Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia

Jan E Leyden; Alan C Moss; Padraic MacMathuna

doi:10.1002/14651858.CD005046.pub2

Dilatación neumática endoscópica versus inyección de toxina botulínica en el tratamiento de la acalasia primaria

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Referencias

Referencias de los estudios incluidos en esta revisión

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estudios excluidos
otras referencias

Annese V, Basciani M, Perri F, Lombardi G, Frusciante V, Simone P, et al. Controlled trial of botulinum toxin injection versus placebo and pneumatic dilation in achalasia. Gastroenterology 1996;111(6):1418‐24. [MEDLINE: 310]

Bansal R, Nostrant TT, Scheiman JM, Koshy S, Barnett JL, Elta GH, et al. Intrasphincteric botulinum toxin versus pneumatic balloon dilation for treatment of primary achalasia. Journal of Clinical Gastroenterology 2003;36(3):209‐14. [MEDLINE: 311]

Ghoshal UC, Chaudhuri S, Pal BB, Dhar K, Ray G, Banerjee PK. Randomized controlled trial of intrasphincteric botulinum toxin A injection versus balloon dilatation in treatment of achalasia cardia. Diseases of the Esophagus 2001;14(3‐4):227‐31. [MEDLINE: 2]

Mikaeli J, Fazel A, Montazeri G, Yaghoobi M, Malekzadeh R. Randomized controlled trial comparing botulinum toxin injection to pneumatic dilatation for the treatment of achalasia. Alimentary Pharmacology and Therapeutics 2001;15(9):1389‐96. [MEDLINE: 312]

Muehldorfer SM, Schneider TH, Hochberger J, Martus P, Hahn EG, Ell C. Esophageal achalasia: intrasphincteric injection of botulinum toxin A versus balloon dilation. Endoscopy 1999;31(7):517‐21. [MEDLINE: 313]

Vaezi MF, Richter JE, Wilcox CM, Schroeder PL, Birgisson S, Slaughter RL, Koehler RE, Baker ME. Botulinum toxin versus pneumatic dilatation in the treatment of achalasia: a randomised trial. Gut 1999;44(2):231‐39. [MEDLINE: 5]

Referencias de los estudios excluidos de esta revisión

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estudios incluidos
otras referencias

Allescher HD, Storr M, Seige M, Gonzales‐Donoso R, Ott R, Born P, et al. Treatment of achalasia: botulinum toxin injection vs. pneumatic balloon dilation. A prospective study with long‐term follow‐up. Endoscopy 2001;33(12):1007‐17. [MEDLINE: 1]

Bansal R, Koshy S, Scheiman JM, Barnett JL, Nostrant TT. Interim analysis of a randomized trial of Witzel pneumatic dilation vs intrasphincteric injection of botulinum toxin (Botox) for achalasia. Gastroenterology 1996;110(4):A56. [MEDLINE: 279]

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des Varannes SB, Lemiere S, Guillemot JF, Ducrotte P, Zerbib F, Rolachon A, et al. Botulinum toxin versus pneumatic dilatation in achalasia: Results of a multicentre controlled trial. Gastroenterology 1999;116(4):G0557. [MEDLINE: 191]

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Gaudric M, Guimbaud R, Chaussade S, Palazzo L, Quartier G, Samama J, et al. Pneumatic dilatation (PD) versus intrasphincteric botulinum toxin (BT) in the treatment of achalasia: Preliminary results of a controlled study. Gastroenterology 1996;110(4):A667. [MEDLINE: 284]

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Malekzadeh R, Milkaeli J, Fazel A, Montazeri G, Yaghoobi M, Khatibian M, et al. A randomized controlled trial comparing botulinum toxin injection to pneumatic dilatation for treatment of achalasia. Gastrointestinal Endoscopy 2000;51(4):4468. [MEDLINE: 149]

