2441Peptic Ulcer Disease and Related Disorders CHAPTER 324

ulcer-related complications such as perforation. The mechanism

responsible for increased ulcer diathesis in smokers is unknown.

Theories have included altered gastric emptying, decreased proximal duodenal bicarbonate production, increased risk for H. pylori

infection, and cigarette-induced generation of noxious mucosal free

radicals. Genetic predisposition may play a role in ulcer development.

First-degree relatives of DU patients are three times as likely to develop

an ulcer; however, the potential role of H. pylori infection in contacts is

a major consideration. Increased frequencies of blood group O and of

the nonsecretor status have also been implicated as genetic risk factors

for peptic diathesis. However, H. pylori preferentially binds to group O

antigens. Additional genetic factors have been postulated to predispose

certain individuals to developing PUD and/or upper GI bleeding. Specifically, genes encoding the NSAID-metabolizing enzymes cytochrome

P450 2C9 and 2C8 (CYP2C9 and CYP2C8) are potential susceptibility

genes for NSAID-induced PUD, but unfortunately, the studies have not

been consistent in demonstrating this association. In a United Kingdom

study, the CYP2C19*17 gain-of-function polymorphism was associated

with PUD in a Caucasian cohort, irrespective of ulcer etiology. These

findings need to be confirmed in broader studies. Psychological stress

has been thought to contribute to PUD, but studies examining the role

of psychological factors in its pathogenesis have generated conflicting

results. Although PUD is associated with certain personality traits (neuroticism), these same traits are also present in individuals with nonulcer

dyspepsia (NUD) and other functional and organic disorders.

Diet has also been thought to play a role in peptic diseases. Certain

foods and beverages can cause dyspepsia, but no convincing studies

indicate an association between ulcer formation and a specific diet.

Specific chronic disorders have been shown to have a strong association with PUD: (1) advanced age, (2) chronic pulmonary disease,

(3) chronic renal failure, (4) cirrhosis, (5) nephrolithiasis, (6) α1

-antitrypsin deficiency, and (7) systemic mastocytosis. Disorders with a

possible association are (1) hyperparathyroidism, (2) coronary artery

disease, (3) polycythemia vera, (4) chronic pancreatitis, (5) former

alcohol use, (6) obesity, (7) African-American race, and (8) three or

more doctor visits in a year.

Multiple factors play a role in the pathogenesis of PUD. The

two predominant causes are H. pylori infection and NSAID ingestion.

PUD not related to H. pylori or NSAIDs is increasing. Other less common causes of PUD are shown in Table 324-1. These etiologic agents

should be considered as the incidence of H. pylori is decreasing. Independent of the inciting or injurious agent, peptic ulcers develop as a

result of an imbalance between mucosal protection/repair and aggressive factors. Gastric acid plays an important role in mucosal injury.

■ CLINICAL FEATURES

History Abdominal pain is common to many GI disorders, including DU and GU, but it has a poor predictive value for the presence

of either DU or GU. Approximately two-thirds of patients with

PUD do not have abdominal pain, and up to 87% of patients with

NSAID-induced mucosal disease can present with a complication

(bleeding, perforation, and obstruction) without antecedent symptoms. Despite this poor correlation, a careful history and physical

examination are essential components of the approach to a patient

suspected of having peptic ulcers.

Epigastric pain described as a burning or gnawing discomfort can

be present in both DU and GU. The discomfort is also described as an

ill-defined, aching sensation or as hunger pain. The typical pain pattern

in DU occurs 90 min to 3 h after a meal and is frequently relieved by

antacids or food. Pain that awakes the patient from sleep (between

midnight and 3 a.m.) is the most discriminating symptom, with twothirds of DU patients describing this complaint. Unfortunately, this

symptom is also present in one-third of patients with NUD (see below).

Elderly patients are less likely to have abdominal pain as a manifestation of PUD and may instead present with a complication such as

ulcer bleeding or perforation. The pain pattern in GU patients may be

different from that in DU patients, where discomfort may actually be

precipitated by food. Nausea and weight loss occur more commonly in

GU patients. Endoscopy detects ulcers in <30% of patients who have

dyspepsia.

The mechanism for development of abdominal pain in ulcer patients

is unknown. Several possible explanations include acid-induced activation of chemical receptors in the duodenum, enhanced duodenal

sensitivity to bile acids and pepsin, and altered gastroduodenal

motility.

Variation in the intensity or distribution of the abdominal pain,

as well as the onset of associated symptoms such as nausea and/or

vomiting, may be indicative of an ulcer complication. Dyspepsia that

becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (pancreas). Sudden

onset of severe, generalized abdominal pain may indicate perforation.

Pain worsening with meals, nausea, and vomiting of undigested food

suggest gastric outlet obstruction. Tarry stools or coffee-ground emesis

indicate bleeding.

Physical Examination Epigastric tenderness is the most frequent

finding in patients with GU or DU. Pain may be found to the right of

the midline in 20% of patients. Unfortunately, the predictive value of

this finding is low. Physical examination is critically important for discovering evidence of ulcer complication. Tachycardia and orthostasis

suggest dehydration secondary to vomiting or active GI blood loss. A

severely tender, board-like abdomen suggests a perforation. Presence

of a succussion splash indicates retained fluid in the stomach, suggesting gastric outlet obstruction.

PUD-Related Complications

GASTROINTESTINAL BLEEDING GI bleeding is the most common

complication observed in PUD. Bleeding is estimated to occur in

19.4–57 per 100,000 individuals in a general population or in ~15%

of patients. Bleeding and complications of ulcer disease occur more

often in individuals >60 years of age. The 30-day mortality rate is as

high as 2.5–10%. The higher incidence in the elderly is likely due to

the increased use of NSAIDs in this group. In addition, up to 80% of

the mortality in PUD-related bleeding is due to nonbleeding causes

such as multiorgan failure (24%), pulmonary complications (24%), and

malignancy (34%).

TABLE 324-1 Causes of Ulcers Not Caused by Helicobacter pylori

and NSAIDs

Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease

Infection

Cytomegalovirus

Herpes simplex virus

Helicobacter heilmannii

Drug/Toxin

Bisphosphonates

Chemotherapy

Clopidogrel

Crack cocaine

Glucocorticoids (when combined with NSAIDs)

Mycophenolate mofetil

Potassium chloride

Miscellaneous

Basophilia in myeloproliferative disease

Duodenal obstruction (e.g., annular pancreas)

Infiltrating disease

Ischemia

Radiation therapy

Eosinophilic infiltration

Sarcoidosis

Crohn’s disease

Idiopathic hypersecretory state

Abbreviations: Hp, H. pylori; NSAIDs, nonsteroidal anti-inflammatory drugs.

2442 PART 10 Disorders of the Gastrointestinal System

Greater than 50% of patients with ulcer-related hemorrhage bleed

without any preceding warning signs or symptoms.

