The Clinical Management of Gastroesophageal Reflux

Disease

ABSTRACT: The management of gastroesophageal reflux disease (GERD) is vital for

maintaining patients' quality of life and reducing the risk of complications. Risk factors for
GERD include obesity, family history, alcohol consumption, respiratory disease, reflux chest
pain, particular medications, and certain foods. Practice guidelines emphasize lifestyle
modifications and acid suppression. The three major types of medications utilized for acid
suppression are antacids, histamine2-receptor antagonists, and proton pump inhibitors. The
drug choice depends upon patient presentation. Goals of treatment include symptom
alleviation, prevention of complications, mucosal healing, and reduced disease and symptom
frequency. Pharmacists play an important role in identifying appropriate OTC agents for
treatment, recognizing alarm symptoms, and advising patients who need more care to
immediately seek medical attention.

Gastroesophageal reflux disease (GERD) develops when the reflux of stomach contents
causes symptoms that are troublesome.1 It is the most commonly occurring gastrointestinal
(GI) diagnosis during outpatient visits.2 Episodic heartburn is not considered under this
definition of GERD, since it is not painful or recurrent enough to severely influence quality of
life.3

The prevalence of GERD is estimated to range from 10% to 20% in the Western world, with a
lesser prevalence in Asia. A recent update revealed that GERD is geographically widespread
and that its prevalence is increasing.4 Only East Asia continues to show rates of less than
10%.5 The exact prevalence and incidence are challenging to determine, since patients do not
always seek treatment and there is no universal definition for diagnosis. 6

There is no significant association between GERD and gender, except during pregnancy and
in the development of Barrett's esophagus (BE). 4,6,7 BE, which occurs predominantly in adult
white males, is more prevalent after age 50 years. 4 A major area of concern is the increasing
disease burden of esophageal adenocarcinoma, since there has been an upsurge in incidence
by a factor of 2 to 6 in the last 20 years.2

Recently, updated practice guidelines for the diagnosis and management of GERD were
published in the American Journal of Gastroenterology.4 Lifestyle modifications (LSM) and
pharmacotherapy remain the key components of therapy for GERD management. 4

Definition

Although there are multiple consensus definitions for GERD, the working definition utilized
by current guidelines on the disorder describe GERD as symptoms or complications that
result from the reflux of gastric contents into the esophagus or beyond, into the oral cavity or
lung.4 Because heartburn is one of the most common and typical symptoms of GERD, it is
important to distinguish it from GERD itself, which develops when reflux causes troublesome
symptoms and/or complications.3 By this definition, as previously discussed, episodic
heartburn would not be considered GERD unless the patient found his or her symptoms to be
troublesome or if there were complications. Complications of GERD include esophagitis,
esophageal stricture, BE, and adenocarcinoma.

Pathophysiology

The pathophysiology of GERD is a complicated cyclical process, and determining the

primary etiology is challenging. One of the prevailing etiologies proposed for GERD is the
failure of the lower esophageal sphincter (LES) to maintain adequate pressure (i.e., function
to keep gastric contents in the stomach).6 LES relaxation has been associated with certain
medications, foods, and spontaneous transient causes. 6 Also thought to contribute to reflux are
atony of the LES and transient increases in intra-abdominal pressure. Prolonged esophageal
clearance has been associated with reflux, especially in patients with impaired peristalsis or
reduced salivation.8 Delayed gastric emptying, acidic composition of the refluxate, and poor
esophageal mucosal resistance all have been found to contribute to GERD. 6 Many of the
therapeutic options for GERD target these proposed mechanisms.

Symptoms and Complications

Although heartburn, hypersalivation, and regurgitation are considered the typical reflux
symptoms of GERD, many other symptoms have been associated with the disorder. Atypical
symptoms such as nausea, bloating, chest pain, and belching may be indicative of GERD;
however, because these symptoms may overlap with those of other conditions, other diseases
must be ruled out.4 Reflux chest pain, an atypical symptom of GERD, may also be associated
with cardiac causes; it is recommended that patients seek medical care to rule out cardiac
causes before the symptom can be attributed to GERD. 4 Several symptoms, called alarm
symptoms, may be associated with GERD and warrant a referral for further diagnostic
evaluation to differentiate other diseases as the cause. An esophagogastroduodenoscopy
(EGD) may indicate complications of GERD or other GI disorders, such as peptic ulcer
disease.6 Alarm symptoms include dysphagia, odynophagia, unintentional weight loss, blood
in the stool, and persistent vomiting (TABLE 1).6

