Leyden Et Al-2014-The Cochrane Library

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

Leyden JE, Moss AC, MacMathuna P
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2014, Issue 12
http://www.thecochranelibrary.com
Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia (Review)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 2.
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Figure 3.
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AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
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REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Pneumatic dilation versus botulinum toxin injection, Outcome 1 Initial remission. . .
Analysis 1.2. Comparison 1 Pneumatic dilation versus botulinum toxin injection, Outcome 2 Mean oesophageal pressure
within first four weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.3. Comparison 1 Pneumatic dilation versus botulinum toxin injection, Outcome 3 Remission at six months.
Analysis 1.4. Comparison 1 Pneumatic dilation versus botulinum toxin injection, Outcome 4 Remission at twelve
months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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[Intervention Review]
Endoscopic pneumatic dilation versus botulinum toxin

injection in the management of primary achalasia
Jan E Leyden1 , Alan C Moss2 , Padraic MacMathuna3
1 Department of Gastroenterology, Mater Misericordiae
University Hospital, Dublin, Ireland. 2 Center for Inflammatory Bowel Disease,

Beth Israel Deaconess Medical Center, Boston, MA, USA. 3 Mater Misericordiae University Hospital, Dublin, Ireland
Contact address: Jan E Leyden, Department of Gastroenterology, Mater Misericordiae University Hospital, Eccles Street, Dublin,
Dublin 7, Ireland. janleyden@eircom.net.
Editorial group: Cochrane Upper GI and Pancreatic Diseases Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2014.
Review content assessed as up-to-date: 23 July 2014.
Citation: Leyden JE, Moss AC, MacMathuna P. Endoscopic pneumatic dilation versus botulinum toxin injection in the
management of primary achalasia. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD005046. DOI:
10.1002/14651858.CD005046.pub3.
ABSTRACT
Background
Achalasia is an oesophageal motility disorder, of unknown cause, which results in increased lower oesophageal sphincter (LOS) tone and
symptoms of difficulty swallowing. Treatments are aimed at reducing the LOS tone. Current endoscopic therapeutic options include
pneumatic dilation (PD) or botulinum toxin (BTX) injection.
Objectives
To undertake a systematic review comparing the efficacy and safety of two endoscopic treatments, PD and intrasphincteric BTX
injection, in the treatment of oesophageal achalasia.
Search methods
Trials were initially identified by searching MEDLINE (1966 to August 2008), EMBASE (1980 to September 2008), ISI Web of
Science (1955 to September 2008), The Cochrane Library Issue 3, 2008. Searches in all databases were conducted in October 2005
and updated in September 2008 and April 2014. The Cochrane highly sensitive search strategy for identifying randomised trials
in MEDLINE, sensitivity maximising version in the Ovid format, was combined with specific search terms to identify randomised
controlled trials in MEDLINE. The MEDLINE search strategy was adapted for use in the other databases that were searched.
Selection criteria
Randomised controlled trials comparing PD to BTX injection in individuals with primary achalasia.
Data collection and analysis
Two review authors independently performed study quality assessment and data extraction.
Main results
Seven studies involving 178 participants were included. Two studies were excluded from the meta-analysis of remission rates on the
basis of clinical heterogeneity of the initial endoscopic protocols. There was no significant difference between PD or BTX treatment
in remission within four weeks of the initial intervention; with a risk ratio of remission of 1.11 (95% CI 0.97 to 1.27). There was also
no significant difference in the mean oesophageal pressures between the treatment groups; with a weighted mean difference for PD of
-0.77 (95% CI -2.44 to 0.91, P = 0.37). Data on remission rates following the initial endoscopic treatment were available for three
studies at six months and four studies at 12 months. At six months 46 of 57 PD participants were in remission compared to 29 of 56
in the BTX group, giving a risk ratio of 1.57 (95% CI 1.19 to 2.08, P = 0.0015); whilst at 12 months 55 of 75 PD participants were
in remission compared to 27 of 72 BTX participants, with a risk ratio of 1.88 (95% CI 1.35 to 2.61, P = 0.0002). No serious adverse
outcomes occurred in participants receiving BTX, whilst PD was complicated by perforation in three cases.
Authors conclusions
The results of this meta-analysis suggest that PD is the more effective endoscopic treatment in the long term (greater than six months)
for patients with achalasia.
PLAIN LANGUAGE SUMMARY

Endoscopic balloon dilation versus botulinum toxin (Botox) injection for managing achalasia, a condition causing difficulty
in swallowing
Achalasia is an oesophageal motility disorder which results in increased lower oesophageal sphincter (LOS) tone and symptoms of
difficulty swallowing. Treatments are aimed at reducing the tone of the LOS and include the endoscopic options of pneumatic dilation
(PD) or local botulinum toxin (BTX) injection. We set out to undertake a systematic review comparing randomised controlled trials
that examined the efficacy and safety of PD and BTX injection in people with achalasia. We searched databases (MEDLINE, EMBASE,
ISI Web of Science, and The Cochrane Library) in April 2014 for reports of relevant randomised controlled trials. Seven randomised
controlled trials were identified for inclusion in the review, and five were suitable for meta-analysis. Meta-analysis suggested that,
although both interventions had similar initial response rates, the remission rates at six and 12 months were significantly greater with
PD than with BTX injection.
BACKGROUND
Description of the condition

Achalasia is an oesophageal motility disorder of unknown cause
that manifests as symptoms of difficulty swallowing (dysphagia),
with pooling of food and secretions in the lower oesophagus. The
annual incidence has been estimated at approximately 1:100,000
(Mayberry 1987; Howard 1992). The onset of symptoms is often
insidious, usually between the ages of 25 and 60 years, and symptoms gradually progress over a period of years (Eckardt 1997).
The condition is characterised by degeneration of ganglion cells,
predominantly the inhibitory neurons in the myenteric plexus of
the lower oesophageal sphincter (LOS). This leads to a rise in the
basal tone of the sphincter, loss of peristalsis in the distal oesophagus, and a lack of coordinated LOS relaxation in response to swallowing. Achalasia may be suspected from the clinical history, however radiographic, endoscopic, and, most importantly, manometric assessment are need to confirm the diagnosis (Reynolds 1989).
The function of the degenerated myenteric plexus neurons cannot be restored, therefore treatments are aimed at reducing the
tone of the LOS. These include pharmacological therapy, surgical myotomy, and endoscopic pneumatic dilation (PD) or intrasphincteric botulinum toxin (BTX) injection. Pharmacological
treatments such as oral nitrates, calcium channel blockers, anticholinergic agents, and beta-adrenergic agonists have proven disappointing to date (Bassotti 1999; Wen 2004).
Description of the intervention