PERFORATION The second most common ulcer-related complication

is perforation, being reported in as many as 6–7% of PUD patients

with an estimated 30-day mortality of >20%. Acute abdominal pain,

tachycardia, and abdominal rigidity compose the classic triad associated with this complication. It is essential to remember that elderly

patients or individuals who are immunosuppressed may not have this

classic presentation. As in the case of bleeding, the incidence of perforation in the elderly appears to be increasing secondary to increased

use of NSAIDs. Perforation of DUs has become less common in light

of the increased rates of H. pylori eradication, with NSAID-induced

GUs leading to perforation occurring more commonly. Penetration is

a form of perforation in which the ulcer bed tunnels into an adjacent

organ. DUs tend to penetrate posteriorly into the pancreas, leading to

pancreatitis, whereas GUs tend to penetrate into the left hepatic lobe.

Gastrocolic fistulas associated with GUs have also been described.

Mortality for this complication can be >20% within 30 days.

GASTRIC OUTLET OBSTRUCTION Gastric outlet obstruction is the

least common ulcer-related complication, occurring in 1–2% of

patients. A patient may have relative obstruction secondary to ulcerrelated inflammation and edema in the peripyloric and duodenal region.

This process often resolves with ulcer healing. A fixed, mechanical

obstruction secondary to scar formation in the peripyloric areas is also

possible. The latter requires endoscopic (balloon dilation with or without placement of a biodegradable stent) or surgical intervention with

a stricturoplasty or gastrojejunostomy. Signs and symptoms relative to

mechanical obstruction may develop insidiously. New onset of early

satiety, nausea, vomiting, increase of postprandial abdominal pain, and

weight loss should make gastric outlet obstruction a possible diagnosis.

Differential Diagnosis The list of GI and non-GI disorders that

can mimic ulceration of the stomach or duodenum is quite extensive.

The most commonly encountered diagnosis among patients seen for

upper abdominal discomfort is functional dyspepsia (FD) or essential

dyspepsia, which refers to a group of heterogeneous disorders typified

by upper abdominal pain without the presence of an ulcer. The symptoms can range from postprandial fullness and early satiety to epigastric burning pain. The dichotomy of this symptom complex has led to

the identification of two subcategories of FD including postprandial

distress syndrome (PDS) and epigastric pain syndrome (EPS). Dyspepsia has been reported to occur in up to 30% of the U.S. population. Up

to 80% of patients seeking medical care for dyspepsia have a negative

diagnostic evaluation. The etiology of FD is not established, but recent

studies suggest that postinfectious states, certain foods, and H. pylori

infection may contribute to the pathogenesis of this common disorder.

Several additional disease processes that may present with “ulcerlike” symptoms include proximal GI tumors, gastroesophageal reflux,

vascular disease, pancreaticobiliary disease (biliary colic, chronic pancreatitis), and gastroduodenal Crohn’s disease.

Diagnostic Evaluation In view of the poor predictive value of

abdominal pain for the presence of a gastroduodenal ulcer and the

multiple disease processes that can mimic this disease, the clinician

is often confronted with having to establish the presence of an ulcer.

Documentation of an ulcer requires either a radiographic (barium

study, rarely done in today’s environment) or an endoscopic procedure.

However, a large percentage of patients with symptoms suggestive of an

ulcer have NUD; testing for H. pylori and antibiotic therapy (see below)

are appropriate for individuals who are otherwise healthy and <45 years

of age, before embarking on a diagnostic evaluation (Chap. 45).

Barium studies of the proximal GI tract are rarely used as a first test

for documenting an ulcer. The sensitivity of older single-contrast barium meals for detecting a DU is as high as 80%, with a double-contrast

study providing detection rates as high as 90%. Sensitivity for detection

is decreased in small ulcers (<0.5 cm), with presence of previous scarring, or in postoperative patients. A DU appears as a well-demarcated

crater, most often seen in the bulb (Fig. 324-10A). A GU may represent

benign or malignant disease. Typically, a benign GU also appears as a

discrete crater with radiating mucosal folds originating from the ulcer

margin (Fig. 324-10B). Ulcers >3 cm in size or those associated with

a mass are more often malignant. Unfortunately, up to 8% of GUs that

appear to be benign by radiographic appearance are malignant by

endoscopy or surgery. Radiographic studies that show a GU must be

followed by endoscopy and biopsy.

Endoscopy provides the most sensitive and specific approach for

examining the upper GI tract (Fig. 324-11). In addition to permitting

direct visualization of the mucosa, endoscopy facilitates photographic

documentation of a mucosal defect and tissue biopsy to rule out

malignancy (GU) or H. pylori. Endoscopic examination is particularly helpful in identifying lesions too small to detect by radiographic

examination, for evaluation of atypical radiographic abnormalities, or

to determine if an ulcer is a source of blood loss.

Although the methods for diagnosing H. pylori are outlined in

Chap. 163, a brief summary will be included here (Table 324-2).

Several biopsy urease tests have been developed (PyloriTek, CLOtest,

Hpfast, Pronto Dry) that have a sensitivity and specificity of >90–95%.

Several noninvasive methods for detecting this organism have been

developed. Three types of studies routinely used include serologic testing, the 13C- or 14C-urea breath test, and the fecal H. pylori (Hp) antigen

test (monoclonal antibody test). A urinary Hp antigen test and a home

breath test appear promising.

A B

FIGURE 324-10 Barium study demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.

2443Peptic Ulcer Disease and Related Disorders CHAPTER 324

Occasionally, specialized testing such as serum gastrin and gastric

acid analysis may be needed in individuals with complicated or refractory PUD (see “Zollinger-Ellison Syndrome,” below). Screening for

aspirin or NSAIDs (blood or urine) may also be necessary in refractory

H. pylori–negative PUD patients.

TREATMENT

Peptic Ulcer Disease

Before the discovery of H. pylori, the therapy of PUD was centered

on the old dictum by Schwartz of “no acid, no ulcer.” Although acid

secretion is still important in the pathogenesis of PUD, eradication

of H. pylori and therapy/prevention of NSAID-induced disease is

the mainstay of treatment. A summary of commonly used drugs for

treatment of acid peptic disorders is shown in Table 324-3.

ACID-NEUTRALIZING/INHIBITORY DRUGS

Antacids Before we understood the important role of histamine

in stimulating parietal cell activity, neutralization of secreted acid

with antacids constituted the main form of therapy for peptic ulcers.

They are now rarely, if ever, used as the primary therapeutic agent

but instead are often used by patients for symptomatic relief of

dyspepsia. The most commonly used agents are mixtures of aluminum hydroxide and magnesium hydroxide. Aluminum hydroxide

can produce constipation and phosphate depletion; magnesium

hydroxide may cause loose stools. Many of the commonly used

antacids (e.g., Maalox, Mylanta) have a combination of both aluminum and magnesium hydroxide in order to avoid these side effects.

The magnesium-containing preparation should not be used in

chronic renal failure patients because of possible hypermagnesemia,

and aluminum may cause chronic neurotoxicity in these patients.