The complications of GERD, such as esophagitis and BE, are classified as syndromes with
esophageal injury. Extraesophageal symptoms—cough, laryngitis, asthma, and dental
erosions—also have been associated with reflux. 3 Other extraesophageal symptoms, such as
sinusitis and recurrent otitis media, have been proposed; however, there is not significant
evidence to support a relationship.3
Risk Factors

Knowledge of the many factors that can increase the risk of developing GERD can help the
pharmacist make nonpharmacologic recommendations to patients experiencing GERD
symptoms. Obesity, smoking, and alcohol consumption increase the risk of GERD. Pregnancy
and respiratory diseases also put patients at risk for GERD. Food and medications are some of
the most common risk factors for GERD. High-fat foods, chocolate, garlic, peppermint, and
caffeine can potentially reduce LES pressure, making it easier for reflux to make its way into
the esophagus. Spicy foods, colas, red wine, and tomato-based foods can cause direct
irritation to the GI mucosa, which may lead to symptoms of GERD. Medications such as
anticholinergics, nitrates, dihydropyridine calcium channel blockers, nonsteroidal anti-
inflammatory drugs, and tetracycline also are risk factors for GERD (TABLE 2).6

Diagnosis

Although several tools and tests are available to aid in the diagnosis of GERD and its
potential complications, a non-invasive diagnosis of GERD can be challenging. For patients
with typical heartburn and regurgitation symptoms, an empiric trial of a proton pump
inhibitor (PPI) is recommended. If the patient responds to therapy, a presumptive diagnosis is
made. A patient who presents with significant chest pain must first have cardiac causes ruled
out before any additional diagnosis can be made. An EGD should be performed to visualize
potential complications in patients who have alarm symptoms of GERD or are at high risk for
complications. Males who are overweight, are older than 50 years, and have chronic GERD
symptoms are considered to be at high risk. Barium radiograph, oesophageal biopsy, and
oesophageal manometry should not be used to diagnose GERD, although oesophageal
manometry may be useful for preoperative evaluation in patients who may be candidates for
antireflux surgery. Ambulatory oesophageal reflux monitoring, which can be done via either
telemetry capsule or transnasal catheter, can be useful for symptoms associated with reflux;
however, it is recommended only for preoperative evaluation of nonerosive disease, refractory
GERD symptoms, and situations in which the diagnosis of GERD is in question. 4
Management

Medication therapy for GERD includes antacids, histamine 2-receptor antagonists (H2RAs),
PPIs, and prokinetic (promotility) agents.9 For patients who are unsuccessful with LSM, the
best treatment options include antacids, H2RAs, and PPIs.4 Pharmacologic treatment for
GERD is divided into non-prescription-strength and prescription-strength therapy. Antacids,
H2RAs, and some PPIs are available as OTC products. Prokinetic agents, H 2RAs, and PPIs are
available by prescription.

The goals of GERD treatment are to reduce or eliminate symptoms, lessen the frequency and
duration of reflux, induce healing of any damaged mucosa, and prevent complications. The
approach generally depends upon the patient's current presentation (i.e., frequency of
symptoms, complications, and presence of esophagitis). In the past, a step-up approach
involving 1) LSM, 2) non-prescription-strength pharmacologic therapy, and 3) prescription-
strength pharmacologic therapy was used. Current treatment for GERD should be individually
focused.6

Treatment Overview

Acid-suppression therapy with PPIs and H2RAs is the mainstay of GERD treatment.
Nonprescription therapy is appropriate for patients with mild-to-intermediate symptoms (<2
episodes/week). Patients presenting with moderate-to-severe symptoms (≥2 episodes/week;
severe symptoms impairing quality of life) should be initiated on PPI therapy (TABLE 3).6
PPIs are the drug of choice because they provide the most rapid relief of symptoms and
superior healing.10 Stepping down from PPI therapy to H2RA therapy is an acceptable option
in patients with nonerosive GERD symptoms. GERD symptoms lasting longer than 2 weeks
should be evaluated by the patient's primary care provider (PCP). 4,6