Muehldorfer SM, Schneider T, Hochberger J, Hahn EG, Ell C. Intrasphincteric injection of botulinum toxin A versus balloon dilation in patients with achalasia. A randomized prospective comparative trial. Gastrointestinal Endoscopy 1998;47(4):199. [MEDLINE: 225]

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Nebendahl JC, Brand B, von Schrenck T, Matsui U, Thonke F, Bohnacker S, et al. Prospective randomised comparison of dilation (high compliance balloon) vs. botulinum toxin injection (BTX) in esophageal achalasia. Gastroenterology 1998;114(4):G0985. [MEDLINE: 218]

Referencias adicionales

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estudios incluidos
estudios excluidos

Annese V, Basciani M, Borrelli O, Leandro G, Simone P, Andriulli A. Intrasphincteric injection of botulinum toxin is effective in long‐term treatment of esophageal achalasia. Muscle Nerve 1998;21:1540‐2.

Bassotti G, Annese V. Pharmacological options in achalasia. Alimentary Pharmacology & Therapeutics 1999;13:1391‐6.

Cuilliere C, Ducrotte P, Zerbib F, et al. Achalasia: outcome of patients treated with intrasphincteric injection of botulinum toxin. Gut 1997;41:87‐92.

Eckardt VF, Kohne U, Junginger T, Westermeier T. Risk factors for diagnostic delay in achalasia. Digestive Diseases and Sciences 1997;42(3):580‐5.

Frantzides CT, Moore RE, Carlson MA, et al. Minimally invasive surgery for achalasia: a 10‐year experience. Journal of Gastrointestinal Surgery 2004;8(1):18‐23.

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008].. The Cochrane Collaboration2008. Available from www.cochrane‐handbook.org..

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Howard PJ. Maher L, Pryde A, et al. Five year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edingburgh. Gut 1992;33:1011‐5.

Imperiale TF, O'Connor JB, Vaezi MF, Richter JE. A cost‐minimization analysis of alternative treatment strategies for achalasia. The American Journal of Gastroenterology 2000;95(10):2737‐45.

Kadakia SC, Wong RK. Pneumatic balloon dilation for esophageal achalasia. Gastrointestinal Endoscopy Clinics of North America 2001;11(2):325‐46.

Katz PO, Gilbert J, Costell D. Pneumatic dilation is effective long‐term treatment for achalasia. Digestive Diseases and Sciences 1998;43:1973‐7.

Kolbasnik J, Waterfall WE, Fachnie B, Chen Y, Tougas G. Long‐term efficacy of Botulinum toxin in classical achalasia: a prospective study. The American Journal of Gastroenterology 1999;94(12):3434‐9.

Mayberry JF, Atkinson M. Variations in the prevalence of achalasia in Great Britain and Ireland: an epidemiological study based on hospital admissions. The Quarterly Journal of Medicine 1987;62:67‐74.

Pasricha PJ, Ravich WJ, Hendric TR, Kalloo AN. Treatment of achalasia with intrasphincteric injection of botulinum toxin: a pilot trial. Annals of Internal Medicine 1994;121:590‐1.

Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, Kalloo AN. Botulinum toxin for the treatment of achalasia. The New England Journal of Medicine 1995;322:774‐8.

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Reynolds, JC, Parkman, HP. Achalasia. Gastroenterology Clinics of North America 1989;18:223.

Urbach DR, Hansen PD, Khajanchee YS, Swanstrom LL. A decision analysis of the optimal initial approach to achalasia: laparoscopic Heller myotomy with partial fundoplication, thoracoscopic Heller myotomy, pneumatic dilatation, or botulinum toxin injection. Journal of Gastrointestinal Surgery 2001;5(2):192‐205.

Vela MF, Richter JE, Wachsberger D, Connor J, Rice TW. Complexities of managing achalasia at a tertiary referral center: use of pneumatic dilatation, Heller myotomy, and botulinum toxin injection. The American Journal of Gastroenterology 2004;99(6):1029‐36.

