Reference Section
a report by
Herbert C Wolfsen, MD, FACG, FACP
Associate Professor of Medicine, Mayo Clinic College of Medicine and Consultant,
Division of Gastroenterology and Hepatology, Mayo Clinic
Introduction
Gastroesophageal reflux disease (GERD) is an
extremely common condition typically associated with
symptoms of heartburn, regurgitation or dysphagia.1,2
Anti-secretory medications such as proton pump
inhibitors (PPIs) are considered the mainstay for
GERD treatment3 but do not control symptoms in a
large subset of patients4,5 and have recently been linked
to increased risks of community-acquired pneumonia.6
In these patients with symptomatic GERD despite
medication, the use of minimally invasive, endoscopic
anti-reflux procedures ýis expected to expand quickly if
these approaches can be delivered safely, effectively and
in a cost-effective manner. 7
Radio Frequency Energy ý
The Stretta Procedure
This technique utilizes radio frequency (RF) energy to
heat tissue and induce thermal injury in the region of
the lower esophageal sphincter (LES) and is
commercially referred to as the ýStretta procedureý
(Curon Medical, Fremont, CA).8 The approach involves
the oral placement of a balloon catheter in the region
of the gastroesophageal (GE) junction.The distances to
important esophageal landmarks (GE junction, etc.) are
measured endoscopically and then the balloon catheter
is passed over a guidewire into the upper
gastrointestinal (GI) tract.The location of the balloon is
monitored by markings on the external sheath of the
catheter.During RF ablation,the balloon is inflated and
four needle electrodes are deployed. A pressure relief
valve prevents excessive balloon distention. The
mucosal surface is cooled by chilled saline irrigation
and the tissue temperature is monitored during
ablation. A computer processor controls the RF
generator. In animal studies, RF ablation resulted in
increased LES pressure associated with shrinkage and
subsequent scarring of the LES and tightening of the
GE junction.9
An initial report described the short-term results of an
open-label multicenter trial.10,11 In this prospective trial,
118 patients (72M, 46F) with chronic pyrosis and/or
regurgitation who required daily PPIs were studied.


Patients could not have a significant (>2cm) hiatal hernia,
esophagitis (not >grade 2) or Barrettýs esophagus. GERD
symptom scores, quality of life (via the SF-36
questionnaire) and medication use were assessed for 12
months. Esophageal acid exposure and esophageal
motility were measured at baseline and six months.


Ninety-four patients (80%) were available for evaluation
at 12 months.The median heartburn score, GERD score,
and quality of life scores were significantly reduced at 12
months, as was esophageal acid exposure. Ten (9%)
complications were reported, none of which required
therapeutic intervention.Thirty of the patients were using
PPIs at 12-month follow-up.


More recent reports have confirmed these initial results
including a registry of 558 Stretta patients who were
studied at a mean follow-up of eight months.12 At that
time, 50% of patients were off all anti-secretory
medications and 66% of patients were off all PPIs.


Patient satisfaction was quite good and 90% of patients
said they would recommend the procedure to a friend.


A randomized, sham-controlled, double blind,
multicenter trial of the Stretta procedure studied 64
patients with chronic GERD who were randomized to
receive Stretta or a sham procedure.13 At six months,
47% of treated patients were off daily medications
compared with 37% in the sham group (p=0.5).


However, heartburn scores, SF-36 physical scores and
heartburn quality-of-life scores were significantly
improved in the treated group.


A frequently heard criticism of the Stretta procedure,
however, is that its mechanism of action is partial
desensitization of the esophageal body rather than a
reduction in esophageal acid exposure.14,15 A recent report
studied the correlation between the improvement in
GERD outcomes and esophageal acid exposure after
Stretta. This study utilized subgroup analyses between
responder and non-responder groups from the US Stretta
open-label trial in 118 patients on the basis of post-
treatment responses for GERD health-related quality of
life (HRQL) heartburn, satisfaction, and PPI use.16
Outcomes were then analyzed within and between
subgroups.Statistical analysis included Pearson correlation
ý coefficient analysis was performed comparing distal
esophageal acid exposure with each of the continuous
Endoscopic Alternatives to Medication or Surgery for the Treatment of
Gastroesophageal Reflux Disease
Herbert C Wolfsen, MD, FACG, FACP,
is an Associate Professor of
Medicine at the Mayo Clinic College
of Medicine, and Consultant in the
Division of Gastroenterology and
Hepatology at the Mayo Clinic in
Jacksonville, Florida. He was recently
named the Chair of the American
Society for Gastrointestinal
Endoscopy Special Interest Group
for Endoluminal Therapy for
Esophageal Disease. As the Director
of Photodynamic Therapy and the
Esophageal Disease Group at Mayo
Clinic, Dr Wolfsen specializes in the
diagnosis and endoscopic treatment
of patients with gastroesophageal
reflux disease, Barrettýs esophagus,
and early esophageal carcinoma
including endoscopic
anti-reflux procedures.