Combination therapy with acid-suppression and prokinetic agents does not improve GERD
symptoms and should not be employed. Adding an H2RA to a PPI regimen to relieve
nocturnal symptoms has been found effective; however, the efficacy declines with time owing
to tachyphylaxis caused by the H2RA.11 In determining appropriate therapy for GERD,
characteristics of several patient populations should be taken into account, including patients
presenting with atypical GERD symptoms, pediatric patients, elderly patients, and patients
with refractory GERD. These populations may require individualized dosing and treatment
schedules and more specific LSM (e.g., dietary adjustments, postural management, parental
reassurance [pediatric population]).6

Treatment Options

LSM: Recommendations for LSM should be tailored to the individual patient. It is imperative
for the pharmacist to discuss the benefits of LSM with patients experiencing GERD
symptoms. Many patients are noncompliant with LSM recommendations, and many who do
comply will eventually require acid-suppression therapy (TABLE 4).4,6

Antacids: Antacids neutralize gastric fluids to decrease pepsin activity and increase LES
pressure. They provide rapid, short-term relief from GERD symptoms, but cannot sustain acid
suppression overnight.9 Antacids, which are available OTC, are recommended to patients as a
rapid-acting option for the treatment of mild GERD symptoms. 9 Antacids are the most
beneficial treatment for short-term, occasional, postprandial GERD symptoms; however, they
have not been shown to promote healing of erosive esophagitis. They can be utilized in
combination with other acid-suppression therapy. Antacids are generally the most cost-
effective option for GERD symptoms. Antacids should not be used for more than 2 weeks
without PCP involvement.12 Patients requiring chronic use of antacids for GERD symptom
relief should be started on prescription-strength acid suppression therapy. TABLE 5 lists the
available antacid and alginic acid products and provides dosing information. 6,9,13,14
The different types of antacids have varying adverse events (AEs). AEs for aluminium-based
products include hypophosphatemia, bone demineralization, constipation, and aluminium
accumulation; diarrhea is an AE for magnesium products; and AEs for bismuth subsalicylate
products include GI upset, tinnitus, and Reye syndrome.15 Antacids interact with multiple
medications owing to 1) formation of insoluble complexes with other medications
(tetracycline, fluoroquinolones, azithromycin) and 2) alteration of medication absorption by
increasing gastric pH (ferrous sulfate, ketoconazole, itraconazole). 6

Prokinetic Agents: Prokinetic agents activate cholinergic or dopaminergic receptors to

increase LES pressure and gastric peristalsis. This helps treat delayed esophageal clearance in
patients with GERD.16 These agents have a slow onset of action and provide short-term relief
(4-8 hours).17 Prokinetic agents lack efficacy as acid-suppression therapy and have not been
shown to promote healing of esophagitis. Compared with H2RAs and PPIs alone, only modest
improvements are achieved by combining prokinetic agents with acid-suppression therapy.
Prokinetic agents are useful as an adjunct to acid-suppression therapy in patients with motility
defects. Prokinetic agents have undesirable AEs and have limited effectiveness in treating or
reducing GERD symptoms.

Metoclopramide, a dopamine antagonist, increases LES pressure and gastric emptying.

Although metoclopramide results in symptom improvement in some patients with GERD,
there is no clear role for its use in GERD treatment. 4 The use of metoclopramide has been
limited owing to tachyphylaxis and its AE profile. Metoclopramide can cause extrapyramidal
side effects (dystonia, akathisia, tardive dyskinesia), sedation, and irritability. 18 This agent
should not be used in Parkinson's disease or concomitantly with dopamine antagonists or
anticholinergic agents. Metoclopramide (Reglan) is typically dosed at 10 to 15 mg by mouth
four times per day.13,14

