Gastrointestinal Bleeding

Margaret Shuhart, M.D. , Kris Kowdley, M.D., and Bill Neighbor, M.D.

1.0. INTRODUCTION

Gastrointestinal (GI) bleeding is among the most common gastrointestinal disorders. In this chapter we review the many causes of both upper and lower GI bleeding, and the diagnostic and therapeutic approaches in patients with GI bleeding. General guidelines for the initial management and appropriate referral to a gastroenterologist for patients presenting with GI bleeding are discussed in this chapter.

MeSH search strings used in this review included GASTROINTESTINAL BLEEDING, UPPER GASTROINTESTINAL BLEEDING, LOWER GASTROINTESTINAL BLEEDING, OCCULT GASTROINTESTINAL BLEEDING, AND OBSCURE GASTROINTESTINAL BLEEDING. MeSH terms also included specific causes of GI bleeding as outlined in Sections 3.1 and 4.1. These terms were used in a search of Medline for the years 1990 to 2002. Certain articles published prior to 1990 were also included if they were landmark studies or illustrative case reports.

2.0. MANAGEMENT OF GI BLEEDING

2.1. Initial assessment, resuscitation and triage

Patients with GI bleeding may have different clinical presentations ranging from hematemesis or hematochezia with hemodynamic instability, to melena or rectal bleeding without hemodynamic compromise. Finally, patients may have chronic GI bleeding with asymptomatic iron-deficiency anemia, or hemoccult-positive stool on screening for colorectal cancer.

The severity of illness at presentation dictates the initial patient assessment and resuscitative efforts. Patients presenting to the emergency room with hemodynamic instability require rapid clinical assessment, intravenous access with at least two large-bore lines, nasogastric tube placement, determination of hematocrit and coagulation studies, and type and cross for blood products. Patients with altered mental status should undergo endotracheal intubation for airway protection. Emergent evaluation by a gastroenterologist should be requested. The patient should be stabilized before proceeding to endoscopy, unless there is massive bleeding and no response to resuscitation.

During the initial assessment, it is important to determine whether the bleeding is from an upper or lower GI source (proximal or distal to the ligament of Treitz, respectively) as this will guide the diagnostic approach. Distinguishing between an upper and lower source of bleeding is usually relatively straightforward. However, approximately 5%-10% of patients who present with hematochezia are bleeding from an upper GI source, and some may not have blood in a gastric aspirate. If there is uncertainty about the presence of an upper GI bleeding source, such as when the gastric aspirate is not bile-stained, patients with hematochezia and hemodynamic compromise should undergo upper endoscopy before evaluation of the lower GI tract.

Admission to the hospital is required for most patients presenting with GI bleeding. Those who present with frank hypotension or who have evidence for ongoing bleeding require monitoring in an intensive care unit and urgent endoscopic evaluation. Those who present with mild or no orthostasis, have no evidence for continued bleeding, but have had a significant drop in hematocrit are generally hospitalized on a medical/surgical floor. In general, young patients with self-limited GI bleeding who present without orthostasis or hemodynamic instability and who have no significant comorbid conditions may be managed as outpatients. Early endoscopy may also assist in the identification of patients with a low rebleeding risk who can be managed as outpatients [Rockall, 1990].

2.2. Diagnosis

2.2.1. History and physical

During the initial stabilization and evaluation, a complete history and physical should be performed. First, a detailed history of current and past GI bleeding should be elicited. Patients with upper GI bleeding should be questioned about known ulcer disease, liver disease, malignancy, abdominal surgery or bleeding disorder, weight loss, and alcohol, aspirin or non-steroidal antiinflammatory drug (NSAID) use. A history of antecedent retching suggests a Mallory-Weiss tear. Patients with suspected lower GI bleeding should also be asked about hemorrhoids, associated diarrhea, change in bowel habits, personal or family history of inflammatory bowel disease, and a history of radiation therapy. A family history of GI disorders, malignancy or bleeding disorders should also be obtained. Physical examination should include orthostatic blood pressure and pulse even if the patient appears stable and has no symptoms of orthostasis. Although the physical examination seldom leads to a specific diagnosis, certain findings may provide helpful clues. Such findings include cutaneous stigmata of liver disease, splenomegaly or ascites, abdominal tenderness, an abdominal mass or lymphadenopathy, and cutaneous or mucocutaneous manifestations of systemic disorders associated with GI bleeding (Table 1).

