噻托溴铵可减少哮喘控制不良患者的发作

《新英格兰医学杂志》(New England Journal of Medicine) 9月3日在线发表的一篇关于2项随机对照试验的报告显示，对于虽然使用了吸入性糖皮质激素和长效β受体激动剂(LABA)但哮喘仍控制不良的部分成年患者，在标准联合治疗的基础上加用噻托溴铵可能有助于减少哮喘的发作次数(N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMoa1208606])。

噻托溴铵是全球最常用的治疗慢性阻塞性肺病(COPD)的长效抗胆碱能吸入性支气管扩张剂，但直到最近才开始研究其是否也可以作为哮喘患者的辅助治疗用药。

荷兰格罗宁根大学/格罗宁根哮喘与COPD研究所的Huib A. M. Kerstjens博士及其同事在2项48周随机对照试验中评估了该药用于哮喘患者的疗效，试验在全球15个国家开展，研究经费均由勃林格-殷格翰和辉瑞公司提供。与此同时，Kerstjens博士及其同事还在欧洲呼吸学会(ERS)2012年会上报告了该研究结果。

这2项研究共纳入912例年龄介于18~75岁且哮喘病程≥5年的成年患者，所有患者每日使用吸入性糖皮质激素和LABA但仍然存在持续性气流受限。将受试者随机分为2组，分别自行使用噻托溴铵(第1项试验237例，第2项试验219例)或安慰剂(第1项试验222例，第2项试验234例)气雾剂，每日清晨使用1次，通过软雾吸入器给药，以此作为糖皮质激素和LABA的添加治疗。

试验期间，允许患者继续使用稳定剂量的茶碱缓释剂、白三烯调节剂、抗免疫球蛋白E抗体或口服糖皮质激素，同时也向患者提供了开放标签的沙丁胺醇或舒喘灵作为急救用药。

这2项试验的前2个肺功能终点均为第24周的第1秒用力呼气量(FEV1)峰值反应和FEV1谷值反应，表示为与基线FEV1相比的变化。在第1项试验中，噻托溴铵组的FEV1峰值反应比安慰剂组平均高86 ml，在第2项试验中高154 ml，差异均有统计学意义。在第1项和第2项试验中，噻托溴铵组和安慰剂组在FEV1谷值反应上的平均差异分别为88 ml 和111 ml，这种差异“相对较小”，但仍然具有统计学意义。

研究者指出：“值得注意的是，出现这些差异的是已经使用了长效支气管扩张剂并且存在持续性气流受限的患者。”此外，还应该考虑到“这样的患者人群需要接受进一步治疗，但目前可选的治疗方法很有限”。

第3个肺功能终点是至少25%的患者首次出现哮喘严重发作的时间，结果显示噻托溴铵组(282天)比安慰剂组(226 天)推迟了56天。

哮喘严重发作的次数是这2项试验的次要终点，噻托溴铵组为0.53次/人年，安慰剂组为0.66次/人年，差异有统计学意义。此外，2项试验的噻托溴铵组都只有27%的患者至少出现过1次严重发作，而安慰剂组均有33%，差异也有统计学意义。

不过，在2项试验中噻托溴铵组和安慰剂组在与哮喘相关的生活质量上无显著差异。研究者采用哮喘控制问卷7和32项哮喘生活质量问卷进行评估，但组间差异没有达到最小临床意义。同样，患者每日记录的症状日志显示，两组在无症状天数上的差异“较小或者无统计学意义”。此外，两组急救用药的使用情况也类似。

噻托溴铵组的不良事件发生率为73.5%，安慰剂组为80.3%，并且噻托溴铵组只有过敏性鼻炎的发生率高于安慰剂组。噻托溴铵组与治疗相关的不良事件发生率为5.7%，安慰剂组为4.6%。

噻托溴铵组和安慰剂组严重不良事件的发生率分别为8.1%和8.8%。噻托溴铵组有3例严重不良事件被视为危及生命，包括2例哮喘加重和1例脑梗死。

Kerstjens博士及其同事报告称，两组心脏事件的发生率均低于2%，噻托溴铵组和安慰剂组与药物相关的心脏事件发生率分别为0.4%和0.2%。两组患者在血压、脉率、实验室指标和心电图方面的不良变化相似。在所有受试者中，只有不到2%出现了口干，这是抗胆碱能药物的典型不良事件之一，但噻托溴铵组的发生率高于安慰剂组(8例 vs. 3例)。

Kerstjens博士声明还与Almirall、Chiesi、诺华和Nycomed公司之间存在利益关系，其他作者声明与多家药企存在利益关系。

随刊述评：研究忽略了患者不依从和心血管风险

荷兰阿姆斯特丹学术医疗中心肺病科的Elisabeth H. Bel博士指出，上述研究结果并不能外推至哮喘控制不良的所有患者，因为这2项研究都是选择性地纳入了存在持续性气流受限的患者，从而使受试人群类似于COPD患者，而COPD患者是已知的噻托溴铵获益人群(N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMe1209381])。

Bel博士提醒道，这2项研究都排除了合并心脏病的患者，这可能掩盖了噻托溴铵软雾吸入剂“可能给有心血管病史的患者带来明显风险”的事实。

此外，Bel博士还指出，研究者在招募患者时也没有确认受试者是否完全依从其哮喘背景治疗。因为有研究表明超过80%的哮喘控制不良患者对治疗的依从性较差，所以患者基线时相对治疗不足“可能也给噻托溴铵产生进一步的支气管扩张效应提供了空间”。

Bel博士声明与Actelion、葛兰素史克、默克、诺华、Nycomed和先灵葆雅公司之间存在利益关系。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Adding tiotropium to standard combination therapy may help reduce exacerbations in some adults whose asthma is poorly controlled despite the use of inhaled glucocorticoids and long-acting beta-agonists, according to a report of two randomized, controlled trials published online Sept. 3 in the New England Journal of Medicine.

