JOURNAL OF LAPAROENDOSCOPIC & ADVANCED SURGICAL TECHNIQUES Volume 25, Number 2, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/lap.2014.0454
Peroral Esophageal Myotomy Versus Laparoscopic Heller’s Myotomy for Achalasia: A Meta-analysis Mingtian Wei, MD,* Tinghan Yang, MD,* Xuyang Yang, MD, Ziqiang Wang, MD, PhD, and Zongguang Zhou, MD, PhD, FACS
Abstract
Background: This meta-analysis aims to add convincing evidence on the application of peroral esophageal myotomy (POEM), compared with laparoscopic Heller’s myotomy (LHM), for the treatment of achalasia. Materials and Methods: The electronic databases of PubMed, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Embase (up to December 2013) were systematically searched. EndNote X6 citation software (Thomson Reuters, New York, NY) was used for literature management. A modification of the Newcastle–Ottawa Scale was applied for quality assessment. The data were analyzed using Review Manager version 5.1 software (The Cochrane Collaboration, Oxford, United Kingdom), and sensitivity analysis was performed by sequentially omitting each study. Results: Overall, four studies compared the outcomes between POEM and LHM. All studies were conducted in the United States and published in 2013. POEM was associated with comparable complications (odds ratio [OR] = 1.17, 95% confidence interval [CI] 0.53–2.56, P = .70), gastroesophageal reflux (OR = 1.00, 95% CI 0.38–2.61, P = 1.00), and symptomatic recurrence by Eckardt score (OR = 0.24, 95% CI 0.04–1.55, P = .13). Other outcomes including pain score, operating time, and hospital stay were assessed with no significant difference between POEM and LHM. Conclusions: POEM achieves equivalent short-term outcomes compared with LHM for achalasia. This novel procedure is a promising treatment for achalasia.
Introduction
A
chalasia is a rare esophageal motility disorder characterized by poor relaxation of lower esophageal sphincter (LES) and aperistalsis of the esophageal body.1 Achalasia patients mainly present with dysphagia, as well as regurgitation, heartburn, and chest pain. Conventional treatments include drug therapy, endoscopic pneumatic dilation, and surgical Heller’s myotomy to disrupt the LES. During the past decades, laparoscopic Heller’s myotomy (LHM) with an antireflux Dor fundoplication has been gaining wide popularity for the treatment of achalasia in medical centers. Previous studies have demonstrated short- and long-term favorable symptom relief compared with other treatments such as medicine therapy or pneumatic dilation.2,3 Surgically, LHM with a Dor fundoplication is routinely considered the standard option for achalasia patients.
Most recently, natural orifice translumenal endoscopic surgery has been used for its advantage of effectiveness, decreased pain, and less trauma without a skin incision. Peroral endoscopic myotomy (POEM), as a novel endoscopic surgery, was first reported successfully in a case series for the treatment of 17 achalasia patients in 2010.4 Subsequently, a few studies have proven the efficacy and safety of POEM for the treatment of achalasia.5–7 In 2013, sequential published studies reported the comparison of POEM with standard LHM for achalasia, aiming at setting up the foundation of the less invasive procedure. However, because of the relative novel technique and lower incidence for achalasia, the existing literature has a small sample size, lacking convincing evidence. In the present meta-analysis, we aim to clarify the role of POEM in the treatment of achalasia. We strictly pooled existing studies to further compare the outcomes of POEM with LHM. Parameters including complications, gastroesophageal
Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. *The first two authors contributed equally to this study. An abstract of this study was presented at the SAGES 2014 Annual Meeting, April 2–5, 2014, in Salt Lake City, Utah.
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reflux (GER), and symptomatic recurrence by Eckardt score were statistically synthesized. Materials and Methods Search for studies
The electronic databases of PubMed, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Embase (up to December 2013) were systematically searched with no limits. The search strategy combined terms of ‘‘achalasia,’’ ‘‘peroral esophageal myotomy,’’ and ‘‘Heller myotomy’’ in each database with medical subject heading terms or key words. Moreover, previously published reviews on the topic of interest were obtained and checked. We traced the reference list of relevant articles and used Google Scholar to find potential studies. Study selection
All potential studies, including randomized controlled trials, clinical controlled studies, cohort studies, case-control studies, abstracts, and reviews, were identified. The inclusion criteria were as follows: (1) diagnosis of achalasia confirmed
in an adult patient, (2) the surgical procedure compared POEM and LHM, (3) the studies provided adequate outcomes, and (4) data were available for each surgical regimen. We excluded studies in which (1) an animal model was used, (2) achalasia of children was examined, (3) just one surgical regimen was reported, (4) the studies were reviews, letters, abstracts, and editorial material, and (5) studies were lacking available data. Two reviewers independently screened studies by reading titles and abstracts to roughly identify potential reports. The full texts of articles for all references identified as matching the inclusion criteria were obtained. Inclusion criteria were applied to the full texts. Disagreement was resolved through discussion and asking for advice from corresponding authors. Data extraction and quality assessment
Two reviewers independently extracted data from eligible studies, and any disagreement was adjudicated by discussion or consulting the corresponding author. Baseline information included surgical regimen, numbers of achalasia patients, age, sex, preoperative therapy, follow-up year, and other parameters. The following outcome data
FIG. 1. Flow diagram of the study selection process in this meta-analysis.
F, female; LHM, laparoscopic Heller’s myotomy; M, male; POEM, peroral endoscopic myotomy. a Either mean (standard deviation) or median (range).