2.2.2. Diagnostic studies

2.2.2.1. Upper GI endoscopy

Gastrointestinal endoscopy is the preferred diagnostic modality in patients with upper GI bleeding. Barium studies generally have limited sensitivity and may interfere with subsequent endoscopy or angiography. Furthermore, many abnormalities seen on barium study will require endoscopic evaluation. In addition to its superior sensitivity, other advantages of endoscopy include the ability to obtain biopsies for an accurate histologic diagnosis, to determine the risk of rebleeding (thus influencing decisions such as level of hospital care, when to resume feeding, and the duration of hospitalization), and to provide endoscopic therapy. Endoscopic therapy of bleeding esophageal varices and peptic ulcers with a high risk of rebleeding can reduce the incidence of further bleeding and the need for surgery, and improve survival [Westaby,1985; Williams,1993; Thomopoulos,1997].

Early, judicious use of endoscopy can be of benefit from the standpoint of diagnosis, therapy, and prognosis. Patients with severe upper GI bleeding should have an upper endoscopy, or esophagogastroduodenoscopy (EGD), performed as soon as they are stable. If resuscitation is unsuccessful, an attempt at EGD is still warranted as it might provide useful information. Patients in whom endoscopy cannot be performed due to torrential bleeding should be considered for laparotomy, with or without prior mesenteric angiography. Such decisions must be made in consultation with surgery, gastroenterology and interventional radiology. Early endoscopy is also helpful in patients with milder degrees of upper GI bleeding. The endoscopic findings in such cases can help predict the risk of rebleeding. This information can be helpful in decision-making regarding continued hospitalization versus early discharge. Variables predictive of mortality in patients with upper GI bleeding are listed in (Table 2) [Sanders,2002]. Patients who are young and who present with trivial bleeding may not require endoscopic evaluation, particularly if there is a history of antecedent vomiting, suggesting the presence of a Mallory-Weiss tear. Guidelines for the evaluation of patients with upper GI bleeding are provided in Algorithm 1.

2.2.2.2. Sigmoidoscopy and colonoscopy

Patients with bright red hematochezia and minimal blood loss can undergo initial evaluation with anoscopy and flexible sigmoidoscopy, unless the patient is age 50 or older. In the latter setting, a full colonoscopy is generally recommended to rule out a colonic neoplasm. Those with dark hematochezia or bright red blood per rectum and evidence for significant blood loss should undergo full colonoscopy after a complete bowel preparation. In such patients bowel preparation with an oral lavage solution is preferred unless there is evidence for bowel obstruction. The solution can be administered rapidly via NG tube in order to expedite the procedure. Active, brisk bleeding and continued hemodynamic instability despite ongoing resuscitation is an indication for emergency angiography rather than colonoscopy. Since lower GI bleeding can originate anywhere in the small bowel or colon, angiography is also preferable to laparotomy in the setting of such bleeding. Surgery is generally reserved for patients whose bleeding site is identified by angiography but who are inappropriate for, or fail, angiographic therapy. Guidelines for the evaluation of patients with lower GI bleeding are provided in Algorithm 1.

2.2.2.3. Angiography

Angiography is helpful in the patient with massive GI bleeding from either an upper or lower source. Selective mesenteric angiography reveals a bleeding site in up to 75% of patients with massive upper GI bleeding [Laine,1997]. Among lower GI bleeding sources, diverticular bleeding and angiodysplastic lesions are the most common lesions diagnosed by angiography [Fioritto,1989]. Animal studies have demonstrated that a bleeding rate of 0.5 mL/min is necessary in order for angiography to be positive [Nusbaum,1963]. Contrast extravasation during angiography localizes the site of bleeding, and in some instances can also define the lesion even when extravasation is not noted (e.g., arteriovenous malformation, tumor).

Finally, selective angiography allows for therapy with embolization or vasopressin infusion.

