Beside H. pylori–related peptic ulcers, use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin is another major cause of peptic ulcer complications particularly among older adults.³ Co-therapy with antiulcer drugs and the replacement of conventional nonselective NSAIDs with NSAIDs selective for cyclooxygenase-2 (COX-2 selective NSAIDs) have become alternative treatments for patients who are at risk for peptic ulcer disease. Data suggest that COX-2 selective NSAIDs and some nonselective NSAIDs increase the risk of serious cardiothrombotic events. Prescribing NSAIDs therefore requires a careful assessment of individual patients’ gastrointestinal (GI) and cardiovascular risks.

As discussed in the preceding chapter, due to the declining prevalence of H. pylori infection, the proportion of patients with H. pylori–negative, NSAID-negative idiopathic ulcers is growing. In the United States, the reported proportion of H. pylori–negative, NSAID-negative idiopathic ulcers is between 20% and 30%.^4,⁵ It has been argued that as the incidence of H. pylori–related ulcers falls, a greater proportion of H. pylori–negative, NSAID-negative idiopathic ulcers will be seen.⁶ Of interest, a prospective cohort study has demonstrated a four-fold rise in the absolute incidence of idiopathic bleeding ulcers, and the risk of recurrent ulcer bleeding in these patients is high.⁷ Thus, long-term prophylaxis with antisecretory drugs for idiopathic bleeding ulcers is advisable (see later), although this recommendation is not evidence based.

ANTISECRETORY AND ACID-NEUTRALIZING AGENTS

Before the discovery of H. pylori as a causal factor in peptic ulcer disease, drugs designed to reduce gastric acidity were the mainstays of treatment. Antisecretory or antacid therapy is not routinely required for patients with uncomplicated H. pylori ulcers in whom the bacterium is successfully eradicated, but these classes of drugs do play an important role in promoting healing of large ulcers, preventing early recurrent bleeding after endoscopic therapy for bleeding ulcers, and reducing the risk of ulcer relapse associated with NSAIDs. Specific therapies for peptic ulcer are discussed in the following sections.

Antacids

Mechanisms of Action

When Peterson and coworkers ⁸ showed that a liquid antacid preparation of magnesium-aluminum hydroxide (approximately 1000 mmol HCl neutralizing capacity per day) was more effective than placebo for hastening the healing of duodenal ulcer, it was thought antacids promoted ulcer healing by neutralizing gastric acid. However, later studies showed that far smaller doses of antacids (neutralizing capacity 120 mmol HCl per day) had virtually identical efficacy for healing peptic ulcerations.⁹ The precise mechanisms by which antacids hasten the healing of peptic ulcerations are not clear. Although antacids have been shown to be superior to placebo in healing peptic ulcers, their efficacy in ulcer healing is limited. In one study, the healing rates for gastric ulcer after 6 weeks were 67% in the antacids group and 25% in the placebo group.⁹

Adverse Effects

For the magnesium-containing agents, the most common side effect is diarrhea. In contrast, antacids that contain aluminum hydroxide primarily, and those that contain calcium, may cause constipation. All antacids must be used with caution, if at all, in patients who have chronic kidney disease. In such patients, magnesium-containing agents can cause hypermagnesemia; the use of calcium carbonate can cause hypercalcemia and alkalosis and further renal impairment (milk-alkali syndrome), and aluminum hydroxide antacids can cause aluminum neurotoxicity.¹⁰

Histamine-2 Receptor Antagonists

Mechanisms of Action

Four histamine-2 (H₂) receptor antagonists are available—cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid). These compounds are competitive inhibitors of histamine-stimulated acid secretion, although famotidine appears to have some component of noncompetitive inhibition as well.¹¹ All four agents suppress basal acid output as well as acid output stimulated by meals (see Chapter 49).

Pharmacokinetics

The H₂ receptor antagonists are well absorbed after oral dosing, and their absorption is not affected by food. Peak blood levels are achieved within 1 to 3 hours after an oral dose. These drugs cross the blood-brain barrier and the placenta.^12,¹³ After oral administration, cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism, which reduces their bioavailability by 35% to 60%. In contrast, nizatidine does not undergo first-pass metabolism, and its bioavailability approaches 100% with oral dosing. When administered in the evening, the drugs are especially effective in suppressing nocturnal acid output.¹⁴

All four H₂ receptor antagonists are eliminated by a combination of renal excretion and hepatic metabolism. After intravenous administration, in contrast, all four agents are eliminated principally through renal excretion. For cimetidine and famotidine it is recommended that the doses be cut in half in patients whose creatinine clearance is 15 to 30 mL/minute. For nizatidine and ranitidine, the dose should be halved if the creatinine clearance is less than 50 mL/minute. Dialysis does not remove substantial amounts of the H₂ receptor antagonists, so dose adjustments for dialysis are not necessary. Liver failure has been found to prolong the half-life of cimetidine, but dose reductions are generally not needed for patients with hepatic failure unless it is accompanied by chronic kidney disease.¹¹

Tolerance to the antisecretory effects of H₂ receptor antagonists appears to develop quickly and frequently.¹⁵ The mechanisms that mediate tolerance to the antisecretory effects of H₂ receptor antagonists are not entirely clear.

