Riociguat对肺高压持续有效

芝加哥——两项长期扩展研究显示，接受riociguat治疗1年后，慢性血栓栓塞性肺高压和肺动脉高压患者仍能从中获益。

法国Kremlin Bicêtre医院呼吸与危重症科的Gérald Simonneau医生在近期举行的美国胸科医师协会(ACCP)年会上指出，riociguat(adempas)是第一种被批准用于治疗慢性血栓栓塞性肺高压(CTEPH)的药物，也是第一种能给此类患者带来6分钟步行距离和功能分级方面的持续获益的药物。

Riociguat是一种口服的可溶性鸟苷酸环化酶激活物，基于Ⅲ期CHEST-1和PATENT-1研究的结果，于2013年10月在美国获准用于治疗CTEPH和肺动脉高血压(PAH)。

在CHEST-1中，261例不能手术的CTEPH或持续性PAH患者在动脉内膜切除术后被随机分组，接受安慰剂或剂量最高达2.5 mg、3次/d的riociguat治疗，为期16周。共有237例患者被纳入CHEST-2，维持最佳的riociguat剂量，最高达2.5 mg、3次/d，或者从安慰剂改为riociguat，剂量可增至2.5 mg、3次/d。1年时，只有8%的患者还需要使用其他的PAH药物。

Simonneau医生指出，一直接受riociguat治疗的患者在1年时的6分钟步行距离仅增加了15米，但与基线水平相比总共增加了66米。从安慰剂改为riociguat的患者， 1年时的6分钟步行距离增加了37米，但与基线水平相比总共只增加了45米。

Riociguat维持治疗组和安慰剂转riociguat组分别有15%和30%的患者获得了WHO功能分级的改善。1年时和2年时的无临床恶化率分别为88%和80%，估计总生存率分别为97%和94%。

在对研究结果进行讨论时，Simonneau医生观察发现，在CTEPH患者中，接受手术治疗的患者的2年总生存率约为92%，而接受传统药物治疗的患者仅为70%左右。

不良事件

在CHEST-2中发生了一例致死性肺出血，但研究者认为该事件与研究药物无关。Simonneau医生指出，riociguat说明书包含有关肺出血事件风险的警告。

加州大学圣迭戈分校的Lewis Rubin医生报告称，在PATENT-2中发生了2例致死性肺出血，其中1例与riociguat有关，但最终痊愈。

咯血是另一种PAH和CTEPH患者都很关心的严重不良事件(SAE)。PATENT-1试验中有2例患者(1%)发生严重咯血，在扩展阶段另外发生了7例(2%)。其中只有1例未能痊愈，5例为中度。这些事件均被认为与研究药物无关，尽管不能完全排除相关的可能性。

Rubin医生表示：“肺出血相关性SAE的结局一般是痊愈，而且似乎与riociguat的使用剂量和咯血的发生无关。不过，我们仍需要进一步澄清其发生机制。”

两项CHEST研究分别发生了3例严重咯血事件，其中1例患者需要接受支气管动脉栓塞术。所有患者发生事件时均正在接受抗凝血剂治疗，这些事件均被认为与研究药物无关。

CHEST-2中有100例(42%)患者发生了SAE，其中12例被认为与riociguat有关。PATENT-2中有204例(52%)患者报告SAE，其中7%被认为与研究药物有关。晕厥是最常见的不良事件(2%)。

PATENT研究

PATENT-1将443例PAH患者随机分组，给予安慰剂或riociguat剂量递增至1.5 mg或2.5 mg、3次/d。共有98%的患者(434例)参加了PATENT-2研究，接受riociguat治疗，剂量递增至2.5 mg、3次/d。值得注意的是，54%的患者在1年时正在服用其他PAH药物(最初接受riociguat治疗的患者中的97%，对照组患者中的11%)。

PATENT-1研究结束时，初始即接受最大剂量riociguat治疗的患者的6分钟步行距离从平均400米增至417米，增加17米；初始接受riociguat 1.5 mg治疗的患者，从406米增至417米，增加11米；曾接受安慰剂治疗的患者，从390米增至426米，增加36米。

所有三组患者的WHO功能分级均提高约10%。1年时和2年时的无临床恶化率分别为88%和77%，估计总生存率分别为97%和93%。

CHEST-2和PATENT-2获得了riociguat生产商拜耳医药保健的支持。Simonneau医生和Lewis医生报告称与包括拜耳在内的多家药企有利益关系。

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By: PATRICE WENDLING, Internal Medicine News Digital Network

CHICAGO – Patients with chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension maintained benefits with riociguat at 1 year in two long-term extension studies.