2.2.2.4. Radionuclide scanning

Radionuclide scanning is sometimes helpful in localizing the source of lower GI bleeding. Red blood cells obtained by venipuncture are labeled with technetium 99m (99mTc) and reinjected into the patient. The abdomen is then scanned with a gamma counter. Since prolonged or repeated scanning is possible, bleeding can be detected even if it is intermittent or too slow to be detected on angiography. However, 99mTc-labeled red blood cell scans have their limitations. In earlier studies, the red blood cell scan was negative in up to 70% of patients with a lower GI source of bleeding [Bentley,1991; Voeller,1991] and in up to 50% of positive scans the predicted bleeding location was in correct [Bentley,1991; Dusold,1991]. More recently, digital equipment has allowed for more frequent imaging and cinematic display. In one study using this technology, the site of bleeding was accurately localized in 88% of positive scans [O’Neill,2000]. Despite their limitations, 99mTc-labeled red blood cell scans may be helpful in some patients with recurrent lower GI bleeding in whom all other diagnostic studies are negative.

Since red blood cell scans detect lower rates of bleeding (0.1cc/min) than angiography, these scans are often used as a screen to determine which patients should undergo angiography. If the red blood cell scan is negative, the angiogram is very unlikely to demonstrate active bleeding.

Radionuclide scanning is particularly helpful in the setting of bleeding from a Meckel’s diverticulum. 99mTc pertechnetate is given intravenously, and is taken up by the ectopic gastric mucosa in the Meckel’s diverticulum.

Using surgery as the gold standard, the sensitivity of a Meckel’s scan ranges from 75% to 91%, while the specificity is 97% to 100% [Fries,1984; Kong,1993]. This study should be considered early in the evaluation of a young patient with lower GI bleeding.

2.2.2.5. Radiographic and endoscopic studies of the small bowel

As previously discussed, barium studies are not immediately helpful in the setting of overt GI bleeding. However, a small bowel follow-through or enteroclysis is generally recommended to evaluate the small bowel when endoscopic studies are unrevealing and bleeding has ceased. Enteroscopy also may be helpful in this setting, particularly if small bowel angiodysplasia is suspected.

Wireless capsule endoscopy is currently being studied undergoing study in the evaluation of GI bleeding from a possible small bowel source. The Given Diagnostic Imaging System (Given Imaging Ltd, Norcross, GA) was recently approved by the Food and Drug Administration. The capsule endoscope, which is slightly larger than a large vitamin capsule, is swallowed with water and is propelled through the GI tract by peristalsis. Prior to capsule administration, patients either fast or complete a limited purge to rid the distal small bowel of debris. Images are transmitted to an antenna array worn on the abdomen and stored on a portable data recorder. The capsule battery allows for 8 hours of imaging, after which time the data are downloaded to a personal computer for viewing. In one recent study, video capsule endoscopy was superior to small bowel radiographs in the evaluation of 13 patients with obscure GI bleeding; 12 of 13 capsule endoscopy studies yielded a source of bleeding, while only 1 of 13 small bowel radiographs was positive [Costamanga,2002]. Angiodysplasia was the most common finding. It should be noted that capsule endoscopy has no role in the patient with acute GI bleeding because the test takes 8 hours and the results are not immediately available. Furthermore, capsule endoscopy will not replace push enteroscopy in patients with obscure GI bleeding, since the latter has the ability to provide therapy. It also should not be performed in lieu of a small bowel radiograph. A small bowel follow-through or enteroclysis is generally recommended before capsule endoscopy because a stricture is a contraindication to capsule administration. Finally, the interpretation of nonspecific findings remains problematic, and to date no study has determined its sensitivity and specificity.

2.3. Empiric treatment

Treatment of specific causes of GI bleeding is discussed below. To date, no study has demonstrated any benefit from empiric treatment of acute upper GI bleeding with intravenous H2 receptor antagonists [Zuckerman,1984; Collins,1985]. Furthermore, a large, randomized controlled trial of omeprazole in patients presenting with acute upper GI bleeding found no significant difference between the treatment and placebo groups with respect to transfusion requirements, rates of rebleeding, surgery, and mortality [Daneshmend,1992].

Patients who have known portal hypertension and esophageal or gastric varices may be treated empirically with agents that reduce portal pressure. These agents are discussed in more detail below.

3.0. UPPER GASTROINTESTINAL BLEEDING

3.1. Epidemiology

Upper GI bleeding is defined as bleeding from a gastrointestinal source that is proximal to the ligament of Treitz. It is more common than lower GI bleeding. Over 50% of upper GI bleeds are due to erosive or ulcerative disease of the stomach or duodenum [Gilbert,1990]. Etiologies of upper GI bleeding are listed in (Table 3).

