Aliment Pharmacol Ther 2004; 19 (Suppl. 1): 3542.

Review article: approaches to the long-term management of adults

with GERDproton pump inhibitor therapy, laparoscopic
fundoplication or endoscopic therapy?
J. W. FRESTON* & G . TRIAD AFILOPOULOS
*University of Connecticut Health Center, Farmington Avenue, Farmington, CT, USA; Stanford University School of
Medicine, Gastroenterology Section, Palo Alto VA Health Care System, Miranda Avenue, Palo Alto, CA, USA
Accepted for publication 24 October 2003

SUMMARY

The goals of gastro-oesophageal reflux disease (GERD)

treatment are to control symptoms, heal the injured
oesophageal mucosa, and prevent complications. Pharmacological therapy is effective in producing acute
symptom relief and mucosal healing, as well as the
long-term maintenance of remission. Proton pump
inhibitors are the mainstay of GERD therapy. However,
the need for daily administration, failure to provide
complete symptom relief and costs of these agents may
limit their use in some patients, prompting a consideration of alternative treatment strategies. Laparoscopic
fundoplication may achieve symptom relief and healing
of the oesophagitis in these individuals, but its invasiveness, cost and inherent surgical risks have created
an interest in endoscopic therapies for GERD, with
several emerging during the past few years. These

INTRODUCTION

Every year, more than 18 million Americans suffer from

gastro-oesophageal reflux disease (GERD).1 Of a total
estimated disease cost of $9.3 billion, $5.8 billion is
spent on anti-reflux medications, higher than that of all
other gastrointestinal disorders.2
Correspondence to: Dr James W. Freston, MD, PhD, University of
Connecticut Health Center, 263 Farmington Avenue, Farmington, CT
06030-1111, USA.
E-mail: Freston@nso.uchc.edu
2004 Blackwell Publishing Ltd

interventions may either be viewed as an alternative

therapy or as bridge therapy, with patients still
choosing to be treated with acid anti-secretory drugs
or fundoplication if the endoscopic procedure fails to
provide adequate symptom relief or if symptoms recur.
Patient selection is critical for the success of fundoplication as well as endoscopic procedures, with ideal
candidates being those with well-established endoscopically documented GERD, abnormal pH monitoring,
normal oesophageal motility studies, and who have
experienced at least partial symptom relief with proton
pump inhibitor therapy. Hiatal hernia is not a contraindication to fundoplication, while endoscopic intervention is best suited for those with a hiatal hernia of less
than 3 cm in length. The long-term efficacy, costeffectiveness, and impact of endoscopic procedures on
extra-oesophageal manifestations of GERD and risk for
GERD-related complications has not been determined.

The goals of GERD management are threefold: prompt

and sustained symptom control, healing of the injured
oesophageal mucosa and prevention of GERD-related
complications (including stricture formation, Barretts
oesophagus, and/or adenocarcinoma). Pharmacological
therapy with acid anti-secretory agents forms the basis
of both acute and long-term management of GERD.
Proton pump inhibitors provide effective relief of
symptoms and healing of the oesophagitis, as well as
sustaining long-term remission. While treatment
alternatives also include the histamine-2 receptor
35

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J. W. FRESTON & G. TRIADAFILOPOULOS

antagonists, the proton pump inhibitors are considered

the mainstay of therapy due to their higher rates of
therapeutic response. Proton pump inhibitors are highly
effective; however, issues such as the requirement for
daily administration, incomplete symptom relief in some
patients, and cost result in some patients desiring longterm treatment alternatives.
Laparoscopic anti-reflux surgery, such as Nissen
fundoplication is an alternative to long-term proton
pump inhibitor therapy. While it may heal the oesophageal mucosa effectively, control symptoms and
sustain remission, it carries the inherent risks of
surgery, as well as other limitations. Several endoscopic
techniques have been developed as less-invasive alternatives to surgical fundoplication. While these may
provide effective control of symptoms and may also
decrease the use of medication, they have not been
shown to heal oesophagitis or prevent its complications.
Careful patient selection as well as surgical and
endoscopic expertise are key criteria in determining
the success of fundoplication, as well as endoscopic
procedures for GERD. Long-term cost-effectiveness analyses and post-marketing surveillance of their efficacy,
tolerability and complications are necessary to completely define the characteristics of these procedures.
ACID ANTI-SECRETORY MEDICATIONS