B USINESS BRIEFING: US GASTROENTEROLOGY REVIEW 2005
1
2
B USINESS BRIEFING: US GASTROENTEROLOGY REVIEW 2005
Reference Section
outcomes (GERD-HRQL, heartburn, satisfaction).


Patients who improved after Stretta (ýresponder
subgroupsý) had significant improvements in esophageal
acid exposure, whereas non-responders had no change or
less improvement. Changes in GERD-HRQL and
heartburn severity were correlated with changes in acid
exposure (p=0.01). Changes in satisfaction were
negatively correlated with changes in esophageal acid
exposure (p=0.02) because satisfaction, as expected,
increased as acid exposure decreased. The study
concluded that Stretta responders had significant
improvement in esophageal acid exposure, whereas non-
responders had less or no change.There was a positive
correlation between esophageal acid exposure and both
GERD-HRQL and heartburn. This evidence suggests
that symptomatic improvement after Stretta is attributable
to a decrease in esophageal acid exposure and not to
desensitization of the esophagus. Other important Stretta
effects include a 60% increase in the basal pressure of the
LES when measured six months after the procedure
associated with inflammation, and subsequent collagen
deposition and muscular thickening associated with
decreased esophageal acid exposure.17,18 Another effect of
the Stretta procedure is the neurolytic disruption of the
triggering mechanism for transient LES relaxations.19
These transient LES relaxations are accepted as the most
important pathophysiologic alteration associated with
GERD, and are mediated by vaso-vagal neural pathways,
synapsing in the brainstem.20,21 The Stretta procedure and
drugs such as baclofen have been shown to disrupt these
neural pathways reducing the frequency of transient LES
relaxations and the number of reflux episodes.22ý24
Decreased esophageal inflammation and mucosal
permeability may be related to this effect.25ý28 Compliance
of the gastroesophageal junction may also be an important
factor since the Stretta procedure is known to increase
LES resistance,increase gastric yield pressure,and enhance
compliance of the gastric cardia.8,29,30 This improvement in
gastric emptying associated with significant improvement
in GERD symptoms and medication use provides further
support for the use of the Stretta procedure for the
management of GERD patients considering alternatives
to drug therapy.31ý34
The Stretta procedure continues to benefit from the
largest number of publications with clinical experience
supporting its use, including a randomized sham-
controlled study, single center and multicenter
prospective trials, and community practice
reports,12,13,33,35 and its use has recently been extended to
pediatric patients.36 Continuous improvement has been
made in catheter design including the use of a guide-
wire to facilitate catheter placement, a pressure relief
valve for use with balloon inflation, a thinner, more
flexible catheter shaft, and improved physician training
and education.37 These refinements have dramatically
reduced the number and type of complications
associated with this procedure. The overall serious
complication rate associated with the Stretta procedure
is now estimated to be 0.24% and continues to improve
with a rate of <0.07% since 2002.38,39 These
complication rates compare favorably with anti-reflux
surgery and other recently approved endoscopic anti-
reflux devices based on complications reports to
the US Food and Drug Administration (FDA)
(www.fda.gov/cdrh/maude.html).40,41 Based on this
record of safety and efficacy, Stretta was the first
endoscopic reflux device to advance to the Category I
CPT code facilitating reimbursement issues for catheter
costs,procedure,and facility fees.These results produced
a shift in the GERD treatment paradigm and support
the use of Stretta for patients with persistent symptoms
despite medication, or those seeking an alternative to
drug and surgical therapy.33,42
Endoscopic Gastroplication
Endoscopic gastroplasty creates a plication of the gastric
folds immediately distal to the GE junction.This can be
achieved by an endoscopic suturing device or by placing
a clip to augment the anti-reflux barrier.43 Results from a
multicenter trial of the endoscopic sewing device
(EndoCinch; C.R. Bard, Billerica MA) have been
reported.44 In this trial, 64 (45M, 19F) patients with
GERD were treated and then followed for six months.


Patients were randomized to receive either a linear or
circumferential plication configuration. All patients had
three episodes of pyrosis per week (off medications),
dependency on antisecretory medication, and
documented reflux by 24-hour esophageal pH
monitoring. Patients with dysphagia, significant
esophagitis (grade 3), obesity (body mass index (BMI)
>40), or hiatus hernia >2cm in length were excluded.


The majority (94%) of patients were treated in a single
session. In addition, 11 patients underwent a second
procedure 49ý405 days after the original procedure.


Because of suboptimal results, only 80% of patients were
available for analysis at six months. In this study a
ýheartburn scoreý was used to assess symptom severity, an
unvalidated measure determined by multiplying the
severity (0ý100) by the frequency (0ý1; 1ýoccasional;
2ý3/5 per wk; 3-daily). At baseline, all patients were
taking some type of medication for reflux and 86% of
patients were taking PPIs.At six months, 62% of patients
were using medications fewer than four times per month.


