食管下端电刺激疗法可有效治疗GERD

　　近期开展的3项研究表明，采用植入装置的食管下端括约肌(LES)电刺激疗法用于胃食管反流病(GERD)的治疗前景良好。

　　在10月份召开的美国胃肠病学会(ACG)年会上，南加州大学的临床医学教授/胃肠运动项目主管Edy Soffer博士报告称，一项开放性试点扩展研究纳入了23例GERD患者，平均年龄为53岁；所有受试者至少对质子泵抑制剂(PPI)治疗部分应答，并且非PPI治疗期间的GERD-健康相关生活质量(GERD-HRQL)评分至少达到20分；均存在食管裂孔疝。

　　结果显示，在接受了EndoStim LES刺激系统治疗后，77%的患者12个月随访时的远端食管酸暴露恢复正常(或者至少减少了50%)。此外，患者在植入LES刺激系统(LES-EST)期间的中位GERD-HRQL评分显著优于其在接受PPI治疗期间的评分(增加9分 vs. 2分)以及非PPI治疗期间的评分(增加23.5分 vs. 2分)。

　　Edy Soffer博士称，除1例患者外，其余所有患者都停用了其常规服用的PPI药物，并且随访期间没有出现任何与植入或刺激相关的预料之外的不良事件或者因刺激导致的“不良感受”；基于食管压力测试的吞咽功能也没有受到影响。

　　Edy Soffer博士总结道，采用低能量电脉冲以增强食管下端括约肌减弱或异常的功能的LES-EST疗法可安全有效地长期使用。“在症状控制以及PPI停用情况方面，随访18个月的结果与随访12个月时观察到的结果类似。”他指出，18个月时安全性结果仍然非常好，除12个月随访时观察到的不良事件外没有再报告其他任何新的不良事件。他还表示，将在随访第24个月时开展食管pH值等生理检查。

　　在另一项相关研究中，梅奥医院的Michael Crowell博士通过事后分析进一步评价了LES-EST对远端和近端食管酸暴露的影响。研究所纳入的GERD患者均至少对PPI治疗部分应答，食管裂孔疝均小于3 cm，食管炎分级均低于洛杉矶分级D级。从植入后第1天开始，总共给予6~12次电刺激治疗，每次治疗30分钟；电刺激参数为：脉宽220微秒，刺激频率20 Hz，强度5~8 mA。

　　在19例中位年龄为54岁的患者中，LES-EST与总体和直立位近端食管酸暴露恢复正常相关，分别从基线时的0.4%和0.6%减少至了随访12个月时的0。仰卧位食管酸暴露没有发生变化，仍然是0。

　　即便是在7例近端食管pH值异常的患者中也得到了类似的结果，这7例患者的基线总体、直立位和仰卧位近端食管酸暴露值分别为1.7%、2.9%和0.3%。此外，在所有患者队列中，远端食管pH值从10.2%降至3.6%；在这7例患者中，也从9.3%降至3.4%。

　　患者均未出现任何消化道不良反应，也没有出现任何与装置或操作相关的不良事件。

　　Crowell博士总结道，LES-EST治疗近端GERD可能有效。上述研究结果很重要，尤其是对于那1/3接受PPI治疗期间仍然有症状的患者。

　　Crowell博士指出：“LES功能异常是导致GERD的根本原因。PPI等药物治疗可以阻断胃酸的生成，但不能解决GERD的病理生理特征。因此，超过1/3的患者在接受最大程度的内科治疗后症状依然持续存在。”此外，长期抑酸治疗也有很大的安全性问题。另一方面，LES-EST则可以通过改善LES的压力和功能来恢复LES的生理学特征及其屏障功能，防止胃酸反流进入食管，从而解决导致GERD的根本原因。

　　他还补充道：“LES刺激不会影响LES的正常舒张，患者仍然可以正常吞咽，也不会产生任何副作用。”

