Introduction
Gastroesophageal reflux disease (GERD) is defined as a chronic condition characterized
by backward flow (reflux) of gastroduodenal content into the esophagus and adjacent
organs, resulting in a variable spectrum of symptoms. In recent decades, prevalence
of GERD has been increasing in the Western adult population. It is estimated that
up to 28 % of adults have weekly symptoms of retrosternal burning and acid regurgitation
[1]. In Brazil, close to 12 % of the population is affected by this disease. Not surprisingly,
GERD is the most common reason for outpatient appointments and indication for upper
endoscopy [2].
Proton pump inhibitors (PPIs) in conjunction with lifestyle modifications continues
to be the primary therapy for GERD. However, the effectiveness of this intervention
is often hampered by adherence, costs, and risks associated with long-term use of
PPIs. Anti-reflux surgery is an option for patients with refractory symptoms or in
those in whom medical therapy is contraindicated or undesirable [3]
[4]
[5]
[6]
[7]. Surgical treatment, although effective in the short term, may be associated with
non-negligible morbidities, and there is a growing concern about late recurrence [8]. For this reason, there has been increasing interest in alternative treatments that
may potentially offer similar results and be associated with faster recovery.
With the development of new technologies, different forms of minimally invasive treatment
have been described, aiming to interfere with the mechanism of GERD: injection of
polymers (Enteryx, Durasphere, among others), prosthesis (Gatekeeper), endoluminal
suture (EndoCinch, Plicator, Wilson-Cook ESD, Syntheon Anti-Reflux Device, His-Wiz
Anti-Reflux Device, Medigus SRS; Esophyx), and thermal fibrosis induction by radiofrequency
(Stretta radiofrequency ablation).
Immediate results from these minimally invasive procedures and absence of studies
with late follow-up periods motivated this study, which aimed to investigate efficacy
of two endoscopic techniques – polymer injection and endoluminal full-thickness plication
– in long-term GERD control, up to 60 months.
Patients and methods
This study was approved by the Ethics Committee for Analysis of Research Projects
(Protocol No. 945 /01 and No. 326/03). Reference study number: 1.481.669. The procedures
were carried out in the period between February 11, 2003 and July 5, 2005. This study
was originally set to a 1-year patient follow-up, during which subjects were followed
prospectively by protocol in a non-randomized fashion. It was not the initial intention
of the study to follow patients on an annual basis, but after patient voluntary return
over the years and given promising results at 1 year, we decided to assess long-term
outcomes. Ten years after the initial study, follow-up information was retrospectively
reviewed for up to 5 years. This extension in time caused almost a 50 % loss in patient
follow-up. Many of the patients were lost to follow-up for various reasons, such as
a change of address, death due to other causes and unknown.
Inclusion criteria
Patients were included in the study of they were aged ≥ 18 years and had GERD with
a history of heartburn for more than 6 months, significant symptom relief > 50 % with
antisecretory therapy consisting of PPI, esophageal manometry (performed in the last
6 months) showed a resting lower esophageal sphincter pressure (LESP) ≥ 5 mmHg, prolonged
esophageal pH-metry (performed in the last 6 months) demonstrated pathological reflux,
defined when the total percentage of the pH time less than 4 is ≥ to 4.5 % or a DeMeester
score > 14.7 and agreed to participate in the study with signed informed consent [9]
[10].
Exclusion criteria
Patients were excluded from the study if they were pregnant, had a hiatal hernia > 2 cm,
persistent dysphagia, weight loss, esophageal bleeding, Los Angeles classification
grade C or D esophagitis, Barrettʼs esophagus, any medical condition that impeded
the end of the study, coagulopathy or chronically used anticoagulants, had pathological
changes in connective tissue that could prevent the secure fixation of the endoscopic
plication implant, esophageal or gastric varices, megaesophagus, scleroderma, or esophageal
strictures.
Endoscopic procedures were performed with prophylactic antibiotic therapy (cephalosporin
1 g) and sedation according to American Society of Gastrointestinal Endoscopy (ASGE)
guidelines [11]. Endoscopic equipment used was a standard videogastroscope (Olympus Optical Inc.
model GIF-160).