60.2 (4.7) 64.1 (4.8) 18 (13/5) Ujiki et al.15 (2013)
21 (12/9)
41 (12) 12 (9/3) Teitelbaum et al.14 (2013)
17 (10/7)
38 (22–69) 18 (13/5) Hungness et al.13 (2013)
55 (29/26)
51 (19)
Toupet in most patients, Absence of prior Dor in the case treatment (either of esophageal endoscopic or perforation surgical) Diagnosis of achalasia; age 18–85 years; Endoscopic Toupet in 10 patients, sigmoid esophagus excluded; previous botulinum toxin Dor in 7 patients preoperative myotomy (i.e., reoperative and pneumatic LHM or POEM cases) excluded dilation Confirmed achalasia patients; age > 18 Botulinum toxin, Toupet in 9 patients, years; known coagulopathy, esophageal pneumatic dilation, Dor in 12 patients varices, active esophagitis, pregnancy, and and previous gastroesophageal malignancy excluded Heller’s myotomy
Dilatation and botulinum toxin injection
Age > 18 years; no previous esophageal or mediastinal surgery; body mass index < 40 kg/m2; no massive dilation; absence of sigmoid esophagus 49 (22–79) Diagnosis of achalasia; age 18–85 years; absence of sigmoid esophagus 57 (20) 56 (16) 37 (19/18) Bhayani et al.12 (2013)
64 (31/33)
Prior treatment Inclusion and exclusion criteria LHM POEM LHM
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the detailed selection process is shown in Figure 1. In total, 68 potential abstracts were hit in the primary search, and 14 full-text articles were assessed for eligibility. Based on inclusion and exclusion criteria, four retrospective studies including a total of 242 achalasia patients compared outcomes between POEM and LHM.12–15 There are not 85 distinct and separate patients in the POEM group because patients from two studies by the same group may overlap.13,14 All studies were published in the United States in 2013. No perioperative mortality or conversion to the other procedure was found in any study. Table 1 offers the baseline characteristics of all studies. In addition, perioperative symptom assessment was similar in the four studies, and prior treatment differed in one study, with fewer patients getting endoscopic treatment in the POEM group.14 Lower resting LES pressure was observed in two studies.13,14
POEM
Characteristics and quality judgments
Reference (year)
Results
Age (years)a
The data were analyzed using Review Manager version 5.1 software (The Cochrane Collaboration, Oxford, United Kingdom). Odds ratios (ORs) or risk differences along with 95% confidence intervals (CIs) were used for analyzing dichotomous data, and mean differences (MDs) along with 95% CI for continuous data. To assess the variation across studies, heterogeneity was measured with the I2 index and P value. Based on the method reported by DerSimonian and Laird,9 substantial significance was set when P < .10, and a random effect model was used. Otherwise, a fixed effect model was considered.9,10 Standard deviation (SD) was estimated by a formula when only a range was reported: Estimated SD = Range/4 (15 < n < 70) or Range/6 (n > 70), and the median was approximately equal to the mean.11 A value of P < .05 was considered to indicate statistical significance. With regard to outcomes when significant heterogeneity existed across studies, sensitivity analysis was performed by sequentially omitting each study to test the influence of each individual study on pooled data. If patients in studies overlapped, we would try to contact the authors to get the original data or excluded the patients into final data synthesis.
Sample size (M/F ratio)
Statistical analysis
Table 1. Basic Characteristics of All Pooled Studies in the Meta-analysis
were extracted: complications (major and minor), GER, Eckardt symptom score, pain assessment, operating time, and hospital stay. Because only nonrandomized controlled studies were pooled in the analysis, a modification of the Newcastle– Ottawa Scale was used as an assessment tool from the three aspects of selection, comparability, and outcome assessment.8 Five main factors were considered: prior treatment, preoperative Eckardt score, achalasia subtype, manometry, and antireflux fundoplication. In order to evaluate the comparisons as accurately as possible, age, sex, American Society of Anesthesiologists score, and symptom duration were also taken into consideration. Out of a total of six stars, studies rated at more than four stars were recognized as being moderate to high quality.
Toupet in 27 patients, Dor in 37 patients
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Fundoplication in LHM
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Table 2. Quality Assessment of Studies in the Meta-analysis Based on Modified Newcastle–Ottawa Scale Judgment Selectiona
Comparabilityb
Outcome assessmentc
Reference (year)
1
2
3
4
5
Quality judgment
Bhayani et al.12 (2013) Hungness et al.13 (2013) Teitelbaum et al.14 (2013) Ujiki et al.15 (2013)
+ + + +
+ + — +
++ + + ++
+ + + +
— — + +
+++++ ++++ ++++ ++++++
a Selection: (1) Is the subject definition adequate or described? (if yes, one star). (2) Was the subject representative of the total population? (one star, if truly or obviously; no stars if subjects were selected group or not described). b Comparability: (3) Did the study have no differences between peroral endoscopic myotomy and laparoscopic Heller’s myotomy? Five main factors were considered: prior treatment, preoperative Eckardt score, achalasia subtype, manometry, and antireflux fundoplication. Other four factors—age, sex, American Society of Anesthesiologists score, and symptom duration—were comparative (if yes, two stars; one star if there were no other differences between the two groups even if one or more of these five characteristics was not reported; no star was assigned if the two groups differed). c Outcome assessment: (4) Clearly defined outcome of interest (if yes, one star). (5) Adequacy of follow-up (one star if less than 20% of achalasia patients lost to follow-up, otherwise no stars).
All four studies were retrospective case-control studies due to limitation in surgical blinding or randomization. Table 2 lists the evaluation stars of each study followed by the modified Newcastle–Ottawa Scale. In terms of the three aspects of selection, comparability, and outcome assessment, all included studies were comparable. The four studies were evaluated as being of moderate to high quality.