However, tiotropium use did not increase the number of symptom-free days or boost patients’ asthma-related quality of life scores.

Compared with placebo, tiotropium administered once daily via a soft-mist inhaler significantly lengthened the time to a severe exacerbation of asthma, reduced the number of exacerbations, and provided "modest" bronchodilation when added to inhaled glucocorticoids and LABAs, said Dr. Huib A. M. Kerstjens of the University of Groningen (the Netherlands) and the Groningen Research Institute for Asthma and COPD, and his associates (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMoa1208606]).

However, the improvements in forced expiratory volume in 1 second (FEV1) were "relatively small (less than 10%)," and the number of symptom-free days did not differ between patients who received tiotropium and those who received placebo.

Moreover, the use of rescue medications was the same between the two groups, and patient ratings of asthma-related quality of life also were the same on two measures, the researchers noted.

Tiotropium is the most widely used long-acting anticholinergic inhaled bronchodilator in the world for the treatment of chronic obstructive pulmonary disease, but it has only recently been investigated as a potential adjunctive therapy for asthma.

Dr. Kerstjens and his colleagues assessed the drug’s effects in two 48-week randomized, controlled trials conducted in 15 countries, both of which were funded by Boehringer Ingelheim and Pfizer. They presented their findings at the annual meeting of the European Respiratory Society simultaneously with online publication.

The studies included 912 adults aged 18-75 years who had a 5-year or longer history of asthma and persistent airflow limitation despite self-reported daily use of inhaled glucocorticoids and LABAs. They were randomly assigned to self administer puffs of either tiotropium (237 patients in study 1 and 219 patients in study 2) or placebo (222 patients in study 1 and 234 patients in study 2) every morning as add-on therapy.

Patients were allowed to continue the use of stable doses of sustained-release theophylline, leukotriene modifiers, anti-immunoglobulin E antibody, or oral glucocorticoids, and were given open-label inhalers of salbutamol or albuterol for use as rescue medication.

The first two lung-function end points of both studies were the peak FEV1 response and the trough FEV1 response at week 24, expressed as the change from baseline FEV1. Tiotropium topped placebo in peak FEV1 response by an average of 86 mL in trial 1 and 154 mL in trial 2, differences that were significant.

The average difference in trough FEV1 response between tiotropium and placebo groups was 88 mL in trial 1 and 111 mL in trial 2. Those differences were "relatively small" but also statistically significant.

"It should be noted that [these differences occurred] in patients who were already receiving a long-acting bronchodilator and had fixed airflow limitation," the investigators noted. The results also should be considered "in the context of the need for additional treatments for this patient population and the limitations of current alternatives," they added.

A third lung-function end point was the time until at least 25% of patients had their first severe exacerbation of asthma. That interval was 56 days longer with tiotropium (282 days), compared with placebo (226 days).

The number of severe exacerbations was a secondary end point of both trials. That number was 0.53 exacerbations per patient-year with tiotropium, significantly fewer than the 0.66 per patient-year with placebo. In addition, 27% of patients in both tiotropium groups had at least one severe exacerbation, which was significantly less than the 33% rate in both placebo groups.

However, asthma-related quality of life did not differ significantly between tiotropium and placebo groups in either trial. The minimal clinically important difference between the two groups was not achieved when measured by both the Asthma Control Questionnaire 7 and the 32-item Asthma Quality of Life Questionnaire.

Similarly, daily symptom diaries showed "small or nonsignificant" differences between the active drug and the placebo groups in symptom-free days. And the use of rescue medications also was similar.

Adverse events occurred in 73.5% of the tiotropium group and 80.3% of the placebo group, and allergic rhinitis was the only one that occurred more often in the tiotropium group. Adverse events were judged to be treatment related in 5.7% of the tiotropium group and 4.6% of the placebo group.

Serious adverse events occurred in 8.1% of the tiotropium group and 8.8% of the placebo group. Three of those events – two asthma exacerbations and one cerebral infarction – occurred in the tiotropium group and were considered life threatening.

Cardiac events occurred in less than 2% of both study groups; they were considered drug related in 0.4% of patients in the tiotropium group and 0.2% of those in the placebo group. Adverse changes in blood pressure, pulse rate, laboratory measures, and electrocardiograms were balanced between the two study groups.

Less than 2% of all patients experienced dry mouth – a typical adverse event with anticholinergic agents – but it was reported more frequently in the tiotropium group (eight patients vs. three patients), Dr. Kerstjens and his associates said.

Dr. Kerstjens reported additional associations with Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.

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Studies Miss Noncompliance, CV Risk

These studies’ findings cannot be generalized to all patients with uncontrolled asthma, because both studies selectively enrolled patients who had persistent airflow limitation – thus skewing the study populations to resemble the COPD patients who are already known to benefit from tiotropium, said Dr. Elisabeth H. Bel.

Both studies also excluded patients with heart disease, which may have masked the fact that soft-mist inhaler delivery of tiotropium "may impose a substantial risk in patients with a history of [cardiovascular] events," Dr. Bel cautioned.

In addition, the researchers failed to verify whether subjects were fully compliant with background asthma therapy at enrollment. Because it is known that more than 80% of patients with poorly controlled asthma have poor treatment adherence, the patients’ relative undertreatment at baseline "might have left room for additional bronchodilation by tiotropium," she noted.

DR. BEL is in the department of pulmonology at the Academic Medical Center, Amsterdam. She reported ties to Actelion, GlaxoSmithKline, Merck, Novartis, Nycomed, and Schering Plough. These remarks were taken from her editorial accompanying Dr. Kerstjens’ report (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMe1209381]).