Description of endoscopic devices for GERD
Polymer injection
Enteryx (Boston Scientific, Natick, Massaschusetts, United States) is an inert alcohol-vinyl-ethylene-based
polymer dissolved in dimethyl sulfoxide (DMSO), which is a liquid that when in contact
with water forms a solid, spongy, inert and biocompatible mass. To this solution is
added radiopaque radiological contrast medium, called tantalum [12]. Polymer injection is performed with a 4-mm catheter previously rinsed with DMSO
and filled with Enteryx. The application is performed between 1 and 3 mm proximal
to the squamous-columnar junction within the musculature of the cardia, with 1-mL
syringes filled with Enteryx under simultaneous fluoroscopic and endoscopic observation.
The needle remains in place for 30 seconds and then is removed. Injections are made
in the four quadrants, each with a volume of 1 to 2 mL, at the same level. During
injection, diffusion of the material around the esophagus (ring-like appearance) is
observed and implantation of Enteryx is maintained at the same point up to a volume
of 3 to 4 mL. The total volume injected does not exceed 10 mL.
Endoscopic plicator device
NDO Plicator (NDO Surgical, Inc., Mansfield, Massachusetts, United States) consists
of an endoscopic plicator instrument, tissue-retracting helical catheter and a suture
insert. The plicator instrument is composed of a tissue retractor and a set of two
needles, which allow passage of the wire through the entire gastric wall thickness
and placement of an implant, forming a fold. Plication is performed with one or two
implants, depending on the anatomy identified during the procedure [13].
Clinical evaluation and complementary examination
After obtaining the complete clinical and physical examination, the following questionnaires
were applied: (1) Visual Analogue Scale (VAS) of severity of discomfort in a typical
episode of heartburn, frequency of heartburn and regurgitation, alone and together;
(2) Health related quality of life with GERD (GERD-HRQL), which uses the manifestation
of heartburn intensity, in decubitus position, relationship with meals, change in
diet, heartburn-induced sleep disorder, difficulty in swallowing, pain when swallowing
and use of the medication affecting the daily activity; (3) Quality of Life in General
(SF-36) in health assessment, with analysis of functional capacity, general health,
emotional, physical and social aspects, vitality, mental health and pain. Questionnaires
1 and 2 aimed to evaluate the severity of GERD-related symptoms and were applied in
the presence and absence of PPI use, with a seven-day interval. It was questioned
the type of PPI, dose, frequency, date of onset and interruption.
The schedule of clinical evaluation, complementary examination, and endoscopic procedures
were done during the pre-procedure evaluation without the use of PPI, pre-procedure
evaluation during the period of use of PPI and, once selected, the endoscopic procedure
was performed and the patient contacted after one week. Clinical evaluation, post-procedure
questionnaires and post-procedure examinations were performed after 1, 3, 6, 12 and
60 months.
Evaluations parameters
Evaluation parameters included reduction in drug use related to GERD (dose and frequency),
reduction in symptoms index through the VAS (VAS evaluates three things: 1. severity
of discomfort in a typical episode of heartburn; 2. frequency of heartburn; and 3.
frequency of episodes of regurgitation), GERD-HRQL, and responses to the health assessment
questionnaire (SF-36) at 1, 3, 6, 12, and 60 months. The evaluation related healing
of esophagitis at 3 and 12 months, modification of the manometric study and 24-hour
pH-metry of the esophagus at 3, 6 and 12 months. The parameters for response to endoscopic
treatment were defined as: total response (RT) = absence of PPI use, partial response
(RP) = 50 % reduction in PPI use, and no response (SR) = daily need for PPI.
Statistical analysis
The SPSS program for statistical analysis was used. An intention-to-treat analysis
was performed. The normality of the data in each period was evaluated through the
Kolmogorov-Smirnov (KS) test. For analysis, the ANOVA, Friedman non-parametric test
and Mauchly test were used. The level of significance was set at 0.05 (α = 5 %). Descriptive
levels (P) below this value were considered significant. The paired Wilcoxon test was performed
to compare the variables over time with baseline time. Analysis of adverse events
was performed using Fisherʼs Exact Test, which verifies the association between the
crossed variables.