Quantitative synthesis of outcomes Complications. Complication assessment was based on the Clavien–Dindo grade.16 Major complications included perioperative perforation and bleeding. Minor complications were recorded as subcutaneous emphysema, anterior vagus nerve division, splenic capsule tear, aspiration, atrial fibrillation,
FIG. 2. Forest plot of the odds ratio for all complications.12,13,15 CI, confidence interval; LHM, laparoscopic Heller’s myotomy; M-H, Mantel–Haenszel; POEM, peroral esophageal myotomy.
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FIG. 3. Forest plot of the odds ratio for perforations.12,14,15 CI, confidence interval; LHM, laparoscopic Heller’s myotomy; M-H, Mantel–Haenszel; POEM, peroral esophageal myotomy. urinary retention, and re-admission for chest pain. Figure 2 shows the forest plot of three pooled studies. The results of meta-analysis of all complications, major complications, and minor complications were comparable between POEM and LHM (OR = 1.17, 95% CI 0.53–2.56, P = 0.70; OR = 0.86, 95% CI 0.32–2.26, P = .75; and OR = 2.00, 95% CI 0.57–6.98, P = .28, respectively). Moreover, perforation by itself pooled with no statistical difference (OR = 0.79, 95% CI 0.28–2.19, P = .64) (Fig. 3). GER. Two studies reported the incidence of postoperative GER, which was estimated by a DeMeester score of q14.7 or a GerdQ questionnaire score of q7.17 The fixedeffect analysis model was used because of low heterogeneity (I2 = 3%, P = .31). No significant difference was detected between POEM and LHM (OR = 1.00, 95% CI 0.38–2.61, P = 1.00). The forest plot is shown in Figure 4. Symptomatic recurrence by Eckardt score. Eckardt
symptom score was measured by the four aspects of dysphagia, regurgitation, chest pain, and amount of weight loss.18 With a total possible score of 12, an Eckardt score of q4 was evaluated as symptomatic recurrence. Two studies were hit in the meta-analysis. The outcome showed no significant difference between POEM and LHM (OR = 0.24, 95% CI 0.04–1.55, P = .13). The test for heterogeneity was not significant (I2 = 0%, P = .97) (Fig. 5). Pain assessment and medication usage. Two studies reported postoperative pain score and medication usage. The meta-analysis of pain score was comparable between POEM and LHM (MD = - 0.72, 95% CI - 2.97 to 1.53, P = .53). Significant heterogeneity existed, and a random-effect analysis model was used (I2 = 93%, P = .0001). Operating time and hospital stay. With respect to operating time, three studies reported available data. There was no
significant difference between POEM and LHM for achalasia (MD = - 16.09, 95% CI - 40.63 to 8.45, P = .20). Significant heterogeneity existed among the included studies (I2 = 90%, P < .0001), and a random-effect analysis model was used then. Sensitivity analysis by sequentially omitting each study did not alter the primary outcome. In the quantitative analysis of hospital stay, three studies were pooled in the analysis. POEM required similar hospital time compared with LHM (MD = - 0.09, 95% CI - 1.38 to 0.40, P = .28). Because of high heterogeneity among studies (I2 = 70%, P = .04), sensitivity analysis showed a lower hospital time in POEM when omitting the study of Ujiki et al.,15 which may influence the primary outcome. In addition, the studies on Institutional Review Board trials require many patients to stay in-house for 24–48 hours per the protocol, which becomes a confounding factor. Discussion
POEM was introduced as a promising minimally invasive technique for the clinical practice of achalasia patients by Inoue et al.4 in 2010. Since then, its feasibility, safety, and efficacy have been consistently confirmed by subsequent case series. With the maturity of the endoscopic procedure, some institutions began to report their initial practice on the comparison of POEM with other treatments, most recently standard LHM. However, the studies are retrospectively observational or include a small number of patients. There is no adequate evidence on the safety and efficacy of POEM in the treatment of achalasia. In this meta-analysis, our group pooled the comparative data between POEM and LHM, aiming to provide strong evidence on the application of POEM for achalasia. Overall, our analysis outcomes demonstrate comparable short-term results in POEM compared with LHM based on complications, GER, and Eckardt score. The Newcastle– Ottawa Scale was modified in the baseline characteristics on
FIG. 4. Forest plot of the odds ratio for postoperative gastroesophageal reflux.12,14 CI, confidence interval; IV, inverse variance; LHM, laparoscopic Heller’s myotomy; POEM, peroral esophageal myotomy.