Calcium carbonate and sodium bicarbonate are potent antacids

with varying levels of potential problems. The long-term use of

calcium carbonate (converts to calcium chloride in the stomach)

can lead to milk-alkali syndrome (hypercalcemia and hyperphosphatemia with possible renal calcinosis and progression to renal

insufficiency). Sodium bicarbonate may induce systemic alkalosis.

H2

 Receptor Antagonists Four of these agents are presently available (cimetidine, ranitidine, famotidine, and nizatidine), and their

structures share homology with histamine. Although each has

different potency, all will significantly inhibit basal and stimulated

acid secretion to comparable levels when used at therapeutic doses.

Moreover, similar ulcer-healing rates are achieved with each drug

when used at the correct dosage. Presently, this class of drug is often

used for treatment of active ulcers (4–6 weeks) in combination with

antibiotics directed at eradicating H. pylori (see below).

Cimetidine was the first H2

 receptor antagonist used for the

treatment of acid peptic disorders. Cimetidine may have weak

A B

FIGURE 324-11 Endoscopy demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.

TABLE 324-2 Tests for Detection of Helicobacter pylori

TEST

SENSITIVITY/

SPECIFICITY, % COMMENTS

Invasive (Endoscopy/Biopsy Required)

Rapid urease 80–95/95–100 Simple, false negative with recent use of

PPIs, antibiotics, or bismuth compounds

Histology 80–90/>95 Requires pathology processing and

staining; provides histologic information

Culture —/— Time-consuming, expensive, dependent

on experience; allows determination of

antibiotic susceptibility

Noninvasive

Serology >80/>90 Inexpensive, convenient; not useful for

early follow-up

Urea breath test >90/>90 Simple, rapid; useful for early follow-up;

false negatives with recent therapy (see

rapid urease test); exposure to low-dose

radiation with 14C test

Stool antigen >90/>90 Inexpensive, convenient

Abbreviation: PPIs, proton pump inhibitors.

TABLE 324-3 Drugs Used in the Treatment of Peptic Ulcer Disease

DRUG TYPE/MECHANISM EXAMPLES DOSE

Acid-Suppressing Drugs

Antacids Mylanta, Maalox,

Tums, Gaviscon

100–140 meq/L 1 and 3 h

after meals and hs

H2

 receptor antagonists Cimetidine 400 mg bid

Ranitidine 300 mg hs

Famotidine 40 mg hs

Nizatidine 300 mg hs

Proton pump inhibitors Omeprazole 20 mg/d

Lansoprazole 30 mg/d

Rabeprazole 20 mg/d

Pantoprazole 40 mg/d

Esomeprazole 20 mg/d

Dexlansoprazole 30 mg/d

Mucosal Protective Agents

Sucralfate Sucralfate 1 g qid

Prostaglandin analogue Misoprostol 200 μg qid

 Bismuth-containing

compounds

Bismuth subsalicylate

(BSS)

See anti–H. pylori

regimens (Table 324-4)

Abbreviation: hs, at bedtime (hora somni).

2444 PART 10 Disorders of the Gastrointestinal System

antiandrogenic side effects resulting in reversible gynecomastia and

impotence, primarily in patients receiving high doses for prolonged

periods of time (months to years). In view of cimetidine’s ability

to inhibit cytochrome P450, careful monitoring of drugs such as

warfarin, phenytoin, and theophylline is indicated with long-term

usage. Other rare reversible adverse effects reported with cimetidine include confusion and elevated levels of serum aminotransferases, creatinine, and serum prolactin. Ranitidine, famotidine, and

nizatidine are more potent H2

 receptor antagonists than cimetidine.

Each can be used once a day at bedtime for ulcer prevention, which

was commonly done before the discovery of H. pylori and the development of proton pump inhibitors (PPIs). Patients may develop

tolerance to H2

 blockers, a rare event with PPIs (see below). Comparable nighttime dosing regimens are cimetidine 800 mg, ranitidine

300 mg, famotidine 40 mg, and nizatidine 300 mg.

Additional rare, reversible systemic toxicities reported with H2

receptor antagonists include pancytopenia, neutropenia, anemia, and

thrombocytopenia, with a prevalence rate varying from 0.01 to 0.2%.

Cimetidine and ranitidine (to a lesser extent) can bind to hepatic

cytochrome P450; famotidine and nizatidine do not. Ranitidine and

nizatidine were taken off of the market due to contamination of the

drug with N-nitrosodimethylamine (NDMA), a known carcinogen.

Proton Pump (H+

,K+

-ATPase) Inhibitors Omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole are substituted

benzimidazole derivatives that covalently bind and irreversibly

inhibit H+,K+-ATPase. Esomeprazole is the S-enantiomer of omeprazole, which is a racemic mixture of both S- and R-optical isomers. The R-isomer of lansoprazole, dexlansoprazole, is the most

recent PPI approved for clinical use. Its reported advantage is a

dual delayed-release system aimed at improving treatment of gastroesophageal reflux disease (GERD). These are the most potent

acid inhibitory agents available. Omeprazole and lansoprazole

are the PPIs that have been used for the longest time. Both are

acid-labile and are administered as enteric-coated granules in a

sustained-release capsule that dissolves within the small intestine at

a pH of 6. Lansoprazole is available in an orally disintegrating tablet

that can be taken with or without water, an advantage for individuals who have significant dysphagia. Absorption kinetics are similar

to the capsule. In addition, a lansoprazole-naproxen combination

preparation that has been made available is targeted at decreasing

NSAID-related GI injury (see below). Omeprazole is available as

non–enteric-coated granules mixed with sodium bicarbonate in a

powder form that can be administered orally or via gastric tube. The

sodium bicarbonate has two purposes: to protect the omeprazole

from acid degradation and to promote rapid gastric alkalinization

and subsequent proton pump activation, which facilitates rapid

action of the PPI. Pantoprazole and rabeprazole are available as

enteric-coated tablets. Pantoprazole is also available as a parenteral formulation for intravenous use. These agents are lipophilic

compounds; upon entering the parietal cell, they are protonated

and trapped within the acid environment of the tubulovesicular

and canalicular system. These agents potently inhibit all phases of

gastric acid secretion. Onset of action is rapid, with a maximum

acid inhibitory effect between 2 and 6 h after administration and

duration of inhibition lasting up to 72–96 h. With repeated daily

dosing, progressive acid inhibitory effects are observed, with basal

and secretagogue-stimulated acid production being inhibited by

>95% after 1 week of therapy. The half-life of PPIs is ~18 h; thus,

it can take between 2 and 5 days for gastric acid secretion to return

to normal levels once these drugs have been discontinued. Because

the pumps need to be activated for these agents to be effective, their

efficacy is maximized if they are administered before a meal (except

for the immediate-release formulation of omeprazole) (e.g., in the

morning before breakfast). Mild to moderate hypergastrinemia has

been observed in patients taking these drugs. Carcinoid tumors

developed in some animals given the drugs preclinically; however,

extensive experience has failed to demonstrate gastric carcinoid

tumor development in humans. Serum gastrin levels return to

normal levels within 1–2 weeks after drug cessation. Rebound gastric acid hypersecretion has been described in H. pylori–negative

individuals after discontinuation of PPIs. It occurs even after relatively short-term usage (2 months) and may last for up to 2 months

after the PPI has been discontinued. The mechanism involves

gastrin-induced hyperplasia and hypertrophy of histamine-secreting

ECL cells. The clinical relevance of this observation is that individuals may have worsening symptoms of GERD or dyspepsia upon

stopping the PPI. Gradual tapering of the PPI and switching to an

H2

 receptor antagonist may prevent this from occurring. H. pylori–

induced inflammation and concomitant decrease in acid production

may explain why this does not occur in H. pylori–positive patients.