Results
Inert polymer injection (Enteryx) (G0) was performed in 21 patients and endoluminal
full-thickness plication (NDO plicator) (G1) was used in 26 patients, and from this
group, five received a second endoscopic suture because of failure of treatment at
1 year follow-up. There was a predominance of male patients (12 men, 9 women) in the
group submitted to the Enteryx technique, as well in the endoluminal full-thickness
plication group (20 men, 6 women), with median ages of 39 (20 – 70) and 48 (21 – 69),
respectively. The mean time for performing the polymer injection technique was 45
minutes (13 to 60 min) and for the endoluminal full-thickness plication technique
was 20 minutes (10 to 59 min).
There was no loss of follow-up in either group for up to 6 months. However, in the
polymer injection group, there was a loss to follow-up of 9.6 % at 12 months and 47.7 %
at 60 months. In the plicator group, there was loss to follow-up of 6.9 % in 12 months
and 58.7 % in 60 months.
[Fig. 1] shows the correlation between endoscopic
therapies and reduction in PPI use. Although there was a trend of increasing patients
with no response to treatment from the third month on (P = 0.017) in the polymer injection group, there is no statistical evidence to prove
that no response to treatment increased over time (P = 0.060). In the plicator group, there was a tendency to increase the frequency of
patients with no response to treatment over time (P < 0.001) ([Fig. 1]).
Fig.1 Correlation between therapeutic response and use of PPI. RT, total response; RP, partial
response; SR, no response.
According to the analysis by VAS and with respect to the HRQL-GERD, there was a statistically
significant improvement in both groups (P < 0.001) during the first 12 months. After the 3-month mark, we observed an increase
in non-responders in the endoluminal full-thickness plication group and after the
6-month mark in the polymer injection therapy group. After 12 months, there was a
significant increase in non-responders in both groups with a greater frequency of
regurgitation and need for PPIs. The 60-month analysis demonstrated a significant
increase in the number of patients with no response in both groups ([Fig. 2], [Fig. 3]).
Fig. 2 Analysis of health-related quality of life in patients with GERD (HRQL-GERD). w/meds,
with medication; w/o, without medication.
Fig. 3 Visual analogue scale (VAS) after intervention in patients with total response and
no response. w/meds, with medication; w/o meds, without medication.
In the analysis of quality of life in general (SF-36), functional capacity improvement
was observed in the polymer injection group after 1, 3 and 6 months (P = 0.015, P = 0.05, P = 0.04, respectively). However, in the endoscopic plicator group there was no improvement
at any point in time.
There were complications related to the procedure such as fever, abdominal distension,
halitosis, dysphagia and vomiting only in the polymer injection group, There were
no complications in patients in the plicator group ([Table 1]).
Table 1
Post-procedure complications in the polymer injection and endoluminal plication groups.
|
Complications
|
Polymer injection
|
Endoscopic plicator
|
|
n
|
%
|
n
|
%
|
|
Cough
|
2
|
9.50
|
0
|
0.00
|
|
Dyspnea
|
1
|
4.80
|
0
|
0.00
|
|
Fever
|
4
|
19.00
|
0
|
0.00
|
|
Eructation difficulty
|
8
|
38.10
|
0
|
0.00
|
|
Halitosis
|
7
|
33.30
|
0
|
0.00
|
|
Dysphagia
|
6
|
28.60
|
0
|
0.00
|
|
Bloating
|
2
|
9.50
|
0
|
0.00
|
|
Vomit
|
8
|
44.70
|
0
|
0.00
|
|
Regurgitation
|
2
|
9.50
|
0
|
0.00
|
Three months after the initial intervention, normalization of the endoscopic findings
was achieved in 45 % of patients who received polymer injection and 40 % in the plicator
group. In contrast, in the same period, there was worsening of esophagitis in 5 %
of the polymer injection group and 12 % of the plicator group.
At 12 months, we observed complete healing esophagitis in 43 % of patients in the
polymer injection group and 65 % in the plicator group. Pre-procedure findings were
maintained in 50 % of the patients who received polymer injection and in 30 % of the
patients who received endoluminal full-thickness plication. On the other hand, we
observed worsening of esophagitis in 6 % of the polymer injection group and 5 % in
the plicator group.
The techniques used to increase the length of the lower esophageal sphincter had a
significant impact only in the initial 3-month post-procedure control. No benefit
was observed in the posterior manometric controls. The techniques employed had no
impact on increasing mean respiratory pressure of the lower esophageal sphincter which
leads to the conclusion that there was no interference in the motor aspect of the
organ.