　　在本次年会上报告的第三项研究也证实了LES-EST的类似疗效。这项研究与前两项研究无关。荷兰鹿特丹Utrecht医学学术中心的Arjan J. Bredenoord博士报告称，作为一项国际性多中心研究的一部分，共有11例患者接受了EndoStim LES刺激系统的治疗。其中10例患者在随访3~6个月后可以终止其PPI治疗。

　　此外，这10例患者的中位GERD-HRQL评分也显著改善，分别从非PPI治疗期间的32分和PPI治疗期间的22分降至LES-EST治疗3个月后的9分；在接受了6个月随访的3例患者中，GERD-HRQL评分仍然维持在9分。

　　Bredenoord博士报告称，中位食管酸暴露则从基线时的11.8%降至3个月时的7.8%和6个月时的7.3%。

　　另1例患者在植入装置时出现了小肠穿刺针(trocar)穿孔，但之后成功修复。此外，还有4例患者报告了13例不良事件，包括1例严重不良事件。其中9例事件与治疗装置或操作相关，包括7例植入部位疼痛和1例术后恶心。

　　Bredenoord博士总结道，LES-EST治疗是安全的，不会导致消化道或心脏不良反应。他表示，目前正在更大规模的患者人群中分析这种治疗的长期安全性和疗效结果。

　　不过，使用经验仍然比较有限，还需开展更多的比较这种装置与其他治疗和/或安慰剂的试验，也需要更长期的结局数据。他补充道：“我认为虽然这些结果表明这是一种很有希望的治疗，但就目前而言，最好还是只在试验中使用。”因为试验的受试者是经过仔细挑选的，现在还不清楚这种治疗是否适用于整个GERD人群。

　　Soffer博士对此表示赞同，他说如果这些结果能在更大样本量的其他研究中得到复制，那么这种干预措施将成为GERD患者的另一种治疗选择，主要适用于那些对PPI治疗效果不满意、或者对药物治疗的副作用或长期使用存在担忧也对GERD现行手术治疗存在担忧的患者。

　　他说：“这种干预措施的重要意义在于提供了一种介于现行药物治疗(PPI)与手术治疗(胃底折叠术)之间的过渡治疗。虽然PPI对于很大一部分GERD患者有效，但由于其不能纠正GERD的潜在病理生理学特征，因此仍有相当多患者经药物治疗后症状依然持续。”他补充道，这类患者可以接受胃底折叠术，症状可能有效改善，但手术有副作用，这种手术的使用频率也越来越低。

　　Soffer博士说：“因此，人们开始寻找用于GERD治疗过渡的干预措施。LES-EST治疗操作简单，没有破坏性，而且还能解决GERD的病理生理学特征。从已有的研究数据来看，这种治疗的安全性也非常好，其对于食管酸暴露、症状和PPI药物治疗的影响至少可持续12~18个月。此外，这种治疗还可以根据症状和反流的发作规律来调整电刺激的发送时间，从而满足个体患者的需求，实现治疗优化。”

　　会上报告的所有这3项研究均由EndoStim BV公司资助。Soffer博士声明享有这家公司的股东/所有者权益。Crowell博士声明担任这家公司的顾问。Bredenoord博士声明接受了这家公司提供的研究经费和/或支持。

　　相关评论：临床使用的良好开端

　　胃食管反流病(GERD)是最常见的慢性消化道疾病之一。目前内科治疗以抑制胃酸分泌的药物为主，比如PPI。抑制胃酸的另一种方法是调节抗反流的屏障，这道屏障由食管下端括约肌(LES)和脚膈肌组成。胃底折叠术是一种已经确立的能增强这道抗反流屏障功能的手术方式。高质量的试验证明了胃底折叠术的疗效，但也充分暴露了其潜在的副作用，比如一部分患者会出现吞咽困难、腹胀和腹泻。

　　其他能提高这道抗反流屏障功能的方法包括采用各种药物抑制一过性LES松弛(TLESR)以及多种内镜下抗反流操作。遗憾的是，由于副作用和不良事件较多，加之疗效不够明显，因此TLESR抑制剂和内镜下操作用于GERD的治疗范围很有限。