IF production is also inhibited, but vitamin B12 deficiency anemia is

uncommon, probably because of the large stores of the vitamin. As

with any agent that leads to significant hypochlorhydria, PPIs may

interfere with absorption of drugs such as ketoconazole, ampicillin,

iron, and digoxin. Hepatic cytochrome P450 can be inhibited by the

earlier PPIs (omeprazole, lansoprazole). Rabeprazole, pantoprazole,

and esomeprazole do not appear to interact significantly with drugs

metabolized by the cytochrome P450 system. The overall clinical

significance of this observation is not definitely established. Caution

should be taken when using theophylline, warfarin, diazepam, atazanavir, and phenytoin concomitantly with PPIs.

The list of potential side effects with long-term PPI use has

steadily grown over the years. These agents are commonly used

since several formulations have become available as over-thecounter medications. Moreover, up to 70% of current prescriptions

for long-term PPIs may be unwarranted and between 35 and 60% of

in-hospital use of PPIs may be inappropriate. Interpretation of the

multiple studies should take into consideration that the vast majority were retrospective observational studies in which confounding

factors could not be accounted for entirely.

Long-term acid suppression, especially with PPIs, has been associated with a higher incidence of community-acquired pneumonia

as well as community- and hospital-acquired Clostridium difficile–

associated disease. A meta-analysis showed a 74% increased risk of

C. difficile infection and a 2.5-fold higher risk of reinfection as compared to nonusers. In light of these concerns, the FDA published a

safety alert regarding the association between C. difficile infection

and PPI use. Although the risk of spontaneous bacterial peritonitis

in cirrhotics was thought to be increased, the data here are less

supportive. The impact of PPI-induced changes in the host microbiome is postulated to play a role in the increased risk of infection,

but this theory needs to be confirmed. These observations require

confirmation but should alert the practitioner to take caution when

recommending these agents for long-term use, especially in elderly

patients at risk for developing pneumonia or C. difficile infection.

Diarrhea is also associated with PPI use, which in some cases has

been associated with the development of collagenous colitis (hazard ratio of 4.5), particularly with lansoprazole. The mechanism

for PPI-induced collagenous colitis is unclear, but in vitro studies

demonstrate that PPIs may induce collagen gene expression. The

colitis usually resolves with cessation of the PPI.

A population-based study revealed that long-term use of PPIs was

associated with the development of hip fractures in older women.

The absolute risk of fracture remained low and may be zero despite

an observed increase associated with the dose and duration of acid

suppression. The mechanism for this observation is not clear, and

this finding must be confirmed before making broad recommendations regarding the discontinuation of these agents in patients who

benefit from them. Long-term use of PPIs has also been implicated

in the development of iron, vitamin B12, and magnesium deficiency.

A meta-analysis of nine observational studies found a 40% increase

in hypomagnesemia in PPI users as compared to nonusers. One

approach to consider in patients needing to take PPIs long term is to

check a complete blood count looking for evidence of anemia due to

iron or vitamin B12 deficiency, vitamin B12 level, and a magnesium

level after 1–2 years of PPI use, but these recommendations are not

evidence based or recommended by expert opinion. PPIs may exert

2445Peptic Ulcer Disease and Related Disorders CHAPTER 324

a negative effect on the antiplatelet effect of clopidogrel. Although

the evidence is mixed and inconclusive, a small increase in mortality and readmission rate for coronary events was seen in patients

receiving a PPI while on clopidogrel in earlier studies. Subsequently,

three meta-analyses reported an inverse correlation between clopidogrel and PPI use; therefore, the influence of this drug interaction

on mortality is not clearly established. The mechanism involves the

competition of the PPI and clopidogrel with the same cytochrome

P450 (CYP2C19). Whether this is a class effect of PPIs is unclear;

there appears to be at least a theoretical advantage of pantoprazole

over the other PPIs, but this has not been confirmed. This drug

interaction is particularly relevant in light of the common use of

aspirin and clopidogrel for prevention of coronary events and the

efficacy of PPIs in preventing GI bleeding in these patients. The

FDA has made several recommendations while awaiting further

evidence to clarify the impact of PPI therapy on clopidogrel use.

Health care providers should continue to prescribe clopidogrel to

patients who require it and should reevaluate the need for starting

or continuing treatment with a PPI. From a practical standpoint,

additional recommendations to consider include the following:

Patients taking clopidogrel with aspirin, especially with other GI

risk factors for bleeding, should receive GI protective therapy.

Although high-dose H2

 blockers have been considered an option,

these do not appear to be as effective as PPIs. If PPIs are to be given,

some have recommended that there be a 12-h separation between

administration of the PPI and clopidogrel to minimize competition

of the two agents with the involved cytochrome P450. One option

is to give the PPI 30 min before breakfast and the clopidogrel at

bedtime. Insufficient data are available to firmly recommend one

PPI over another. Additional concerning side effects with long-term

PPI use include increased cardiac risks independent of clopidogrel

use, dementia, and acute and chronic kidney injury. Again, the data

are often retrospective and confounding variables were not consistently eliminated, thus making it difficult to establish a definitive

association between PPIs and the toxicities outlined. A summary

of the side effects with the corresponding relative risks is shown

in Fig. 324–12. Ultimately, heightened awareness of inappropriate

long-term use of PPIs is paramount. Patients aged ≥65 years of age

have a higher risk for some of the long-term side effects of PPIs

highlighted above, in part due to the higher prevalence of concomitant chronic diseases. It is therefore essential to carefully select

individuals, especially among the elderly, who need long-term PPI

therapy and discontinue it in those individuals who do not need it.

Abrupt withdrawal of a PPI in a long-term user may result in a component of rebound hyperacidity; thus, this agent should be tapered

gradually over the course of 1–2 weeks with possible transition to

an H2

 blocker for a short period of time.