Adverse Effects

The H₂ receptor antagonists are a remarkably safe and well-tolerated group of agents. The overall incidence of side effects is less than 4%, and serious side effects are decidedly uncommon. One meta-analysis of randomized clinical trials concluded that the overall rate of adverse effects reported for the H₂ blockers did not differ significantly from that for placebo.¹⁶ Nevertheless, a number of untoward effects have been described, primarily in anecdotal reports and uncontrolled series. Cimetidine has weak antiandrogenic activity that occasionally can cause gynecomastia and impotence.¹⁷ Myelosuppression is an uncommon, presumably idiosyncratic side effect of the H₂ receptor antagonists. In one large series of patients with bone marrow transplants, however, ranitidine was implicated as a possible cause of myelosuppression in 5%.¹⁸ The contribution of ranitidine to the bone marrow suppression in such patients is not clear, but pending further data, it seems prudent to avoid the use of H₂ receptor antagonists in bone marrow transplant recipients.

Drug Interactions

Both cimetidine and ranitidine bind to the hepatic cytochrome P-450 (CYP) mixed-function oxidase system, and this binding can inhibit the elimination of other drugs that are metabolized through the same system, including theophylline, phenytoin, lidocaine, quinidine, and warfarin.¹⁹ Famotidine and nizatidine have no significant avidity for the CYP system, and these agents do not appear to have any important drug interactions.

Proton Pump Inhibitors

Mechanisms of Action

The proton pump inhibitors (PPIs) are a class of drugs that decrease gastric acid secretion through inhibition of H⁺,K⁺-ATPase, the proton pump of the parietal cell (see Chapter 49). Five PPIs are used widely as antisecretory agents—omeprazole (Prilosec), esomeprazole (Nexium; the S optical isomer of omeprazole), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (Aciphex). These agents are prodrugs that must be activated by acid to inhibit the H⁺,K⁺-ATPase. However, PPIs as prodrugs are acid-labile compounds that must be protected from degradation by stomach acid after oral administration.²⁰

Pharmacokinetics

The PPIs are well absorbed after oral dosing. Absorption of the enteric-coated agents may be erratic, and peak serum concentrations are not achieved until 2 to 5 hours after oral administration. Although the plasma half-life of the PPIs is short (about 2 hours), the duration of acid inhibition is long (about 24 hours) as a result of covalent binding of the active metabolite to the H⁺,K⁺-ATPase.

All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, dose adjustments are not required even in patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the CYP isoenzymes involved in PPI metabolism, CYP2C19. Approximately 3% of white persons and 15% of Asians are deficient in CYP2C19. This polymorphism has been shown to substantially raise plasma levels of omeprazole, lansoprazole, and pantoprazole but not those of rabeprazole.^21,²²

As a result of their requirement for concentration and activation in acidic compartments, the PPIs bind predominantly to those proton pumps that are actively secreting acid. Thus, the efficacy of the PPIs for inhibiting acid secretion is limited if they are administered during the fasting state, when only approximately 5% of the stomach’s proton pumps are active. With meal stimulation, in contrast, 60% to 70% of the proton pumps actively secrete acid. Thus, the PPIs are most effective if they are administered immediately before meals. For once-daily dosing, it is recommended that the PPIs be taken immediately before breakfast.²³ Unlike H₂ receptor antagonists, tolerance to the antisecretory effects of PPI therapy has not been seen during short-term investigations.

Adverse Effects

The PPIs are a remarkably safe and well-tolerated group of agents. The most commonly reported side effects are headache and diarrhea, yet the rate at which patients experience these symptoms does not differ significantly from that for patients treated with placebo.²⁴

PPIs and other antisecretory agents cause hypergastrinemia by inhibiting gastric acid secretion (see Chapter 49). In addition to stimulating acid secretion, gastrin has been shown to have trophic effects on the GI enterochromaffin-like (ECL) cells. Female rats in which protracted hypergastrinemia has been induced by PPIs develop ECL cell hyperplasia and gastric carcinoid tumors.²⁵ However, there are no reports of gastric carcinoid tumors attributable to PPIs in humans. Even in patients with Zollinger-Ellison syndrome who have severe hypergastrinemia, carcinoid tumors are uncommon and occur predominantly in patients with multiple endocrine neoplasia type I (MEN-I).²⁶

Some data suggest that the long-term administration of PPIs to patients who are infected with H. pylori might accelerate the development of gastric atrophy.²⁷ However, these early observations have not been conformed by subsequent studies.²⁸ The U.S. Food and Drug Administration (FDA) advisory group concluded that the available data did not establish such an effect, and did not recommend routine testing for and treatment of H. pylori before initiation of PPI therapy.²⁹

Data from observational studies have found that PPIs increase the risk of osteoporosis-related fracture. The strength of the association increases with increasing duration and dose of PPI therapy.^30,³¹ The mechanisms underlying such an association are unknown.