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FIG. 5. Forest plot of the odds ratio for symptomatic recurrence by Eckardt score.14,15 CI, confidence interval; LHM, laparoscopic Heller’s myotomy; M-H, Mantel–Haenszel; POEM, peroral esophageal myotomy. five aspects that are potential prognosis factors (Table 2). The four studies are all scored at least four stars, which are estimated as moderate to high quality. Although follow-up of pooled studies differs, there is no obvious heterogeneity in comparison of symptom assessment. On the contrary, two short-term outcomes of operating time and hospital stay are appraised with high heterogeneity. Also, sensitivity analysis disclosures in one study contributed to the heterogeneity.15 Postoperative complication is the main concern after POEM and LHM for the treatment of achalasia. The outcomes show no significant differences on either major or minor complications. Moreover, perforation, as the most dangerous complication, was by itself pooled without obvious difference between groups. We further investigated previous studies with reported complications. Swanstrom et al.5 reported a 16.7% perforation complication during POEM in their preliminary experience. These perforations were repaired with endoscopic Veress needle or clips intraoperatively. Some case series of small sample size determined no serious POEM-related complications.19–21 The most common side effect that develops after minimally invasive treatment is GER. As is universally known, the aim of treatment for achalasia is to definitively destroy the LES, which, in contrast, induces abnormal acid reflux in LHM. So an antireflux fundoplication, which was previously regarded as the cause of postoperative dysphagia, is routinely suggested following LHM. The current evidence base supports the idea that the fibrosis around the esophagogastric junction may contribute to the dysphagia rather than the fundoplication procedure.22 POEM is likely both to relieve dysphagia and to decrease the acid reflux rate by only dividing circular muscle fiber. Our pooled outcome on GER, which showed a rate of 31.4% in POEM, is consistent with that (33%, 30%, and 37% in the 3-, 6-, and 12-month followup) in an international prospective multicenter study.7 However, the rate (31.9%) of GER in LHM is higher than that (17.4%) in published reports.23 In terms of symptomatic efficacy, the Eckardt score, which is defined as four stages, is a comprehensive assessment of disease severity.18 Indeed, both POEM and LHM patients experienced successful improvement of symptom relief. In this present meta-analysis, we found a comparable decrease in Eckardt score between groups, although the number of follow-up months in studies differs. The outcomes agree with other POEM series in which the successful rate ranges from 91.7% to 100%.19,24,25 Besides, previous published LHM reports demonstrated similar symptom remission.26 There are also some limitations in this meta-analysis. Important follow-up outcomes such as objective measures of esophageal contraction amplitudes, LES relaxation, and
resting pressures could not be synthesized owing to inadequate data. Obviously, there were only four studies that were hits in our final analysis, although we had made efforts to systematically search enough databases as we possibly could. Moreover, we failed to conduct subgroup analysis based on the type of achalasia. Third, some indirect data acquisition methods were used, such as when dealing with the SD from the range, which may decrease the reliability. Thus, caution should be taken care to explain the pooled results because of the aforementioned limitations. Conclusions
In summary, we identified comparable outcomes between POEM and LHM with respect to complications, GER, symptomatic recurrence, and other short-term outcomes. Thus POEM is a promising treatment for achalasia. Acknowledgments
We thank Senlin Yin and Yifei Li, West China Medical School of Sichuan University, Chengdu, Sichuan Province, China, for their help in scientific English editing and literature searching. Disclosure Statement
No competing financial interests exist. References
1. Zaninotto G, Rizzetto C. Endoscopic and surgical management of achalasia. Eur Surg Acta Chir Austriaca 2008; 40:146–153. 2. Rosemurgy AS, Morton CA, Rosas M, Albrink M, Ross SB. A single institution’s experience with more than 500 laparoscopic Heller myotomies for achalasia. J Am Coll Surg 2010;210:637–647. 3. Lopushinsky SR, Urbach DR. Pneumatic dilatation and surgical myotomy for achalasia. JAMA 2006;296:2227– 2233. 4. Inoue H, Minami H, Kobayashi Y, Sato Y, Kaga M, Suzuki M, Satodate H, Odaka N, Itoh H, Kudo S. Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy 2010;42:265–271. 5. Swanstrom L, Kurian A, Dunst C, Sharata A, Bhayani N, Rieder E. Long-term outcomes of an endoscopic myotomy for achalasia: The POEM procedure. Ann Surg 2012;256: 659–667. 6. Ponsky JL, Marks JM, Pauli EM. How I do it: Per-oral endoscopic myotomy (POEM). J Gastrointest Surg 2012; 16:1251–1255.
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7. Von Renteln D, Fuchs KH, Fockens P, Bauerfeind P, Vassiliou MC, Werner YB, Fried G, Breithaupt W, Heinrich H, Bredenoord AJ, Kersten JF, Verlaan T, Trevisonno M, Rosch T. Peroral endoscopic myotomy for the treatment of achalasia: An international prospective multicenter study. Gastroenterology 2013;145:309–311. 8. Athanasiou T, Al-Ruzzeh S, Kumar P, Crossman M, Amrani M, Pepper J, Del Stanbridge R, Casula R, Glenville B. Off-pump myocardial revascularization is associated with less incidence of stroke in elderly patients. Ann Thorac Surg 2004;77:745–753. 9. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188. 10. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–560. 11. Hozo S, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13. 12. Bhayani NH, Kurian AA, Dunst CM, Sharata AM, Rieder E, Swanstrom LL. A comparative study on comprehensive, objective outcomes of laparoscopic Heller myotomy with per-oral endoscopic myotomy (POEM) for achalasia. Ann Surg 2014;259:1098–1103. 13. Hungness E, Teitelbaum E, Santos B, Arafat F, Pandolfino J, Kahrilas P, Soper N. Comparison of perioperative outcomes between peroral esophageal myotomy (POEM) and laparoscopic Heller myotomy. J Gastrointest Surg 2013; 17:228–235. 14. Teitelbaum EN, Rajeswaran S, Zhang R, Sieberg RT, Miller FH, Soper NJ, Hungness ES. Peroral esophageal myotomy (POEM) and laparoscopic Heller myotomy produce a similar short-term anatomic and functional effect. Surgery 2013;154:885–892. 15. Ujiki MB, Yetasook AK, Zapf M, Linn JG, Carbray JM, Denham W. Peroral endoscopic myotomy: A short-term comparison with the standard laparoscopic approach. Surgery 2013;154:893–900. 16. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–213. 17. Jones R, Junghard O, Dent J, Vakil N, Halling K, Wernersson B, Lind T. Development of the GerdQ, a tool for the diagnosis and management of gastro-oesophageal reflux disease in primary care. Aliment Pharmacol Ther 2009;30: 1030–1038. 18. Eckardt VF. Clinical presentations and complications of achalasia. Gastrointest Endosc Clin N Am 2001;11:281–292. 19. Zhou PH, Li QL, Yao LQ, Xu MD, Chen WF, Cai MY, Hu JW, Li L, Zhang YQ, Zhong YS, Ma LL, Qin WZ, Cui Z. Peroral endoscopic remyotomy for failed Heller myotomy: A prospective single-center study. Endoscopy 2013;45: 161–166.
