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LABA/LAMA联用对中、重度COPD患者有益

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发表于 2013-12-11 20:06 |只看该作者 |倒序浏览

LABA/LAMA联用对中、重度COPD患者有益LABA/LAMA combo beneficial in moderate, severe COPD
来源：爱思唯尔 2013-12-02 11:26点击次数：236发表评论分享到

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Ⅲ期AUGMENT试验结果显示，对中、重度慢性阻塞性肺病（COPD）患者采用固定剂量的阿地溴铵与福莫特罗联合治疗改善肺功能的效果优于单用这两种药物，而且未增加毒副作用。

阿地溴铵（TudorzaPressair）400 μg/d是一种长效毒蕈碱受体拮抗剂（LAMA），在2012年获准用作COPD引起的支气管痉挛的长期维持用药。福莫特罗（ForadilAerolizer）是一种长效β2受体激动剂（LABA），也用于控制COPD患者的症状，预防喘息发作。目前有多种固定剂量的LABA/LAMA复方制剂正在研发中，但均未获准用于COPD的治疗。

Anthony D'Urzo医生

多伦多大学初级保健肺科门诊主任Anthony D’Urzo医生在美国胸科医师协会(ACCP)年会的最新摘要会议上指出，往往推荐对COPD患者联用两种作用机制不同的药物，以改善支气管扩张、患者的依从性以及成本效益。

在AUGMENT研究中，研究者将1,692例中、重度COPD患者均衡的随机分配接受以下5种每天2次的计量吸入器治疗方案：阿地溴铵400 μg+福莫特罗6 μg或12 μg；阿地溴铵400 μg单药治疗；福莫特罗12 μg单药治疗，或安慰剂。支气管扩张剂使用前的平均1秒用力呼气量（FEV1）为1.36 ml，患者的平均年龄为64岁。约半数患者为当前吸烟者，这是研究者们有意选择的，以便于反映日常的临床实践。

在第24周时，与单用阿地溴铵相比，低剂量和高剂量的福莫特罗联合治疗在早晨用药1小时后显著增加了FEV1，增幅分别为87 ml和108 ml。具体而言，阿地溴铵单药治疗组FEV1峰值增加176 ml，福莫特罗单药治疗组增加201 ml，低剂量联合用药组增加263 ml，高剂量联合用药组增加284 ml，而使用安慰剂减少37 ml。在24周时，与福莫特罗单药治疗相比，低剂量和高剂量福莫特罗联合治疗也增加了联合主要终点——早晨用药前（谷）FEV1，增幅分别为45和26 ml，但仅较高剂量的联合治疗组的增幅有统计学意义（P=0.010）。细言之，阿地溴铵单药治疗组FEV1谷值增加102 ml，福莫特罗单药治疗组增加85 ml，高剂量联合治疗组增加130 ml，而安慰剂组减少35 ml。

会议共同主持人、美国罗格斯新泽西医学院肺部与重症医学科主任Andrew Berman医生指出，靶向作用于两种不同的受体可明显增加支气管扩张的程度，但问题是联合的作用机制是什么，另外，两药联用是否会产生负面作用。D’Urzo医生对此回应，联合作用机制尚不确定，但有证据表明β2激动剂可以增加支气管平滑肌的松弛程度，而毒蕈碱受体拮抗剂通过调节胆碱能神经传导，减少乙酰胆碱的释放，直接引起支气管平滑肌松弛。

导致治疗终止的不良事件在各个治疗组中相似，严重不良事件亦如此，在高剂量联合治疗组、低剂量联合治疗组、阿地溴铵单药治疗组、福莫特罗单药治疗组以及安慰剂组中的报告率分别为5.7%、5.4%、5%、4.5%以及3.6%。阿地溴铵单药治疗组死亡3例，高剂量福莫特罗联合治疗组和福莫特罗单药治疗组各死亡1例，但均与治疗无关。

还有一项临床试验也报告了正面的结果，但联合开发商森林实验室和Almirall公司在8月份宣布，拟于2013年下半年提交的新药申请正在向后推迟，以便于解决美国食品药品管理局（FDA）提出的与复方制剂有关的“化学、生产和控制规范”方面的顾虑。森林实验室研发总监Marco Taglietti在10月份的盈利电话会议上说，该公司也在为阐释FDA的顾虑做充分的准备，希望能在2014年初将文件提交到FDA。

D’Urzo医生报告与多家药企存在经济联系，其中包括研究的赞助者森林研究所；两位合著者为森林实验室的员工。

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By: PATRICE WENDLING, Internal Medicine News Digital Network

CHICAGO – A fixed-dose combination of aclidinium bromide and formoterolfumarate improved lung function better than either drug alone without increasing toxicity in patients with moderate to severe chronic obstructive pulmonary disease in the phase III AUGMENT trial.

