雾化吸入噻托溴铵不增加COPD死亡风险

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雾化吸入噻托溴铵不增加COPD死亡风险Tiotropium via Respimat didn’t raise COPD mortality risk
来源：爱思唯尔2013-09-12 09:09点击次数：646发表评论分享到

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一项大型研究显示，与干粉吸入给药系统相比，通过雾化吸入装置给予支气管扩张剂噻托溴铵不会增加慢性阻塞性肺病(COPD)患者的死亡风险。该研究发表于9月8日的《新英格兰医学杂志》(New England Journal of Medicine)，并同时在欧洲呼吸学会（ERS）年会上展示(N. Eng. J. Med. 2013 [doi:10.1056/NEJMoa1303342])。

已经证实，噻托溴铵5 mcg雾化吸入剂量与18 mcg干粉吸入剂量的药代动力学等效。但主要研究者、巴尔的摩市约翰霍普金斯医学中心的Robert A. Wise博士报告称：“对3项为期1年的试验和1项为期6个月的安慰剂对照试验的事后汇总分析显示，[5 mcg剂量]与计划治疗时期内的死亡率增高相关（相对风险为1.33），尤其是在已知有心脏节律异常的患者中。”后续的荟萃分析似乎确认了这一结果。

故研究者设计了这项TIOSPIR （噻托溴铵雾化吸入给药的安全性与性能）试验，在大量患者人群（很多合并已有的心脏疾病）中检验死亡风险是否增加。TIOSPIR试验中包括1,825例心律失常患者和3,152例缺血性心脏病、冠心病或心力衰竭患者。研究共纳入17,135例COPD患者，患者被随机分配到噻托溴铵（Respimat）2.5 mcg 或5 mcg经雾化吸入装置每日给药1次治疗组或噻托溴铵18 mcg经干粉吸入装置给药组。根据设计，研究将持续至死亡≥1,266例。平均随访时间为2.3年。

患者平均年龄为65岁；其中71%为男性。约有1/3 (38%)为当前吸烟者。平均1秒用力呼气量为预测值的48%。患者中心脏疾病并不少见：11%有心律失常病史，6%有既往心脏意外病史；2%有既往卒中病史；15%有缺血性心脏病或冠心病。多数患者(62%)正在接受长效2受体激动剂治疗，68%使用了吸入性糖皮质激素。主要终点为任何原因导致的死亡。

结果显示，Respimat 2.5 mcg、Respimat 5 mcg和HandiHaler组的死亡率分别为7.7%、7.4%和7.7%。HandiHaler与Respimat 2.5 mcg或5 mcg组的死亡风险无统计学差异（危险比分别为1.00和0.96）。每组中判断为心血管原因和呼吸原因的死亡病例分别占2%和2.5%。“值得注意的是， Respimat 5 mcg组中的 1,221例有心律失常病史的患者死亡风险较HandiHaler组无增高（分别为10.6%和12.9%）。”相当于危险比为0.81，无统计学意义。

次要终点为首次COPD加重的风险。对于这项指标，所有治疗组的表现相似。Respimat 5 mcg相对于HandiHaler的危险比为0.98；Respimat 5 mcg和HandiHaler组分别有48% 和49%的患者发生COPD加重，中位至加重时间分别为756和719天。

研究者还进行了一项呼吸量测定亚组研究。结果显示，Respimat 5 mcg不劣于HandiHaler治疗；但2.5 mcg剂量的疗效不及HandiHaler。每组中大约有1/3的患者发生严重不良事件。多数为呼吸系统事件（每组大约17%），其次为心血管事件（每组4%）

研究者总结认为，与通过干粉吸入装置给药相比，通过雾化吸入装置给予噻托溴铵不会增加COPD死亡风险。

这项研究是由雾化吸入装置的生产商勃林格-殷格翰公司申办的。Wise博士披露接受了该公司提供的顾问费。在11位合著者中，6位为勃林格殷格翰公司雇员，4位报告接受了该公司提供的顾问费用、研究支持或存在其他利益关系。

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By: MICHELE G. SULLIVAN, Internal Medicine News Digital Network

Delivering the bronchodilator tiotropium with the Respimat inhaler did not increase the risk of death in chronic obstructive pulmonary disease, compared with the HandiHaler delivery system, according to a large study.