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20. Costamagna G, Marchese M, Familiari P, Tringali A, Inoue H, Perri V. Peroral endoscopic myotomy (POEM) for oesophageal achalasia: Preliminary results in humans. Dig Liver Dis 2012;44:827–832. 21. Minami H, Yamaguchi N, Matsushima K, Akazawa Y, Ohnita K, Takeshima F, Nakayama T, Hayashi T, Inoue H, Nakao K, Isomoto H. Improvement of endocytoscopic findings after per oral endoscopic myotomy (POEM) in esophageal achalasia; does POEM reduce the risk of developing esophageal carcinoma? Per oral endoscopic myotomy, endocytoscopy and carcinogenesis. BMC Gastroenterol 2013; 13:22. 22. Boeckxstaens GE, Zaninotto G, Richter JE. Achalasia. Lancet 2014;383:83–93. 23. Yaghoobi M, Mayrand S, Martel M, Roshan-Afshar I, Bijarchi R, Barkun A. Laparoscopic Heller’s myotomy versus pneumatic dilation in the treatment of idiopathic achalasia: A meta-analysis of randomized, controlled trials. Gastrointest Endosc 2013;78:468–475. 24. Lee BH, Shim KY, Hong SJ, Bok GH, Cho JH, Lee TH, Cho JY. Peroral endoscopic myotomy for treatment of achalasia: Initial results of a Korean study. Clin Endosc 2013;46:161–167. 25. Verlaan T, Rohof WO, Bredenoord AJ, Eberl S, Rosch T, Fockens P. Effect of peroral endoscopic myotomy on esophagogastric junction physiology in patients with achalasia. Gastrointest Endosc 2013;78:39–44. 26. Campos GM, Vittinghoff E, Rabl C, Takata M, Gadenstatter M, Lin F, Ciovica R. Endoscopic and surgical treatments for achalasia: A systematic review and metaanalysis. Ann Surg 2009;249:45–57.
Address correspondence to: Ziqiang Wang, MD, PhD Department of Gastrointestinal Surgery West China Hospital, Sichuan University No. 37 Guo Xue Alley Chengdu 610041, Sichuan Province China E-mail: [email protected] or Zongguang Zhou, MD, PhD, FACS Department of Gastrointestinal Surgery West China Hospital, Sichuan University No. 37 Guo Xue Alley Chengdu 610041, Sichuan Province China E-mail: [email protected]
Peroral Esophageal Myotomy Versus Laparoscopic Heller’s Myotomy for Achalasia: A Meta-analysis Mingtian Wei, MD,* Tinghan Yang, MD,* Xuyang Yang, MD, Ziqiang Wang, MD, PhD, and Zongguang Zhou, MD, PhD, FACS
Abstract
Background: This meta-analysis aims to add convincing evidence on the application of peroral esophageal myotomy (POEM), compared with laparoscopic Heller’s myotomy (LHM), for the treatment of achalasia. Materials and Methods: The electronic databases of PubMed, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Embase (up to December 2013) were systematically searched. EndNote X6 citation software (Thomson Reuters, New York, NY) was used for literature management. A modification of the Newcastle–Ottawa Scale was applied for quality assessment. The data were analyzed using Review Manager version 5.1 software (The Cochrane Collaboration, Oxford, United Kingdom), and sensitivity analysis was performed by sequentially omitting each study. Results: Overall, four studies compared the outcomes between POEM and LHM. All studies were conducted in the United States and published in 2013. POEM was associated with comparable complications (odds ratio [OR] = 1.17, 95% confidence interval [CI] 0.53–2.56, P = .70), gastroesophageal reflux (OR = 1.00, 95% CI 0.38–2.61, P = 1.00), and symptomatic recurrence by Eckardt score (OR = 0.24, 95% CI 0.04–1.55, P = .13). Other outcomes including pain score, operating time, and hospital stay were assessed with no significant difference between POEM and LHM. Conclusions: POEM achieves equivalent short-term outcomes compared with LHM for achalasia. This novel procedure is a promising treatment for achalasia.
Introduction
A
chalasia is a rare esophageal motility disorder characterized by poor relaxation of lower esophageal sphincter (LES) and aperistalsis of the esophageal body.1 Achalasia patients mainly present with dysphagia, as well as regurgitation, heartburn, and chest pain. Conventional treatments include drug therapy, endoscopic pneumatic dilation, and surgical Heller’s myotomy to disrupt the LES. During the past decades, laparoscopic Heller’s myotomy (LHM) with an antireflux Dor fundoplication has been gaining wide popularity for the treatment of achalasia in medical centers. Previous studies have demonstrated short- and long-term favorable symptom relief compared with other treatments such as medicine therapy or pneumatic dilation.2,3 Surgically, LHM with a Dor fundoplication is routinely considered the standard option for achalasia patients.