Drug Interactions

The elevation of gastric pH induced by the PPIs can affect the absorption of a number of medications. However, this antisecretory action rarely has clinically important effects on drug pharmacokinetics, except when the PPIs are given with ketoconazole or digoxin.³² Ketoconazole requires stomach acid for absorption, and this drug may not be absorbed effectively after PPIs have inhibited gastric acid secretion. Conversely, an elevated gastric pH facilitates the absorption of digoxin, resulting in higher plasma levels of this agent. If a patient requires both PPI and antifungal therapy, it is recommended that an agent other than ketoconazole be chosen. For patients treated concomitantly with PPIs and digoxin, clinicians should consider monitoring plasma digoxin levels.

Because the PPIs are metabolized by the CYP system, there is potential for them to alter the metabolism of other drugs that are eliminated by CYP enzymes. Among the available PPIs, omeprazole appears to have the greatest potential for such drug interactions and has been shown to delay the clearance of warfarin, diazepam, and phenytoin.³³ Lansoprazole, pantoprazole, and rabeprazole do not appear to interact significantly with drugs metabolized by the CYP system. Even with omeprazole, however, clinically important drug interactions are uncommon. Evidence is accumulating that several PPIs may inhibit the activation of clopidogrel to its active metabolite, thus impairing the antiplatelet effect of clopidogrel, with adverse cardiovascular outcomes.

MUCOSA-PROTECTIVE AGENTS

Sucralfate

Mechanisms of Action

Sucralfate (Carafate) has demonstrated efficacy (similar to that of the H₂ receptor antagonists) in healing duodenal ulcer when given in a dose of 1 g four times daily.³⁴ The drug has demonstrated efficacy in the treatment of gastric ulcer as well, but sucralfate has not been approved by the FDA for this indication. Sucralfate is a complex metal salt of sulfated sucrose. Although the sucralfate molecule contains aluminum hydroxide, the agent has little acid-neutralizing capacity. When exposed to gastric acid, the sulfate anions can bind electrostatically to positively charged proteins in damaged tissue, thereby forming a protective barrier that may prevent further acid-peptic attack. Other proposed beneficial effects of sucralfate are enhancement of mucosal prostaglandin levels, stimulation of mucus and bicarbonate secretion, binding of mucosa-irritating bile salts, binding of epidermal growth factors, and promotion of angiogenesis.³⁴

Pharmacokinetics

Less than 5% of the sucralfate administered is absorbed owing to its poor solubility.³⁴ The drug is excreted in the feces. The high aluminum content causes a small but significant rise in serum and urine aluminum levels within 2 days. In patients with normal renal function, the minor amounts of aluminum absorption with short-term therapy are of no clinical significance.

Toxicity and Drug Interactions

Because of the lack of systemic absorption, sucralfate appears to have no systemic toxicity. The effect on the disposition of aluminum in the body has not been adequately studied in patients with chronic kidney disease. Sucralfate is best avoided in this population. The drug can bind to a number of medications, including phenytoin and warfarin, reducing their absorption. Important drug interactions appear to be rare, however, and can be avoided entirely if sucralfate is administered at a time separate from other medications.³⁴

Bismuth

Mechanisms of Action

Two colloidal preparations of bismuth have been most commonly used, colloidal bismuth subcitrate and bismuth subsalicylate (e.g., Pepto-Bismol). These agents have some efficacy in healing peptic ulcers, but the mechanisms underlying this therapeutic effect are not clear.³⁵ The bismuth forms complexes with mucus that appear to coat ulcer craters. Effects on increasing mucosal prostaglandin synthesis and bicarbonate secretion also have been proposed, and bismuth has documented antimicrobial actions against H. pylori. Bismuth has been approved by the FDA for use in combination with other agents for the treatment of H. pylori infection (see Chapter 50).

Pharmacokinetics

Bismuth is largely unabsorbed and is excreted in the feces. Colonic bacteria convert bismuth subcitrate and bismuth subsalicylate to bismuth sulfide, which turns the stools black. Trace amounts of bismuth are absorbed in the upper GI tract. Absorbed bismuth is slowly excreted in the urine for three months or longer.³⁵

Toxicity

Short-term, standard-dose therapy with bismuth appears to carry little risk of toxicity. However, there is the potential for bismuth neurotoxicity if the agent is given for extended periods in high dosage, especially in patients with chronic kidney disease.³⁵

Prostaglandin E Analogs

Mechanisms of Action

Endogenous prostaglandins, including prostaglandin E₂ (PGE₂), regulate mucosal blood flow, epithelial cell proliferation, epithelial restitution, mucosal immunocyte function, mucus and bicarbonate secretion, and basal acid secretion.³⁶ There is substantial evidence that the ulcerogenic effect of an NSAID correlates well with its ability to suppress prostaglandin synthesis.³⁷ Misoprostol, a prostaglandin E₁ analog, is the only prostaglandin analog approved by the FDA for the prevention of NSAID-induced ulcer disease. The drug not only enhances mucosal defense mechanisms but also inhibits gastric acid secretion. After binding to the prostaglandin receptor on the parietal cell, misoprostol inhibits gastric acid secretion in a dose-dependent manner that is mediated through inhibition of histamine-stimulated cyclic adenosine monophosphate (cAMP) production.³⁸ It has been shown that misoprostol significantly reduces nocturnal, basal, and meal-stimulated acid secretion at a standard therapeutic dose, although the effect is not as potent as that of other classes of antisecretory agents.³⁹