Surgical myotomy (Hellers myotomy) is an effective treatment option with good long-term results. Whilst laparoscopic Hellers myotomy is generally accepted as the operative procedure of choice,
endoscopic therapy remains a valid option in the primary management of achalasia (Urbach 2001; Frantzides 2004; Vela 2004).
Standard endoscopic therapeutic options include PD or BTX injection. A variety of balloon types and protocols have been used
to treat this condition, with reported long-term efficacy of up to
90%. The major complication associated with PD is oesophageal
perforation, which occurs in up to 3% of cases (Katz 1998; Kadakia

2001). PD appears to be the least costly treatment (Imperiale
2000). Recently, a novel endoscopic myotomy procedure, peroral
endoscopic myotomy (POEM), has been developed which has
shown similar short-term outcomes to Hellers myotomy (Pasricha
2007; Inoue 2010; Von Renteln 2013). POEM is a complex endoscopic procedure which is only performed in specialist centres.
Why it is important to do this review

Intrasphincteric injection of BTX is an alternative endoscopic therapy to PD (Pasricha 1994; Pasricha 1995). It is a safe procedure,
being associated with few side effects or complications (Cuilliere
1997). Usually 80 to 100 units of BTX are injected with a sclerotherapy needle in divided doses into the four quadrants of the
LOS, under direct vision. Although an efficacy of about 85% in
the short-term period has been reported, this decreases to 50% at
six months and 30% after one year (Annese 1998; Bassotti 1999;
Kolbasnik 1999).
Types of interventions
The following interventions were compared in the treatment of
achalasia:
endoscopic BTX injection;
endoscopic PD.
Varying doses and frequencies of BTX, and different types of balloon and methods of PD were considered.
Types of outcome measures
Primary outcomes
Symptom remission rates within the first month, at six months,

and at 12 months
Secondary outcomes
Lower oesophageal sphincter (LOS) pressure confirmed by oesophageal manometry post-treatment

Complications directly related to the endoscopic therapy
Quality of life post-intervention
Cost-effectiveness
OBJECTIVES
To undertake a systematic review comparing the efficacy and safety
of two endoscopic treatments, intrasphincteric botulinum toxin
(BTX) injection and pneumatic dilation (PD), in the treatment
of oesophageal achalasia.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised controlled trials, with or without blinding, comparing endoscopic intrasphincteric BTX injection to endoscopic PD
in the treatment of achalasia.
Search methods for identification of studies
Electronic searches
Searches were conducted to identify all published and unpublished randomised controlled trials. Articles published in any language were included. Trials were identified by searching MEDLINE (1946 to week 3 March 2014), EMBASE (1980 to week 12
2014), ISI Web of Science (1955 to March 2014), Cochrane Central Register of Controlled Trials(January 2014). Searches in all
databases were conducted initially in October 2005 and updated in
September 2008, July 2011, and April 2014. The Cochrane highly
sensitive search strategy for identifying randomised trials in MEDLINE, sensitivity maximising version in the Ovid format (Higgins
2008), was combined with the search terms in Appendix 1 to identify randomised controlled trials in MEDLINE. The MEDLINE
search strategy was adapted for use in the other databases that were
searched for this review.
Searching other resources
Types of participants
Individuals of any age diagnosed with achalasia by a combination of clinical, endoscopic, radiographic, or manometric investigations, including patients who had received previous endoscopic
treatments.
Reference lists from trials selected by electronic searching were

handsearched to identify further relevant trials. Published abstracts
from conference proceedings in the United European Gastroenterology Week (published in Gut) and Digestive Disease Week
(published in Gastroenterology) were handsearched.
Data collection and analysis
Selection of studies
Two review authors independently scanned the abstract of each
trial identified by the search to determine eligibility. The authors
were not blinded to the sources of the trials. We selected full articles
for further assessment if the abstract suggested the study was a
randomised controlled trial of patients with achalasia comparing
balloon dilation to BTX injection. If these criteria were unclear
from the abstract, the full article was retrieved for clarification.
Studies meeting the inclusion criteria were included for review
and data extraction. Papers not meeting the inclusion criteria were
excluded. Any disagreements were resolved by discussion.
Quality assessment of trials
Two review authors independently assessed the methodological

quality of the selected trials using the following criteria:
1. the method of randomisation;
2. allocation concealment;
3. baseline comparability of study groups;
4. blinding and completeness of follow up.
We did not use blinding of participants or intervention providers
as an assessment criterion given the nature of the interventions
being studied. Trials were graded: A - adequate, B - unclear, C inadequate on each criterion and thus each randomised controlled
trial (RCT) was graded as having low, moderate, or high risk of
bias. If it was unclear whether a criterion had been met, we sought
further information from the author. Any disagreements were resolved by discussion.
Data extraction and management

We extracted data from published reports using predetermined
standardised forms. Disagreements were resolved by discussion
between the review authors. The following data were extracted
wherever possible:
method of randomisation;
blinding for outcome assessor, patient, and carer;
criteria for patient inclusion and exclusion;
history of previous treatment for achalasia;
participants characteristics including mean or median age,
age range, sex ratio;
number of participants assigned to each treatment group;
number of co-morbid conditions, with details of
intervention;
type of intervention per endoscopic session, type of balloon
and pressures attained;
effect on symptoms;
effect on LOS pressure;
effect on quality of life;
number and frequency of procedure related complications;
duration of therapy and any co-interventions;
frequency of re-interventions;
number of participants withdrawn and reasons for these
withdrawals;
adverse reactions and outcomes.
Assessment of risk of bias in included studies
Data synthesis
Statistical analyses
Statistical guidance was available from the editorial base and the
review authors host institutions. The variation in type of balloon
used and pressures attained at dilation, the dose of BTX injected,
and the history of previous endoscopic treatment were considered
as potential causes of heterogeneity. Dichotomous data were summarised using the risk ratio and reported with 95% confidence
intervals. The relative risk of remission was calculated at each of
the three time points. Continuous data were summarised using
weighted mean difference and reported with 95% confidence intervals.
RESULTS
Description of studies
Results of the search

We identified studies using the search criteria and assessed nine
full-text articles for eligibility, as shown in Figure 1.
Figure 1. Study flow diagram.
Included studies
The seven included studies were RCTs involving patients with
a diagnosis of primary achalasia based on clinical, endoscopic,
manometric, and radiographic criteria. Please see Characteristics
of included studies.
Treatments
A 30 mm diameter PD balloon was used in five studies