Cisapride has comparable efficacy to H 2RAs in treating mild GERD symptoms. It has caused
life-threatening arrhythmias and is no longer available in the United States, except through a
limited-access program from the manufacturer. Cisapride (Propulsid) is typically dosed at 10
to 20 mg by mouth four times per day.13,14 Prokinetic agents should not be used to treat GERD
without a diagnostic evaluation.4,6
H2RAs: H2RAs competitively inhibit histamine at H2 receptors of gastric parietal cells; this
inhibits gastric acid secretion and volume and increases gastric pH. H 2RAs that are available
both OTC and by prescription include cimetidine, famotidine, nizatidine, and ranitidine
(TABLE 6).13,14 Compared with antacids, H2RAs have a slower onset of action, but a longer
duration of action. Patients with mild-to-moderate GERD symptoms can be treated effectively
with H2RAs in divided doses.10 H2RAs prevent GERD symptoms when taken prior to meals or
drinks that are known to cause irritation.15 They are not as effective as PPIs for healing
erosive esophagitis.19 Prolonged use of H2RAs is not recommended, owing to the
development of tolerance within 1 to 2 weeks.9 These agents should not be used for more than
2 weeks without involvement of a healthcare provider. 12

The effectiveness of H2RAs in the treatment of GERD is variable. Multiple factors play a role
in determining H2RA response, including disease severity, duration of therapy, and regimen.
Low doses or standard doses (twice per day) of H 2RAs are indicated for mildto-moderate
GERD. All H2RAs possess similar efficacy; when selecting an agent, the pharmacokinetics,
cost, and safety profile should be considered. In general, H2RAs are well tolerated.6

AEs associated with H2RA therapy include headaches, somnolence, fatigue, diarrhea,
constipation, and dizziness. Clinically significant drug interactions occur with cimetidine,
which is a moderate inhibitor of CYP1A2, CYP2C19, and CYP3A4. Medications that interact
with cimetidine include theophylline, warfarin, phenytoin, nifedipine, and propranolol. 6 For
all H2RA agents, a decline in renal function may require dosage adjustment or discontinuation
of therapy. H2RAs are contraindicated during pregnancy.6,13,14

PPIs: PPIs block gastric acid secretion by inhibiting gastric H+/K+ adenosine triphosphatase
in gastric parietal cells. PPIs that are available OTC include omeprazole (20 mg) and
lansoprazole (15 mg). Prescriptionstrength PPIs include dexlansoprazole, esomeprazole,
lansoprazole, omeprazole, pantoprazole, and rabeprazole (TABLE 7).5,13,14 PPIs are the drug
of choice for treating GERD symptoms. Their duration of action is longer, but the time to
onset is longer compared with prokinetic agents, antacids, and H 2RAs. It may take 1 to 4 days
to achieve full symptom relief.9,12
PPIs are more effective than H2RAs for treating moderate-to-severe GERD symptoms. In
patients with erosive esophagitis, PPI therapy has been associated with increased healing rates
and reduced relapse rates compared with H2RA therapy.20 In treating nonerosive GERD, PPI
therapy was superior to H2RA and prokinetic therapy for symptom relief. 21 The drug of choice
for symptom relief and healing erosive esophagitis is a PPI taken for 8 weeks. In patients with
partial response to PPI therapy, the regimen may be increased to twice daily, or changed to a
different PPI. A comparison of PPIs found no major differences between them.

Because PPIs degrade in acidic environments, they are produced as delayed-release capsules
or tablets. Lansoprazole, esomeprazole, and omeprazole are available as capsules containing
enteric-coated granules that can be mixed in applesauce or orange juice for pediatric patients
or patients unable to swallow capsules. Esomeprazole granules can be dispersed in water.
Lansoprazole is available as packets for oral suspension and as oral disintegrating tablets.
Pantoprazole and rabeprazole should not be cut, crushed, or chewed. Omeprazole also is
formulated as delayed-release tablets and in combination with sodium bicarbonate as
immediate-release capsules and oral suspension (Zegerid). Zegerid, the first PPI formulated as
an immediate-release product, should be taken on an empty stomach at least 1 hour prior to
meals.6

Dexlansoprazole, the newest PPI on the market, is a dual delayed-release tablet. The first
phase occurs 1 to 2 hours after the dose is taken; the second phase is 4 to 5 hours after the
dose is taken. Dexlansoprazole may be taken without regard to meals. 6 Delayed-release PPIs
should be taken 30 to 60 minutes before meals. PPI therapy should be initiated as once-daily
dosing before breakfast. Patients who fail to respond to once-daily dosing can implement
personalized regimens, altering dose timing and/or dosing twice daily (in patients with
nocturnal symptoms). Patients who do not respond to PPI therapy should be referred to their
healthcare provider.4