Epidemiologic data from Europe indicated an upper GI bleeding annual incidence of 48 to 145 per 100,000 population in the 1960s and 1970s [Gilbert,1990]. In 1978 it was estimated that the total number of hospital admissions for upper GI bleeding in the U.S. was 150 per 100,000 population [Cutler,1990]. A more recent single HMO population-based study found an annual incidence of 102 hospitalizations for upper GI bleeding per 100,000 [Longstreth,1995]. Finally, 1992-1999 data from the National Hospital Discharge Sruvey found an annual hospitalization rate for UGI bleeding ranging from 149-172/100,000 [Lewis,2002].

Despite recent advances in endoscopic therapy, the mortality associated with GI bleeding remains significant at 5% to 11% [Lonstreth,1995; Laine,1993; Rockall,1995a; Rockall,1995b; Lewis,2002]. Factors associated with mortality due to upper GI bleeding have been identified in prospective studies [Rockall,1996; Gilbert,1990]. These included underlying renal, liver, neoplastic, central nervous system or lung disease, and physical findings consistent with cardiorespiratory or hemodynamic compromise, or liver failure. Patients with active bleeding at the time of endoscopy, blood transfusion requirement greater than 5 units, and requirement for surgery also had increased mortality. In addition, patients requiring emergency surgery had increased mortality compared with those undergoing more elective surgery. Other patients with increased mortality include those with recurrent bleeding after hospitalization [Fleischer,1983] and those who develop GI bleeding after hospitalization for other reasons [Longstreth,1995].

3.2. Pathogenesis, diagnosis and therapy of specific lesions

3.2.1. Gastric and duodenal erosive or ulcerative disease

Peptic ulcer disease is the most common cause of upper GI bleeding; over 50% of episodes are due to gastric or duodenal erosions or ulcers [Longstreth,1995; Silverstein,1981].

GI bleeding due to ulcer disease may be brisk, subacute or chronic. In erosive disease, the mucosal defect by definition is not deep enough to result in brisk bleeding. Patients with gastric/duodenal erosions typically have modest blood loss and may present with coffee-ground emesis or melena. If gastric and/or duodenal erosive disease is diagnosed on EGD, therapy should be initiated with either proton-pump inhibitors or H2-receptor antagonists.

In patients with acute GI bleeding from a gastric or duodenal ulcer, endoscopic findings can be used to guide medical therapy. While treatment with H2-receptor antagonists, when compared to placebo, has not been shown to reduce the risk of rebleeding in such patients [Laine,1994], several studies have shown that omeprazole is beneficial in selected patients [Khuroo,1997; Schaffalitzdy,1997; Hasselgren,1997; Lau,2000; Javid,2001]. Specifically, in those who have undergone endoscopic therapy for acute UGI bleeding from a peptic ulcer that is at high risk of rebleeding, treatment with omeprazole therapy is associated with a significant reduction in rebleeding rates [Khuroo,1997; Schaffalitzdy,1997; Lau,2000; Javid,2001], emergency surgery [Khuroo,1997; Schaffalitzdy,1997; Javid,2001], transfusion requirement [Schaffalitzdy,1997; Javid,2001], and length of hospital stay [Javid,2001]. Studies have differed with respect to route of administration (p.o or I.V.) and duration of treatment (3 or 5 days). Since patients with a high risk of rebleeding should be kept NPO, the I.V. route is generally preferred. Both of the positive studies with I.V. omeprazole used an 80 mg bolus followed by an 8 mg/hour continuous infusion for 72 hours, after which time patients were transitioned to omeprazole 20 mg p.o. daily for up to 8 weeks [Schaffalitzdy,1997; Lau,2000]. Finally, two studies have compared omeprazole and H2 antagonists in patients with acute GI bleeding from high-risk ulcers [Lin,1998; Lanas,1995]. One of the studies found a significant reduction in rebleeding rates in the omeprazole group [Lin,1998], while the second study found trends toward decreased rates of rebleeding and surgery in those receiving omeprazole [Lanas,1995]. IV omeprezole is currently unavailable in the United States. The only intravenous PPI available in the U.S. is pantoprazole, and we await studies of this agent in acute ulcer bleeds. Given that the beneficial effect of IV omeprezole is likely related to the ability of an IV PPI to maintain continuous elevation of the intragastric pH, it appears reasonable to extrapolate from the IV omeprezole studies and use IV pantoprazole at a dose of 80 mg bolus, 8 mg/hr for ulcers at high risk of rebleeding.