Most recently, natural orifice translumenal endoscopic surgery has been used for its advantage of effectiveness, decreased pain, and less trauma without a skin incision. Peroral endoscopic myotomy (POEM), as a novel endoscopic surgery, was first reported successfully in a case series for the treatment of 17 achalasia patients in 2010.4 Subsequently, a few studies have proven the efficacy and safety of POEM for the treatment of achalasia.5–7 In 2013, sequential published studies reported the comparison of POEM with standard LHM for achalasia, aiming at setting up the foundation of the less invasive procedure. However, because of the relative novel technique and lower incidence for achalasia, the existing literature has a small sample size, lacking convincing evidence. In the present meta-analysis, we aim to clarify the role of POEM in the treatment of achalasia. We strictly pooled existing studies to further compare the outcomes of POEM with LHM. Parameters including complications, gastroesophageal
Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. *The first two authors contributed equally to this study. An abstract of this study was presented at the SAGES 2014 Annual Meeting, April 2–5, 2014, in Salt Lake City, Utah.
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reflux (GER), and symptomatic recurrence by Eckardt score were statistically synthesized. Materials and Methods Search for studies
The electronic databases of PubMed, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Embase (up to December 2013) were systematically searched with no limits. The search strategy combined terms of ‘‘achalasia,’’ ‘‘peroral esophageal myotomy,’’ and ‘‘Heller myotomy’’ in each database with medical subject heading terms or key words. Moreover, previously published reviews on the topic of interest were obtained and checked. We traced the reference list of relevant articles and used Google Scholar to find potential studies. Study selection
All potential studies, including randomized controlled trials, clinical controlled studies, cohort studies, case-control studies, abstracts, and reviews, were identified. The inclusion criteria were as follows: (1) diagnosis of achalasia confirmed
in an adult patient, (2) the surgical procedure compared POEM and LHM, (3) the studies provided adequate outcomes, and (4) data were available for each surgical regimen. We excluded studies in which (1) an animal model was used, (2) achalasia of children was examined, (3) just one surgical regimen was reported, (4) the studies were reviews, letters, abstracts, and editorial material, and (5) studies were lacking available data. Two reviewers independently screened studies by reading titles and abstracts to roughly identify potential reports. The full texts of articles for all references identified as matching the inclusion criteria were obtained. Inclusion criteria were applied to the full texts. Disagreement was resolved through discussion and asking for advice from corresponding authors. Data extraction and quality assessment
Two reviewers independently extracted data from eligible studies, and any disagreement was adjudicated by discussion or consulting the corresponding author. Baseline information included surgical regimen, numbers of achalasia patients, age, sex, preoperative therapy, follow-up year, and other parameters. The following outcome data
FIG. 1. Flow diagram of the study selection process in this meta-analysis.
F, female; LHM, laparoscopic Heller’s myotomy; M, male; POEM, peroral endoscopic myotomy. a Either mean (standard deviation) or median (range).
60.2 (4.7) 64.1 (4.8) 18 (13/5) Ujiki et al.15 (2013)
21 (12/9)
41 (12) 12 (9/3) Teitelbaum et al.14 (2013)
17 (10/7)
38 (22–69) 18 (13/5) Hungness et al.13 (2013)
55 (29/26)
51 (19)
Toupet in most patients, Absence of prior Dor in the case treatment (either of esophageal endoscopic or perforation surgical) Diagnosis of achalasia; age 18–85 years; Endoscopic Toupet in 10 patients, sigmoid esophagus excluded; previous botulinum toxin Dor in 7 patients preoperative myotomy (i.e., reoperative and pneumatic LHM or POEM cases) excluded dilation Confirmed achalasia patients; age > 18 Botulinum toxin, Toupet in 9 patients, years; known coagulopathy, esophageal pneumatic dilation, Dor in 12 patients varices, active esophagitis, pregnancy, and and previous gastroesophageal malignancy excluded Heller’s myotomy
Dilatation and botulinum toxin injection
Age > 18 years; no previous esophageal or mediastinal surgery; body mass index < 40 kg/m2; no massive dilation; absence of sigmoid esophagus 49 (22–79) Diagnosis of achalasia; age 18–85 years; absence of sigmoid esophagus 57 (20) 56 (16) 37 (19/18) Bhayani et al.12 (2013)
64 (31/33)
Prior treatment Inclusion and exclusion criteria LHM POEM LHM
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the detailed selection process is shown in Figure 1. In total, 68 potential abstracts were hit in the primary search, and 14 full-text articles were assessed for eligibility. Based on inclusion and exclusion criteria, four retrospective studies including a total of 242 achalasia patients compared outcomes between POEM and LHM.12–15 There are not 85 distinct and separate patients in the POEM group because patients from two studies by the same group may overlap.13,14 All studies were published in the United States in 2013. No perioperative mortality or conversion to the other procedure was found in any study. Table 1 offers the baseline characteristics of all studies. In addition, perioperative symptom assessment was similar in the four studies, and prior treatment differed in one study, with fewer patients getting endoscopic treatment in the POEM group.14 Lower resting LES pressure was observed in two studies.13,14
POEM
Characteristics and quality judgments
Reference (year)
Results
Age (years)a
The data were analyzed using Review Manager version 5.1 software (The Cochrane Collaboration, Oxford, United Kingdom). Odds ratios (ORs) or risk differences along with 95% confidence intervals (CIs) were used for analyzing dichotomous data, and mean differences (MDs) along with 95% CI for continuous data. To assess the variation across studies, heterogeneity was measured with the I2 index and P value. Based on the method reported by DerSimonian and Laird,9 substantial significance was set when P < .10, and a random effect model was used. Otherwise, a fixed effect model was considered.9,10 Standard deviation (SD) was estimated by a formula when only a range was reported: Estimated SD = Range/4 (15 < n < 70) or Range/6 (n > 70), and the median was approximately equal to the mean.11 A value of P < .05 was considered to indicate statistical significance. With regard to outcomes when significant heterogeneity existed across studies, sensitivity analysis was performed by sequentially omitting each study to test the influence of each individual study on pooled data. If patients in studies overlapped, we would try to contact the authors to get the original data or excluded the patients into final data synthesis.
