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Advanced Studies inMedicine I S123

ABSTRACT
Gastroesophageal reflux disease (GERD) affects
approximately 20%of the US population and is
one of the most common acid-related disorders in
US adults.
1
One of the key symptoms of this often
chronic disorder is heartburn. Gastroesophageal
reflux disease is known to cause heartburn, and the
presence of acid in the esophagus for prolonged
periods is now known to place patients at risk for
serious sequelae, such as Barretts esophagus and
esophageal cancer. Therefore, long-termmanage-
ment options are needed, including lifestyle
changes, pharmacological therapy, surgery, and
endoscopic intervention. Proton pump inhibitors
have been found to be superior to other medica-
tions both in inducing symptomresolution and heal-
ing esophagitis. The outcomes reported from
surgical and endoscopic treatments are mixed.
Recent data suggest that approximately one fourth
of surgically treated patients will require continued
antisecretory therapy for persistent GERD symp-
toms postoperation.
1
Though a number of endo-
scopic procedures have been approved for use in
the United States, their effectiveness and their roles
in clinical practice remain controversial.
(Adv Stud Med. 2003;3(3A):S123-S127)
T
he major treatment options, other than
lifestyle changes, for the long-term care of
adult gastroesophageal reflux disease
(GERD) patients are medical therapy,
surgery, and newer endoscopic proce-
dures. This article will review evidence surrounding
each of these treatment options and guide the clinician
in choosing appropriate management plans for
patients heartburn relief, healing of erosive esophagi-
tis, and maintenance of clinical remission.
MEDICAL THERAPY FOR HEARTBURN
HISTAMINE-TYPE 2 RECEPTOR ANTAGONISTS
VERSUS PROTON PUMP INHIBITORS
There are 2 main classes of drugs available today
that are used in the long-term treatment of GERD in
adults: histamine type-2 receptor antagonists (H2RAs)
and proton pump inhibitors (PPIs). However, evi-
dence clearly indicates that of the two, PPIs should be
the mainstay of medical therapy for most patients. In
a large community-based trial conducted by Howden
et al, 593 individuals with symptomatic GERD were
randomized to receive either an initial dose of the
H2RA, ranitidine, or the PPI, lansoprazole. Four
therapeutic strategies were compared in which some
subjects remained on a constant dose of ranitidine 150
mg bid or lansoprazole 30 mg qd for 20 weeks, while
others began initially on either ranitidine 150 mg bid
or lansoprazole 30 mg qd and then were switched to
the other medication. Subjects were asked to keep
diaries of their symptoms, specifically to log the sever-
ity of their daytime and nighttime heartburn as well as
PROCEEDINGS
LO NG-TERM MANAGEMENT O F GERD: PRO TO N PUMP INHIBITO RS
VERSUS NEWER ENDO SCO PIC INTERVENTIO NS VERSUS SURGERY
*

William D. Chey, MD, FACP, FACG

* Thisarticle isbased on a presentation given by Dr Chey


at the PRI-M ED East Conference.