Wen ZH, Gardener E, Wang YP. Nitrates for achalasia. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD002299. CD002299.pub2. [DOI: 10.1002/14651858]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Annese 1996

Methods	RCT. Method of randomisation was not stated. Initially BTX vs placebo saline injection. All placebos relapsed and treated by PD. BTX relapsers were retreated. Remission ‐ symptom score </= 2. Exclusion criteria: < 18yrs, previous PD or myotomy, sigmoid shaped oesophagus.
Participants	16 treatment naive adult participants. Baseline characteristics of both treatment groups were similar.
Interventions	8 participants received 100U BTX and 8 participants underwent PD. PD: day 1 ‐ Rigiflex 30mm, day 2 & 3 ‐ 35mm balloon.
Outcomes	Mean symptom score ‐ dysphagia (0‐3), chest pain (0‐3) , regurgitation (0‐3) Mean LOS Pressure (mmHg) Barium retention studies (mean % retained at 10 min) Outcomes assessed at 1, 6, 12 months . Remission defined as a symptom score</=2.
Notes	No complications reported. 10 reached 12 month follow up. High risk of bias as not double blind.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Unclear risk	Method not stated
Blinding? All outcomes	High risk
Incomplete outcome data addressed? All outcomes	Low risk
Free of selective reporting?	Low risk
Free of other bias?	Low risk

Bansal 2003

Methods	Double blind RCT. Method of randomisation was not stated. Crossover to other treatment if failed treatment at any time. Exclusion criteria: previous treatment, <18 yrs, pregnant, large epiphrenic diverticulae or hiatus hernia, secondary achalasia, poor surgical candidates. Remission ‐ decrease in symptom grade >/= 1.
Participants	34 treatment naive adults Baseline characteristics of both treatment groups were similar.
Interventions	BTX 80U 4 quadrants Witzel 40mm balloon ‐ 180‐300 mmHg x 3 min Sham injection or dilatation
Outcomes	Mean symptom score ‐ dysphagia, chest pain, regurgitation (0‐9) Dysphagia score (0‐21) Dysphagia severity (0‐10) Pain severity (0‐10) Global assessment (0‐10, graded 0, 1, 2, 3) Weight gain (%) Mean LOS Pressure (mmHg)at 3 weeks, 3 months and 12 months.
Notes	2 perforations in PD group. 2 Loss to follow up. Low bias
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Unclear risk	Method not stated
Blinding? All outcomes	Low risk
Incomplete outcome data addressed? All outcomes	Low risk
Free of selective reporting?	Low risk
Free of other bias?	Low risk

Ghoshal 2001

Methods	RCT. Method of randomisation ‐ computer generated random numbers. Non responders/relapsers retreated with PD. Remission ‐ dysphagia score 0 or 1.
Participants	17 participants 2 BTX group had previous PD. Baseline characteristics of both treatment groups were similar.
Interventions	BTX 60‐80 units Rigiflex 30mm ‐ 1 min 10‐15psi
Outcomes	Dysphagia (0‐3), chest pain (Y/N), regurgitation (Y/N) Symptoms assessed at 1 week, 3‐6 monthly Mean LOS pressure at 1 week
Notes	No complications High risk of bias as not double blind.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk
Allocation concealment?	Low risk
Blinding? All outcomes	High risk
Incomplete outcome data addressed? All outcomes	Low risk
Free of selective reporting?	Low risk
Free of other bias?	Low risk