(Annese 1996; Vaezi 1999; Ghoshal 2001; Mikaeli 2001; Zhu
2009). In one of these PD was performed on three consecutive
days (Annese 1996), with a 35 mm balloon being used on the
second and third day. The total BTX dose administered varied
from 60 to 100 units in these five studies.
defined as symptom scores of 0 to 1, 2 to 3, 4 to 6, and > 6

respectively. Remission was defined as a symptom score
reduction of > 1 grade, with a sustained response. Remission was
not specifically defined in the study by Ghoshal (Ghoshal 2001)
but all responders experienced at least a 50% reduction in
symptoms. Annese (Annese 1996) calculated a similar symptom
score (0 to 9) and defined remission as a score of < 2. Zhu (Zhu
2009) calculated a total symptom score derived from the
combination of the symptoms of solid and liquid dysphagia,
active and passive regurgitation, and chest pain. The severity of
each of these symptoms was scored on a scale of 0 to 3, thus the
highest obtainable score was 15. A symptom score < 4 was
deemed a clinical response. Only two studies used Kaplan-Meier
survival analysis to assess remission rates after a single endoscopic
treatment (Ghoshal 2001; Mikaeli 2001).
The two remaining studies compared a 40 mm balloon

either as a single PD session (Bansal 2003) or two sessions one
day apart (Muehldorfer 1999) to a total BTX dose of 80 U.
Quality of life and cost-effectiveness were not measured in

any of the included studies.
In one study participants not responding to the initial BTX

injection received a further injection one week later
(Muehldorfer 1999).
Excluded studies
Some participants who either failed to respond to the initial

endoscopic treatment or who relapsed during the study period
underwent a repeat procedure or were crossed over to the
alternative treatment in all six studies.
Outcomes
Changes in achalasia symptoms and LOS pressure in

response to both treatments were assessed between one and four
weeks after the initial treatment in all studies. The methods used
for scoring achalasia symptoms varied between studies; however,
most defined remission as 50% or greater improvement in the
symptom score. The symptom scores were further assessed in all
studies, and LOS pressure in three of the studies, over a 12
month period (Annese 1996; Bansal 2003; Zhu 2009). Data on
the response to the initial endoscopic treatment only, at six and
12 months, were available in five of the studies (Annese 1996;
Muehldorfer 1999; Ghoshal 2001; Mikaeli 2001; Zhu 2009).
All studies compared cumulative remission over a 12 month
period, however the definition of remission varied between
studies. Remission was defined as a 50% or greater reduction in
symptoms in three studies (Muehldorfer 1999; Vaezi 1999;
Mikaeli 2001). A further study (Bansal 2003) calculated a total
symptom score derived from the combination of the symptoms
of dysphagia, chest pain, and regurgitation, each given a score of
0 to 3. This score was then divided into four grades (0 to 3),
We excluded 10 studies from the analysis (Figure 1). One full-text

paper (Allescher 2001) and one meeting abstract (Jung 2012) reported non-randomised studies. Three studies, published as meeting abstracts, were preliminary results of included studies (Bansal
1996; Muehldorfer 1998; Malekzadeh 2000). Four studies, published as meeting abstracts only, were excluded as we were unable
to contact the authors to obtain additional information regarding the studies (Gaudric 1996; Nebendahl 1998; des Varannes
1999; Linghu 2013). One study (Zhou 2012) was not included
as only the abstract was published in English and we were unable
to contact the author to obtain additional information. Please see
Characteristics of excluded studies.
Risk of bias in included studies
Allocation
Method of randomisation
The method of randomisation was adequate in four studies (Vaezi

1999; Ghoshal 2001; Mikaeli 2001; Zhu 2009), and unclear in the
remaining three (Annese 1996; Muehldorfer 1999; Bansal 2003).
Blinding
Two of the seven studies were double blind trials (Bansal 2003; Zhu
2009). A further study reported blinding of those assessing LOS
pressure (Vaezi 1999). In the studies by Annese 1996; Ghoshal

2001; and Mikaeli 2001 the assessors were not blinded. The study
by Annese 1996 had been classified as double blind in the original
review but has been reclassified in this update. Blinding was unclear
in the remaining study (Muehldorfer 1999).
The clinical characteristics of participants in both treatment

groups were similar in all but one study: the BTX group were older
in the study by Mikaeli 2001. Two studies included participants
who had been unsuccessfully treated with PD in the past: eight
of the PD group and seven of the BTX group in the study by
Muehldorfer 1999; two of the BTX group in the study by Ghoshal
2001.
Mikaeli 2001; Bansal 2003; Zhu 2009). The remaining study reported median and interquartile scores; individual patient data
were not available (Vaezi 1999). There was no significant difference in the mean oesophageal pressures between the treatment
groups, with a weighted mean difference for PD of -0.79 (95% CI
-2.29 to 0.71; Analysis 1.2). Sensitivity analysis was performed by
altering the statistical test (odds ratio or risk difference) and model
(random-effects or fixed-effect) and did not change the results.
There was no statistical heterogeneity between the studies.
In the study by Annese 1996 eight participants were randomised
to receive 100 U of BTX and eight to undergo PD. Two further
PD sessions were performed on consecutive days. Remission was
defined as a symptom score of 2 (range 0 to 9). All participants
were in remission at one month. The mean LOS pressure was reduced by 73% (37 to 9.9 mm Hg) in the PD group and by 48%
(34.1 to 17.6 mm Hg) in the BTX group at one month; this was
not statistically significant (Table 1). In the study by Muehldorfer
1999 12 participants were randomised to receive 80 U BTX and
12 to undergo PD. A further PD was performed two days later.
Remission was defined as a 50% or greater improvement in the
median symptom score (range 0 to 20). At one week 10 of 12
(83%) PD participants compared to 8 of 12 (67%) BTX participants were in remission (P = 0.64). A second injection achieved
therapeutic success in one of 4 non-responders; thus, 9 of 12 BTX
participants (75%) responded positively overall. Mean LOS pressure readings before and after treatment were assessed in 7 PD and
9 BTX participants. The mean LOS pressure was reduced by 50%,
from 35 mm Hg to 17 mm Hg in the PD group (P < 0.001). In
the BTX group a 44% reduction was observed, 39 mm Hg to 22
mm Hg (P < 0.001) (Table 1).
Effects of interventions
Remission at six months and 12 months
Incomplete outcome data
Follow up
A total of 11 out of 239 participants were excluded from the

post-treatment analysis either due to loss to follow up or noncompliance with the study protocols. In one study five (11%) of
the initially randomised patients were excluded from the posttreatment analysis (Vaezi 1999).
Other potential sources of bias
Baseline comparability of treatment groups
Response to initial endoscopic treatment