　　之前曾有动物模型研究表明电刺激LES能提高LES的静息张力(Am. J. Physiol. Gastrointest. Liver Physiol. 2008;295:G389-94)。最近也有一项6个月开放性试验表明电刺激LES用于至少对PPI治疗部分应答的GERD患者，不但能减少甚至停止PPI的使用，还能改善症状和24小时食管pH参数(Surg. Endosc. 2012 Oct. 17 [doi: 10.1007/s00464-012-2561-4])。

　　在本次年会上，Soffer博士、Crowell博士及其同事报告了上述开放性试验的1年数据，结果显示LES电刺激疗法改善患者症状、PPI使用情况和远端食管酸暴露的作用在随访12个月后仍然持续，并且副作用或不良事件非常少。

　　会上，Bredenoord博士及其同事也报告了一项关于LES电刺激疗法用于难治性GERD的国际性多中心试验的初步结果。结果显示，LES电刺激疗法能改善这组患者的症状、PPI使用情况以及食管酸暴露，但初步统计的患者人数较少，而且随访时间大多只有3个月。重要的是，研究者也的确报告了一些不良事件。

　　上述研究提供了进一步的信息证明电刺激LES可能是一种有效的GERD治疗方法。虽然现有数据很令人关注，但仍需开展更多的工作以评估这种治疗疗效的持久性及其长期安全性和副作用，并了解电刺激对于食管感觉的影响，确定哪些GERD患者最适合接受这种治疗。要解答上述问题，最理想的是开展随机对照试验来比较LES电刺激疗法与目前已经确立的用于治疗GERD的药物治疗和手术治疗方法。

　　MARCELO F. VELA, M.D.是美国休斯敦贝勒医学院/ Michael E. DeBakey退伍军人医疗中心的医学副教授/消化道动力研究项目主管。他声明担任了Given Imaging公司顾问专家组的成员。

　　By: SHARON WORCESTER, Internal Medicine News Digital Network

　　Electrical stimulation of the lower esophageal sphincter using an implanted device shows promise for the treatment of gastroesophageal reflux, according to findings from three recent studies.

{nextpage} 　　In one open-label pilot extension study, 77% of 23 patients treated with EndoStim’s Lower Esophageal Sphincter (LES) stimulation system reported normalization of (or at least a 50% reduction in) distal esophageal acid exposure at 12 months’ follow-up, Dr. Edy Soffer reported in October at the annual meeting of the American College of Gastroenterology.

　　The patients also experienced significant improvement in their median GERD-Health Related Quality of Life (GERD-HRQL) score while implanted with the LES stimulation system (LES-EST), compared with their score while on proton pump inhibitor (PPI) therapy (increase of 9 vs. 2 points) and while off PPI therapy (increase of 23.5 vs. 2), said Dr. Soffer, professor of clinical medicine and director of the GI motility program at the University of Southern California, Los Angeles.

　　All but one patient reported cessation of regular PPI use, and no implantation- or stimulation-related unanticipated adverse events or "untoward sensation" due to stimulation occurred during follow-up; nor was swallowing function as assessed by manometry affected.

　　Patients included in the study were GERD patients with a mean age of 53 years who were at least partially responsive to PPI therapy, and who had off-PPI GERD-HRQL scores of at least 20, as well as hiatal hernia.

　　The findings indicate that LES-EST, which uses low-energy electrical pulses to strengthen a weak or dysfunctional lower esophageal sphincter, is safe and effective for long-term use, he said.

　　In an interview, Dr. Soffer said that the findings have held up at 18 months of follow-up.

　　"The results are comparable to those observed at 12 months with regard to control of symptoms, and with near elimination of the use of PPIs," he said, noting that the safety profile remains excellent, with no new adverse event reported beyond those seen at 12 months’ follow-up.

　　Physiological studies such as esophageal pH will be conducted at 24 months, he said.

　　In a related study presented in a poster at the meeting, Michael Crowell, Ph.D., looked more closely at the effects of LES-EST on both distal and proximal esophageal acid exposure in a post hoc analysis.