There is no evidence that high-dose I.V. PPI therapy is beneficial in patients with GI bleeding from an ulcer that has a low risk of rebleeding (i.e., a clean-based ulcer on endoscopy). In these patients, oral PPI therapy can be instituted after the patient has recovered from the endoscopy. PPIs are generally recommended over H2 blockers because healing of uncomplicated gastric and duodenal ulcers is more rapid with proton-pump inhibitors (PPIs) than with H2-antagonists [Lauritsen,1985; McFarland,1990; Marks,1991; Hotz,1992; Delle,1992].

3.2.1.1. Helicobacter pylori

The discovery of Helicobacter pylori (H. pylori) infection has revolutionized our diagnostic and therapeutic approaches to ulcer disease. Over 90% of duodenal ulcers and 80% of gastric ulcers can be attributed to H. pylori, while the vast majority of remaining ulcers are due to NSAID use [Graham,1996]. The pathogenesis of H. pylori-related ulcer disease, and H. pylori testing and treatment are discussed in Chapter 2.

Patients who are found to have a gastric ulcer, duodenitis or duodenal ulcer on endoscopy should have gastric mucosal biopsies to assess for H. pylori infection. Infection with H. pylori can be diagnosed by rapid urease testing of a single antral biopsy or by submitting biopsies for histologic examination. Non-invasive tests such as the urea breath test or stool antigen test are as sensitive and specific as endoscopic biopsy and may be more appropriate in patients with brisk bleeding (performed once bleeding has stopped), when it may be unwise to prolong the endoscopy in order to take biopsies. Patients with duodenitis or duodenal/gastric ulcer who test positive for H. pylori should be treated with an acid-reducing agent (PPI BID) and at least two antibiotics (clarithromycin 500 mg BID, amoxicillin 1 gm BID) for at least 1 week. More information about specific H. pylori treatment regimens can be found in Chapter 2. Patients with complicated ulcer disease (bleeding or perforation) should have confirmation of H. pylori cure by either urea breath test, stool antigen test or endoscopic biopsy. Repeat testing should be performed a minimum of four weeks after completion of therapy [Rollan,1997]. Proton pump inhibitor therapy should also be discontinued for 1 week prior to repeat testing for H. pylori because of the suppressive effect of these drugs on H. pylori growth, which may lead to false negative urea breath tests and stool antigen tests [Laine,1998]. Because serology for H. pylori may remain positive for up to two years following successful eradication, it cannot be relied upon for confirmation of successful cure patients.

3.2.1.2. NSAID erosions/ulcer

It is well recognized that NSAID use is associated with an increased risk of gastric or duodenal ulcer. Antral erosions are present within 1 to 2 days in virtually all individuals taking NSAIDs [O’Laughlin,1981; Larkai,1987]. However, these erosions are usually asymptomatic, often disappear with continued NSAID use, and do not predict ulcer development. Symptomatic ulcers and ulcer complications develop in only 2% to 4% of patients taking NSAIDs for a year [Paulus,1985]. The risk of hospitalization or death from such complications is 1.3% to 1.6% per year in patients with rheumatoid arthritis [Fries,1991]. Although the risk appears small, the millions of U.S. patients taking NSAIDS for arthritis or aspirin for cardiovascular prophylaxis translates into a large number of patients at risk. Even low-dose aspirin, with or without enteric coating, is associated with an increased risk of UGI bleeding (standardized incidence ratio 2.6 in both groups) [Sorenson,2000].

The pathogenesis of NSAID-induced ulcer disease relates to both local and systemic effects [Bjorkman,1995]. Aspirin and NSAIDs are lipid soluble at acid pH and thus diffuse across gastric epithelial cell membranes. Furthermore, these agents are cytotoxic, leading to a breakdown of the gastric mucosal barrier. These local effects rarely lead to acute ulceration and symptomatic disease. It is the systemic inhibition of prostaglandins that leads to symptomatic chronic ulceration. Such inhibition further compromises the gastric mucosal barrier by decreasing mucus and bicarbonate secretion and mucosal blood flow. NSAIDs also inhibit platelet function, and their use has been associated with GI bleeding from throughout the GI tract [Lanas,1996].