Five studies compared a single BTX injection to a single PD initially (Vaezi 1999; Ghoshal 2001; Mikaeli 2001; Bansal 2003;
Zhu 2009). In the two remaining studies the initial PD treatment
consisted of repeated dilatations within a period of three days and
was compared to a single BTX injection (Annese 1996), or an
initial injection and a subsequent injection one week later in nonresponders (Muehldorfer 1999). Due to this clinical heterogeneity
in treatment protocols neither of these studies were included in
this analysis.
Following the initial endoscopic therapy 82 out of 95 PD participants were in remission compared to 73 out of 94 BTX participants, with a risk ratio of remission of 1.11 (95% CI 0.97 to 1.27;
Analysis 1.1) for PD. This did not reach statistical significance (P
= 0.12).
Four of the five studies reported mean oesophageal pressures within
four weeks of the initial endoscopic treatment (Ghoshal 2001;
Data on remission rates following both initial treatments were

available for three studies (Ghoshal 2001; Mikaeli 2001; Zhu
2009) at six months, and four studies at 12 months (Ghoshal
2001; Mikaeli 2001; Bansal 2003; Zhu 2009). The six and 12
month remission rates in the study by Vaezi 1999 included participants who had undergone a second endoscopic treatment, therefore these data were not included in our analysis.
At six months 46 of 57 PD participants were in remission compared to 29 of 56 in the BTX group, giving a risk ratio of 1.57
(95% CI 1.19 to 2.08, P = 0.0015; Analysis 1.3); whilst at 12
months 55 of 75 PD participants were in remission compared to
27 of 72 BTX participants, with a risk ratio of 1.88 (95% CI 1.35
to 2.61, P = 0.0002; Analysis 1.4). Sensitivity analysis was performed by altering the statistical test (odds ratio or risk difference)
and model (random-effects or fixed-effect) and did not change the
results at the one and 12 month analysis of remission but did at the
six month analysis. The risk ratio random-effects model in the six
month analysis was 1.94 (95% CI 0.77 to 4.85, P = 0.16). There
was evidence of statistical heterogeneity in the six month remis-
sion analysis (Analysis 1.3). The remission rates for BTX in the
largest study (Zhu 2009) were greater than the other two studies
included in this analysis (Ghoshal 2001; Mikaeli 2001).
In the study by Annese 1996 six of eight (80%) BTX patients
were in remission at six months, while only one (12.5%) was
in remission at 12 months. All of the PD patients remained in
remission (Table 1). In the study by Muehldorfer 9 of 12 (75%)
PD patients were in remission at six months compared to 6 of
12 (50%) BTX patients, whilst the numbers in remission at 12
months were 8 (66%) and 3 (25%) respectively (Muehldorfer
1999) (Table 1).
Complications
A total of 188 PD procedures and 151 BTX injections were performed in the six studies, either as the initial treatment or as a
subsequent treatment in those who failed to respond to the initial treatment (PD or BTX) or who relapsed. BTX injection was
not associated with any serious complications. Three oesophageal
perforations were reported following PD.
Quality of life and cost-effectiveness
Quality of life and cost-effectiveness analyses were not performed
in this review as they were not assessed in any of the selected
studies.
the study by Vaezi a second endoscopic treatment was performed

in participants who relapsed during the study period and these
participants were included in the outcomes analysis at six and 12
months (Vaezi 1999). It was not possible to obtain data from the
corresponding author of this study on the outcomes at six and 12
months for participants who did not receive a second endoscopic
treatment. It is unlikely that the missing data would significantly
alter the outcome of this meta-analysis. The differences in outcomes highlighted in this analysis could be due to differences in
the number of studies and of participants included at the various
time points.
A comparison of the effect of either treatment on achalasia symptoms was not possible due to inter-study variation in the scoring
of symptoms, therefore we looked at remission rates at the various
time points. Remission was defined as a 50% or greater reduction
in symptoms in the studies by Vaezi 1999 and Mikaeli 2001. Remission in the study by Ghoshal 2001 equated to a 50% or greater
reduction in symptoms, whilst in the study by Bansal 2003 remission was approximately equivalent to a 50% reduction in achalasia
symptoms (individual patient data were not available). Zhu 2009
calculated a total symptom score derived from symptoms of solid
and liquid dysphagia, active and passive regurgitation, and chest
pain; each scored on a scale of 0 to 3. A symptom score < 4 was
deemed a clinical response, which roughly equated to a 50% or
greater response. We analysed LOS pressure within the first four
weeks of treatment as this was assessed in all six of the selected
studies.
DISCUSSION
Overall completeness and applicability of

evidence
Summary of main results
Both the number of studies and the number of participants randomised to either treatment were small. A total of 239 achalasia
participants were enrolled across the seven studies, with the largest
study having 60 participants (Zhu 2009); 122 participants were
randomised to undergo PD and 117 to receive BTX. One RCT
that involved 80 participants was not included as the only information that was available was from the abstract of the paper (Zhou
2012). The outcomes reported in the abstract are in keeping with
the result of this meta-analysis and allowing for the possibility of a
high risk of bias, the 12 month clinical remission rates in this study
were greater for PD than BTX, 73.2% and 61.5% respectively.
The initial PD protocols of two studies (Annese 1996;

Muehldorfer 1999) involved repeated dilation over a short period,
whilst the remaining five studies initially compared a single PD
session to a single BTX injection. This was felt by both of the
study authors to be clinically relevant but precluded these studies from inclusion in the meta-analysis (Table 1). Ideally KaplanMeier plots and log-rank testing should be used to compare duration of remission, however only two studies used this approach
to compare remission rates after a single endoscopic treatment
(Ghoshal 2001; Mikaeli 2001).
There was no significant difference in remission within the first
four weeks. Remission rates were greater at both six and 12 months
for PD compared to BTX (PD rate approximately double the rate
for BTX at 12 months), however two of the four studies were excluded from the six month analysis (Vaezi 1999; Bansal 2003) and
one from the 12 month analysis (Vaezi 1999) due to incomplete
data. Data on the remission rate at six months following BTX
injection were not clear in the study by Bansal 2003. We were unable to contact the corresponding author for more information. In
Quality of the evidence