Associate Professor of M edicine, University of M ichigan


M edical Center, Ann Arbor, M ichigan.
Address correspondence to: William D. Chey, M D,
University of M ichigan Health System, 3912 Taubman Center,
Box 0362, Ann Arbor, M I 48109. E-mail: wchey@ umich. edu
S124 Vol. 3 (3A) I March 2003
PROCEEDI NGS
the percentage of 24-hour heartburn-free days. Results
indicated that regardless of whether a trial participant
was given the PPI first or second, the individual expe-
rienced significantly greater heartburn relief and relief
of other reflux-related symptoms when treated with a
PPI. For example, the lansoprazole group had a signif-
icantly higher percentage of 24-hour heartburn-free
days (median 81.4%; P<.01) than other groups
(66.6%, 66.9%, and 73.6%, respectively).
2
A COMPARISON OF PPIS
Castell et al studied a large number of patients with
GERD who were randomized to receive either lanso-
prazole 30 mg qd or esomeprazole 40 mg qd. After 4
weeks of treatment, patients in both groups experi-
enced heartburn-free days for approximately 70% of
the study period. For both lansoprazole and esomepra-
zole, relief of nighttime symptoms occurred after 1
day; daytime symptom resolution was achieved in 2
days. Both medications were capable of completely
resolving heartburn symptoms among study partici-
pants after 4 weeks of therapy approximately 60% of
the time.
3
A similar study recently completed by
Howden et al compared the effectiveness of lansopra-
zole and esomeprazole in patients with heartburn and
erosive esophagitis and found no statistically signifi-
cant difference between the 2 drugs at either day 1 or
week 1 of therapy.
4
MEDICAL THERAPY FOR HEALING ESOPHAGITIS
While heartburn is the hallmark symptom of
GERD, results of North American studies indicate
that 40% to 60% of patients with GERD have evi-
dence of esophagitis at endoscopy. Evidence shows a
causal relationship between GERD and Barretts
esophagus as well as an increased risk of esophageal
adenocarcinoma from Barretts.
5
Thus, prompt resolu-
tion of heartburn aswell ashealing of esophagitisshould
be the long-term goals in individuals with GERD.
Richter and investigators compared lansoprazole and
omeprazole to placebo in a randomized, double-blind,
multicenter study of 3510 patients with erosive
esophagitisdiagnosed via endoscopy. Their data indicate
that PPIsare statistically significantly better than placebo
in healing erosive GERD, and that lansoprazole 30 mg
qd relieved heartburn faster and more effectively than
omeprazole 20 mg qd. Eighty-one percent of patients
receiving lansoprazole were healed of erosive esophagitis
by week 4 compared with only 33% of those random-
ized to placebo. By week 8, 95% of patientstreated with
lansoprazole were healed compared with 53% of patients
receiving placebo.
6
These data further support the stud-
iesby Castell and Howden that showed that both lanso-
prazole and esomeprazole achieve excellent rates of
healing in patientswith GERD after both 4 and 8 weeks
of treatment.
3,4
MEDICAL THERAPY FOR MAINTAINING REMISSION
What about maintenance of healing and symptom-
free remission?In clinical practice, PPIs and H2RAs
are most frequently prescribed for sufferers of GERD.
Proton pump inhibitors have consistently been
deemed superior to H2RAs. In a study published by
Gough et al in 1996, data indicate that even a high
dose of ranitidine (300 mg bid) is inferior to the PPI,
lansoprazole (30 mg qd or 15 mg qd) in maintaining
remission of symptoms. This may be due in part to the
fact that patients with chronic GERD who take
H2RAs frequently develop tolerance to these medica-
tionsa phenomenon that so far has not been found
to occur with PPI use.
7
When pH-related endpoints
(either intragastric pH or intraesophageal acid exposure)
were examined in a trial performed in 23 individuals
with GERD who were treated with the PPI, omeprazole
20 mg/day, there were no significant differencesin those
measurements at 3 or 6 months. This suggests that
patientsdo not develop a tolerance to PPIs.
8
SAFETY OF LONG-TERMPPI TREATMENT
Long-term use of PPIs appears to be both effective
and safe. The incidence and spectrum of adverse
events associated with the use of PPIs is very similar to
that associated with H2RAs. Both classes of drugs are
considered to be very safe. In the 16 years since physi-
cians began prescribing PPIs worldwide there has been
no evidence to indicate that long-term exposure to
PPIs causes the development of gastric carcinoids,
atrophic gastritis, intestinal metaplasia, or gastric ade-
nocarcinoma. Furthermore, since no cases of clinically
significant B
12
deficiency have been associated with
PPI therapy, it is not necessary to monitor B
12
levels in
routine practice (Table 1).
9-11
Because pregnant women frequently suffer with
GERD, a review of 5 cohort studies was conducted by
Nikfar et al to examine the safety of PPI use during
Advanced Studies inMedicine I S125
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pregnancy. In approximately 600 pregnanciesexposed to
PPI therapy during the first trimester, the relative risk of
a major malformation was1.18 (95% confidence inter-
val). Thus, thisstudy found that PPIspresent no major
teratogenic risk when used in the first trimester of preg-
nancy.
12
The majority of PPIsare Category B, according
to the Food and Drug Administration, although
omeprazole israted asCategory C.
SURGICAL INTERVENTION
Surgery is another management option for the
treatment of GERD. However, several factors must
be taken into consideration before proceeding with
surgery. The first is to evaluate the nature of an indi-
viduals symptoms. It is vital to understand that a
patient presenting with typical reflux-related symp-
toms is much more likely to do well with surgical
therapy than one with atypical symptoms. Heartburn
sufferers, for example, are more likely to experience
better outcomes with fundoplication than individuals
whose primary symptom is cough, hoarseness, or asth-
ma. Furthermore, individuals who respond well to
medical therapy have a better chance for success with
surgery than those who do not. Likewise, individuals
with erosive esophagitis are more likely to experience a
good outcome with surgery than those with nonero-
sive disease. Data from Fenton et al reported that