Riociguat (Adempas) is the first drug approved for chronic thromboembolic pulmonary hypertension (CTEPH) and the first to show sustained benefits in 6-minute walk distance and functional class in this setting, Dr. GéraldSimonneau said in a late-breaking session at the annual meeting of the American College of Chest Physicians.

The oral soluble guanylatecyclase stimulator was approved in the United States in October 2013 to treat CTEPH and pulmonary arterial hypertension (PAH) based on the phase III CHEST-1 and PATENT-1 studies.

CHEST-1 randomized 261 patients with inoperable CTEPH or persistent pulmonary hypertension after endarterectomy to placebo or riociguat up to 2.5 mg three times daily for 16 weeks.

In all, 237 patients entered CHEST-2, and were either maintained on their optimum riociguat dose, up to 2.5 mg three times daily, or switched to riociguat titrated up to 2.5 mg three times daily. Only 8% of patients required additional PAH drugs at 1 year.

Patients maintained on riociguat gained only 15 m on the 6-minute walk test at 1 year, but added 66 m overall from baseline, said Dr. Simonneau, head of pneumology and intensive care medicine at Hôpital Kremlin Bicêtre, University of Paris-Sud, Le Kremlin-Bicêtre, France.

Patients switching from placebo to riociguat gained 37 m in the walk test at 1 year, but only 45 m from baseline.

WHO functional class improved in about 15% of patients in the riociguat maintenance arm and about 30% of those switched from placebo, he reported.

Freedom from clinical worsening at years 1 and 2 were 88% and 80%, with estimated overall survival rates of 97% and 94%.

During a discussion of the results, Dr. Simonneau observed that the 2-year overall survival rate for CTEPH patients is approximately 92% for patients treated surgically, but only about 70% for those receiving traditional medical therapy.

Adverse events

One fatal pulmonary hemorrhage occurred during CHEST-2, but it was not considered related to the study drug, said Dr. Simonneau, who noted that riociguat's label includes a warning about the risk of pulmonary bleeding events.

Two fatal pulmonary hemorrhages occurred in PATENT-2, and one was related to riociguat, Dr. Lewis Rubin reported during the same session. A third serious pulmonary hemorrhage occurred that was considered related to riociguat, but it resolved.

Hemoptysis was another serious adverse event (SAE) of "interest and concern" in both pulmonary arterial hypertension and CTEPH patients, said Dr. Rubin of the University of California, San Diego. Two patients (1%) had serious hemoptysis in PATENT-1, with seven additional events occurring in the extension phase (2%). All but one case resolved, five were moderate, and no cases were considered related to the study drug, although this could not be entirely excluded.

"The outcome of pulmonary bleeding-related SAEs was, in general, resolved in most cases, and there does not appear to be an association between dose of riociguat used and the occurrence of hemoptysis," said Dr. Rubin. However, "we need some further clarification on the mechanism responsible," he added.

Six serious hemoptysis events occurred in the two CHEST studies (three each), and one patient required bronchial artery embolization. All patients were receiving anticoagulants and none of these events was considered related to the study drug, Dr. Simonneau said.

Overall, 100 (42%) patients in CHEST-2 had a serious AE, and 12 were considered related to riociguat. SAEs were reported in 204 patients (52%) in PATENT-2, with 7% considered study drug related. Syncope was the most common adverse event (2%).

PATENT study

PATENT-1 randomized 443 patients with PAH to placebo or riociguat titrated to 1.5 mg or 2.5 mg three times daily. In all, 98% of patients (434) entered PATENT-2 and received riociguat titrated up to 2.5 mg three times daily. Notably, 54% of patients were on additional PAH medications at 1 year (97% of those pretreated with riociguat and 11% of controls).

Six-minute walk distances increased from a mean of 400 m at the close of PATENT-1 to 417 m in patients initially given the maximum dose of riociguat, for a gain of 17 m; from 406 to 417 m in those initially capped at riociguat 1.5 mg; and from 390 to 426 m in the former placebo group, Dr. Rubin said.

WHO functional class improved by approximately 10% in all three arms.

Freedom from clinical worsening at 1 and 2 years was 88% and 77%, with overall survival estimated at 97% and 93%, he said.

CHEST-2 and PATENT-2 are supported by Bayer Healthcare, maker of riociguat. Dr. Simonneau and Dr. Lewis reported financial relationships with several drug companies including Bayer.