The overall methodological quality of these studies was good although the risk of bias is high (Figure 2 and Figure 3). Only one
of the included studies was double blind (Bansal 2003). Because
of the nature of the interventions in the included studies blinding
was not always possible; therefore these studies are open to the
possibility of bias.
Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.
Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.
10
The overall clinical characteristics of the participants in both treatment groups in the studies included in the meta-analysis were similar. However, in the study by Mikaeli 2001 the BTX group were
slightly older. Two patients who received BTX had previously had
an unsuccessful PD (Ghoshal 2001). Of the 239 participants only
11 were excluded from the post-treatment analysis; five of these
were from the same study (Vaezi 1999).
Despite the small number of studies and participants, four of the
studies that were identified by the search were excluded (Gaudric
1996; Nebendahl 1998; des Varannes 1999; Linghu 2013) as they
were only published as meeting abstracts and further information
regarding the exact nature of the treatments and methodological
quality, in particular the method of randomisation and the baseline
comparability of the treatment groups, was not available. A further
study was excluded as only the information in the papers abstract
was available (Zhou 2012).
In summary, the results of this review suggest that PD has a better
long-term efficacy. These studies suggest little difference in the
response rates to initial treatment, however at 12 months the remission rate with PD was approximately twice that of BTX. No
serious adverse outcomes occurred in participants receiving BTX.
PD was complicated by perforation in three cases.
AUTHORS CONCLUSIONS
Implications for practice
Existing randomised controlled trials in this area measure multiple interventions and outcomes, making comparisons difficult
for clinicians. Pneumatic dilation (PD) appears to be associated
with better long-term outcomes and reduced re-intervention rates
when compared to botulinum toxin (BTX) injection. However,
oesophageal perforation remains a risk with balloon dilatation.
Implications for research

Large blinded randomised controlled trials with comparable treatment protocols and outcome assessment criteria are lacking.
ACKNOWLEDGEMENTS
We thank the Cochrane Upper Gastrointestinal and Pancreatic
Disease Review Group.
REFERENCES
References to studies included in this review

Annese 1996 {published data only}
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):141824. [MEDLINE: 310]
Bansal 2003 {published data only}
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):
20914. [MEDLINE: 311]
Ghoshal 2001 {published data only}
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):22731. [MEDLINE: 2]
Mikaeli 2001 {published data only}
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):138996. [MEDLINE: 312]
Muehldorfer 1999 {published data only}

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):51721. [MEDLINE: 313]
Vaezi 1999 {published data only}
Vaezi MF, Richter JE, Wilcox CM, Schroeder PL, Birgisson
S, Slaughter RL, et al. Botulinum toxin versus pneumatic
dilatation in the treatment of achalasia: a randomised trial.
Gut 1999;44(2):2319. [MEDLINE: 5]
Zhu 2009 {published data only}
Zhu Q, Liu J, Yang C. Clinical study on combined therapy
of botulinum toxin injection and small balloon dilation in
patients with esophageal achalasia. Digestive Surgery 2009;
26:4938.
References to studies excluded from this review

Allescher 2001 {published data only}
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):
100717. [MEDLINE: 1]
Bansal 1996 {published data only}
Bansal R, Koshy S, Scheiman JM, Barnett JL, Nostrant TT.
Interim analysis of a randomized trial of Witzel pneumatic
11
dilation vs intrasphincteric injection of botulinum toxin

(Botox) for achalasia. Gastroenterology 1996;110(4):A56.
[MEDLINE: 279]
des Varannes 1999 {published data only}
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]
Gaudric 1996 {published data only}
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]
Jung 2012 {published data only}
Jung HE, Lee JS, Kim JO, Hong SJ, Lee TH, Kim HG, et al.
The long-term outcome in patients with primary achalasia
according to the balloon dilatation or intrasphincteric
botulinum toxin injection. Neurogastroenterology and
Motility 2012;24 Suppl 2:97.
Linghu 2013 {published data only}
Linghu E, Li H. Randomized study comparing peroral

endoscopic myotomy, botulinum toxin injection and
balloon dilation for achalasia: one-year follow-up. Program
and abstracts of the American College of Gastroenterology
2013 Annual Scientific Meeting; October 11-16, 2013;
San Diego, California. American Journal of Gastroenterology
2013;108:Abstract 28.
Malekzadeh 2000 {published data only}
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 1998 {published data only}
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]
Nebendahl 1998 {published data only}
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]
Zhou 2012 {published data only}
Zhou H, Dai Y, Lu L, Luo S, Qian Y, Wan X. Endoscopic
water-filled balloon dilatation and botulinum toxin
injection for treatment of achalasia: A comparison of
clinical effectiveness. Academic Journal of Second Military
Medical University 2012;33(9):10006.
Additional references
Annese 1998
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;21:15402.
Bassotti 1999
Bassotti G, Annese V. Pharmacological options in achalasia.
Alimentary Pharmacology & Therapeutics 1999;13:13916.
Cuilliere 1997
Cuilliere C, Ducrotte P, Zerbib F, et al. Achalasia: outcome
of patients treated with intrasphincteric injection of
botulinum toxin. Gut 1997;41:8792.
Eckardt 1997
Eckardt VF, Kohne U, Junginger T, Westermeier T. Risk
factors for diagnostic delay in achalasia. Digestive Diseases
and Sciences 1997;42(3):5805.
Frantzides 2004
Frantzides CT, Moore RE, Carlson MA, et al. Minimally
invasive surgery for achalasia: a 10-year experience. Journal
of Gastrointestinal Surgery 2004;8(1):1823.
Higgins 2008
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.0.1 [updated
September 2008]. The Cochrane Collaboration 2008.
Available from www.cochranehandbook.org.
Howard 1992
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;33:10115.
Imperiale 2000
Imperiale TF, OConnor JB, Vaezi MF, Richter JE. A costminimization analysis of alternative treatment strategies for
achalasia. The American Journal of Gastroenterology 2000;95
(10):273745.
Inoue 2010
Inoue H, Minami H, Kobayashi Y, Sato Y, Kaga M, Suzuki
M, et al. Peroral endoscopic myotomy (POEM) for
esophageal achalasia. Endoscopy 2010;42:26571.
Kadakia 2001
Kadakia SC, Wong RK. Pneumatic balloon dilation for
esophageal achalasia. Gastrointestinal Endoscopy Clinics of
North America 2001;11(2):32546.
Katz 1998
Katz PO, Gilbert J, Costell D. Pneumatic dilation is
effective long-term treatment for achalasia. Digestive
Diseases and Sciences 1998;43:19737.
Kolbasnik 1999
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):34349.
12
Mayberry 1987
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;62:6774.
Pasricha 1994
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:
5901.
Pasricha 1995
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;322:7748.
Pasricha 2007
Pasricha PJ, Hawari R, Ahmed I, Chen J, Cotton PB, Hawes
RH, et al. Submucosal endoscopic esophageal myotomy: a
novel experimental approach for the treatment of achalasia.
Endoscopy 2007;39:7614.
Reynolds 1989
Reynolds, JC, Parkman, HP. Achalasia. Gastroenterology
Clinics of North America 1989;18:223.
Urbach 2001
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):192205.
Vela 2004
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):102936.
Von Renteln 2013
Von Renteln D, Fuchs KH, Fockens P, Bauerfeind P,
Vassiliou MC, Werner YB, et al. Peroral endoscopic
myotomy for the treatment of achalasia: an international
prospective multicenter study. Gastroenterology 2013;145
(2):30911.
Wen 2004
Wen ZH, Gardener E, Wang YP. Nitrates for achalasia.
Cochrane Database of Systematic Reviews 2004, Issue 1.
[DOI: 10.1002/14651858.CD002299.pub2]
Indicates the major publication for the study
13
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Annese 1996
Methods
RCT
Method of randomisation was not stated
Initially BTX versus placebo saline injection. All placebos relapsed and treated by PD
BTX relapsers were retreated
Remission - symptom score 2
Exclusion criteria: < 18 yrs, 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 100 U BTX and 8 participants underwent PD