PPIs are generally well tolerated; however, there are precautions and AEs. Precautions for PPI
use include nonresponse, rebound gastritis, atrophic gastritis, Helicobacter pylori or
Clostridium difficile infection, and community-acquired pneumonia (CAP).4,9 Literature is
conflicting regarding whether PPIs are a risk factor for CAP. There is some evidence that
short-term, but not long-term, PPI use can increase the risk of CAP. 4 AEs associated with PPI
therapy include headache, nausea, insomnia, and dyspepsia (<2% of patients). Other potential
AEs include vitamin and mineral deficiencies, hip fractures, osteoporosis, and diarrhea. 18 If
AEs are present, switching the patient to a different PPI should be considered. PPIs are safe to
take during pregnancy when clinically indicated.

PPIs may play a role in the acquisition of C difficile infections during acid suppression, so
special care should be exercised in at-risk patients. 4 During acid suppression, the patient may
have reduced host defenses against ingested spores and bacteria, leading to an increased risk
of exposure.22,23

All PPIs decrease absorption of ketoconazole and itraconazole by elevating the gastric pH,
thus reducing absorption. All PPIs are metabolized to some extent by CYP2C19 and CYP3A4
enzymes. There has been concern about the concomitant use of clopidogrel with PPIs,
specifically omeprazole.24,25 Clopidogrel is a prodrug that is converted via the CYP2C19 and
CYP3A4 enzymes. Inhibition of the CYP2C19 enzyme by PPIs has been thought to decrease
the effectiveness of clopidogrel, potentially leading to cardiovascular AEs. However,
according to current recommendations, patients receiving clopidogrel therapy do not need
their PPI therapy changed, since evidence does not support an increased risk of cardiovascular
AEs.4

Maintenance Therapy

A large number of patients who have achieved GERD symptom relief will relapse once
therapy is discontinued.26 These patients should be considered for long-term maintenance
therapy. Maintenance therapy is intended to reduce symptoms and complications, thus
improving the patient's quality of life. In most cases, the therapy used to achieve initial relief
should not be decreased or changed to a less effective agent. Patients should be educated on
LSM and long-term maintenance therapy with standard dosing to prevent relapse. 10 H2RAs
can be used for maintenance in patients with mild GERD symptoms. PPIs are the drug of
choice in patients with moderate-to-severe GERD symptoms.

The long-term use of PPIs at higher doses than is standard is not indicated. Ranitidine 150 mg
twice daily is the only FDA-approved H2RA for maintenance therapy. H2RA therapy can be
added at bedtime to regimens with PPIs if nocturnal symptoms are present; however, the
addition of H2RA therapy has been associated with tachyphylaxis after several weeks.
Concerns about hip fractures and osteoporosis should not affect long-term PPI use, unless
other risk factors for hip fractures are present. 4

Role of the Pharmacist

The pharmacist can provide many services to the patient with GERD. The pharmacist is often
one of the first healthcare providers whom a patient contacts about GERD-like symptoms. As
the first line of defense, the pharmacist must be able to assess the patient's symptoms, the
frequency of symptoms, and any exacerbating issues. The pharmacist should then recommend
an OTC product to the patient, discuss prescription medications, or refer the patient to his or
her medical provider.27 Exclusion criteria for self-treatment include frequent heartburn (>3
months); heartburn and/or dyspepsia while taking recommended dosages of a nonprescription
H2RA or PPI; heartburn that continues after 2 weeks of treatment with a nonprescription
H2RA or PPI; worsening or severe symptoms; nocturnal heartburn; pregnancy or nursing; and
pediatric patients younger than 2 years (antacids), younger than 12 years (H 2RAs), or younger
than 18 years (PPIs).27

In addition to recommending medication therapy, the pharmacist can educate the patient in
depth about GERD, including conventional symptoms, alarm symptoms, LSM, and specific
details about the medication therapy (e.g., time of day to take drug, duration of therapy, AEs,
drug interactions, and adherence).

Another key role for the pharmacist is in advising patients and providers regarding
discontinuation of inappropriate PPI use. The pharmacist can take the lead in recommending
step-down therapy or discontinuing the PPI after 8 weeks of initial treatment of GERD
symptoms. The pharmacist should also educate patients and providers about possible long-
term AEs with continuous PPI use.

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