Pharmacokinetics

Misoprostol is well absorbed after oral administration. The plasma concentration peaks at about 30 minutes, with a serum half-life of approximately 1.5 hours. The drug has no effect on hepatic cytochrome P-450. Misoprostol metabolites are excreted in the urine, but dose reduction is unnecessary in patients with chronic kidney disease.⁴⁰

Toxicity

Dose-related diarrhea is the most common side effect, occurring in up to 30% of patients and limiting the usefulness of misoprostol.⁴¹ Diarrhea is related to prostaglandin-induced increases in intestinal water and electrolyte secretion or acceleration of intestinal transit time. Administration of misoprostol with food may reduce diarrhea. Prostaglandins stimulate uterine smooth muscle. Misoprostol is therefore contraindicated in women who may be pregnant.

ULCERS ASSOCIATED WITH HELICOBACTER PYLORI INFECTION

The discovery of H. pylori and its role in peptic ulcer disease has revolutionized the approach to management. Before this discovery, annual ulcer recurrence rates were as high as 80%, often requiring long-term maintenance therapy for ulcer prevention. Now it is well established that curing H. pylori infection not only heals peptic ulcer but also prevents relapse. The following sections outline the management of peptic ulcers associated with H. pylori infection. The choice of diagnostic tests and treatment regimens for H. pylori infection is discussed in Chapter 50.

DUODENAL ULCER

Because H. pylori infection accounts for 70% or more of duodenal ulcers, one must test for the infection using one of the noninvasive tests recommended in Chapter 50. If the diagnosis of ulcer disease is made endoscopically, gastric biopsy specimens should be taken to detect H. pylori infection. If H. pylori infection is documented, the patient should be treated with one of the regimens recommended in Chapter 50, irrespective of whether he or she has a history of NSAID use. There is good evidence that a course of H. pylori eradication therapy is sufficient to heal complicated and uncomplicated duodenal ulcers such that additional antisecretory therapy is usually not required. In a meta-analysis of 52 trials, it was found that the eradication of H. pylori alone was superior to use of an ulcer-healing drug (relative risk of ulcer, 0.66) and to no treatment (relative risk, 0.37).⁴² Follow-up endoscopic examination to ensure healing and testing to document H. pylori eradication after antibiotic therapy are not recommended routinely in patients with uncomplicated ulcers. However, noninvasive tests such as the urea breath test and fecal antigen test can be used to confirm H. pylori eradication in patients with ulcer complications.

GASTRIC ULCER

If H. pylori infection is documented, the patient should be treated with one of the regimens recommended in Chapter 50 regardless of whether he or she has a history of NSAID use. Whether antisecretory therapy is required after a course of H. pylori eradication therapy is controversial. It has been shown that 1 week of antibacterial therapy without acid suppression effectively heals gastric ulcers.⁴² In a meta-analysis of ulcer healing trials, treatment with H. pylori eradication therapy was not significantly different from treatment with an ulcer healing drug.⁴³ For patients with large (>1.5 cm) or complicated gastric ulcers, however, additional antisecretory therapy has been shown to promote ulcer healing.^44,⁴⁵ Routine follow-up endoscopy is recommended to document ulcer healing, to exclude malignancy, and to confirm successful H. pylori eradication (see also Chapter 52).

ROLE OF MAINTENANCE THERAPY

After the eradication of H. pylori infection, there is little evidence that maintenance therapy with antisecretory agents is required, even for patients with complicated peptic ulcers.^46,⁴⁷ A meta-analysis showed that H. pylori eradication therapy was superior to no treatment in preventing recurrence of duodenal ulcer (relative risk, 0.19) or gastric ulcer (relative risk, 0.31).⁴² In another meta-analysis of H. pylori eradication therapy versus maintenance antisecretory therapy in prevention of recurrent ulcer bleeding, rebleeding occurred in 1.6% of the H. pylori eradication therapy group and 5.6% of the maintenance therapy group (odds ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.76).⁴⁸ Although some prospective trials reported that patients with duodenal ulcer had asymptomatic ulcer recurrences after eradication of H. pylori,⁴⁹ these asymptomatic ulcers probably had little clinical significance.