Mikaeli 2001

Methods	RCT. Method of randomisation ‐ computer generated random numbers. Repeat treatment for non response/relapse (same BTX dose or 35mmPD). Remission ‐ > 50% improvement in symptom score. Exclusion criteria: < 40 yrs, pregnancy, coagulopathy, recent MI or CCF, Epiphrenic diverticulae or hiatus hernia, oesophageal ulcer, oesophageal varices, gastrooesophageal carcinoma
Participants	40 participants(>40yr) BTX group older
Interventions	BTX 200(80)U 4 quadrants Rigiflex 30mm ‐ 10psi x 30 sec
Outcomes	Mean symptom (0‐15) 1, 6, 12 months Mean LOS pressure at 1 month
Notes	No complication 1 lost to follow up High risk of bias as not double blind.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk
Allocation concealment?	Low risk
Blinding? All outcomes	High risk
Incomplete outcome data addressed? All outcomes	Low risk
Free of selective reporting?	Low risk
Free of other bias?	Low risk

Muehldorfer 1999

Methods	RCT. Method of randomisation not stated. Exclusion criteria: secondary achalasia, dysphagia score <10/20, coagulopathy, previous gastro‐oesophageal surgery, large epiphrenic diverticulum or hiatuas hernia. Remission ‐ >/= 50% reduction in symptoms.
Participants	24 participants ‐ 15 had previously undergone PD Baseline characteristics of both treatment groups were similar.
Interventions	BTX 80 Units 40mm PD ‐ up to 300mmHg x 3 min day 1 & 3
Outcomes	Median score (0‐20) for 4 symptoms ‐ dysphagia, regurgitation, chest pain and heartburn at 1 week, 1 month and 6 monthly for 30 months. Mean LOS pressure post treatment in 16 patients
Notes	No complications. Possible high risk of bias if not double blind.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Unclear risk	Method not stated
Incomplete outcome data addressed? All outcomes	Low risk
Free of selective reporting?	Low risk
Free of other bias?	Low risk

Vaezi 1999

Methods	RCT. Method of randomisation ‐ computer generated random numbers. Retreated if no response at 1 month (35mm PD balloon). Exclusion criteria: previous treatment, < 18yrs, secondary achalasia, pregnancy, neuromuscular disorder, NYHA grade III or IV, coagulopathy. Remission ‐ > 50% improvement in symptoms.
Participants	47 treatment naive participants. Baseline characteristics of both treatment groups were similar. 5 participants were excluded from the analysis ‐ 2 BTX group and 3 PD group.
Interventions	BTX 100U Rigiflex 30mm ‐ 9‐15psi x 1 minute
Outcomes	Median symptom score (0‐15) Symptoms assessed at 1, 3, 6, 9, 12 months Median LOS pressure at 1 month Barium retention ‐height and width 1, 6, 12 months
Notes	1 perforation in PD group ‐ excluded from analysis. 4 lost to follow up ‐ excluded from analysis. High risk of bias as not double blind..
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk
Allocation concealment?	Low risk
Blinding? All outcomes	High risk
Incomplete outcome data addressed? All outcomes	Low risk
Free of selective reporting?	Low risk
Free of other bias?	Low risk

Vs:versus

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos

Study	Reason for exclusion
Allescher 2001	Not a RCT.
Bansal 1996	Duplicate ‐ Meeting abstract. Full paper later published.
des Varannes 1999	Meeting abstract ‐ unable to contact author.
Gaudric 1996	Meeting abstract ‐ unable to contact author.
Malekzadeh 2000	Duplicate ‐ Meeting abstract. Full paper later published.
Muehldorfer 1998	Duplicate ‐ Meeting abstract. Full paper later published.
Nebendahl 1998	Meeting abstract ‐ unable to contact author.