heartburn resolved in 91% of patients with erosive
esophagitis versus 56% of patients with negative endo-
scopies. Likewise, 94% of patients who underwent
laparoscopic fundoplication for erosive esophagitis
reported being satisfied with the outcome of the
surgery as compared with 79% who did not have
esophagitis confirmed on diagnostic testing.
13
Thus, it is critical that careful preoperative diag-
nostic testing be performed to confirm that GERD
is the cause of symptoms. Some patients with sus-
pected symptoms of GERD, particularly those
with atypical symptoms or nonerosive disease, may
actually be suffering from a disease other than
GERD. The symptoms of GERD certainly can be
misleading and may overlap those of other condi-
tions. Ambulatory esophageal pH monitoring helps
to confirm the diagnosis of acid reflux and estab-
lishes a link between acid reflux and symptoms.
Therefore, an appropriate preoperative evaluation
can help to avoid the performance of unnecessary
surgical procedures.
Patients preferences must also be taken into
account when deciding whether to manage GERD via
surgical therapy. A younger patient who does not want
to commit to a lifetime of medication or who has dif-
ficulty complying with pharmacotherapy is an ideal
surgical candidate. For each patient, it is very impor-
tant to assess the likelihood of a successful outcome
following surgical antireflux therapy. The key criteria
to allow the risk stratification of potential candidates
for surgical antireflux therapy are stated in Table 2.
Table 1. Safety of Long-term PPI Treatment
PPI = proton pump inhibitor; H2RA = histamine type-2 receptor antagonist.
Data adapted from references9, 10, 11.
Table 2. Criteria for Surgery
GERD = gastroesophageal reflux disease; PPI = proton pump inhibitor.
Incidence and spectrum of adverse eventssimilar to
H2RAs
16 yearsof worldwide experience and over 219 million
treatments
No evidence that long-term PPI treatment promotes
development of:
gastric carcinoids
atrophic gastritis
intestinal metaplasia
gastric adenocarcinoma
No need to monitor B
12
levelsin routine practice
Good surgical candidate
Trained, experienced surgeon
Confirmed diagnosisof GERD
Demonstrated response to PPI ( failure to respond to PPI
predictspoor response to surgery)
In addition, it is important to take into considera-
tion the potential risks associated with surgical anti-
reflux therapy. According to a study published in The
Journal of Gastrointestinal Surgeryin 2001, a number
of adverse events may be associated with surgery.
Bammer and investigators examined the 5- to 8-year
outcomes of the first laparoscopic Nissen fundoplica-
tions performed compared with traditional open
abdominal surgery. Of 171 patients who underwent
laparoscopic surgery and could be followed for at least
5 years, 96.5% reported continued satisfaction with
the outcome of the procedure. This was comparable to
open surgical procedures. However, these patients did
report some persistent symptoms, including 28%
reporting dysphagia. Bloating occurred in 21% of
patients postoperatively. Seven percent of patients in
this study required dilatation and 14% required con-
tinued PPI use in spite of surgical treatment.
14
Whereas the prior study examined cases per-
formed in a tertiary care center known for their
expertise in gastrointestinal procedures, Vakil con-
ducted a similar outcomes study, but in patients
whose procedures were performed in community-
based centers. Eighty-three GERD patients were
interviewed approximately 2 years after their surgical
anti reflux procedures. The reasons they provided for
opting for surgery included inadequate symptomatic
relief with medical therapy (46%), hope for a cure
(26%), fear of long-term PPI effects (17%), and
cancer prevention (10%). These findings were quite
interesting in that those unresponsive to medical
therapy are less likely to improve with surgery. In
addition, no adverse effects have been attributed to
long-term PPI use. Finally, there is no convincing
evidence to suggest that surgery decreases the likeli-
hood of developing esophageal cancer. Fifty-eight
percent of patients reported overall satisfaction;
29% of patients were somewhat satisfied and 13% of
patients were dissatisfied. Sixty-seven percent of
patients presented with new dysphagia, bloating,
and gas. Twenty-seven percent of patients were still
taking drugs for GERD at follow-up. Furthermore,
8% of patients had dilatation and approximately
another 8% underwent repeat surgery.
15
This fairly high incidence of side effects and the
need for repeat procedures leaves open the question as
to whether an alternative therapy to medication or
surgery might prove more successful. Let us consider
endoscopic management of GERD.
ENDOSCOPIC THERAPY
There are a number of endoscopic therapies cur-
rently under evaluation for the treatment of GERD.
The 2 on which we will focus are the Stretta and
Endocinch procedures. The Stretta procedure involves
the delivery of radio frequency energy to the lower
esophageal sphincter to create thermal lesions below
the mucosa at the gastroesophageal junction.
16
With
Endocinch treatment, sutures or plications are placed
in the area of the lower esophageal sphincter to create
a reflux barrier.
17
The findings reported by Triadafilopoulos et al of
an open trial performed on 118 patients with symp-
toms of GERD but with either no esophagitis or
Grade I or II esophagitis indicate that patients with
nonerosive conditions or with mild esophagitis experi-
enced improvements in GERD-related health and
quality of life after the Stretta procedure. In addition,
there were some improvements in certain domains of
the 36-item Short Form Health Survey, a validated
general survey instrument used to assess quality of life.
However, at 6 months after the Stretta procedure was
performed, 23% of patients still had esophagitis; 12
months post-Stretta, 34% of patients were still using
PPIs for their GERD-related symptoms.
16
By comparison, when endoscopic plication was
studied in a multicenter trial of 64 patients with mild
S126 Vol. 3 (3A) I March 2003
PROCEEDI NGS
Table 3. Complications of Endoscopic Therapies
for GERD
GERD = gastroesophageal reflux disease; ELGP = endoluminal gastroplication.
Data adapted from references16, 17.
Stretta