The superiority of proton pump inhibitors over histamine-2 receptor antagonists relates directly to the
ability of the former to hold the intragastric pH at or
above 4 for longer periods of time. The effectiveness of
histamine-2 receptor antagonists is further impeded by
their inability to inhibit meal-induced acid secretion and
their potential to induce tachyphylaxis within 24 h of
administration, thereby establishing the proton pump
inhibitors as primary agents in the pharmacological
management of GERD.
Among the currently available proton pump inhibitors
there are slight differences in pharmacokinetic as well as
pharmacological parameters. Because all proton pump
inhibitors only bind to actively secreting proton pumps,
patients should be reminded to take their medication
3060 min before a meal in order to optimize their
effectan instruction that is conveyed by only 36% of
US primary care physicians.3
Omeprazole and esomeprazole induce their bioavailability over 5 days, with their anti-secretory effect increasing during this period.48 On the other hand, the

bioavailability of lansoprazole attains near-peak levels

after the first dose, with significantly (P 0.001) greater
percentages of time with the intragastric pH above 4 in
the first 5 h post-dose as compared to rabeprazole.9
Clinical trials show that the differences in antisecretory effect between the proton pump inhibitors
may result in symptom control disparity. In head-tohead controlled trials of lansoprazole and omeprazole, a
faster onset of symptom relief was reported by those
treated with lansoprazole (Figure 1).10 Treatment with
esomeprazole or rabeprazole has also been found to
produce faster symptom relief compared to omeprazole.
On the other hand, in trials comparing lansoprazole
with esomeprazole, no consistent or significant differences have been noted in parameters for heartburn
relief (Figure 2).11, 12 Interestingly, recent studies have
indicated that symptom relief may be linked to patients
preference for one proton pump inhibitor over another.13, 14
The superiority of any proton pump inhibitor in
healing erosive oesophagitis has rarely been demonstrated to a clinically relevant extent.11, 15 However,
histamine-2
receptor
antagonist
comparative
(Figure 3), and placebo-controlled studies (Figure 4)
have confirmed that continued maintenance therapy
with a proton pump inhibitor is essential to maintaining
the healed mucosa. 16, 17

Figure 1. Speed of heartburn relief: lansoprazole vs. omeprazole.

A total of 3510 patients with endoscopically diagnosed erosive
GERD were treated with 30 mg lansoprazole or 20 mg omeprazole
once daily for 8 weeks. At the end of day 1, a significantly greater
percentage of lansoprazole-treated patients reported complete
heartburn relief. This significant benefit with lansoprazole persisted throughout the treatment period. Figure reprinted from
ref. 10, with permission from the American College of Gastroenterology.

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19 (Suppl. 1), 3542

REVIEW: LONG-TERM MANAGEMENT OF GERD

Figure 2. Percentage of days without heartburn: 30 mg lansoprazole vs. 40 mg esomeprazole once-daily. During each of the
treatment evaluation time-points the percentages of days without
heartburn were similar in patients treated with 30 mg lansoprazole or 40 mg esomeprazole, each administered once daily.
Figure reproduced with permission, ref. 12.

Figure 3. Maintenance therapy with lansoprazole or step-down to

high-dose ranitidine. Maintenance therapy with 15 mg or 30 mg
lansoprazole once daily maintained remission in significantly
greater percentages of patients compared to 300 mg ranitidine
twice daily. Figure reproduced with permission from ref. 17.

Substantial progress has been made in developing

alternative proton pump inhibitor formulations, thereby
offering more and better options for the treatment of
patients in which conventional capsules or tablets
cannot be administered. These individuals include
children and the elderly, as well as those who can take
nothing by mouth and those fed by nasogastric tube.
Lansoprazole is now available as an oral suspension,
while both lansoprazole and omeprazole granules may
be given in a variety of soft foods or liquid dietary
supplements prior to oral administration, or mixed with
fruit juices or prepared as a sodium-bicarbonate based
solution prior to administration through a nasogastric
tube. One study of a lansoprazole in apple juice solution
found that it achieves better pH control as compared to
intravenously administered pantoprazole.7

37

Figure 4. Time to recurrence by initial oesophagitis grade:

lansoprazole vs. placebo maintenance therapy. As calculated
using life-table methodology, lansoprazole-treated patients
remained in remission longer than those treated with placebo,
regardless of grade of oesophagitis at baseline. No placebo-treated
patient with grade 3 or 4 before healing remained healed by
1 month compared with 89% of those treated with lansoprazole.
Figure reprinted from ref. 16, with permission from the American
College of Gastroenterology.