Sample size (M/F ratio)
Statistical analysis
Table 1. Basic Characteristics of All Pooled Studies in the Meta-analysis
were extracted: complications (major and minor), GER, Eckardt symptom score, pain assessment, operating time, and hospital stay. Because only nonrandomized controlled studies were pooled in the analysis, a modification of the Newcastle– Ottawa Scale was used as an assessment tool from the three aspects of selection, comparability, and outcome assessment.8 Five main factors were considered: prior treatment, preoperative Eckardt score, achalasia subtype, manometry, and antireflux fundoplication. In order to evaluate the comparisons as accurately as possible, age, sex, American Society of Anesthesiologists score, and symptom duration were also taken into consideration. Out of a total of six stars, studies rated at more than four stars were recognized as being moderate to high quality.
Toupet in 27 patients, Dor in 37 patients
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Fundoplication in LHM
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Table 2. Quality Assessment of Studies in the Meta-analysis Based on Modified Newcastle–Ottawa Scale Judgment Selectiona
Comparabilityb
Outcome assessmentc
Reference (year)
1
2
3
4
5
Quality judgment
Bhayani et al.12 (2013) Hungness et al.13 (2013) Teitelbaum et al.14 (2013) Ujiki et al.15 (2013)
+ + + +
+ + — +
++ + + ++
+ + + +
— — + +
+++++ ++++ ++++ ++++++
a Selection: (1) Is the subject definition adequate or described? (if yes, one star). (2) Was the subject representative of the total population? (one star, if truly or obviously; no stars if subjects were selected group or not described). b Comparability: (3) Did the study have no differences between peroral endoscopic myotomy and laparoscopic Heller’s myotomy? Five main factors were considered: prior treatment, preoperative Eckardt score, achalasia subtype, manometry, and antireflux fundoplication. Other four factors—age, sex, American Society of Anesthesiologists score, and symptom duration—were comparative (if yes, two stars; one star if there were no other differences between the two groups even if one or more of these five characteristics was not reported; no star was assigned if the two groups differed). c Outcome assessment: (4) Clearly defined outcome of interest (if yes, one star). (5) Adequacy of follow-up (one star if less than 20% of achalasia patients lost to follow-up, otherwise no stars).
All four studies were retrospective case-control studies due to limitation in surgical blinding or randomization. Table 2 lists the evaluation stars of each study followed by the modified Newcastle–Ottawa Scale. In terms of the three aspects of selection, comparability, and outcome assessment, all included studies were comparable. The four studies were evaluated as being of moderate to high quality.
Quantitative synthesis of outcomes Complications. Complication assessment was based on the Clavien–Dindo grade.16 Major complications included perioperative perforation and bleeding. Minor complications were recorded as subcutaneous emphysema, anterior vagus nerve division, splenic capsule tear, aspiration, atrial fibrillation,
FIG. 2. Forest plot of the odds ratio for all complications.12,13,15 CI, confidence interval; LHM, laparoscopic Heller’s myotomy; M-H, Mantel–Haenszel; POEM, peroral esophageal myotomy.
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FIG. 3. Forest plot of the odds ratio for perforations.12,14,15 CI, confidence interval; LHM, laparoscopic Heller’s myotomy; M-H, Mantel–Haenszel; POEM, peroral esophageal myotomy. urinary retention, and re-admission for chest pain. Figure 2 shows the forest plot of three pooled studies. The results of meta-analysis of all complications, major complications, and minor complications were comparable between POEM and LHM (OR = 1.17, 95% CI 0.53–2.56, P = 0.70; OR = 0.86, 95% CI 0.32–2.26, P = .75; and OR = 2.00, 95% CI 0.57–6.98, P = .28, respectively). Moreover, perforation by itself pooled with no statistical difference (OR = 0.79, 95% CI 0.28–2.19, P = .64) (Fig. 3). GER. Two studies reported the incidence of postoperative GER, which was estimated by a DeMeester score of q14.7 or a GerdQ questionnaire score of q7.17 The fixedeffect analysis model was used because of low heterogeneity (I2 = 3%, P = .31). No significant difference was detected between POEM and LHM (OR = 1.00, 95% CI 0.38–2.61, P = 1.00). The forest plot is shown in Figure 4. Symptomatic recurrence by Eckardt score. Eckardt
symptom score was measured by the four aspects of dysphagia, regurgitation, chest pain, and amount of weight loss.18 With a total possible score of 12, an Eckardt score of q4 was evaluated as symptomatic recurrence. Two studies were hit in the meta-analysis. The outcome showed no significant difference between POEM and LHM (OR = 0.24, 95% CI 0.04–1.55, P = .13). The test for heterogeneity was not significant (I2 = 0%, P = .97) (Fig. 5). Pain assessment and medication usage. Two studies reported postoperative pain score and medication usage. The meta-analysis of pain score was comparable between POEM and LHM (MD = - 0.72, 95% CI - 2.97 to 1.53, P = .53). Significant heterogeneity existed, and a random-effect analysis model was used (I2 = 93%, P = .0001). Operating time and hospital stay. With respect to operating time, three studies reported available data. There was no
significant difference between POEM and LHM for achalasia (MD = - 16.09, 95% CI - 40.63 to 8.45, P = .20). Significant heterogeneity existed among the included studies (I2 = 90%, P < .0001), and a random-effect analysis model was used then. Sensitivity analysis by sequentially omitting each study did not alter the primary outcome. In the quantitative analysis of hospital stay, three studies were pooled in the analysis. POEM required similar hospital time compared with LHM (MD = - 0.09, 95% CI - 1.38 to 0.40, P = .28). Because of high heterogeneity among studies (I2 = 70%, P = .04), sensitivity analysis showed a lower hospital time in POEM when omitting the study of Ujiki et al.,15 which may influence the primary outcome. In addition, the studies on Institutional Review Board trials require many patients to stay in-house for 24–48 hours per the protocol, which becomes a confounding factor. Discussion