Nabumetone and etodolac, NSAIDs that have partial selectivity for prostaglandin synthesis inhibition in inflamed tissues, appear to have lower rates of GI ulceration and related complications. In three large postmarketing survey studies of nabumetone, GI ulcer and complication rates ranged from .02% to .7% [Jenner,1990; Stroelmann,1990; Willkens,1990]. Two large open-label studies of etodolac reported adverse reactions in 0.1% and .005%, respectively [Benhamou,1990]. Although these newer agents appear promising with respect to GI complications, complication rates attributed to newer versus older NSAIDs cannot be directly compared due to differences in dose, patient characteristics and study design. Large, randomized trials comparing these newer agents with older NSAIDs are lacking. Small, short-term endoscopic studies have reported fewer GI erosions and/or ulcers in patients taking nabumetone or etodolac compared with other NSAIDs [Roth,1987; Bianchi,1991; Laine,1995]. Newer NSAIDs (celecoxib, rofecoxib) that are even more selective for prostaglandin synthesis in inflamed tissues are now available. In prospective endoscopic studies, these drugs caused fewer ulcers when compared with other NSAIDs [Simon,1999; Laine,1999; Hawkey,2000; Goldstein,2001], and caused no more ulcers than placebo [Simon,1999; Laine,1999; Hawkey,2000]. Two large randomized trials also found significantly reduced rates of symptomatic ulcer and ulcer complications in patients assigned to rofecoxib [Bombardier,2000] or celecoxib [Silverstein,2000] when compared to nonselective NSAIDs (naproxen and ibuprofen/diclofenac, respectively). In the latter study, subjects were allowed to take low-dose aspirin for cardiovascular prophylaxis. Interestingly, aspirin use appeared to negate the GI benefits of celecoxib. A recently published study randomized over 8000 patients with rheumatoid arthritis to rofecoxib or naproxen and followed them for a median of 9 months [Laine,2002]. Overall, upper GI events (symptomatic or complicated ulcer) were significantly decreased in the rofecoxib group, and the number needed to treat to prevent an event was 31. However, when taking into account the highest risk patients (age = 75, prior upper GI event, or severe rheumatoid arthritis), the number needed to treat was only 10-12.

3.2.1.2.1. Risk factors for NSAID ulcer complications

Risk factors for NSAID-induced ulcer complications include age greater than 65-75 years, history of peptic ulcer or gastrointestinal bleeding, history of heart disease, prednisone or warfarin use, and severe rheumatoid arthritis [Fries,1991; Silverstein,1995; Wolfe,1999; Laine,2002]. NSAIDs should be avoided, if possible, in these high-risk patients. If an NSAID is necessary, rofecoxib or celecoxib should be considered, although the cost-effectiveness of this approach has not been determined. Other options includeprophylaxis with misoprostol or omeprazole.

3.2.1.2.2. Prevention of NSAID ulcers and ulcer complications

In a randomized, placebo-controlled study of three misoprostol dosing regimens in the prophylaxis of NSAID-related ulcer disease, doses of 200 mcg bid, tid and qid all significantly decreased the rate of gastric and duodenal ulcer when compared to placebo [Raskin,1995]. A dose-reponse effect was noted in the prevention of gastric, but not duodenal, ulcer. Due to side effects such as abdominal pain, nausea, flatulence, and diarrhea, twice daily dosing is generally better tolerated than more frequent dosing [Silverstein,1995; Raskin,1995]. Misoprostol also has been show to reduce the risk of NSAID-related ulcer complications [Silverstein,1995].

Prophylaxis with H2-blockers is as effective as misoprostol in reducing the rate of NSAID-induced duodenal ulcer, but is significantly less effective in the prevention of gastric ulcers [Raskin,1996]. Three randomized, placebo controlled studies have demonstrated that omeprazole, 20 mg daily, is effective in the primary prophylaxis against gastroduodenal ulcers in patients taking NSAIDs [Ekstrom,1996; Cullen1998; Bianchi,1998]. In a recently published randomized, placebo-controlled trial of omeprazole versus misoprostol for the prophylaxis of NSAID-related ulcer, omeprazole 20 mg daily was more effective than misoprostol 200 mcg twice daily in patients with prior NSAID-related erosive or ulcerative disease, and either drug was more effective than placebo [Hawkey,1998]. Finally, a recent placebo-controlled trial demonstrated that lansoprazole 30 mg daily significantly reduced the risk of recurrent aspirin-related ulcer complications in patients who continued on low dose aspirin [Lai,2002].