　　In 19 patients with a median age of 54 years, LES-EST was associated with normalization of total and upright proximal esophageal acid exposure, which improved from 0.4% and 0.6%, respectively, at baseline to 0% at 12 months’ follow-up. Supine esophageal acid exposure was unchanged from 0% at baseline, said Dr. Crowell of the Mayo Clinic, Scottsdale, Ariz.

　　This was true even among seven patients with abnormal proximal esophageal pH, whose total, upright, and supine proximal esophageal acid exposure values at baseline were 1.7%, 2.9%, and 0.3%, respectively. Distal esophageal pH improved from 10.2% to 3.6% for the entire cohort, and from 9.3% to 3.4% in those seven patients.

　　Patients in this study had GERD that was at least partially responsive to PPIs, a hiatal hernia of less than 3 cm, and esophagitis of less than Los Angeles Classification grade D. Electrical stimulation was administered for 220 microseconds at 20 Hz and 5-8 mA in 6-12 30-minute sessions starting on day 1 after implantation.

　　No gastrointestinal side effects occurred in the patients, nor were there any device- or procedure-related adverse events.

　　LES-EST may be effective in treating proximal GERD, Dr. Crowell concluded.

　　In an interview, he added that the findings are important, particularly for the one-third of patients who remain symptomatic on PPIs.

　　"LES dysfunction is the root cause of GERD. Medications such as PPIs block stomach acid production, but do not address the pathophysiology of GERD. Hence, more than a third of patients continue to suffer from symptoms despite maximal medical therapy," he said.

　　Additionally, there are significant safety concerns with long-term acid suppression, he noted.

　　LES-EST, on the other hand, addresses the root cause of GERD by improving LES pressure and function, thereby restoring the LES physiology and its barrier function, preventing reflux of gastric acid into the esophagus.

{nextpage} 　　"LES stimulation does not affect normal LES relaxation, allowing for the patient to swallow normally, and has no side effects," he said.

　　In a third, unrelated study also reported in a poster at the meeting, LES-EST was similarly effective.

　　Of 11 patients treated with EndoStim’s LES stimulation system as part of an international multicenter study, 10 were able to discontinue PPI therapy at 3-6 months of follow-up, according to Dr. Arjan J. Bredenoord of Academic Medical Center Utrecht, Rotterdam.

　　Those 10 patients experienced significant improvements in median GERD-HRQL scores from 32 (off PPIs) and 22 (on PPIs) to 9 (on LES-EST) at 3 months, and the scores remained stable at 9 points in 3 patients who were followed for 6 months.

　　Median esophageal acid exposure improved from 11.8% at baseline to 7.8% at 3 months and 7.3% at 6 months, Dr. Bredenoord said.

　　The remaining patient suffered a small bowl trocar perforation during implantation of the device and underwent successful repair. An additional 13 adverse events, including 1 serious adverse event, were reported in 4 patients. Nine of these were related to the device or procedure, including seven complaints of pain at the implant site and one case of postoperative nausea.

　　The treatment was safe, with no GI or cardiac side effects, Dr. Bredenoord concluded, noting that long-term safety and efficacy results in a larger group of patients are currently being analyzed.

　　In an interview, Dr. Bredenoord noted that the findings are among the first in patients outside South America, where the earliest trials of the EndoStim LES stimulation system were conducted.

　　"The data confirm the favorable outcome of the patients in Chile, and show that both symptoms and reflux are reduced in European patients as well," he said.

　　However, the experience remains limited, and additional study comparing the device with other treatments and/or with placebo is needed, as are longer-term outcomes data.

　　"I think that although these results suggest this is a promising treatment, it would be best to treat patients only in trials" at this point, he said. Because trial participants have been carefully selected, it remains unclear whether this treatment is suitable for the entire GERD population, he added.

　　Dr. Soffer agreed, and said that if the results are reproduced in additional studies with a larger number of patients, the intervention will provide an alternative therapy for GERD patients who are not satisfied with PPIs or who have concerns about side effects and the chronic use of treatment, and who also have concerns about the established surgical treatment for GERD.