PD: day 1 - Rigiflex 30 mm, day 2 and 3 - 35 mm balloon
Outcomes
Clinical assessment using mean symptom score - dysphagia, chest pain and regurgitation;
each scored 0 to 3
Mean LOS pressure (mm Hg)
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
All patients were assessed at 6 months; 6 participants were lost to follow up at 12 months
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Unclear risk

bias)
Method not stated
Allocation concealment (selection bias)
High risk
Initial randomisation and therapy was double blind - BTX or placebo saline injection.
The placebo group then had three PD sessions as they all failed to respond. This aspect of the study was not blinded
Blinding (performance bias and detection High risk

bias)
All outcomes
14
Annese 1996
(Continued)
Blinding of participants and personnel High risk

(performance bias)
All outcomes
Blinding of outcome assessment (detection Unclear risk

bias)
All outcomes
It is unclear whether the assessors were

blinded to the therapies
Incomplete outcome data (attrition bias)

All outcomes
Low attrition bias at 1 and 6 months but

high at 12 months
Unclear 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, poor surgical candidates
Remission - decrease in symptom grade 1
Participants
34 treatment naive adults

Interventions
BTX 80 U 4 quadrants
Witzel 40 mm balloon - 180 to 300 mm Hg x 3 min
Sham injection or dilatation
Outcomes
Mean symptom score - dysphagia, chest pain, regurgitation (0 to 9)

Dysphagia score (0 to 21)
Dysphagia severity (0 to 10)
Pain severity (0 to 10)
Global assessment (0 to 10, graded 0, 1, 2, 3)
Weight gain (%)
Mean LOS pressure (mm Hg)at 3 weeks, 3 months, and 12 months
Notes
2 perforations in PD group
2 lost to follow up
Low bias
Risk of bias
Bias
Authors judgement

bias)

Method not stated
15
Bansal 2003
(Continued)
Low risk
Allocation concealment and sham procedures
Blinding (performance bias and detection Low risk

bias)
All outcomes
Double blinding to initial therapy
Blinding of participants and personnel Low risk

(performance bias)
All outcomes
Double blinding to initial therapy
Blinding of outcome assessment (detection Low risk

bias)
All outcomes
Assessors blinded to therapy

All outcomes
Two lost to follow up
Low risk
Ghoshal 2001
Methods
RCT
Method of randomisation - computer generated random numbers
Non-responders and relapsers retreated with PD
Remission - dysphagia score 0 or 1
Participants
17 participants
2 BTX group had previous PD
Interventions
BTX 60 to 80 units
Rigiflex 30 mm - 1 min 10 to 15 psi
Outcomes
Dysphagia (0 to 3), chest pain (Yes or No), regurgitation (Yes or No)

Symptoms assessed at 1 week, 3 to 6 monthly
Mean LOS pressure at 1 week
Notes
No complications
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Low risk

bias)
Patients were unblinded
High risk
16
Ghoshal 2001
(Continued)

bias)
All outcomes
Patients were unblinded. Nature of therapies administered did not allow blinding of
endoscopists

(performance bias)
All outcomes
endoscopists

bias)
All outcomes


All outcomes
Low risk
Mikaeli 2001
Methods
RCT
Repeat treatment for non-response and relapse (same BTX dose or 35 mm PD)
Remission - > 50% improvement in symptom score
Exclusion criteria: < 40 yrs
Participants
40 treatment naive participants (> 40 yr old)

BTX group older
Interventions
BTX 200 (80) U 4 quadrants

Rigiflex 30 mm - 10 psi x 30 sec
Outcomes
Mean symptom (0 to 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

bias)
Computer generated random numbers
High risk

bias)
All outcomes
17
Mikaeli 2001
(Continued)
endoscopists
Blinding of participants and personnel Unclear risk
(performance bias)
All outcomes
endoscopists
Blinding of outcome assessment (detection High risk

bias)
All outcomes
Clinical assessor was aware of the treatment

received by the patient

All outcomes
One participant lost to follow up
Low risk
Muehldorfer 1999
Methods
RCT
Method of randomisation not stated
Exclusion criteria: secondary achalasia, dysphagia score < 10/20, previous gastro-oesophageal surgery
Remission - 50% reduction in symptoms
Participants
24 participants - 15 had previously undergone PD

Interventions
BTX 80 Units
40 mm PD - up to 300 mm Hg x 3 min day 1 and 3
Outcomes
Median score (0 to 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
Risk of bias
Bias
Authors judgement

bias)
Method not stated
High risk

bias)
All outcomes
endoscopists
18
Muehldorfer 1999
(Continued)

(performance bias)
All outcomes
endoscopists

bias)
All outcomes


All outcomes
No participants lost to follow up
Low risk
Vaezi 1999
Methods
RCT
Retreated if no response at 1 month (35 mm PD balloon)
Exclusion criteria: previous treatment, < 18 yrs, neuromuscular disorder, NYHA grade
III or IV
Remission - > 50% improvement in symptoms
Participants
47 treatment naive participants

5 participants were excluded from the analysis - 2 BTX group and 3 PD group
Interventions
BTX 100 U
Rigiflex 30 mm - 9 to 15 psi x 1 minute
Outcomes
Median symptom score (0 to 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
Risk of bias
Bias
Authors judgement

bias)
Unclear risk

bias)
All outcomes
endoscopists
19
Vaezi 1999
(Continued)