Development of novel acid inhibitory agents continues in an

attempt to primarily address the need for better agents to treat

Chronic

kidney disease

Acute kidney disease

Acute interstitial

nephritis

Bone fracture

Hypermagnesemia

C. difficile infection

Community-acquired

pneumonia

(2 studies)

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

5.00

5.50

6.00

6.50

Adjusted odds ratio (95% confidence interval)

Side effect

FIGURE 324-12. Evidence supporting the potential adverse effects of

proton pump inhibitor drugs. (Adapted from AJ Schoenfeld, D Grady:

Adverse effects associated with proton pump inhibitors. JAMA Intern

Med 176:172, 2016.)

GERD. For example, modified H2

 blockers with greater potency

and duration as well as novel PPIs with longer half-life and potency

are under study. For example, tenatoprazole is a PPI containing an

imidazopyridine ring instead of a benzimidazole ring, which promotes irreversible proton pump inhibition. This agent has a longer

half-life than the other PPIs and may be beneficial for inhibiting

nocturnal acid secretion, which has significant relevance in GERD.

Additional PPIs with longer half-life and combined with other

agents are being studied, but the details are beyond the scope of this

chapter. A second new class of agents is the potassium-competitive

acid pump antagonists (P-CAPs). These compounds inhibit gastric

acid secretion via potassium competitive binding of the H+,K+-ATPase. Revaprazan, vonoprazan and tegoprazan are agents approved

for use in Korea and Japan. Vonoprazan may be superior to PPIs

when combined with antibiotics for the treatment of H. pylori, and

this novel agent has been awarded Fast Track status by the FDA for

the treatment of H. pylori in combination with both amoxicillin and

clarithromycin and with amoxicillin alone.

CYTOPROTECTIVE AGENTS

Sucralfate Sucralfate is a complex sucrose salt in which the

hydroxyl groups have been substituted by aluminum hydroxide and

sulfate. This compound is insoluble in water and becomes a viscous

paste within the stomach and duodenum, binding primarily to sites

of active ulceration. Sucralfate may act by several mechanisms:

serving as a physicochemical barrier, promoting a trophic action

by binding growth factors such as EGF, enhancing prostaglandin synthesis, stimulating mucus and bicarbonate secretion, and

enhancing mucosal defense and repair. Toxicity from this drug

is rare, with constipation being most common (2–3%). It should

be avoided in patients with chronic renal insufficiency to prevent

aluminum-induced neurotoxicity. Hypophosphatemia and gastric

bezoar formation have also been reported rarely. Standard dosing

of sucralfate is 1 g qid.

Bismuth-Containing Preparations Sir William Osler considered

bismuth-containing compounds the drug of choice for treating

PUD. The resurgence in the use of these agents is due to their effect

against H. pylori. Colloidal bismuth subcitrate (CBS) and bismuth

subsalicylate (BSS; Pepto-Bismol) are the most widely used preparations. The mechanism by which these agents induce ulcer healing

is unclear. Adverse effects with short-term use include black stools,

constipation, and darkening of the tongue. Long-term use with high

doses, especially with the avidly absorbed CBS, may lead to neurotoxicity. These compounds are commonly used as one of the agents

in an anti–H. pylori regimen (see below).

Prostaglandin Analogues In view of their central role in maintaining mucosal integrity and repair, stable prostaglandin analogues

were developed for the treatment of PUD. The mechanism by which

this rapidly absorbed drug provides its therapeutic effect is through

enhancement of mucosal defense and repair. The most common

toxicity noted with this drug is diarrhea (10–30% incidence).

Other major toxicities include uterine bleeding and contractions;

misoprostol is contraindicated in women who may be pregnant,

and women of childbearing age must be made clearly aware of this

potential drug toxicity. The standard therapeutic dose is 200 μg qid.

Miscellaneous Drugs A number of drugs including anticholinergic agents and tricyclic antidepressants were used for treating acid

peptic disorders, but in light of their toxicity and the development

of potent antisecretory agents, these are rarely, if ever, used today.

Newer agents such as teprenone, an acyclic polyisoprenoid compound used as a gastric mucosal protector that is employed to treat

gastritis and GUs outside of the United States; plant-based therapies; and CCK2 receptor antagonists are intriguing therapies but

require further evaluation.

THERAPY OF H. PYLORI

The physician’s goal in treating PUD is to provide relief of symptoms (pain or dyspepsia), promote ulcer healing, and ultimately

2446 PART 10 Disorders of the Gastrointestinal System

prevent ulcer recurrence and complications. The greatest influence

of understanding the role of H. pylori in peptic disease has been the

ability to prevent recurrence. Documented eradication of H. pylori

in patients with PUD is associated with a dramatic decrease in ulcer

recurrence to <10–20% as compared to 59% in GU patients and

67% in DU patients when the organism is not eliminated. Eradication of the organism may lead to diminished recurrent ulcer bleeding. The effect of its eradication on ulcer perforation is unclear.

Extensive effort has been made in determining who of the many

individuals with H. pylori infection should be treated. The common

conclusion arrived at by multiple consensus conferences around

the world is that H. pylori should be eradicated in patients with

documented PUD. This holds true independent of time of presentation (first episode or not), severity of symptoms, presence of

confounding factors such as ingestion of NSAIDs, or whether the

ulcer is in remission. Some have advocated treating patients with a

history of documented PUD who are found to be H. pylori positive

by stool antigen or breath testing. Between 60 and 90% of patients

with gastric MALT lymphoma experience complete remission of

the tumor in response to H. pylori eradication. The Maastricht IV/

Florence Consensus Report recommends a test-and-treat approach

for patients with uninvestigated dyspepsia if the local incidence

of H. pylori is >20%. The American College of Gastroenterology

(ACG) clinical guidelines (developed for North America) recommend that individuals aged <60 years with uninvestigated dyspepsia

should be tested and treated for H. pylori. In addition, recommendations from this consensus report and the ACG clinical guidelines

include testing and offering eradication of H. pylori in patients who

will be using NSAIDs (including low-dose aspirin) on a long-term

basis, especially if there is a prior history of PUD. These individuals

will require continued PPI treatment as well as eradication treatment, because eradication of the organism alone does not eliminate

the risk of gastroduodenal ulcers in patients already receiving

long-term NSAIDs. Treating patients with NUD to prevent gastric

cancer or patients with GERD requiring long-term acid suppression

remains controversial. Guidelines from the ACG suggest eradication of H. pylori in patients who have undergone resection of early

gastric cancer. The Maastricht IV/Florence Consensus Report also

evaluated H. pylori treatment in gastric cancer prevention and recommends that eradication should be considered in the following

situations: first-degree relatives of family members with gastric cancer; patients with previous gastric neoplasm treated by endoscopic

or subtotal resection; individuals with a risk of gastritis (severe pangastritis or body-predominant gastritis) or severe atrophy; patients

with gastric acid inhibition for >1 year; individuals with strong

environmental risk factors for gastric cancer (heavy smoking; high

exposure to dust, coal, quartz, or cement; and/or work in quarries);

and H. pylori–positive patients with a fear of gastric cancer. Finally,

the ACG clinical guidelines recommend testing and offering H.

pylori eradication to patients with unexplained iron deficiency anemia and idiopathic thrombocytopenic purpura. Despite this, concerns have been raised about the widespread use of antibiotics for

the therapy of all cases of H. pylori positivity, including the potential

for increased bacterial resistance rates, reported weight gain, and

alteration of the microbiome.