In a two-week placebo-controlled study of sucralfate gel prophylaxis in NSAID users, the incidence of gastroduodenal erosions and/or ulcers on 2-week endoscopy were significantly less frequent in the sucralfate group [Miglioli,1996]. However, no study has demonstrated that long-term prophylaxis with sucralfate prevents gastroduodenal ulcer or ulcer complications. A randomized trial comparing misoprostol to sucralfate found that the former was significantly more effective in preventing gastric ulcers in patients on chronic NSAID therapy [Agrawai,1991]. Thus sucralfate and related agents have no role in the prophylaxis of NSAID-related ulceration.

3.2.1.2.3. Treatment

In patients with GI bleeding from an NSAID-induced gastric or duodenal ulcer, it is best to discontinue the NSAID and treat with a PPI for four weeks. If it is necessary to continue the NSAID, the ulcer is likely to heal if treated, but PPIs rather than H2 blockers should be used in this setting [Yeomans,1998]. In a recently published randomized trial of NSAID ulcer treatment, omeprazole 20 mg or 40 mg daily and misoprostol 200 mcg qid all were equally effective in healing NSAID-related erosive or ulcerative disease in patients who continued to take NSAIDs, with healing rates of 71% to 76% at 8 weeks [Hawkey,1998]. However, patients with “clinically important” GI bleeding were excluded from this study. Certain factors should be considered before deciding if NSAID use should be continued in the setting of GI bleeding. Such variables include the significance of the GI bleed, patient comorbidity (that is, the ability to tolerate another bleed), and whether or not the patient had warning symptoms such as dyspepsia before presenting with GI bleeding. If long-term NSAID therapy is deemed necessary, ulcer prophylaxis should be continued indefinitely. Whether to use misoprostol or a proton pump inhibitor in this setting is uncertain. Hawkey and colleagues recently reported that duodenal ulcer recurrence was significantly lower with omeprazole maintenance at 20 mg daily (39%) than with misoprostol maintenance at 200 mcg bid (52%), but that both agents were superior to placebo (73%) [Hawkey,1998].

3.2.1.2.4. Role of H. pylori infection in NSAID ulcer

The role of H. pylori infection in NSAID ulcer is not certain. Furthermore, it may be difficult to definitively prove that an ulcer is due to NSAIDs rather than H. pylori, since an ulcer may have been present before NSAID therapy was initiated. In general, all patients who develop an ulcer while on NSAIDs should be tested for H. pylori infection and treated if positive. However, although there are some data to indicate that endoscopic ulcers may be less frequent if patients are treated for H.pylori before beginning NSAIDs, we await further clinical outcome studies of this question before recommending routine testing and treatment of H. pylori prior to initiating NSAIDs.

3.2.1.3. Ulcers not associated with H. pylori or NSAID use

An increasing proportion of gastric and duodenal ulcers cannot be attributed to H. pylori infection or NSAID use [Laine,1998]. In the case of gastric ulcers, it is important to rule out malignancy. If malignancy (in the case of gastric ulcer) and Zollinger-Ellison syndrome have been excluded, it is recommended that the patient with a complicated ulcer continue on life-long acid-suppression therapy once the ulcer has healed. In the majority of cases a single dose of H2-antagonist at bedtime will reduce the risk of ulcer recurrence to approximately 15% to 25%, although some patients will require twice this dose [Strum,1986; Texter,1986] or a proton pump inhibitor for effective prophylaxis . In general the appropriate dose for prophylaxis can be individualized according to the patient’s symptoms. Patients who develop recurrent ulcer disease despite medical prophylaxis should be considered for anti-ulcer surgery.

3.2.1.4. Indications for follow-up endoscopy

Since approximately 1% of gastric ulcers are malignant, gastric ulcers should be biopsied at the time of diagnosis. If they are not, follow-up endoscopy to document ulcer healing is recommended regardless of endoscopic appearance or evidence for H. pylori infection or NSAID use. The follow-up endoscopy is performed approximately 8 weeks after the initial diagnosis. If the ulcer is still present and has not shown signifi…