变的难度和数量。在利奥西呱组中，每天三次口服 1·0 mg 利奥西呱。当收缩压维持在 95 mm Hg 或更高时，剂量每 2 周增加 0·5 mg，最大剂量为 2·5 mg，每日三次；剂量调整在首次给药日期后 4 个月内完成。主要终点是平均肺动脉压从基线到 12 个月的变化，在完整分析集中测量（入组并随机分配到其中一项研究治疗的患者，并在随机化后至少进行了一次评估）。在整个研究期间记录 BPA 相关并发症和与临床恶化相关的指标。在整个研究期间记录不良事件，并在安全性分析集中进行评估（入选并随机分配到其中一种研究治疗，并已接受部分或全部研究治疗的患者）。

发现

2016 年 1 月 8 日至 2019 年 10 月 31 日期间，61 名无法手术的 CTEPH 患者被纳入并随机分配至 BPA（n=32）或 riociguat（n=29）。BPA 组患者平均接受了 4·7 (SD 1·6) 次 BPA 手术。在利奥西呱组中，12 个月时的平均维持剂量为 7·0 (SD 1·0) mg/天。12 个月时，BPA 组的平均肺动脉压提高了 −16·3 (SE 1·6) mm Hg，利奥西呱组的平均肺动脉压提高了 −7·0 (1·5) mm Hg（组间差异为 −9·3毫米汞柱 [95% CI -12·7 至 -5·9]；p<0·0001）。riociguat 组发生了 1 例肺动脉高压临床恶化，而 BPA 组没有发生。最常见的不良事件是咳血、咯血或肺出血，影响 BPA 组 14 名患者 (44%) 和利奥西呱组 1 名 (4%) 患者。

解释

与利奥西呱相比，BPA 与不能手术的 CTEPH 患者在 12 个月时的平均肺动脉压有更大的改善相关，尽管有手术相关并发症的报道。这些发现支持 BPA 作为具有经验丰富的 BPA 操作员的中心不能手术的 CTEPH 的合理选择，并注意与手术相关的并发症。

资金

拜耳药品。

翻译

有关摘要的日文翻译，请参阅补充材料部分。