Multiple drugs have been evaluated in the therapy of H. pylori.

No single agent is effective in eradicating the organism. Combination therapy for 14 days provides the greatest efficacy, although

regimens based on sequential administration of antibiotics also

appear promising (see below). A shorter administration course

(7–10 days), although attractive, has not proved as successful as

the 14-day regimens. The agents used with the greatest frequency

include amoxicillin, metronidazole, tetracycline, clarithromycin,

and bismuth compounds.

Suggested treatment regimens for H. pylori are outlined in

Table 324-4. Choice of a particular regimen will be influenced by

several factors, including efficacy, patient tolerance, existing antibiotic resistance, prior antibiotic use, and cost of the drugs. The

aim for initial eradication rates should be 85–90%. Dual therapy

(PPI plus amoxicillin, PPI plus clarithromycin, ranitidine bismuth

citrate [Tritec] plus clarithromycin) is not recommended in view of

studies demonstrating eradication rates of <80–85%. The combination of bismuth, metronidazole, and tetracycline was the first triple

regimen found effective against H. pylori. The combination of two

antibiotics plus either a PPI, H2

 blocker, or bismuth compound has

comparable success rates. Addition of acid suppression assists in

providing early symptom relief and enhances bacterial eradication.

Triple therapy, although effective, has several drawbacks, including the potential for poor patient compliance and drug-induced side

effects. Compliance is being addressed by simplifying the regimens

so that patients can take the medications twice a day. Simpler (dual

therapy) and shorter regimens (7 and 10 days) are not as effective as

triple therapy for 14 days. Two anti–H. pylori regimens are available

in prepackaged formulation: Prevpac (lansoprazole, clarithromycin,

and amoxicillin) and Helidac (BSS, tetracycline, and metronidazole). The contents of the Prevpac are to be taken twice per day

for 14 days, whereas Helidac constituents are taken four times per

day with an antisecretory agent (PPI or H2

 blocker), also for at least

14 days. Clarithromycin-based triple therapy should be avoided in

settings where H. pylori resistance to this agent exceeds 15%.

Side effects have been reported in up to 20–30% of patients on

triple therapy. Bismuth may cause black stools, constipation, or

darkening of the tongue. The most feared complication with amoxicillin is pseudomembranous colitis, but this occurs in <1–2% of

patients. Amoxicillin can also lead to antibiotic-associated diarrhea,

nausea, vomiting, skin rash, and allergic reaction. Concomitant use

of probiotics may ameliorate some of the antibiotic side effects (see

below). Tetracycline has been reported to cause rashes and, very

rarely, hepatotoxicity and anaphylaxis.

One important concern with treating patients who may not

need therapy is the potential for development of antibioticresistant strains. The incidence and type of antibiotic-resistant

H. pylori strains vary worldwide. Strains resistant to metronidazole,

clarithromycin, amoxicillin, and tetracycline have been described,

with the latter two being uncommon. Antibiotic-resistant strains

are the most common cause for treatment failure in compliant

patients. Unfortunately, in vitro resistance does not predict outcome

in patients. Culture and sensitivity testing of H. pylori is not performed routinely. Although resistance to metronidazole has been

found in as many as 30% of isolates in North America and 80%

in developing countries, triple therapy is effective in eradicating

the organism in >50% of patients infected with a resistant strain.

Clarithromycin resistance is seen in 13–16% of individuals in the

United States, with resistance to amoxicillin being <1% and resistance to both metronidazole and clarithromycin in the 5% range.

Resistance to tetracycline and rifabutin (see below) is reported to

be <2% in the United States. In light of the paucity of H. pylori

antibiotic real-time resistance data, asking the patient about prior

antibiotic exposure should be included in the decision-making and

used as a surrogate for potential antibiotic resistance, especially

when it comes to prior macrolide use. Clarithromycin use should

be excluded in patients with prior macrolide usage. An approach to

antibiotic selection for H. pylori therapy has been recommended in

the ACG clinical guidelines (Fig. 324-13).

Failure of H. pylori eradication with triple therapy in a compliant

patient is usually due to infection with a resistant organism. A series

of salvage therapies for H. pylori are shown in Table 324-5. Quadruple therapy (Table 324-4), where clarithromycin is substituted for

metronidazole (or vice versa), should be the next step. The combination of PPI, amoxicillin, and rifabutin for 10 days has also been

used successfully (86% cure rate) in patients infected with resistant

strains. Additional regimens considered for second-line therapy

include levofloxacin-based triple therapy (levofloxacin, amoxicillin,

PPI) for 10 days and furazolidone-based triple therapy (furazolidone, amoxicillin, PPI) for 14 days. Unfortunately, there is no universally accepted treatment regimen recommended for patients in

whom two courses of antibiotics have failed. If eradication is still not

achieved in a compliant patient, then culture and sensitivity of the

2447Peptic Ulcer Disease and Related Disorders CHAPTER 324

organism should be considered. One challenge with this approach

is that culture and sensitivity testing is cumbersome and not widely

available; thus, H. pylori resistance data within specific communities are often not available. Non-culture-based approaches using

molecular markers to determine potential resistance through stool

testing are being developed but are not widely available. Additional

factors that may lower eradication rates include the patient’s country of origin (higher in Northeast Asia than other parts of Asia or

Europe) and cigarette smoking. In addition, meta-analysis suggests

that even the most effective regimens (quadruple therapy including

PPI, bismuth, tetracycline, and metronidazole and triple therapy

including PPI, clarithromycin, and amoxicillin) may have suboptimal eradication rates (<80%), thus demonstrating the need for the

development of more efficacious treatments.

In view of the observation that 15–25% of patients treated with

first-line therapy may still remain infected with the organism,

new approaches to treatment have been explored. One promising

approach is sequential therapy. Regimens examined consist of

5 days of amoxicillin and a PPI, followed by an additional 5 days

of PPI plus tinidazole and clarithromycin or levofloxacin. One

promising regimen that has the benefit of being shorter in duration,

easier to take, and less expensive is 5 days of concomitant therapy

(PPI twice daily, amoxicillin 1 g twice daily, levofloxacin 500 mg

twice daily, and tinidazole 500 mg twice daily). Initial studies

have demonstrated eradication rates of >90% with good patient

tolerance. Confirmation of these findings and applicability of this

approach in the United States are needed, although some experts

are recommending abandoning clarithromycin-based triple therapy

in the United States for the concomitant therapy or the alternative

sequential therapies highlighted above.

Innovative non-antibiotic-mediated approaches have been

explored in an effort to improve eradication rates of H. pylori.