　　"The importance of this intervention is in providing a bridge between the currently established drug therapy for GERD [PPIs] and the established surgical therapy [fundoplication]. While PPIs are effective in a substantial number of GERD patients, they do not correct the underlying pathophysiology of GERD, resulting in a substantial number of patients who remain symptomatic in spite of therapy," he said.

　　These patients can be offered fundoplication, which is effective in expert hands, but the surgery has side effects and is performed less and less often, he added.

　　"Consequently, there is a search for a bridge intervention, endoscopic or surgical, for the treatment of GERD," he said.

　　LES-EST appears to have the potential to be such a bridge intervention.

　　"The procedure is simple and nondisruptive, and addresses pathophysiology. The safety profile thus far is excellent, and the effect on esophageal acid exposure, symptoms, and PPI use is sustained over a period of 12-18 moths. Furthermore, the treatment can be optimized to individual needs by adjusting delivery of stimulation to coincide with periods when symptoms and acid reflux are detected," he said.

　　All three of these studies presented at the meeting were supported by EndoStim BV. Dr. Soffer disclosed that he has stockholder/ownership interest in the company. Dr. Crowell disclosed that he has served as a consultant to the company. Dr. Bredenoord reported receiving grant and/or research support from the company.

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　　A promising start to clinical use

　　Gastroesophageal reflux disease is one of the most common chronic gastrointestinal disorders. The mainstay of medical therapy is to suppress gastric acid secretion with medications such as PPIs. An alternative approach to acid suppression is modulation of the antireflux barrier, composed of the lower esophageal sphincter (LES) and the crural diaphragm. Surgical fundoplication is a well-established method to augment the function of the antireflux barrier. Fundoplication has proven effective in high-quality trials, but it also has well-documented side effects such as dysphagia, bloating, and diarrhea in a subset of patients.

　　Additional means of enhancing the function of the antireflux barrier include pharmacological inhibition of transient LES relaxations (TLESR) with various agents and several endoscopic antireflux procedures. Unfortunately, the use of TLESR inhibitors and endoscopic procedures for GERD is very limited due to side effects and adverse events, along with insufficient efficacy.

　　Electrical stimulation of the LES has been previously shown to increase LES resting tone in an animal model (Am. J. Physiol. Gastrointest. Liver Physiol. 2008;295:G389-94). More recently, in a 6-month, open-label trial, electrical stimulation of the LES was found to reduce or eliminate PPI use and to improve symptoms and 24-hour esophageal pH parameters in GERD patients who were at least partially responsive to PPIs (Surg. Endosc. 2012 Oct. 17 [doi: 10.1007/s00464-012-2561-4]).

　　During the recent American College of Gastroenterology meeting, 1-year data for the open-label trial mentioned above was presented by Dr. Soffer, Dr. Crowell, and their collaborators, showing that improvement in symptoms, PPI use, and distal esophageal acid exposure persisted at 12 months with minimal side effects or adverse events.

　　Preliminary results of an international multicenter trial of LES electrical stimulation for refractory GERD were also presented at the meeting by Dr. Bredenoord and his colleagues. They found that LES electrical stimulation improved symptoms, PPI use, and esophageal acid exposure in this group of patients, but the preliminary number of patients was small and follow-up was mostly limited to 3 months. Importantly, they did report some adverse events.

　　These studies provide additional information to suggest that electrical stimulation of the LES may be an effective treatment for GERD. While the available data is compelling, more work will be required to evaluate the durability of the procedure, assess long-term safety and side effects, study the effects of stimulation on esophageal sensation, and define which GERD patients are best suited for this treatment. This will be ideally accomplished by randomized controlled trials that will compare electrical stimulation of the LES to the well-established pharmacological and surgical approaches currently used to treat GERD.

　　MARCELO F. VELA, M.D., is an associate professor of medicine and director of gastrointestinal motility at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center, both in Houston. He is a member of an advisory panel for Given Imaging.