ULCERS ASSOCIATED WITH NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

ACTIVE ULCERS

Histamine-2 Receptor Antagonists

There are limited data on the efficacy of H₂ receptor antagonists in healing NSAID-associated ulcers. Current evidence suggests that conventional doses of H₂ receptor antagonists effectively heal duodenal ulcers but are ineffective for gastric ulcers. In a multicenter study, the effects of ranitidine on ulcer healing were compared in a group of patients who had stopped NSAID therapy and another group who continued NSAID therapy. Gastric ulcers healed in 63% of those still taking NSAIDs compared with 95% of those who had stopped. At 12 weeks, 79% of gastric ulcers and 92% of duodenal ulcers were healed in the group continuing NSAIDs, whereas all ulcers healed in those who had stopped taking NSAIDs.⁵⁰ The ability of H₂ receptor antagonists given in conventional doses to heal NSAID-associated ulcers also depends on the size of the ulcers. One early study reported that when NSAIDs were continued, 90% of gastric ulcers smaller than 5 mm healed after 8 weeks of cimetidine, whereas only 25% of ulcers larger than 5 mm healed.⁵¹

Proton Pump Inhibitors

Several large-scale studies have investigated the efficacy of PPIs for healing of NSAID-associated ulcers.⁵²^–⁵⁵ Current evidence indicates that PPIs are superior to standard-dose H₂ receptor antagonist therapy in healing NSAID-associated ulcers. In a large-scale randomized comparison of two doses of esomeprazole, 20 and 40 mg, and ranitidine, 150 mg twice daily, in patients who continue to take NSAIDs, ulcer healing at eight weeks was found in 85.7% of patients given esomeprazole 40 mg daily, in 84.8% of those given esomeprazole 20 mg daily, and in 76.3% of those given ranitidine 150 mg twice daily.⁵² In another study of 350 patients with NSAID-associated gastric ulcers who continued to use NSAIDs, ulcer healing at eight weeks was found in 69% of patients given lansoprazole 15 mg daily, in 73% of those given lansoprazole 30 mg daily, but in only 53% of those given ranitidine 150 mg twice daily.⁵⁵

Misoprostol

In a randomized placebo-controlled trial in which patients continued NSAID therapy, misoprostol resulted in healing of gastric and duodenal ulcers in 67% of patients at eight weeks, compared with 26% of patients treated with placebo.⁵⁶ However, misoprostol is not as effective as PPIs in healing NSAID-associated ulcers. One large-scale, randomized trial compared misoprostol 200 µg four times daily with omeprazole 20 or 40 mg daily in patients who continued NSAID treatment.⁵³ After eight weeks, duodenal ulcers healed in 89% of patients receiving either dose of omeprazole and in 77% of those receiving misoprostol. Gastric ulcers healed in 80% of those receiving 40 mg of omeprazole, in 87% of those receiving 20 mg of omeprazole, and in 73% of those receiving misoprostol.

Sucralfrate

In a single-blind endoscopic study, sucralfate was significantly less effective than omeprazole in healing NSAID-associated gastroduodenal ulcers.⁵⁷

Adverse Role of Cyclooxygenase-2 Inhibitors in Ulcer Healing

There is good evidence that COX-2 inhibitors induce less gastric mucosal injury than conventional NSAIDs. However, animal experiments have consistently shown that COX-2, but not COX-1, is up-regulated in gastric ulcer.^58,⁵⁹ The administration of COX-2 inhibitors actually retards the healing of rodent gastric ulcers.⁶⁰^–⁶² These results suggest that prostaglandins generated by COX-2 contribute to restoring the integrity of gastric mucosa. A double-blind randomized trial of celecoxib on the healing of bleeding gastric ulcer found that after eight weeks, the ulcer healing rate was 65.7% in the celecoxib group and 80% in the placebo group.⁶³ This finding indicates that treatment with COX-2 inhibitors such as celecoxib delays the healing of complicated gastric ulcers.

Recommendations

For patients in whom ulcers develop in association with the use of NSAIDs, it is recommended that NSAIDs should be discontinued if possible. Current evidence indicates that PPIs are more effective than H₂ receptor antagonists, sucralfate, and misoprostol in healing NSAID-associated ulcers when continuous NSAID treatment is required. When NSAIDs can be discontinued, an H₂ receptor antagonist is an effective alternative. Treatment with COX-2 inhibitors in patients with active ulcers who continue to require anti-inflammatory therapy is not recommended. In the Maastricht III Consensus Report, eradication of H. pylori is advisable in patients who plan to start long-term NSAID therapy.² The influence of H. pylori infection on the healing and relapse of NSAID-associated ulcer is discussed later.

ULCER PROPHYLAXIS

For many years an ulcer visible at endoscopy has been extensively used as a surrogate endpoint to assess the efficacy of prophylactic agents in preventing complications of NSAID-induced ulcers. An “endoscopic ulcer” has been arbitrarily defined as a circumscribed mucosal defect having a diameter of 5 mm or more with a perceivable depth.⁶³ However, many studies have loosened this criterion to include flat mucosal breaks with a diameter of 3 mm or more as ulcers. The distinction between small ulcers and erosions is arbitrary and is prone to interobserver bias. The clinical relevance of these minor endoscopic lesions is uncertain. Although endoscopic findings roughly correlate with clinical outcomes in subjects at low to average risk for complications, current evidence indicates that the results of endoscopic studies cannot be generalized to high-risk patients.⁶⁴ Because there are few prospective outcome trials to evaluate the true efficacy of prophylactic agents, clinical judgment relies on data largely using endoscopic endpoints.