Adverse events included pharyngitis (31%), chest pain
(16%), and mediastinitis/suture perforation (2%).


A one-year follow-up in a small group of patients has
been published.45ý47 Only 22 of 26 patients (85%) were
available for assessment 12 months after endoscopic
suturing.45ý47 At one year, 64% of patients were off PPIs.


Similarly, quality-of-life scores at 12 months were
significantly improved over baseline. Longer-term
3
B USINESS BRIEFING: US GASTROENTEROLOGY REVIEW 2005
Reference Section
results,however,have not been as favorable.Three of the
original centers in the open-label study have reported
their two-year results after gastric plication and found
that most patients have returned to use of their anti-
secretory medications (75%) including nearly half the
patients who were back on full dose PPI or had
undergone fundoplication (47%).48 These reports have
raised questions about the long-term durability of the
gastric plication treatment results.49,50 Demonstration of
long-term efficacy based on objective parameters is
critically important to the viability of this technique in
its current form.51 Similar suturing devices for GERD
patients are under development, including the
Endoscopic Suturing Device from Wilson-Cook
Medical (Winston-Salem, NC), although clinical
experience with this device is limited thus far.52,53
Endoscopic Full-thickness Plication
Another device has been developed that performs full
thickness endoscopic gastric plication and has recently
been FDA-approved (NDO Surgical; Mansfield,
MA).54,55 In this method, a pre-tied suture-based
implant is used to create a full-thickness plication in a
single step.56 In a recently published multicenter study, a
total of 64 patients (mean age 46.3 years, range 23ý71
years) underwent endoscopic full-thickness plication
(mean procedure time 17.2 minutes). At six months
after plication, the use of PPI therapy had been
eliminated in 74% of previously medication-dependent
patients.The median GERD-HRQL scores were found
to have improved in 67% (19.0 versus 5.0; p<0.001).


Improvements were also observed in median
Gastrointestinal Symptom Rating Scale and SF-36
Health Survey mental and physical composite scores.


Median esophageal acid exposure improved
significantly (10 versus eight; p<0.008), with
normalization of pH noted in 30% of patients. No
significant change in esophageal manometry was noted.


One gastric perforation occurred and was managed
endoscopically by clip placement and surgery was not
required.57 This plication device seems to mimic the
effect of fundoplication of anti-reflux surgery, and the
initial multicenter study results are promising including
the 12-month follow up report.58 There are currently,
however, no published data available from sham-
controlled studies or studies comparing this technology
with anti-secretory medication or anti-reflux surgery.59
LES Injection or Implantation
In this approach to treating GERD, a biocompatible
agent is injected into the submucosa of the LES.60ý63 This
augmentation or ýbulkingý of the LES is thought to
diminish reflux. These materials are said to be non-
allergenic, stable, and resistant to degradation by
phagocytosis.The Enteryxý procedure (Boston Scientific
Inc.; Natick, MA) and the Gatekeeper procedure
(Medtronic, Tolochenaz, Switzerland) have thus far
received FDA approval. Another technology is the
injection of polymethylmethacrylate (PMMA) beads
into the LES and limited preliminary results have been
reported.64 In this study, 10 patients (3M, 7F) with PPI-
dependent or refractory GERD had PMMA injected
into the submucosa of the LES. Patients with hiatal
hernias >3cm, dysphagia, Barrettýs esophagus, or
connective tissue disease were excluded. The primary
outcome was severity of GERD symptoms based on a
one to five scale for heartburn, regurgitation, pain, and
dysphagia. Injections of 3ml were performed 2cm
proximal to the z-line using a sclerotherapy needle until
the esophageal folds were in close approximation.This
typically required five to six injections.The mean volume
injected was 32ml.At follow-up, seven of the 10 patients
were off all medications. Interestingly, although seven of
the 10 patients were able to discontinue all medications,
only one patient had normalization of their DeMeester
score.Adverse effects were said to be minimal, although
chest pain requiring analgesics occurred in two patients,
minor bleeding was seen in one patient, and transient
dysphagia occurred in one patient.


Another approach to LES augmentation is to implant
an expandable hydrogel prosthesis in the region of the
gastroesophageal junction under direct endoscopic
guidance ý the Gatekeeper reflux repair system,the fifth
and most recently approved endoscopic anti-reflux
device.65,66 After placement, these prostheses swell and
increase the bulk of the LES muscle complex.An Italian
study has described the results of Gatekeeper in nine
patients with non-significant improvement in the distal
esophagus acid exposure time from 11.7% at baseline to
7.7% at follow-up with normalization in three patients.