Aclidinium bromide (TudorzaPressair) 400 mcg twice daily is a long-acting muscarinic antagonist (LAMA) approved in 2012 for the long-term maintenance treatment of COPD-associated bronchospasm. Formoterolfumarate (ForadilAerolizer), a long-acting beta2-agonist (LABA), is also used in COPD to control symptoms and prevent wheezing.

Several fixed-dose LABA/LAMA combinations are in development, but none have been approved in COPD.

Combining two agents with different mechanisms of action is often recommended for improved bronchodilation, patient compliance, and cost-effectiveness in patients with COPD, Dr. Anthony D’Urzo said during a late-breaking abstract session at the annual meeting of the American College of Chest Physicians.

AUGMENT investigators (Chest 2013;144[4 MeetingAbstracts]:1025A) evenly randomized 1,692 patients with moderate to severe COPD to one of five twice-daily, metered-dose inhaler treatments: aclidinium 400 mcg plus formoterol 6 mcg or 12 mcg, aclidinium 400 mcg monotherapy, formoterol 12 mcg monotherapy, or placebo. Mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.36 ml, and the mean age of the patients was 64 years. About half of the patients were current smokers, an intentional choice to reflect daily clinical practice, he said.

At week 24, the low- and high-dose formoterol combinations significantly increased FEV1 1 hour after morning dosing by 87 ml and 108 ml, respectively, compared with aclidinium alone (both P< .0001), said Dr. D’Urzo, director of the Primary Care Lung Clinic, University of Toronto.

Specifically, peak FEV1 increased by 176 ml with aclidinium alone, 201 ml with formoterol alone, 263 ml with the low-dose combination, and 284 ml with the high-dose combination, and decreased by 37 ml with placebo.

The low- and high-dose formoterol combinations also increased the coprimary endpoint of morning predose (trough) FEV1 at week 24 by 45 ml and 26 ml, respectively, compared with formoterol alone, but the increase was significant only for the higher-dose combination (P = .010), he said.

Specifically, trough FEV1 increased by 102 ml with aclidinium alone, 85 ml with formoterol alone, 111 ml with the low-dose combination, and 130 ml with the high-dose combination, and decreased by 35 ml with placebo.

Session comoderator Dr. Andrew Berman, division director of pulmonary and critical care medicine at Rutgers New Jersey Medical School in Newark, said targeting two different receptors clearly increases the degree of bronchodilation, but he questioned what the combined mechanism of action is and whether there’s perhaps a negative effect when combining two drugs since most clinicians would agree there’s only so much the airways can dilate.

Dr. D’Urzo said the combined mechanism is uncertain, but that there is evidence which suggests that beta2-agonists may augment the bronchial smooth muscle relaxation that is directly induced by muscarinic antagonists via a mechanism that decreases the release of acetylcholine via a modulation of cholinergic neurotransmission.

Adverse events leading to treatment discontinuation were similar across treatment arms, as were serious adverse events reported in 5.7% of patients on the high-dose combination, 5.4% on the low-dose combination, 5% on aclidinium alone, 4.5% on formoterol alone, and 3.6% on placebo. Three deaths occurred in the aclidiniummonotherapy arm and one each in the high-dose formoterol combination and formoterolmonotherapy arms, but none were thought related to treatment, he said.

Positive results have been reported from a second clinical trial, but codevelopers Forest Laboratories and Almirallannounced in August that the New Drug Application submission planned for late 2013 was being delayed in order to resolve concerns raised by the Food and Drug Administration related to "chemistry, manufacturing, and control specifications associated with the combination formula." Forest is preparing a "robust package to address the FDA’s concerns" and is hoping to meet with its officials in early 2014, Forest R&D president Marco Taglietti said during an October earnings conference call.

Dr. D’Urzo reported having financial ties with several drug firms, including study sponsor Forest Research Institute; two coauthors are Forest employees.

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学科代码：呼吸病学　　　关键词：阿地溴铵与福莫特罗联用美国胸科医师协会(ACCP)年会
来源： 爱思唯尔
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