(performance bias)
All outcomes
endoscopists

bias)
All outcomes


All outcomes
5 patients not included in analysis, 4 in the

PD group
Unclear risk
Zhu 2009
Methods
RCT
Participants
90 participants divided into three groups. Adults > 40 yrs. Treatment naive
Three treatment groups - A) 100 U BTX, B) PD with 30 mm Rigifex balloon, C) PD
followed by BTX injection 15 days later
Baseline characteristics similar in the two relevant groups
Outcomes based on single treatment
Interventions
Three treatment groups - A) 100 U BTX, B) PD with 30 mm Rigifex balloon, C) PD

followed by BTX injection 15 days later
Outcomes
Clinical assessment (mean symptoms score based on dysphagia for solids and liquids,
active and passive regurgitation. and chest pain; each scored 0 to 3) and mean lower
oesophageal sphincter pressure were assessed after therapy at 1 month, 6 months, 12
months, 18 months, and 24 months
Notes
No major complications reported - significant bleeding requiring hospitalisation, oesophageal perforation, and aspiration
3 lost to follow up (one from BTX and 2 from PD group) - excluded from analysis
Risk of bias
Bias
Authors judgement

bias)
Computer generated random numbers
Allocation concealed, randomisation occurred after enrolment.

Patients blinded to therapy
Low risk
Blinding (performance bias and detection Low risk

bias)
All outcomes
Patients and assessors blinded to therapy
20
Zhu 2009
(Continued)
Blinding of participants and personnel Low risk

(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk

bias)
All outcomes

All outcomes
3 lost to follow up
Low risk
Characteristics of excluded studies [ordered by study ID]
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 for more information
Gaudric 1996
Jung 2012
Not a RCT - meeting abstract
Linghu 2013
Malekzadeh 2000
Muehldorfer 1998
Nebendahl 1998
Zhou 2012
RCT published in Chinese

Unable to contact author to obtain more information
Key points from abstract:
80 patients randomly assigned to PD or BTX
clinical symptoms and oesophageal kinematics of patients were evaluated before and 1 week, 1 month,
and clinical outcomes were recorded during a follow up of 24 months
clinical symptom scores and the lower oesophageal sphincter pressure were significantly improved in
both treatment groups at 1 week and 1 month after therapy (P < 0.01)
at 12 months, the clinical remission rates in PD group and BTX group were 73.2% and 61.5%,
respectively
21
DATA AND ANALYSES
Comparison 1. Pneumatic dilation versus botulinum toxin injection
Outcome or subgroup title

1 Initial remission
2 Mean oesophageal pressure
within first four weeks
3 Remission at six months
4 Remission at twelve months
No. of
studies
No. of
participants
5
4
189
147
Risk Ratio (M-H, Fixed, 95% CI)

Std. Mean Difference (IV, Fixed, 95% CI)
1.11 [0.97, 1.27]

-0.19 [-0.51, 0.14]
3
4
113
147

1.57 [1.19, 2.08]

1.88 [1.35, 2.61]
Statistical method
Effect size
Analysis 1.1. Comparison 1 Pneumatic dilation versus botulinum toxin injection, Outcome 1 Initial
remission.
Review:
Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia
Comparison: 1 Pneumatic dilation versus botulinum toxin injection

Outcome: 1 Initial remission
Study or subgroup
PD
BTX
n/N
n/N
17/18
12/16
17.4 %
1.26 [ 0.93, 1.71 ]
Ghoshal 2001
8/10
6/7
9.6 %
0.93 [ 0.61, 1.44 ]
Mikaeli 2001
17/19
13/20
17.3 %
1.38 [ 0.96, 1.97 ]
Vaezi 1999
14/20
16/22
20.8 %
0.96 [ 0.66, 1.41 ]
Zhu 2009
26/28
26/29
34.9 %
1.04 [ 0.88, 1.22 ]
95
94
100.0 %
1.11 [ 0.97, 1.27 ]
Bansal 2003
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 82 (PD), 73 (BTX)

Heterogeneity: Chi2 = 3.90, df = 4 (P = 0.42); I2 =0.0%
Test for overall effect: Z = 1.51 (P = 0.13)
Test for subgroup differences: Not applicable
0.1 0.2
0.5
Favours BTX
10
Favours PD
22
Analysis 1.2. Comparison 1 Pneumatic dilation versus botulinum toxin injection, Outcome 2 Mean
oesophageal pressure within first four weeks.
Review:

Outcome: 2 Mean oesophageal pressure within first four weeks
Study or subgroup
PD
Std.
Mean
Difference
BTX
Weight
Mean(SD)
Mean(SD)
Bansal 2003
18
19.6 (3.3)
16
20 (2.3)
23.2 %
-0.14 [ -0.81, 0.54 ]
Ghoshal 2001
10
15.5 (4.5)
17.5 (4.4)
11.0 %
-0.43 [ -1.41, 0.55 ]
Mikaeli 2001
19
46.06 (11.5)
20
48.2 (8.24)
26.6 %
-0.21 [ -0.84, 0.42 ]
Zhu 2009
28
17.4 (7.4)
29
18.3 (5.6)
39.1 %
-0.14 [ -0.66, 0.38 ]
100.0 %
-0.19 [ -0.51, 0.14 ]
Total (95% CI)
75
IV,Fixed,95% CI
Std.
Mean
Difference
IV,Fixed,95% CI
72
Heterogeneity: Chi2 = 0.29, df = 3 (P = 0.96); I2 =0.0%

-100
-50
Favours PD
50
100
Favours BTX
23
Analysis 1.3. Comparison 1 Pneumatic dilation versus botulinum toxin injection, Outcome 3 Remission at
six months.
Review:

Outcome: 3 Remission at six months
Study or subgroup
PD
BTX
n/N
n/N
Ghoshal 2001
8/10
2/7
8.2 %
2.80 [ 0.83, 9.40 ]
Mikaeli 2001
14/19
5/20
16.9 %
2.95 [ 1.32, 6.59 ]
Zhu 2009
24/28
22/29
74.9 %
1.13 [ 0.88, 1.46 ]
57
56
100.0 %
1.57 [ 1.19, 2.08 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Heterogeneity: Chi2 = 9.68, df = 2 (P = 0.01); I2 =79%
0.1 0.2
0.5
Favours BTX
10
Favours PD
24
Analysis 1.4. Comparison 1 Pneumatic dilation versus botulinum toxin injection, Outcome 4 Remission at
twelve months.
Review:

Outcome: 4 Remission at twelve months
Study or subgroup
PD
BTX
n/N
n/N
16/18
6/16
23.2 %
2.37 [ 1.23, 4.56 ]
Ghoshal 2001
7/10
2/7
8.6 %
2.45 [ 0.71, 8.46 ]
Mikaeli 2001
10/19
3/20
10.7 %
3.51 [ 1.14, 10.83 ]
Zhu 2009
20/28
16/29
57.5 %
1.29 [ 0.87, 1.94 ]
75
72
100.0 %
1.88 [ 1.35, 2.61 ]
Bansal 2003
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Heterogeneity: Chi2 = 5.13, df = 3 (P = 0.16); I2 =42%
0.01
0.1
Favours BTX
10
100
Favours PD
ADDITIONAL TABLES
Table 1. Studies meeting selection criteria but excluded from the meta-analysis
Study
methods
Remission
month
1 Remission
months
6 Remission
months
12 Mean LOS pres- Complications

sure
Annese 1996
8
par- PD 8/8
ticipants 100 U BTX 8/8
BTX and 8 participants PD
PD: day 1 - Rigiflex 30 mm. Day
2 and 3 - 35 mm
balloon
BTX relapsers
retreated
PD 8/8
BTX 6/8
PD 8/8
BTX 1/8
PD -72%
BTX -44%
none
Muehldorfer
1999
12 participants PD 10/12
80 U BTX and BTX 9/12
12 PD 40m day
1 and 3
BTX repeated at
PD 9/12
BTX 6/12
PD 8/12
BTX 3/12
PD -50%
BTX -44%
none
25
Table 1. Studies meeting selection criteria but excluded from the meta-analysis
(Continued)
1 week in 4 nonresponders
APPENDICES
Appendix 1. MEDLINE search strategy
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. humans.sh.
11. 9 and 10
12. exp esophageal achalasia/
13.(esophageal adj2 achalasia).tw.
14. achalasi$.tw.
15. or/12-14
16. exp botulinum toxins/
17. botox.tw.
18. botulinum$.tw.
19. or/16-18
20. exp balloon dilatation/
21. angioplasty.tw.
22. (balloon adj5 dilat$).tw.
23. (pneumatic adj5 balloon).tw.
24. or/20-23
25. 11 and 15 and 19 and 24
WHATS NEW
Last assessed as up-to-date: 23 July 2014.
26
Date
Event
Description
21 August 2014
New citation required but conclusions have not changed One new RCT identified and included in meta-analysis.
Conclusions remain unchanged
23 July 2014
New search has been performed
Searches rerun and review updated.
HISTORY
Protocol first published: Issue 1, 2005
Review first published: Issue 4, 2006
Date
Event
Description
5 October 2010
Amended
Contact details updated.
2 July 2009
Amended
Revision to the risk of bias characteristic of included

studies
2 February 2009
Review updated. No new studies. Conclusions not

changed.
16 October 2008
Amended
Converted to new review format.
23 July 2006
New citation required and conclusions have changed
Substantive amendment.
29 October 2005
Amended
New studies found and included or excluded.
18 October 2005
Amended
New studies sought but none found.
1 October 2005
Minor update.
27
CONTRIBUTIONS OF AUTHORS
Leyden J: protocol development, eligibility and quality assessment, data extraction and analysis, drafting of final review.
Moss A: protocol development, eligibility and quality assessment, data extraction and analysis, drafting of final review.
MacMathuna P: clinical and scientific advice, assessment of eligibility and quality, drafting of final review.
DECLARATIONS OF INTEREST
None known
SOURCES OF SUPPORT
Internal sources
Department of Gastroenterology, Mater Misericordiae University Hospital, Dublin, Ireland.
External sources
Upper GI and Pancreatic Cochrane Group, UK.
INDEX TERMS
Medical Subject Headings (MeSH)
Anti-Dyskinesia Agents [ therapeutic use]; Botulinum Toxins [ therapeutic use]; Catheterization [ methods]; Dilatation [ methods];
Esophageal Achalasia [ therapy]; Randomized Controlled Trials as Topic; Remission Induction; Time Factors
MeSH check words

Humans
28

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Endoscopic pneumatic dilation versus botulinum toxin

injection in the management of primary achalasia (Review)

Endoscopic pneumatic dilation versus botulinum toxin

University Hospital, Dublin, Ireland. 2 Center for Inflammatory Bowel Disease,

Editorial group: Cochrane Upper GI and Pancreatic Diseases Group.

PLAIN LANGUAGE SUMMARY

Description of the condition

Description of the intervention

perforation, which occurs in up to 3% of cases (Katz 1998; Kadakia

Why it is important to do this review

Types of outcome measures

Symptom remission rates within the first month, at six months,

Lower oesophageal sphincter (LOS) pressure confirmed by oesophageal manometry post-treatment

Criteria for considering studies for this review

Search methods for identification of studies

Reference lists from trials selected by electronic searching were

Data collection and analysis

Quality assessment of trials

Two review authors independently assessed the methodological

Data extraction and management

Results of the search

Figure 1. Study flow diagram.

A 30 mm diameter PD balloon was used in five studies

defined as symptom scores of 0 to 1, 2 to 3, 4 to 6, and > 6

The two remaining studies compared a 40 mm balloon

Quality of life and cost-effectiveness were not measured in

In one study participants not responding to the initial BTX

Some participants who either failed to respond to the initial

Changes in achalasia symptoms and LOS pressure in

We excluded 10 studies from the analysis (Figure 1). One full-text

Risk of bias in included studies

The method of randomisation was adequate in four studies (Vaezi

pressure (Vaezi 1999). In the studies by Annese 1996; Ghoshal

The clinical characteristics of participants in both treatment

Remission at six months and 12 months

Incomplete outcome data

A total of 11 out of 239 participants were excluded from the

Other potential sources of bias

Baseline comparability of treatment groups

Response to initial endoscopic treatment

Data on remission rates following both initial treatments were

the study by Vaezi a second endoscopic treatment was performed

Overall completeness and applicability of

Summary of main results

The initial PD protocols of two studies (Annese 1996;

Quality of the evidence

Implications for research

References to studies included in this review

Muehldorfer 1999 {published data only}

References to studies excluded from this review

Allescher HD, Storr M, Seige M, Gonzales-Donoso R, Ott

dilation vs intrasphincteric injection of botulinum toxin

Gaudric M, Guimbaud R, Chaussade S, Palazzo L,

Linghu E, Li H. Randomized study comparing peroral

Indicates the major publication for the study

16 treatment naive adult participants

8 participants received 100 U BTX and 8 participants underwent PD

Support for judgement

Random sequence generation (selection Unclear risk

Method not stated

Allocation concealment (selection bias)

Blinding (performance bias and detection High risk

Blinding of participants and personnel High risk

Blinding of outcome assessment (detection Unclear risk