A randomized trial of more than 17,000 patients with COPD found that tiotropium Respimat 2.5 mcg and 5 mcg were both noninferior to tiotropium HandiHaler 18 mcg with respect to mortality, Dr. Robert A. Wise and his colleagues reported in the Sept. 8 issue of the New England Journal of Medicine and presented simultaneously at the European Respiratory Society Annual Congress (N. Eng. J. Med. 2013 [doi:10.1056/NEJMoa1303342]).

The 5-mcg Respimat dose also was as effective as the HandiHaler at preventing a first exacerbation of COPD, wrote Dr. Wise of Johns Hopkins Medical Center, Baltimore, and his colleagues.

Boehringer Ingelheim, which makes the Respimat inhaler, sponsored the study.

The 5-mcg Respimat dose and the 18-mcg HandiHaler dose have been shown to be pharmacokinetically equivalent. However, "concern about the safety of tiotropium Respimat was expressed when a post hoc pooled analysis of three 1-year trials and one 6-month placebo-controlled trial showed that [the 5-mcg dose] was associated with excess mortality in the planned treatment period (relative risk, 1.33), particularly among patients with known cardiac-rhythm disorders," Dr. Wise and the coauthors said. Subsequent meta-analyses appeared to confirm the finding.

The researchers designed the TIOSPIR (Tiotropium Safety and Performance in Respimat) trial to investigate the possible increased mortality risk in a large number of patients – many with preexisting cardiac disease. TIOSPIR included 1,825 patients with cardiac arrhythmias and 3,152 with ischemic heart disease, coronary artery disease, or heart failure.

The study comprised 17,135 patients with COPD, who were randomized to once-daily tiotropium at 2.5 mcg or 5 mcg delivered by Respimat, or 18 mcg delivered by HandiHaler. The study was designed to continue until at least 1,266 deaths had occurred. The mean follow-up was 2.3 years.

Average age of the patients was 65 years; 71% were male. About a third (38%) were current smokers. The mean forced expiratory volume in 1 second was 48% of predicted value.

Cardiac disease was not uncommon: 11% had a history of arrhythmia; 6% a prior heart attack; 2% a prior stroke; and 15% ischemic heart disease or coronary artery disease. Most (62%) were taking a long-acting beta2-agonist, and 68% used inhaled glucocorticoids.

The primary endpoint was the risk of death from any cause. Death occurred in 7.7% of the 2.5-mcg Respimat group, 7.4% of the 5-mcg Respimat group, and 7.7% of the HandiHaler group. There was no significant difference in the risk of death between the HandiHaler and either the 2.5-mcg or 5-mcg Respimat dose (hazard ratios, 1.00 and 0.96, respectively).

Cause of death was judged to be cardiovascular in 2% of cases from each group, and respiratory in about 2.5% of cases in each group.

"In particular, there was no increased risk of death among the 1,221 patients with a history of cardiac arrhythmia in the Respimat 5-mcg group as compared with the HandiHaler group (10.6% and 12.9%, respectively)," the authors noted, resulting in a nonsignificant hazard ratio of 0.81.

The risk of first COPD exacerbation was the secondary endpoint. In that measure, all of the treatments performed similarly. The hazard ratio for Respimat 5 mcg vs. HandiHaler was 0.98; exacerbations occurred in 48% of the Respimat 5-mcg group and 49% of the HandiHaler group, with median time to exacerbation of 756 and 719 days, respectively.

The investigators also performed a spirometry substudy. That showed that Respimat 5 mcg was noninferior to the HandiHaler treatment; the 2.5-mcg dose, however, was not as effective as the HandiHaler.

About a third of patients in each group experienced a serious adverse event. Most were respiratory in nature (about 17% in each group), followed by cardiovascular events (4% in each group).

Dr. Wise reported that he receives consulting fees from the company. Of the 11 coauthors, 6 are Boehringer Ingelheim employees and 4 reported consulting fees, research support, or other financial relationships with the company.