Pretreatment of patients with N-acetylcysteine as a mucolytic agent

to destroy the H. pylori biofilm and therefore impair antibiotic

resistance has been examined, but more studies are needed to confirm the applicability of this approach. In vitro studies suggest that

certain probiotics like Lactobacillus or its metabolites can inhibit

H. pylori. Administration of probiotics has been attempted in several clinical studies in an effort to maximize antibiotic-mediated

eradication with varying results. Overall, it appears that the use of

certain probiotics, such as Lactobacillus spp., Saccharomyces spp.,

Bifidobacterium spp., and Bacillus clausii, did not alter eradication

rates but importantly decreased antibiotic-associated side effects

including nausea, dysgeusia, diarrhea, and abdominal discomfort/

pain, resulting in enhanced tolerability of H. pylori therapies.

Additional studies are needed to confirm the potential benefits

of probiotics in this setting. Statins, specifically atorvastatin, have

been used with some success as an adjunct to quadruple therapy in

patients with NUD.

Reinfection after successful eradication of H. pylori is rare in the

United States (<1% per year). If recurrent infection occurs within

the first 6 months after completing therapy, the most likely explanation is recrudescence as opposed to reinfection.

THERAPY OF NSAID-RELATED GASTRIC

OR DUODENAL INJURY

Medical intervention for NSAID-related mucosal injury includes

treatment of an active ulcer and primary prevention of future

injury. Recommendations for the treatment and primary prevention of NSAID-related mucosal injury are listed in Table 324-6.

TABLE 324-4 Recommended First-Line Therapies for H. pylori Infection

REGIMEN DRUGS (DOSES) DOSING FREQUENCY DURATION (DAYS) FDA APPROVAL

Clarithromycin triple PPI (standard or double dose) bid 14 Yesa

Clarithromycin (500 mg)

Amoxicillin (1 g) or metronidazole (500 mg tid)

Bismuth quadruple PPI (standard dose) bid 10–14 Nob

Bismuth subcitrate (120–300 mg) or subsalicylate (300 mg) qid

Tetracycline (500 mg) qid

Metronidazole (250–500 mg) qid (250 mg)

tid to qid (500 mg)

Concomitant PPI (standard dose) bid 10–14 No

Clarithromycin (500 mg)

Amoxicillin (1 g)

Nitroimidazole (500 mg)c

Sequential PPI (standard dose) bid 5–7 No

PPI, clarithromycin (500 mg) + nitroimidazole (500 mg)c bid 5–7

Hybrid PPI (standard dose) + amoxicillin (1 g) bid 7 No

PPI, amoxicillin, clarithromycin (500 mg), nitroimidazole (500 mg)c bid 7

Levofloxacin triple PPI (standard or double dose) + amoxicillin (1 g) bid 5–7 No

Levofloxacin (500 mg) qd

Amoxicillin (1 g) bid

Levofloxacin sequential PPI (standard or double dose) + amoxicillin (1 g) bid 5–7 No

PPI, amoxicillin, levofloxacin (500 mg qd), nitroimidazole (500 mg)c bid 5–7

LOAD Levofloxacin (250 mg) qd 7–10 No

PPI (double dose) qd

Nitazoxanide (500 mg) bid

Doxycycline (100 mg) qd

a

Several PPI, clarithromycin, and amoxicillin combinations have achieved FDA approval. The regimen of a PPI, clarithromycin, and metronidazole is not an FDA-approved

treatment regimen. b

The regimen of a PPI, bismuth, tetracycline, and metronidazole combined with a PPI for 10 days is an FDA-approved treatment regimen. c

Metronidazole

or tinidazole.

Abbreviations: bid, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; tid, three times daily; qd, once daily; qid, four times daily.

Source: Reproduced with permission from WD Chey et al: ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol 112:212, 2017.

2448 PART 10 Disorders of the Gastrointestinal System

Key Questions:

1. Is there a penicillin (PCN)

allergy?

2. Previous macrolide (MCL)

exposure for any reason?

*In regions where clarithromycin resistance is known

to be >15%, utilize recommendations for patients

with a history of macrolide exposure.

PCN allergy: No

MCL exposure: No

Recommended

treatments:

Bismuth quadruple

CONCOMITANT

Clarithromycin triple

With amoxicillin

Other options:

Sequential

HYBRID

Levofloxacin triple

Levofloxacin

sequential

LOAD?

PCN allergy: No

MCL exposure: Yes*

Recommended

treatments:

Bismuth quadruple

Levofloxacin triple

Levofloxacin

sequential

Other options:

Concomitant therapy?

Sequential therapy?

Hybrid therapy?

LOAD?

PCN allergy: Yes

MCL exposure: No

Recommended

treatments:

Clarithromycin

triple with

metronidazole

Bismuth quadruple

PCN allergy: Yes

MCL exposure: Yes*

Recommended

treatments:

Bismuth quadruple

FIGURE 324-13 Approach to selecting antibiotics for patients with H. pylori infection. LOAD, levofloxacin, omeprazole, nitazoxanide, and doxycycline. (Reproduced with

permission from WD Chey et al: ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol 112:212, 2017.)

TABLE 324-5 Salvage Therapies for H. pylori Infection

REGIMEN DRUGS (DOSES) DOSING FREQUENCY DURATION (DAYS) FDA APPROVAL

Bismuth quadruple PPI (standard dose) bid 14 Noa

Bismuth subcitrate (120–300 mg) or

subsalicylate (300 mg)

qid

Tetracycline (500 mg) qid

Metronidazole (500 mg) tid or qid

Levofloxacin triple PPI (standard dose) bid 14 No

Levofloxacin (500 mg) qd

Amoxicillin (1 g) bid

Concomitant PPI (standard dose) bid 10–14 No

Clarithromycin (500 mg) bid

Amoxicillin (1 g) bid

Nitroimidazole (500 mg) bid or tid

Rifabutin triple PPI (standard dose) bid 10 No

Rifabutin (300 mg) qd

Amoxicillin (1 g) bid

High-dose dual PPI (standard to double dose) tid or qid 14 No

Amoxicillin (1 g tid or 750 mg qid) tid or qid

a

PPI, bismuth, tetracycline, and metronidazole prescribed separately is not an FDA-approved treatment regimen. However, Pylera, a combination

product containing bismuth subcitrate, tetracycline, and metronidazole, combined with a PPI for 10 days is an FDA-approved treatment regimen.

Abbreviations: bid, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; tid, three times daily; qd, once daily; qid, four times daily.

Source: Reproduced with permission from WD Chey et al: ACG clinical guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol

112:212, 2017.

2449Peptic Ulcer Disease and Related Disorders CHAPTER 324

Ideally, the injurious agent should be stopped as the first step in the

therapy of an active NSAID-induced ulcer. If that is possible, then

treatment with one of the acid inhibitory agents (H2

 blockers, PPIs)

is indicated. Cessation of NSAIDs is not always possible because of

the patient’s severe underlying disease. Only PPIs can heal GUs or

DUs, independent of whether NSAIDs are discontinued.