Considering analysis of the prolonged pH of the esophagus, there was no interference
in the acid exposure time and the DeMeester score in the polymer injection group. In
the plicator group, there was improvement in the DeMeester score at the initial control
of 3 months, which was not maintained over time. There was no interference in control
of gastroesophageal reflux with the either technique.
Discussion
Patients with poorly controlled GERD symptoms despite maximal PPI therapy or daily
PPI dependence are good candidates for anti-reflux procedures. Long-term PPI use is
expensive and has several well-known side effects. Laparoscopic Nissen fundoplication
is the surgical “gold standard,” however, endoscopic treatments are minimally invasive
and provide prompt recovery [14]
[15].
Although different endoscopic techniques can improve reflux symptoms for most patients,
short- and long-term efficacy has been variable between the different treatments.
Our initial results with inert polymer injection were encouraging, showing that 71.4 %
did not require PPIs at the 3-month mark, and 61.9 % at 6 months. However, there was
a progressive increase in non-responders, observing that 50 % did not require PPIs
after 12 months and only 27.2 % at 60 months. The same conclusion was obtained in
the analysis of patients in the endoluminal plication group. In the first month, 84.6 %
presented total response, in the third month this dropped to 69.2 %, in the sixth
month to 42.3 %, and at 60 months to 16.67 %. This study demonstrates the fleeting
effect of these therapies.
We can find similar results described in the literature ([Table 2]). Several prospective observational studies included patients with GERD treated
with the NDO plicator. By intention to treat (ITT) analysis, 65 % of patients were
able to discontinue PPI medications at 6 months [16]. At 12 months, 70 % were no longer taking a PPI medication [17]. At 36 months, nearly 60 % continued to not require their pretreatment PPI therapy
[18].
Table 2
Descriptive table of NDO surgical plicator studies.
|
Author/year
|
Population
|
Study type
|
Control
|
Efficacy outcome
|
Follow-up
|
|
Pleskow/2004
|
Chronic GERD > months on PPI
|
Observational
|
N/a
|
Quality of life -GERD-HRQL scores and reduction on PPI medication
|
6 months
|
|
Pleskow/2005
|
Chronic GERD > months on PPI
|
Observational
|
N/a
|
Quality of life -GERD-HRQL scores and reduction on PPI medication
|
12 months
|
|
Pleskow/2007
|
Chronic GERD > months on PPI
|
Observational
|
N/a
|
Quality of life -GERD-HRQL scores and reduction on PPI medication
|
36 months
|
|
Pleskow/2008
|
Chronic GERD > months on PPI
|
Observational
|
N/a
|
Quality of life -GERD-HRQL scores and reduction on PPI medication
|
60 months
|
|
Rothstein/2006
|
Chronic GERD > months on PPI
|
Randomized
|
Sham
|
Quality of life -GERD-HRQL scores and reduction on PPI medication
|
3 months
|
|
Kaindlstorfer/2007
|
Chronic GERD > months on PPI
|
Randomized
|
Laparoscopic surgery (Nissen and Toupet)
|
Quality of life -GERD-HRQL scores and reduction on PPI medication
|
3 months
|
|
Antoniou/2012
|
Chronic GERD > months on PPI
|
Randomized
|
Laparoscopic Fundoplication
|
Quality of life -GERD-HRQL scores and reduction on PPI medication
|
3 months
|
|
Domagk/2006
|
Chronic GERD > months on PPI
|
Randomized
|
Enteryx device
|
Quality of life -GERD-HRQL scores and reduction on PPI medication
|
6 months
|
GERD, gastroesophageal reflux disease; GERD-HRQL, gastroesophageal reflux disease
health-related quality of life; PPI, proton pump inhibitor
In contrast to our study, another clinical trial that assessed long-term efficacy
of the NDO plicator showed that of the subjects who were PPI-dependent prior to treatment,
67 % remained off daily PPI therapy at 60 months [19].
A randomized NDO plicator sham-controlled trial at 3-month analysis demonstrated that
the proportion of patients achieving complete cessation of PPI therapy was significantly
higher in the NDO- treated group [20].
Another randomized clinical trial directly compared two endoscopic anti-GERD techniques:
The EndoCinch and the Enteryx. At the 6-month analysis, PPI therapy could be stopped
or the dosage reduced by ≥ 50 % in 77 % of EndoCinch-treated patients and in 87 %
of Enteryx-treated patients [21].