Antacids

Antacids have no proven efficacy in the prevention of NSAID-induced ulcers. However, many clinicians still prescribe antacids as co-therapy for patients taking NSAIDs, both for symptom relief and prevention of ulcers. A case-control study showed that NSAID users receiving prophylaxis with antacids and H₂ receptor antagonists had a more than two-fold increased risk of ulcer complications compared with those not taking these prophylactic agents.⁶⁵ This finding was attributed to the possibility that antacids might have masked the dyspeptic symptoms, thereby creating a false sense of protection and raising the risk of silent ulcer complications. Co-prescription of antacids in patients taking NSAIDs who are at risk for ulcer should be discouraged.

Histamine-2 Receptor Antagonists

Several endoscopic studies investigated the efficacy of standard-dose H₂ receptor antagonist therapy for the prevention of NSAID-induced ulcers.⁶⁶ A systematic review of randomized trials showed that H₂ receptor antagonists significantly reduce the risk of endoscopic duodenal ulcers but not gastric ulcers.⁹⁶ In contrast, it has been shown that double-dose famotidine significantly reduced the risk of both endoscopic duodenal and gastric ulcers. In one study, NSAID-related gastric ulcers developed in 20% of patients receiving placebo, in 13% of those receiving 40 mg of famotidine once daily, and in only 8% of those receiving 40 mg of famotidine twice daily.⁶⁷ In another study, however, the gastric ulcer rates at 24 weeks were 41% and 19% in the groups receiving placebo and double-dose famotidine, respectively.⁶⁸ The large discrepancy (8% vs. 19%) in the efficacy of double-dose famotidine between these two studies raises doubt about the true efficacy of this agent in preventing NSAID-induced gastric injury. To date there is no clinical outcome study to assess whether high-dose H₂ receptor antagonist therapy prevents NSAID-induced ulcer complications.

Misoprostol

More than 20 randomized controlled trials assessed the efficacy of misoprostol in preventing NSAID-induced ulcers. A meta-analysis of the randomized trials indicated that all doses of misoprostol (400 to 800 µg per day) reduce the risk of NSAID-induced endoscopic ulcers.⁶⁶ Only 800 µg per day of misoprostol is documented to reduce ulcer complications, however. In a large-scale, randomized double-blind trial in patients with rheumatoid arthritis who received NSAIDs, misoprostol (200 µg four times daily) significantly lowered the rate of GI complications, by 40% (0.95% in the placebo group vs. 0.57% in the misoprostol group). However, up to 30% of misoprostol-treated patients experienced GI upset, thus limiting its clinical use.⁶⁹ Subsequent endoscopic studies suggested that lower doses of misoprostol, such as 200 µg two or three times per day, prevented NSAID-induced endoscopic ulcers with fewer side effects.⁷⁰ However, there is evidence that low-dose misoprostol therapy fails to prevent ulcer complications.⁷¹

Misoprostol has been found to be superior to H₂ receptor antagonists for the prevention of NSAID-induced gastric ulcers. In one study, ranitidine (150 mg twice daily) was compared with misoprostol (200 µg four times daily) in long-term NSAID users.⁷² After four to eight weeks, about 1% of patients in each group demonstrated endoscopic duodenal ulcers. In contrast, gastric ulcers occurred in 5.7% of patients receiving ranitidine, compared with 0.6% of those receiving misoprostol.

Proton Pump Inhibitors

A systematic review of randomized controlled trials of PPIs for prophylaxis against NSAID-induced endoscopic ulcers found that PPIs significantly reduce the risk of endoscopic duodenal and gastric ulcers.⁶⁶ The efficacy of PPIs has been compared with that of H₂ receptor antagonists and misoprostol in patients who continued to receive NSAIDs. Two studies compared omeprazole 20 mg once daily with standard-dose ranitidine (150 mg twice daily) and half-dose misoprostol (200 µg twice daily) for six months.^53,⁵⁴ Omeprazole was found to be more effective than standard-dose ranitidine but only comparable with half-dose misoprostol in preventing gastric ulcers. However, it should be noted that the superiority of omeprazole in preventing NSAID-related ulcer was due to a significant reduction of duodenal ulcers. A post hoc analysis revealed that most of the added protection attributable to omeprazole occurred among those with H. pylori infection. Another study compared high-dose misoprostol (200 µg four times daily) with two doses of lansoprazole (15 and 30 mg daily) for the prevention of ulcers in long-term NSAID users without H. pylori infection and with a history of gastric ulcer.⁷³ Misoprostol was more effective than the two doses of lansoprazole in preventing gastric ulcer, but there was no practical advantage of misoprostol over lansoprazole because of the high withdrawal rate in the misoprostol group. In a head-to-head endoscopic ulcer prevention study comparing two doses of pantoprazole with 20 mg/day of omeprazole in patients with rheumatoid arthritis receiving NSAIDs, the six-month probabilities of remaining ulcer free were 91%, 95%, and 93% for pantoprazole 20 mg, pantoprazole 40 mg, and omeprazole 20 mg, respectively.⁷⁴