The proximal extent of acid reflux events significantly
decreased in all patients at follow-up (37.3% versus
9.5%), reaching values observed in asymptomatic
controls and there was significant improvement in
median GERD-HRQL scores.67 A Dutch report
combined data from two prospective, non-randomized
European multicenter trials where GERD patients with
heartburn and regurgitation and abnormal esophageal
acid exposure who had responded to PPI therapy
underwent prostheses placed at the gastroesophageal
junction. Surveillance studies included esophageal
manometry, endoscopy, ambulatory esophageal pH
monitoring and symptom scoring at baseline and one,
three, and six months after the procedure.A total of 77
procedures were performed in 67 patients with
placement of 270 total prostheses (mean 4.3 per
procedure). Most of these prosthesis were retained at
follow-up (at one and six months, 80.4% and 70.4% of
the prostheses were retained, respectively). At six
months, significant improvements were noted in
abnormal esophageal acid contact times (9.1% to 6.1%
in 45 patients) and the median LES pressure increased
significantly from 8.8 to 13.8mmHg in 42 patients.


Median GERD heartburn-related quality-of-life scores
also improved significantly in patients no longer
receiving PPI therapy. Two serious adverse events
(3.0%) occurred and the prostheses were endoscopically
removed from one patient without any adverse events.


These studies support the on-going development of
this technique.65,68ý70
The recently approved Enteryxý procedure uses a
similar approach with a liquid polymer (ethinyl-vinyl-
alcohol ý EVA) injected into the LES with a
sclerotherapy needle.71 Following injection,the polymer
absorbs water and swells.The results of a multicenter
trial of this technique were recently reported.72,73
Eighty-five patients with chronic GERD were treated.


At six months, 74% of patients were off PPIs and there
was a significant improvement in the median HRQL
score. Twenty-four-hour pH studies improved
significantly, but total acid exposure time remained
abnormal. Mean LES length increased from 2.0cm to
3.0cm (p=0.003). Four of 15 patients were back on
PPIs at follow-up. Except for retrosternal pain lasting
up to several weeks and mild dysphagia, no side effects
were noted initially. A European trial has reported
results at 12 months after Enteryx with symptomatic
improvement in 86% and elimination of PPI therapy in
65% of 74 evaluable patients.The treatment success rate
by intent-to-treat analysis, however, was 69%.


Significant symptomatic improvement was noted for
heartburn, regurgitation, and physical as well as mental
quality of life. Reported complications were chest pain
(77%), dysphagia or odynophagia (27%), and fever
(26%).74 Safety issues have emerged with this device,
however; reports include six deaths and serious
complications including esophageal-aortic ulceration
and fistula, esophageal perforation, chemical and
infectious mediastinitis, pleural and pericardial
effusions, dysphagia, polymer-related renal
embolization, and difficulty performing subsequent
anti-reflux surgery, with an on-going FDA investigation
of this device, according to Investors Business Daily
(August 23, 2004) (http://www.accessdata.fda.gov/
scripts/cdrh/cfdocs/cfMAUDE).41,74,75 More recent
studies have focussed on refinements in accurate
injection of Enteryx material into the deep layers of the
esophageal wall and improved patient selection based
on treatment outcomes.62,76
Summary
The use of endoscopic GERD therapies will continue
to develop alongside established medical and surgical
treatment options.77 While anti-reflux medication is
generally considered quite safe and effective, patients
requiring chronic drug treatment often demand
treatment alternatives. Surgical alternatives to chronic
drug treatment are associated with increased morbidity
and long-term failure rates in more than 50% of
surgically treated patients.These endoluminal therapies
using modifications of standard endoscopy techniques
currently under evaluation represent as alternatives to
chronic drug treatment or surgical intervention for
GERD.78 Critics of these techniques have suggested
that clinical application of endoscopic anti-reflux
devices is premature since they have not consistently
demonstrated normalization of acid contact times in
ambulatory esophageal pH testing, despite sympto-
matic improvement.79ý81 It is increasingly apparent,
however, that most GERD patients treated with PPI
drugs in standard doses fit the same profile ý
symptomatic improvement despite persistently
abnormal esophageal pH testing. The same is likely
true for many patients who have undergone anti-reflux
surgery. Furthermore, GERD patients and their
physicians are increasingly aware of the importance of
correcting the underlying pathology of the weakened
lower esophageal sphincter with minimally invasive
endoscopic techniques rather than using indefinite
drug therapy to affect long-term alterations in gastric
acid secretion.82 For patients who experience
incomplete responses to acid blocking drugs or simply
desire a non-drug therapy, these endoscopic anti-reflux
techniques increasingly represent an important
innovation in GERD treatment.83 a73
Treatment of Gastroesophageal Reflux Disease
B USINESS BRIEFING: US GASTROENTEROLOGY REVIEW 2005
4
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Reference Section