On the near horizon, new and novel dosage formulations of lansoprazole are anticipated. An intravenous
formulation of lansoprazole is under study and has been
found to be equivalent to lansoprazole oral capsules in
suppressing stimulated acid output in patients with
erosive oesophagitis.18 A novel lansoprazole orally
disintegrating tablet (LODT) disintegrates in the mouth
in seconds, and has a bioavailability equal to that of
lansoprazole capsules.19 Alternatively, the tablet may
be dissolved in a small amount of water (5 mL) prior to
oral administration, or given through a nasogastric or
gastric tube.
The safety profile of the proton pump inhibitors
continues to evolve favourably. However, reduced
serum vitamin B12 levels have been occasionally
documented during long-term treatment with proton
pump inhibitors, primarily in patients with Zollinger
Ellison syndrome who have sustained drug-induced
achlorhydria. The mechanism for this is likely to be a
diminished extraction of protein-bound cobalamin in
food due to a pharmacological increase in intragastic
pH.20 Patients receiving long-term proton pump inhibitor therapy may require monitoring of their vitamin
B12 status or, alternatively, administration of a multivitamin containing vitamin B12.21
Rebound acid hypersecretion has recently been reported in patients following Helicobacter pylori eradication,
an effect that may in part explain why some of these
individuals report heartburn following cure of their
infection.22 However, a recent post hoc analysis of eight
double-blind trials involving 1165 patients refuted this

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J. W. FRESTON & G. TRIADAFILOPOULOS

hypothesis.23 In this study, patients cured of their

H. pylori infection were not found to develop erosive
oesophagitis, new symptomatic GERD, or a worsening of
symptoms in those with pre-existing GERD. The most
recent study of the effects of chronic proton pump
inhibitor therapy on gastric mucosa found no increase
in the degree of gastric atrophy or intestinal metaplasia
in H. pylori-infected patients.24 Thus, opinion remains
divided as to whether patients with GERD should be
tested and treated for H. pylori infection before embarking on long-term proton pump inhibitor treatment. This
strategy is recommended in Europe but not in North
America, where the prevalence of H. pylori infection is
low and the prevalence of GERD is high.
SURGICAL AND ENDOSCOPIC PROCEDURES

While proton pump inhibitor therapy remains the

mainstay of GERD management, some patients may
consider endoscopic or surgical interventions because
they wish to avoid daily medication administration,
have an inadequate symptom response to medications,
or because of cost.25 While some patients may perceive
that anti-reflux procedures reduce their risk of GERDrelated complications,25 to date no study has shown
that they either heal oesophagitis or prevent complications. As compared to proton pump inhibitor therapy, a
recent study found that 5-year symptom remission rates
were similar between those patients undergoing open
anti-reflux therapy and those allowed to titrate their
omeprazole dose.26
Surgical fundoplication
Laparoscopic surgery (i.e. Nissen fundoplication) may
lead to effective healing, symptom control and maintenance of remission in more than 90% of patients, with
reduced rates of perioperative and post-operative morbidity compared to an open approach using laparotomy
or thoracotomy.2630 Objective evidence of acid exposure normalization has been observed in between 91%
and 97% of patients more than 1 year following the
surgery.27, 30, 31
The best candidates for fundoplication are those with
well-established GERD, with or without a hiatal hernia,
oesophagitis documented by endoscopy, abnormal pH
monitoring studies, and normal oesophageal motility
studies, and who have demonstrated at least partial
symptom relief with proton pump inhibitor therapy.