In our study, when evaluating the HRQL-GERD scores, we observed a significant improvement
in total response to Enteryx therapy up to the 12-month mark (P = 0.002), but these results were outlived at 60 months (P = 0.250). The same was observed in the endoluminal full-thickness plication group,
where there was an initial improvement in symptoms at 12 months (P < 0.001), with a progressive increase in non-responders at 60 months.
When analyzing the impact of polymer injection on quality of life score (SF-36), an
initial improvement in almost all domains was seen, with progressive loss of response
over time. It should be noted that this loss was not so evident because many patients
restarted PPIs. There was no improvement in quality of life score (SF-36) in the endoscopic
plication group at any point in time.
In the literature, it is described that at 6 months post-treatment, HRQL-GERD scores
improved significantly. By ITT analysis, 64 % of patients achieved a reduction of
> 50 % in GERD-HRQL scores and SF-36 scores improved significantly [16]. At 12 months, median GERD-HRQL scores were significantly improved compared with
baseline off medication and baseline on medication [17].
Another study assessed efficacy of endoscopic plication, providing evidence of a reduction
in GERD symptoms subjects up to 36 and 60 months post-treatment. [18]
[19].
A randomized NDO plicator sham-controlled trial at 3-month analysis demonstrated that
the proportion of patients achieving > 50 % improvement in GERD-HRQL score was significantly
higher in the NDO-treated group [20].
The two randomized controlled trials of NDO surgical plicator vs laparoscopic-assisted
anti-reflux surgery (LARS) for GERD showed similar improvements in GERD-HRQL scores
in both groups at 3-month analysis. The LARS group was more effective in controlling
heartburn and regurgitation symptoms compared to the NDO plicator [22]
[23].
In addition, there was no long-term benefit for the therapies in an analysis with
more objective parameters such as endoscopic healing, manometric studies and prolonged
pH-metry. Analysis of our results, compared with the literature, clearly shows that
there is no relation between normalization of subsidiary exams and improvement or
worsening of clinical manifestations.
Only four patients from the entire study underwent LARS at our institution, two patients
from polymer injection group and two from the NDO plication group. These operations
presented greater technical difficulty and duration of surgery was prolonged. One
patient in the NDO plicator group had compromised diaphragmatic pillars, pleura and
pericardium.
The rate of complications was comparable to others studies in the literature. Serious
adverse events with the NDO surgical plicator included dyspnea after placement of
the overtube in two subjects, one pneumothorax, one pneumoperitoneum and one gastric
perforation. These patients were treated clinically and with complete resolution,
without sequelae. The device was modified after this original experience and no longer
requires use of an overtube, and no trauma has been noted subsequently [17].
The Enteryx device was an early option that was ultimately recalled in 2005 following
reports of 11 severe adverse events in which the injection procedure resulted in esophageal
perforation and 1 death because of aortic puncture.
Absence of severe complications observed with Enteryx injection in this study is probably
due to the technical modification employed, in which the LES-ring was obtained after
injection of multiple aliquots of 1 mL, in contrast to techniques described in other
studies, in which the ring was obtained by single injection or even two punches with
large volumes of 10 mL. Considering that the thickness of the organ wall at the level
of the esophagogastric junction is up to 5 mm, it is possible that such complications
occurred in response to the correlation between volume injected, accommodation capacity
and ischemia, as well as by transfixation of the organ wall and injection in an inappropriate
place.
There is a clear limitation in the analysis of most of the published studies due to
multiple factors, such as lack of uniform objective data and of endoscopic, manometric
and long-term pH-metry evaluation. Some parameters evaluated are subjective, such
as symptomatology related to use of PPIs. These results may not reflect the reality
of the study and the placebo factor should be considered. For that reason, it is necessary
to include a control group although a sham study or placebo would also be valid.
Considering the analysis of systematic reviews [24]
[25] and our results, there is insufficient evidence to support use of these therapies
in routine practice. Based on our personal experience, compared with the vast literature,
we do not recommend adoption of these techniques for GERD therapy.
Conclusion
This study demonstrated that polymer injection and endoluminal plication therapies
are ineffective in controlling GERD in the long term.
