Background

Riociguat and balloon pulmonary angioplasty (BPA) are treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, randomised controlled trials comparing these treatments are lacking. We aimed to evaluate the efficacy and safety of BPA versus riociguat in patients with inoperable CTEPH.

Methods

In this phase 3, multicentre, open-label, parallel-group, randomised controlled trial done in 23 French centres of expertise for pulmonary hypertension, we enrolled treatment-naive patients aged 18–80 years with newly diagnosed, inoperable CTEPH and pulmonary vascular resistance of more than 320 dyn·s/cm⁵. Patients were randomly assigned (1:1) to BPA or riociguat via a web-based randomisation system, with block randomisation (block sizes of two or four patients) without stratification. The primary endpoint was change in pulmonary vascular resistance at week 26, expressed as percentage of baseline pulmonary vascular resistance in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of riociguat or had at least one BPA session. Patients who completed the RACE trial continued into an ancillary 26-week follow-up during which symptomatic patients with pulmonary vascular resistance of more than 320 dyn·s/cm⁵ benefited from add-on riociguat after BPA or add-on BPA after riociguat. This trial is registered at ClinicalTrials.gov, NCT02634203, and is completed.

Findings

Between Jan 19, 2016, and Jan 18, 2019, 105 patients were randomly assigned to riociguat (n=53) or BPA (n=52). At week 26, the geometric mean pulmonary vascular resistance decreased to 39·9% (95% CI 36·2–44·0) of baseline pulmonary vascular resistance in the BPA group and 66·7% (60·5–73·5) of baseline pulmonary vascular resistance in the riociguat group (ratio of geometric means 0·60, 95% CI 0·52–0·69; p<0·0001). Treatment-related serious adverse events occurred in 22 (42%) of 52 patients in the BPA group and five (9%) of 53 patients in the riociguat group. The most frequent treatment-related serious adverse events were lung injury (18 [35%] of 52 patients) in the BPA group and severe hypotension with syncope (two [4%] of 53 patients) in the riociguat group. There were no treatment-related deaths. At week 52, a similar reduction in pulmonary vascular resistance was observed in patients treated with first-line riociguat or first-line BPA (ratio of geometric means 0·91, 95% CI 0·79–1·04). The incidence of BPA-related serious adverse events was lower in patients who were pretreated with riociguat (five [14%] of 36 patients vs 22 [42%] of 52 patients).

Interpretation

At week 26, pulmonary vascular resistance reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. The finding of fewer BPA-related serious adverse events among patients who were pretreated with riociguat in the follow-up study compared with those who received BPA as first-line treatment points to the potential benefits of a multimodality approach to treatment in patients with inoperable CTEPH. Further studies are needed to explore the effects of sequential treatment combining one or two medications and BPA in patients with inoperable CTEPH.

Funding

Programme Hospitalier de Recherche Clinique of the French Ministry of Health and Bayer HealthCare.

Translation

For the French 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 (RACE)：一项多中心、3 期、开放标签、随机对照试验和辅助随访研究

背景

Riociguat 和球囊肺血管成形术 (BPA) 是无法手术的慢性血栓栓塞性肺动脉高压 (CTEPH) 的治疗选择。然而，缺乏比较这些治疗的随机对照试验。我们旨在评估 BPA 与利奥西呱对无法手术的 CTEPH 患者的疗效和安全性。

方法

在这项在法国 23 个肺动脉高压专业中心进行的多中心、开放标签、平行组、随机对照试验中，我们招募了年龄在 18-80 岁之间的初治患者，他们患有新诊断的、不能手术的 CTEPH 和肺血管阻力超过 320 dyn·s/cm ⁵. 通过基于网络的随机化系统，患者被随机分配 (1:1) 至 BPA 或 riociguat，块随机化（块大小为 2 名或 4 名患者），没有分层。主要终点是第 26 周时肺血管阻力的变化，表示为意向治疗人群中基线肺血管阻力的百分比。对接受至少一剂利奥西呱或至少接受过一次 BPA 疗程的所有患者进行了安全性分析。完成 RACE 试验的患者继续进行为期 26 周的辅助随访，在此期间肺血管阻力超过 320 dyn·s/cm ⁵的有症状患者受益于 BPA 后附加利奥西呱或利奥西呱后附加 BPA。该试验在 ClinicalTrials.gov 注册，NCT02634203，并已完成。

发现

2016 年 1 月 19 日至 2019 年 1 月 18 日期间，105 名患者被随机分配至利奥西呱 (n=53) 或 BPA (n=52)。在第 26 周，BPA 组的几何平均肺血管阻力下降至基线肺血管阻力的 39·9% (95% CI 36·2–44·0) 和 66·7% (60·5–73·5) ) 利奥西呱组的基线肺血管阻力（几何平均值比 0·60，95% CI 0·52–0·69；p<0·0001）。BPA 组 52 名患者中的 22 名 (42%) 和利奥西呱组 53 名患者中的 5 名 (9%) 发生了与治疗相关的严重不良事件。最常见的治疗相关严重不良事件是 BPA 组的肺损伤（52 名患者中的 18 名 [35%]）和利奥西呱组的严重低血压伴晕厥（53 名患者中的 2 名 [4%]）。没有与治疗相关的死亡。在第 52 周，在接受一线利奥西呱或一线 BPA 治疗的患者中观察到类似的肺血管阻力降低（几何平均值比为 0·91，95% CI 0·79–1·04）。BPA 相关严重不良事件的发生率在接受利奥西呱预治疗的患者中较低（36 名患者中有 5 名 [14%]对比52 名患者中的 22 名 [42%]）。

解释

在第 26 周时，双酚 A 组的肺血管阻力降低比利奥西呱更明显，但双酚 A 组与治疗相关的严重不良事件更常见。与接受 BPA 作为一线治疗的患者相比，在后续研究中接受利奥西呱预治疗的患者中 BPA 相关严重不良事件的发现表明，对无法手术的 CTEPH 患者采用多模式治疗方法具有潜在益处. 需要进一步的研究来探索结合一种或两种药物和 BPA 的序贯治疗对不能手术的 CTEPH 患者的影响。

资金

法国卫生部和 Bayer HealthCare 的 Hospitalier de Recherche Clinique 计划。

翻译

有关摘要的法语翻译，请参阅补充材料部分。