Data and analyses

Open in table viewer

Comparison 1. Pneumatic Dilation versus Botulinum Toxin Injection

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Initial remission Show forest plot	4	132	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.95, 1.38]
Open in figure viewer Analysis 1.1 Comparison 1 Pneumatic Dilation versus Botulinum Toxin Injection, Outcome 1 Initial remission.
2 Mean oesophageal pressure within first four weeks Show forest plot	3	90	Mean Difference (IV, Fixed, 95% CI)	‐0.77 [‐2.44, 0.91]
Open in figure viewer Analysis 1.2 Comparison 1 Pneumatic Dilation versus Botulinum Toxin Injection, Outcome 2 Mean oesophageal pressure within first four weeks.
3 Remission at six months Show forest plot	2	56	Risk Ratio (M‐H, Fixed, 95% CI)	2.90 [1.48, 5.67]
Open in figure viewer Analysis 1.3 Comparison 1 Pneumatic Dilation versus Botulinum Toxin Injection, Outcome 3 Remission at six months.
4 Remission at twelve months Show forest plot	3	90	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [1.58, 4.52]
Open in figure viewer Analysis 1.4 Comparison 1 Pneumatic Dilation versus Botulinum Toxin Injection, Outcome 4 Remission at twelve months.

Analysis 1.1

Comparison 1 Pneumatic Dilation versus Botulinum Toxin Injection, Outcome 1 Initial remission.

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Analysis 1.2

Comparison 1 Pneumatic Dilation versus Botulinum Toxin Injection, Outcome 2 Mean oesophageal pressure within first four weeks.

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Analysis 1.3

Comparison 1 Pneumatic Dilation versus Botulinum Toxin Injection, Outcome 3 Remission at six months.

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Analysis 1.4

Comparison 1 Pneumatic Dilation versus Botulinum Toxin Injection, Outcome 4 Remission at twelve months.

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Table 1. Studies meeting selection criteria but excluded from the meta‐analysis

Study	methods	Remission 1 month	Remission 6 months	Remission 12 months	Mean LOS pressure	Complications
Annese 1996	8 participants 100U BTX and 8 participants PD. PD: day 1 ‐ Rigiflex 30mm. Day 2 and 3 ‐ 35mm balloon BTX relapsers retreated.	PD 8/8 BTX 8/8	PD 8/8 BTX 6/8	PD 8/8 BTX 1/8	PD ‐72% BTX ‐44%	none
Muehldorfer 1999	12 participants 80 Units BTX and 12 PD 40mm day 1 & 3. BTX repeated at 1 week in 4 non responders.	PD 10/12 BTX 9/12	PD 9/12 BTX 6/12	PD 8/12 BTX 3/12	PD ‐50% BTX ‐44%	none

Table 1. Studies meeting selection criteria but excluded from the meta‐analysis

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Comparison 1. Pneumatic Dilation versus Botulinum Toxin Injection

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Initial remission Show forest plot	4	132	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.95, 1.38]

2 Mean oesophageal pressure within first four weeks Show forest plot	3	90	Mean Difference (IV, Fixed, 95% CI)	‐0.77 [‐2.44, 0.91]

3 Remission at six months Show forest plot	2	56	Risk Ratio (M‐H, Fixed, 95% CI)	2.90 [1.48, 5.67]

4 Remission at twelve months Show forest plot	3	90	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [1.58, 4.52]

Comparison 1. Pneumatic Dilation versus Botulinum Toxin Injection

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Referencias

Referencias de los estudios incluidos en esta revisión

Annese 1996 {published data only}

Bansal 2003 {published data only}

Ghoshal 2001 {published data only}

Mikaeli 2001 {published data only}

Muehldorfer 1999 {published data only}

Vaezi 1999 {published data only}

Referencias de los estudios excluidos de esta revisión

Allescher 2001 {published data only}

Bansal 1996 {published data only}

des Varannes 1999 {published data only}

Gaudric 1996 {published data only}

Malekzadeh 2000 {published data only}

Muehldorfer 1998 {published data only}

Nebendahl 1998 {published data only}

Referencias adicionales

Annese 1998

Bassotti 1999

Cuilliere 1997

Eckardt 1997

Frantzides 2004

Higgins 2008

Howard 1992

Imperiale 2000

Kadakia 2001

Katz 1998

Kolbasnik 1999

Mayberry 1987

Pasricha 1994

Pasricha 1995

Reynolds 1989

Urbach 2001

Vela 2004

Wen 2004

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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