Two identical multicenter randomized clinical trials (RCTs) have been reported together. They compared esomeprazole (20 or 40 mg) with placebo in the prevention of ulcers in patients taking NSAIDs or COX-2 inhibitors over a six-month period. Patients in both studies were H. pylori negative, older than 60, and had a history of gastric or duodenal ulcer. Overall, the rates of ulcers were 17.0%, 5.2%, and 4.6% in the groups receiving placebo, esomeprazole 20 mg, and esomeprazole 40 mg, respectively.⁷⁵

Whether PPIs can reduce the risk of NSAID-associated ulcer bleeding is largely based on observational studies and one randomized trial in high-risk patients. A large-scale case control study found that PPI therapy was associated with a significant reduction in risk of upper GI bleeding among chronic NSAID users (relative risk, 0.13; 95% CI, 0.09 to 0.19).⁷⁶ One randomized trial compared long-term (six-month) omeprazole therapy with one week of H. pylori eradication therapy for the prevention of recurrent ulcer bleeding in H. pylori–infected patients with a recent history of NSAID-related ulcer bleeding who continued to use naproxen.⁷⁷ Recurrent ulcer bleeding was seen in 18.8% of patients undergoing eradication therapy, compared with 4.4% of patients receiving omeprazole. In a randomized comparison of diclofenac plus omeprazole versus celecoxib for secondary prevention of ulcer bleeding in patients who either were H. pylori negative or had undergone H. pylori eradication,⁷⁸ a similar proportion had recurrent bleeding in six months (6.4% in the combination therapy group compared with 4.9% of patients in the celecoxib group). These results indicate that omeprazole reduces but does not eliminate the risk of ulcer bleeding associated with NSAID use in very-high-risk patients. However, the following two important issues remain unresolved: first, the actual risk reduction achieved by PPI is unknown because of the lack of a placebo group, and second, there are no data on the efficacy of PPIs in preventing ulcer complications in low- or moderate-risk users of NSAIDs.

Role of Cyclooxygenase-2 Inhibitors in Ulcer Prevention

Consistent with the notion that inhibition of COX-2 spares the gastric mucosa, clinical trials using endoscopic ulcer as the endpoint have consistently shown that COX-2 inhibitors induced fewer ulcers than do conventional NSAIDs. Five COX-2 inhibitors have been evaluated in clinical trials: the sulfonamides celecoxib [Celebrex] and valdecoxib [Bextra] (parecoxib is a prodrug of valdecoxib), the methylsulfones rofecoxib [Vioxx] and etoricoxib, and the phenylacetic acid derivative lumiracoxib. Four large-scale clinical outcome studies—the Celecoxib Long-Term Arthritis Safety Study (CLASS),⁷⁹ the Vioxx Gastrointestinal Outcomes Research Study (VIGOR),⁸⁰ the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET),⁸¹ and the Multinational Etoricoxib and Diclofenac Arthritis Long-term programme (MEDAL)⁸²—evaluated the gastrointestinal safety of celecoxib, rofecoxib, lumiracoxib, and etoricoxib, respectively. In the CLASS trial, patients with osteoarthritis or rheumatoid arthritis were randomized to receive celecoxib versus diclofenac or ibuprofen in two substudies of identical design. On primary analysis, there was no significant difference in the incidence of ulcer complications between the celecoxib group and the nonselective NSAIDs group.⁷⁹ Whether the failure of CLASS was due to flaws in the study design remains controversial. The VIGOR study compared rofecoxib with naproxen in patients with rheumatoid arthritis.⁸⁰ Unlike CLASS, VIGOR demonstrated that treatment with rofecoxib significantly reduced clinical GI events (combined endpoint of ulcer complications and symptomatic ulcers) by about 50%, compared with treatment with naproxen. Patients requiring low-dose aspirin were excluded from the VIGOR study, whereas 20% of patients in CLASS received low-dose aspirin concomitantly. The TARGET study compared lumiracoxib with naproxen or ibuprofen in patients with osteoarthritis using two substudies of identical design.⁸¹ Randomization was stratified for low-dose aspirin use and age. TARGET showed that treatment with lumiracoxib significantly reduced the incidence of ulcer complications compared with nonselective NSAIDs in the subgroup of patients not taking low-dose aspirin. Current evidence indicates that low-dose aspirin negates the GI mucosa-sparing effect of COX-2 inhibitors. The MEDAL program was a prespecified pooled analysis of data from three prospective trials. A total of 34,701 arthritic patients were treated with 60 or 90 mg of etoricoxib or 150 mg of diclofenac daily. Unlike the previous large-scale studies, the primary endpoint of this study was cardiothrombotic events. Therefore, patients on low-dose aspirin were enrolled and encouraged to receive PPI co-therapy. There was no between-group difference in terms of complicated GI events including bleeding, perforation, or obstruction. However, the overall incidence of uncomplicated GI events was significantly less with etoricoxib than with diclofenac. The reduction in uncomplicated GI events with etoricoxib is maintained in patients treated with PPIs and is also observed with regular low-dose aspirin use.⁸² In a systematic review of randomized trials of COX-2 inhibitors, COX-2 inhibitors produced significantly fewer gastroduodenal ulcers (relative risk, 0.26; 95% CI, 0.23 to 0.30) and ulcer complications (relative risk, 0.39; 95% CI, 0.31 to 0.5), as well as fewer withdrawals caused by GI symptoms when compared with nonselective NSAIDs.⁸³