POEM was introduced as a promising minimally invasive technique for the clinical practice of achalasia patients by Inoue et al.4 in 2010. Since then, its feasibility, safety, and efficacy have been consistently confirmed by subsequent case series. With the maturity of the endoscopic procedure, some institutions began to report their initial practice on the comparison of POEM with other treatments, most recently standard LHM. However, the studies are retrospectively observational or include a small number of patients. There is no adequate evidence on the safety and efficacy of POEM in the treatment of achalasia. In this meta-analysis, our group pooled the comparative data between POEM and LHM, aiming to provide strong evidence on the application of POEM for achalasia. Overall, our analysis outcomes demonstrate comparable short-term results in POEM compared with LHM based on complications, GER, and Eckardt score. The Newcastle– Ottawa Scale was modified in the baseline characteristics on
FIG. 4. Forest plot of the odds ratio for postoperative gastroesophageal reflux.12,14 CI, confidence interval; IV, inverse variance; LHM, laparoscopic Heller’s myotomy; POEM, peroral esophageal myotomy.
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FIG. 5. Forest plot of the odds ratio for symptomatic recurrence by Eckardt score.14,15 CI, confidence interval; LHM, laparoscopic Heller’s myotomy; M-H, Mantel–Haenszel; POEM, peroral esophageal myotomy. five aspects that are potential prognosis factors (Table 2). The four studies are all scored at least four stars, which are estimated as moderate to high quality. Although follow-up of pooled studies differs, there is no obvious heterogeneity in comparison of symptom assessment. On the contrary, two short-term outcomes of operating time and hospital stay are appraised with high heterogeneity. Also, sensitivity analysis disclosures in one study contributed to the heterogeneity.15 Postoperative complication is the main concern after POEM and LHM for the treatment of achalasia. The outcomes show no significant differences on either major or minor complications. Moreover, perforation, as the most dangerous complication, was by itself pooled without obvious difference between groups. We further investigated previous studies with reported complications. Swanstrom et al.5 reported a 16.7% perforation complication during POEM in their preliminary experience. These perforations were repaired with endoscopic Veress needle or clips intraoperatively. Some case series of small sample size determined no serious POEM-related complications.19–21 The most common side effect that develops after minimally invasive treatment is GER. As is universally known, the aim of treatment for achalasia is to definitively destroy the LES, which, in contrast, induces abnormal acid reflux in LHM. So an antireflux fundoplication, which was previously regarded as the cause of postoperative dysphagia, is routinely suggested following LHM. The current evidence base supports the idea that the fibrosis around the esophagogastric junction may contribute to the dysphagia rather than the fundoplication procedure.22 POEM is likely both to relieve dysphagia and to decrease the acid reflux rate by only dividing circular muscle fiber. Our pooled outcome on GER, which showed a rate of 31.4% in POEM, is consistent with that (33%, 30%, and 37% in the 3-, 6-, and 12-month followup) in an international prospective multicenter study.7 However, the rate (31.9%) of GER in LHM is higher than that (17.4%) in published reports.23 In terms of symptomatic efficacy, the Eckardt score, which is defined as four stages, is a comprehensive assessment of disease severity.18 Indeed, both POEM and LHM patients experienced successful improvement of symptom relief. In this present meta-analysis, we found a comparable decrease in Eckardt score between groups, although the number of follow-up months in studies differs. The outcomes agree with other POEM series in which the successful rate ranges from 91.7% to 100%.19,24,25 Besides, previous published LHM reports demonstrated similar symptom remission.26 There are also some limitations in this meta-analysis. Important follow-up outcomes such as objective measures of esophageal contraction amplitudes, LES relaxation, and
resting pressures could not be synthesized owing to inadequate data. Obviously, there were only four studies that were hits in our final analysis, although we had made efforts to systematically search enough databases as we possibly could. Moreover, we failed to conduct subgroup analysis based on the type of achalasia. Third, some indirect data acquisition methods were used, such as when dealing with the SD from the range, which may decrease the reliability. Thus, caution should be taken care to explain the pooled results because of the aforementioned limitations. Conclusions
In summary, we identified comparable outcomes between POEM and LHM with respect to complications, GER, symptomatic recurrence, and other short-term outcomes. Thus POEM is a promising treatment for achalasia. Acknowledgments
We thank Senlin Yin and Yifei Li, West China Medical School of Sichuan University, Chengdu, Sichuan Province, China, for their help in scientific English editing and literature searching. Disclosure Statement
No competing financial interests exist. References
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Address correspondence to: Ziqiang Wang, MD, PhD Department of Gastrointestinal Surgery West China Hospital, Sichuan University No. 37 Guo Xue Alley Chengdu 610041, Sichuan Province China E-mail: [email protected] or Zongguang Zhou, MD, PhD, FACS Department of Gastrointestinal Surgery West China Hospital, Sichuan University No. 37 Guo Xue Alley Chengdu 610041, Sichuan Province China E-mail: [email protected]