The widespread use of NSAIDs has created some concern due to

the increasing likelihood of GI and CV side effects associated with

these agents. The approach to primary prevention has included

avoiding the agent, using the lowest possible dose of the agent for

the shortest period of time possible, using NSAIDs that are theoretically less injurious, using newer topical NSAID preparations, and/

or using concomitant medical therapy to prevent NSAID-induced

injury. Several nonselective NSAIDs that are associated with a lower

likelihood of GI and CV toxicity include naproxen and ibuprofen,

although the beneficial effect may be eliminated if higher dosages

of the agents are used. Primary prevention of NSAID-induced

ulceration can be accomplished by a PPI and, if not tolerated,

misoprostol (200 μg qid). High-dose H2

 blockers (famotidine 40 mg

bid) have also shown some promise in preventing endoscopically

documented ulcers, although PPIs are superior. The highly selective COX-2 inhibitors, celecoxib and rofecoxib, are 100 times more

selective inhibitors of COX-2 than standard NSAIDs, leading to

gastric or duodenal mucosal injury that is comparable to placebo;

their utilization led to an increase in CV events and withdrawal

from the market. Additional caution was engendered when the

CLASS study demonstrated that the advantage of celecoxib in

preventing GI complications was offset when low-dose aspirin

was used simultaneously. Therefore, gastric protection therapy is

required in individuals taking COX-2 inhibitors and aspirin prophylaxis. Finally, much of the work demonstrating the benefit of

COX-2 inhibitors and PPIs on GI injury has been performed in

individuals of average risk; it is unclear if the same level of benefit

will be achieved in high-risk patients. For example, concomitant use

of warfarin and a COX-2 inhibitor was associated with rates of GI

bleeding similar to those observed in patients taking nonselective

NSAIDs. A combination of factors, including withdrawal of the

majority of COX-2 inhibitors from the market, the observation

that low-dose aspirin appears to diminish the beneficial effect of

COX-2–selective inhibitors, and the growing use of aspirin for prophylaxis of CV events, has significantly altered the approach to gastric protective therapy during the use of NSAIDs. A set of guidelines

for the approach to the use of NSAIDs was published by the ACG

and is shown in Table 324-7. Individuals who are not at risk for CV

events, do not use aspirin, and are without risk for GI complications

can receive nonselective NSAIDs without gastric protection. In

those without CV risk factors but with a high potential risk (prior

GI bleeding or multiple GI risk factors) for NSAID-induced GI

toxicity, cautious use of a selective COX-2 inhibitor and co-therapy

with high-dose PPI or misoprostol are recommended. Individuals

at moderate GI risk without cardiac risk factors can be treated with

a COX-2 inhibitor alone or with a nonselective NSAID with PPI or

misoprostol. Individuals with CV risk factors, who require low-dose

aspirin and have low potential for NSAID-induced toxicity, should

be considered for a non-NSAID agent or use of a traditional NSAID

such as naproxen (lower CV side effects) in combination with

gastric protection, if warranted. Finally, individuals with CV and

GI risks who require aspirin must be considered for non-NSAID

therapy, but if that is not an option, then gastric protection with

any type of NSAID must be considered. Any patient, regardless

of risk status, who is being considered for long-term traditional

NSAID therapy should also be considered for H. pylori testing

and treatment if positive. Assuring the use of GI protective agents

with NSAIDs is difficult, even in high-risk patients. This is in part

due to underprescribing of the appropriate protective agent; other

times, the difficulty is related to patient compliance. The latter may

be due to patients forgetting to take multiple pills or preferring not

to take the extra pill, especially if they have no GI symptoms. Several NSAID gastroprotective-containing combination pills are now

commercially available, including double-dose famotidine with ibuprofen, diclofenac with misoprostol, and naproxen with esomeprazole. Although initial studies suggested improved compliance and a

cost advantage when taking these combination drugs, their clinical

benefit over the use of separate pills has not been established. One

additional concern with NSAID-induced GI complications is the

relatively low rate of primary care provider compliance with established guidelines outlining preventative measures. An intervention

including professional education, informatics to facilitate review,

and financial incentives for practices to review patients’ charts to

assess appropriateness showed a reduced rate of high-risk prescribing of antiplatelet medications and NSAIDs with a tendency toward

improved clinical outcomes. Efforts continue toward developing

safer NSAIDs, including topical NSAIDs, NSAID formulations that

are rapidly absorbed (diclofenac potassium powder mixed with a

buffering agent, Prosorb and SoluMatrix technology), NO-releasing

NSAIDs, hydrogen sulfide–releasing NSAIDs, dual COX/5-LOX

inhibitors, NSAID prodrugs, and agents that can effectively sequester unbound NSAIDs without interfering with their efficacy.

APPROACH AND THERAPY: SUMMARY

Controversy continues regarding the best approach to the patient who

presents with dyspepsia (Chap. 45). The discovery of H. pylori and its

role in pathogenesis of ulcers has added a new variable to the equation.

Previously, if a patient <50 years of age presented with dyspepsia and

without alarming signs or symptoms suggestive of an ulcer complication or malignancy, an empirical therapeutic trial with acid suppression

was commonly recommended. Although this approach is practiced by

some today, an approach presently gaining approval for the treatment

of patients with dyspepsia is outlined in Fig. 324-14. The referral to a

gastroenterologist is for the potential need of endoscopy and subsequent

evaluation and treatment if the endoscopy is negative.

Once an ulcer (GU or DU) is documented, the main issue at

stake is whether H. pylori or an NSAID is involved. With H. pylori

TABLE 324-6 Recommendations for Treatment of NSAID-Related

Mucosal Injury

CLINICAL SETTING RECOMMENDATION

Active ulcer

NSAID discontinued H2

 receptor antagonist or PPI

NSAID continued PPI

Prophylactic therapy Misoprostol

PPI

Selective COX-2 inhibitor

H. pylori infection Eradication if active ulcer present or there is a

past history of peptic ulcer disease

Abbreviations: COX-2, isoenzyme of cyclooxygenase; NSAID, nonsteroidal antiinflammatory drug; PPI, proton pump inhibitor.

TABLE 324-7 Guide to NSAID Therapy

NO/LOW NSAID

GI RISK NSAID GI RISK

No CV risk (no

aspirin)

Traditional NSAID Coxib or

Traditional NSAID + PPI or

misoprostol

Consider non-NSAID therapy

CV risk (consider

aspirin)

Traditional NSAID +

PPI or misoprostol

if GI risk warrants

gastroprotection

Consider non-NSAID

therapy

A gastroprotective agent must

be added if a traditional NSAID is

prescribed

Consider non-NSAID therapy

Abbreviations: CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal

anti-inflammatory drug; PPI, proton pump inhibitor.

Source: Republished with permission of MJH Life Sciences, LLC, from COX-2

inhibitor use after Vioxx: careful balance orend of the rope?, Fendrick AM,

10(11 Pt 1): 2004; permission conveyed through Copyright Clearance Center, Inc.