Limitations to the use of fundoplication include the need

for surgical expertise, the need for 1 day of hospitalization and 3 weeks of post-operative recovery, with
dietary modification and restriction of certain activities.
While laparoscopic fundoplication is effective, up to onehalf of patients continue to require medications during
the ensuing 18 months, with the mean cost of care in
these individuals being significantly higher than in
those who are medically managed.32 In those with
symptom control, the efficacy of fundoplication may
wane over time, with up to 50% of patients continuing
to require acid anti-secretory therapy to control symptoms for up to 10 years following the procedure. In
addition, some patients report the development of new
symptoms (e.g. dysphagia, gas, bloating, increased
flatus and difficulty with belching or vomiting) following the procedure.33, 34 The invasiveness, costs and
risks of surgery have resulted in an exploration of the
potential of the various recently introduced endoscopic
anti-reflux procedures.35
Endoscopic procedures
Several endoscopic techniques for GERD have been
developed as less invasive alternatives to laparoscopic
fundoplication. These procedures have been found to
control symptoms in up to 80% of patients and to
eliminate or reduce the need for anti-reflux medication.
Like laparoscopic fundoplication, the best candidates
for endoscopic procedures are those with well-established GERD, documented by endoscopy and pH monitoring studies and normal oesophageal motility studies
and who have, at least in part, responded to proton
pump inhibitor therapy. Unlike laparoscopic fundoplication, endoscopic technique candidates should not
have a hiatal hernia of greater than 3 cm in length.
Given their recent introduction, the long-term efficacy
and cost-effectiveness of endoscopic therapies as compared to proton pump inhibitor therapy or surgery is
still not known, as are the efficacy of these procedures in
controlling extra-oesophageal manifestations of GERD
and their potential to reduce Barretts oesophagus or
oesophageal adenocarcinoma.
Stretta
The Stretta (Curon Medical, Sunnyvale CA) system
consists of a radio-frequency generator and a delivery
catheter comprised of a soft shaft, and a balloon-basket

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REVIEW: LONG-TERM MANAGEMENT OF GERD

assembly with four electrodes positioned radially

around the balloon. When the catheter is positioned
and the needles deployed into the circular muscle of the
gastro-oesophageal junction, energy is delivered to each
electrode to create a series of thermal lesions in the
muscle.36 The procedure is generally well-tolerated,
with favourable impacts upon oesophageal acid exposure, medication requirement, and GERD symptom
scores.26, 3642 The procedure appears to improve
gastric myoelectrical activity and gastric emptying,43
although it has been criticized as producing ablative
denervation of the oesophageal body rather than a
reduction in oesophageal acid exposure due to an
augmentation of the anti-reflux barrier.44 This desensitizing theory was refuted in a post hoc analysis of 118
patients who underwent Stretta and were compared for
proximal and distal oesophageal acid exposure. Clinical
responders were found to have significant improvements and normalization in both proximal and distal
oesophageal acid exposure, while nonresponders had
either no improvement or less improvement. 44
Richards and colleagues27 compared the effects of
Stretta performed in 65 patients to those of laparoscopic fundoplication performed in 75 patients with
GERD. Specific clinical criteria were applied to appropriately selected patients, with the Stretta system
being offered to those having hiatal hernia less than
2 cm in length, lower oesophageal sphincter pressure
of more than 8 mmHg, and no evidence of Barretts
oesophagus. Six months following the procedure, there
was a significant improvement in quality-of-life questionnaire scores and short-form health surveys in each
group, with an equal magnitude of pre to postoperative improvement in them. While 97% of those
who underwent laparoscopic fundoplication reported
not taking proton pump inhibitors, only 42% of those
who underwent Stretta were able to discontinue
therapy. Both groups were highly satisfied with their
procedure.
Twenty-four hour pH monitoring performed 6 months
following Stretta treatment in 13 patients found a
significant decrease in acid exposure time (13% to 5%,
P < 0.05) in a study by Arts et al.42 These investigators
also noted a significant increase in time to report
symptoms during Bernstein testing in these patients
(from 9 min to 17 min, P < 0.05).
Among 94 patients available for follow-up in a
12-month study, proton pump inhibitor use decreased
from 88% to 30%.37 Of the 118 patients who

39

underwent the Stretta procedure, 10 complications

(8.6%) occurred although none required therapeutic
intervention.
EndoCinch
EndoCinch (Bard Endoscopic Technologies, Billerica,
MA) is an endoscopic suturing multicomponent system
that is introduced through an overtube and can place
single or multiple sutures to alter the anatomy of the
gastro-oesophageal junction, by tightening the cardia
within the lesser curve, accentuating the angle of His.45
The procedure increases lower oesophageal sphincter
pressure and decreases acid exposure by tightening the
cardia and increasing the smooth muscle layer thickness adjacent to the plication.46, 47 Initial studies
indicate that the EndoCinch improves symptoms and
reduces usage of anti-secretory medication, although
the optimal technique, including the number of plications (two vs. three) and their placement remains
unclear.48
Among 26 patients (mean age 39 years, range 2262)
in the UK who underwent EndoCinch treatment, 22
were available for follow-up 1 year later.49 At 3 months
the pH DeMeester acid score decreased from 44 to 33
(P 0.028). At 12 months, heartburn symptom score
was reduced from a mean of 19.22 at baseline to 7.5
(P < 0.001), regurgitation score decreased from a mean
of 2.27 to 0.86 (P < 0.001), and the use of proton
pump inhibitor therapy was reduced by 64%. All
quality-of-life assessments showed significant improvement (P 0.01).
Patients who undergo the EndoCinch procedure and
experience symptom recurrence should be reassessed by
endoscopy, as loose or lost sutures have been noted in
most of these individuals.50
Enteryx
Enteryx (Boston Scientific, Natick, USA) is a biopolymer
that is slowly injected along the muscle layer or the deep
submucosal layer of the cardia, allowing polymerization
of the implanted material. The procedure is performed
endoscopically under fluoroscopic control at or below
the Z-line. Fluoroscopy allows for optimal visualization
of the injection, and confirms that the implant has been
placed intramurally by observing the radio-opaque
marker in a ring-like distribution.51 The procedure
improves gastric pH parameters including total pH,