Current evidence indicates that COX-2 inhibitors probably are as effective as a combination of nonselective NSAIDs combined with a PPI in patients at risk for ulcers. In a double-blind randomized outcome trial of celecoxib and the combination of omeprazole and diclofenac in patients with a recent history of ulcer bleeding, approximately 5% of patients in the two treatment groups still had recurrent ulcer bleeding at 6 months.⁷⁸ Although the two treatments were comparable in terms of the incidence of ulcer bleeding, a subsequent follow-up endoscopic study showed that 20% to 25% of patients receiving either treatment developed recurrent ulcers at 6 months.⁸⁴ These findings suggest that neither treatment could eliminate the risk of recurrent bleeding in very-high-risk patients. Recently, a double-blind randomized trial compared celecoxib alone with combination of celecoxib and esomeprazole in patients with a history of NSAID-associated ulcer bleeding. All patients had a negative test for H. pylori infection before randomization. After a median follow-up of 13 months, 8.9% of the celecoxib-alone group had recurrent ulcer bleeding compared with none of the combined therapy group (P = 0.0004).⁸⁵

Cardiovascular Risk of COX-2 Inhibitors and Nonselective NSAIDs

Despite the improved gastric safety profile of COX-2 inhibitors, the cardiovascular risk associated with this new class of NSAIDs has been the subject of much concern. In the VIGOR study, the incidence of acute myocardial events, although low, was four times higher among patients receiving rofecoxib than among patients receiving naproxen.⁸⁰ Whether the observed difference in infarction rates between the two treatments was related to an antiplatelet property of naproxen or to a thrombotic effect of rofecoxib was hotly debated. Further data regarding the cardiovascular hazard of COX-2 inhibitors were derived from two long-term studies of colon polyp prevention using rofecoxib (Adenomatous Polyp Prevention on Vioxx [APPROVE] study)⁸⁶ and celecoxib (Adenoma Prevention with Celecoxib [APC] study).⁸⁷ In the APPROVE study, interim data at 18 months indicated that patients who received 25 mg rofecoxib a day had double the risk of serious cardiovascular events compared with patients who received placebo.⁸⁶ In September 2004, rofecoxib was voluntarily withdrawn from worldwide markets in light of this unexpected finding. In APC study, interim data at 33 months showed that the occurrence of serious cardiovascular events was significantly higher for celecoxib at the very high dose of 400 mg twice a day (hazard ratio, 1.9; 95% CI, 1 to 3.3).⁸⁷ In addition, a randomized, placebo-controlled trial of parecoxib and valdecoxib in patients who had undergone coronary artery bypass surgery found an almost four-fold increased risk of myocardial infarction.⁸⁸

Do COX-2 inhibitors as a class increase the risk of myocardial infarction? Results of these three placebo-controlled trials indicate that this is the case. Both polyp prevention trials, however, investigated by design supratherapeutic doses of rofecoxib and celecoxib for extended time periods.^86,⁸⁷ In the TARGET study, rates of myocardial infarction with lumiracoxib were lower than with ibuprofen but higher than with naproxen. Neither result was statistically significant because the trial was underpowered to detect a difference in cardiovascular outcomes between treatment groups.⁸⁴ The MEDAL program was a prespecified pooled analysis of cardiothrombotic events from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). After an average treatment of 18 months, rates of cardiothrombotic events were similar between the two treatment groups.⁸⁹

Emerging evidence suggests that not only COX-2 inhibitors but also nonselective NSAIDs, with the exception of full-dose naproxen (1000 mg a day), increase cardiothrombotic risk. In a meta-analysis of randomized trials of COX-2 inhibitors (data mostly derived from rofecoxib and celecoxib), all COX-2 inhibitors increased the cardiothrombotic risk compared with placebo (risk ratio, 1.42; 95% CI, 1.13 to 1.78). This was largely attributable to an increased risk of myocardial infarction, with little difference in other vascular outcomes. A dose-dependent increase in cardiothrombotic events was observed with celecoxib. Importantly, there was no significant difference in cardiothrombotic risk between COX-2 inhibitors and nonselective NSAIDs. Naproxen (500 mg twice daily) was the only exception.^90,⁹¹ In a meta-analysis of observational studies, high-dose rofecoxib (>25 mg a day), diclofenac, and indomethacin were associated with an increase in cardiothrombotic events, whereas celecoxib did not significantly increase the cardiothrombotic risk, though an increased risk could not be excluded with doses greater than 200 mg a day.⁹²

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