Assistance Publique-Hôpitaux de Paris (APHP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France; INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France; INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Service de Radiologie, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
Lancet Respir Med. 2022 Oct;10(10):961-971. doi: 10.1016/S2213-2600(22)00214-4. Epub 2022 Aug 1.
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.
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/cm. 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/cm benefited from add-on riociguat after BPA or add-on BPA after riociguat. This trial is registered at ClinicalTrials.gov, NCT02634203, and is completed.
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).
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.
Programme Hospitalier de Recherche Clinique of the French Ministry of Health and Bayer HealthCare.
For the French translation of the abstract see Supplementary Materials section.
利奥西呱和球囊肺动脉成形术（BPA）是治疗不能手术的慢性血栓栓塞性肺动脉高压（CTEPH）的选择。然而，缺乏比较这些治疗方法的随机对照试验。我们旨在评估 BPA 与利奥西呱在不能手术的 CTEPH 患者中的疗效和安全性。
在这项由法国 23 个肺动脉高压专业中心进行的 3 期、多中心、开放标签、平行组、随机对照试验中，我们纳入了年龄在 18-80 岁之间、新诊断为不能手术的 CTEPH 和肺血管阻力大于 320 dyn·s/cm 的初次接受治疗的患者。患者通过基于网络的随机化系统（无分层）以 1:1 的比例随机分配到 BPA 或利奥西呱组。主要终点是第 26 周时肺血管阻力的变化，以意向治疗人群中基线肺血管阻力的百分比表示。安全性分析在所有至少接受过一次利奥西呱剂量或至少接受过一次 BPA 治疗的患者中进行。完成 RACE 试验的患者继续进行 26 周的辅助随访，在此期间，肺血管阻力大于 320 dyn·s/cm 的有症状患者在 BPA 后加用利奥西呱或在利奥西呱后加用 BPA。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT02634203，已经完成。
在 2016 年 1 月 19 日至 2019 年 1 月 18 日期间，共有 105 名患者被随机分配到利奥西呱组（n=53）或 BPA 组（n=52）。在第 26 周时，BPA 组的肺血管阻力几何平均值下降到基线肺血管阻力的 39.9%（95%CI 36.2-44.0），利奥西呱组下降到基线肺血管阻力的 66.7%（60.5-73.5）（几何均数比 0.60，95%CI 0.52-0.69；p<0.0001）。BPA 组有 22 名（42%）患者和利奥西呱组有 5 名（9%）患者发生与治疗相关的严重不良事件。最常见的与治疗相关的严重不良事件是肺损伤（BPA 组 18 [35%]例和利奥西呱组 2 [4%]例）和严重低血压伴晕厥（利奥西呱组 2 例[4%]）。没有与治疗相关的死亡。在第 52 周时，接受一线利奥西呱或一线 BPA 治疗的患者肺血管阻力的降低程度相似（几何均数比 0.91，95%CI 0.79-1.04）。在预先接受利奥西呱治疗的患者中，BPA 相关的严重不良事件发生率较低（36 名患者中有 5 名[14%]和 52 名患者中有 22 名[42%]）。
在第 26 周时，BPA 降低肺血管阻力的效果比利奥西呱更明显，但 BPA 相关的严重不良事件更常见。在随访研究中，与接受 BPA 作为一线治疗的患者相比，预先接受利奥西呱治疗的患者中 BPA 相关的严重不良事件较少，这表明在不能手术的 CTEPH 患者中采用多模式治疗方法可能有潜在的益处。需要进一步的研究来探索在不能手术的 CTEPH 患者中联合使用一种或两种药物和 BPA 的序贯治疗的效果。
法国卫生部和拜耳医疗保健公司的医院临床研究计划。