Fever
Chest pain
Dysphagia
Pleural effusion
Mucosal tear
Perforation
Aspiration
Death
ELGP
Pharyngitis
Abdominal pain
Chest pain
Mucosal tear
Hypoxia
Bleeding
Suture perforation
Advanced Studies inMedicine I S127
GERD requiring PPIs, but who either had no
esophagitis or mild esophagitis, the results of this
study were similar to those reported with the Stretta
procedure. Data reported after 6 months showed
improved symptoms and 24-hour pH-metry scores.
However, in this trial, 11 patients required repeat
surgery, and one third of patients experienced pharyn-
gitis. Others developed a myriad of complications
including vomiting, abdominal pain, chest pain, and 1
patient reported 2 cases of bleeding from suture perfo-
ration. It is important to note that as many as one
third of the patients in this study needed to restart acid
suppressive therapy, mostly with PPIs.
17
In summary, only data from small, uncontrolled
trials in patients with nonerosive disease or mild
esophagitis are available for the endoscopic methods of
treating GERD. A number of complications ranging
from fever and chest/abdominal pain to bleeding and
even aspiration and death have been reported (Table
3).
18
Some of these complications are undoubtedly
related to the learning curve for endoscopists perform-
ing these procedures that affects patient outcomes.
Thus, the use of endoscopic therapies should be con-
fined to clinical trials at centers with an appropriate
level of expertise. In so doing, we can be confident that
our patients best interests are being served.
CONCLUSION
Long-term PPI treatment has been proven safe and
effective for GERD patients. Surgery should be con-
sidered only after a positive diagnosis of GERD has
been established and after carefully considering the
risk-benefit ratio in the individual patient. It should be
noted that many GERD sufferers still require medica-
tion postoperatively. Endoscopic treatment still has
not been adequately studied and, therefore, its appli-
cation in medical practice today may be premature.
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