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J. W. FRESTON & G. TRIADAFILOPOULOS

upright and supine reflux times, as well as the per cent

total acid reflux time, number of reflux episodes, and
patient quality-of-life measures.5254 Patients reported
heartburn symptom relief, with a significant improvement observed at 1 month that was sustained for at
least 12 months.51
Several studies have found a reduction in proton pump
inhibitor use following Enteryx treatment.5256 However, a sloughing of the implant volume over time has
been noted as correlating with increased proton pump
inhibitor use.57 The results of one study comparing
outcomes in patients undergoing endotherapy suggest a
greater decrease in proton pump inhibitor therapy and a
greater improvement in symptoms among those who
underwent Enteryx compared to those who underwent
Endocinch.58
Gatekeeper
The Gatekeeper (Medtronic Inc., Tolochenaz, Switzerland) procedure involves the submucosal placement of
expandable miniature hydrogel prostheses in the region
of the gastro-oesophageal junction under direct endoscopic visualization. After placement, the prostheses
swell up and bulk the region of the gastro-oesophageal
junction. The prosthesis augments the lower oesophageal sphincter and in initial studies has been noted to
reduce proximal acid events and improve patient
quality-of-life parameters. One potential advantage of
this approach is that the prostheses are submucosal and
may be removed if they are found to be ineffective or to
cause side-effects.59, 60

CONCLUSIONS

Pharmacological treatment with proton pump inhibitor

therapy is the mainstay of GERD management. These
agents provide prompt and effective relief of symptoms
and oesophagitis healing. After initial healing of the
oesophagitis, the majority of patients with GERD will
require continuous or intermittent proton pump inhibitor therapy to control their symptoms. Despite the
widespread acceptance of proton pump inhibitor therapy and its cost-effectiveness in the treatment of chronic
GERD, a number of patients may not wish to take longterm therapy or have incomplete relief of their symptoms and desire an alternative treatment strategy.
The best candidates for alternative strategies of
laparoscopic fundoplication or endoscopic procedures
are those who have well-established GERD by endoscopy, and abnormal pH and oesophageal motility
studies who have, at least in part, responded to proton
pump inhibitor therapy. While not a contraindication to
fundoplication, an hiatal hernia of greater than 3 cm in
length excludes patients from undergoing endoscopic
procedures. Patients considering endoscopic therapies
should understand that these procedures may be viewed
as either an alternative therapy or as a bridge therapy
and that they may still require acid anti-secretory
therapy or fundoplication if the endoscopic procedure
fails to provide adequate symptom relief or if symptoms
recur. The long-term symptom relief efficacy of these
endoscopic therapies, as well as their ability to control
extra-oesophageal manifestations of GERD and prevent
complications (i.e. Barretts oesophagus, oesophageal
adenocarcinoma) have not been established.

NDO full-thickness plication

The plicator (NDO Surgical, Inc., Mansfield, MA) creates
a transmural, full-thickness plication using a pre-tied,
suture-based implant that is delivered endoscopically
just below the gastro-oesophageal junction in a retroflexed manner to accentuate and restore the valvular
mechanism. The system includes an overtube (through
which the plicator device is introduced into the
stomach), the plicator, a tissue retracting helical
catheter, and a pre-tied suture insert.61 In a study of
64 patients, improvements in health related quality-oflife parameters, 24 h pH-metry studies, and reductions
in daily proton pump inhibitor requirements were
noted.62

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2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19 (Suppl. 1), 3542