Peptic Ulcer Disease Treatment & Management

Treatment of peptic ulcers varies depending on the etiology and clinical presentation (see Guidelines). The initial management of a stable patient with dyspepsia differs from the management of an unstable patient with upper gastrointestinal (GI) hemorrhage. In the latter scenario, failure of medical management not uncommonly leads to surgical intervention.

Treatment options include empiric antisecretory therapy, empiric triple therapy for H pylori infection, endoscopy followed by appropriate therapy based on findings, and H pylori serology followed by triple therapy for patients who are infected. Breath testing for active H pylori infection may be used.

Endoscopy is required to document healing of gastric ulcers and to rule out gastric cancer. This usually is performed 6-8 weeks after the initial diagnosis of peptic ulcer disease. Documentation of H pylori cure with a noninvasive test, such as the urea breath test or fecal antigen test, is appropriate in patients with complicated ulcers.

Given the current understanding of the pathogenesis of peptic ulcer disease, most patients with peptic ulcer disease are treated successfully with cure of H pylori infection and/or avoidance of nonsteroidal anti-inflammatory agents (NSAIDs), along with the appropriate use of antisecretory therapy. Computer models have suggested that obtaining H pylori serology followed by triple therapy for patients who are infected is the most cost-effective approach; however, no direct evidence from clinical trials provides confirmation.

Endoscopy should be performed early in patients older than 45-50 years and in patients with associated so-called alarm symptoms, such as dysphagia, recurrent vomiting, weight loss, or bleeding. Age is an independent risk factor for the incidence and mortality from bleeding peptic ulcer, with the risk increasing in persons older than 65 years and increasing further in those older than age 75 years. ^[37] In one study, at least two risk factors (previous duodenal ulcer, H pylori infection, use of acetylsalicylic acid (ASA)/NSAID, and smoking) were present in two thirds of persons with acute gastroduodenal bleeding. ^[38]

The indications for urgent surgery include failure to achieve hemostasis endoscopically, recurrent bleeding despite endoscopic attempts at achieving hemostasis (many advocate surgery after two failed endoscopic attempts), and perforation. Many authorities recommend simple oversewing of the ulcer with treatment of the underlying H pylori infection or cessation of NSAIDs for bleeding peptic ulcer disease. Additional surgical options for refractory or complicated peptic ulcer disease include vagotomy and pyloroplasty, vagotomy and antrectomy with gastroduodenal reconstruction (Billroth I) or gastrojejunal reconstruction (Billroth II), or a highly selective vagotomy.

The principles of management of bleeding peptic ulcers outlined below are equally applicable to both gastric and duodenal ulcers.

Endoscopic therapy

Upper gastrointestinal (GI) bleeding secondary to a bleeding peptic ulcer is a common medical condition. Endoscopic evaluation of the bleeding ulcer can decrease the duration of the hospital stay by identifying patients at low risk for rebleeding. Moreover, endoscopic therapy reduces the likelihood of recurrent bleeding and decreases the need for surgery.

A large international study demonstrated that following successful endoscopic hemostasis for Forrest IB (oozing) peptic ulcer bleeding, the risk of rebleeding at 72 hours was very low (4.9%) compared with other stigmata of recent hemorrhage, but was similar to that for patients treated with esomeprazole (5.4%) and placebo (4.9%). ^[39]

Patients can be stratified as having high or low risk for rebleeding depending on the presence or absence of stigmata seen on the initial endoscopic examination.

High-risk stigmata are the following:

• Active hemorrhage (90% risk of rebleeding)

• A visible vessel (50% risk of rebleeding)

• A fresh overlying clot (30% risk of rebleeding)

Ulcers with such stigmata require endotherapy, while ulcers with a clean base need not be treated endoscopically. In the absence of these stigmata, patients can be discharged home on medical therapy within 48 hours.

Several modalities of endoscopic therapy are available, such as injection therapy, coagulation therapy, hemostatic clips, argon plasma coagulator, and combination therapy. ^[40] Injection therapy is performed with epinephrine in a 1:10,000 dilution or with absolute alcohol. Thermal endoscopic therapy is performed with a heater probe, bipolar circumactive probe, or gold probe. Pressure is applied to cause coagulation of the underlying artery (coaptive coagulation). Combination therapy with epinephrine injection followed by thermal coagulation appears to be more effective than monotherapy for ulcers with a visible vessel, active hemorrhage, or adherent clot.

Another study comprising 108 consecutive patients with high-risk bleeding ulcers at a single institution revealed that an injection of epinephrine alone was equally effective as an injection of epinephrine plus fresh frozen plasma in endoscopic hemostasis. ^[41] There were no significant differences between the groups regarding recurrent bleeding, surgical rate, blood transfusion, or mortality.

Hemoclips have been used successfully to treat an acutely bleeding ulcer by approximating two folds and clipping them together. Several clips may need to be deployed to approximate the gastric ulcer folds. In treating high-risk bleeding ulcers, combined therapy with epinephrine and hemoclips seems to be more efficacious than injection alone. However, it is not clear whether hemoclip use or thermal coagulation is more effective in treating an acutely bleeding ulcer; both modalities are used depending on physician experience and the equipment availability.

Urgent esophagogastroduodenoscopy (EGD) is the treatment of choice in the setting of a bleeding peptic ulcer for diagnostic and therapeutic reasons. Endoscopy provides an opportunity to visualize the ulcer, to determine the degree of active bleeding, and to attempt hemostasis by direct measures. Primary endoscopic hemostatic therapy (EHT) is successful in about 90% of patients; when this fails, transcatheter embolization may be useful. ^[42] Medical management usually serves as an adjunct to direct endoscopic therapy.

Risk factors that predict rebleeding following EHT for nonvariceal upper GI bleeding include the following:

• Failure to use a proton pump inhibitor (PPI) after the endoscopic procedure

• Endoscopically demonstrated bleeding, especially peptic ulcer bleeding

• EHT monotherapy

• Post-EHT use of heparin

• Bleeding in a patient with moderate-to-severe liver disease ^[43]

• Pre-endoscopic hemodynamic instability

• Comorbid illness

• Large ulcer size

• Posterior wall duodenal ulcer ^[44]

These high-risk persons may be considered for initial care in the ICU and follow-up (second-look) endoscopy, especially because many of these factors (advanced age, comorbidities, in-hospital bleeding, rebleeding, hypovolemic shock, need for surgery) are associated with hospital mortality. ^[45]

Acid suppression

Acid suppression is the general pharmacologic principle of medical management of acute bleeding from a peptic ulcer. Reducing gastric acidity is believed to improve hemostasis primarily through the decreased activity of pepsin in the presence of a more alkaline environment. Pepsin is believed to antagonize the hemostatic process by degrading fibrin clots. By suppressing acid production and maintaining a pH above 6, pepsin becomes markedly less active. Concomitant H pylori infection in the setting of bleeding peptic ulcers should be eradicated, as this lowers the rate of rebleeding. ^{[46, 47]}

Two classes of acid-suppressing medications currently in use are histamine-2 receptor antagonists (H2RAs) and PPIs. ^[48] Both classes are available in intravenous and oral preparations. Examples of H2RAs include cimetidine, famotidine, and nizatidine. Examples of PPIs include omeprazole, pantoprazole, lansoprazole, and rabeprazole.

H2RAs are an older class of medications, and in the setting of an actively bleeding duodenal ulcer, their use has been largely superseded by the use of PPIs. Many gastroenterologists assert that intravenous PPI therapy maintains hemostasis more effectively than intravenous H2RA. Thus, intravenous H2RA no longer has a role in the management of bleeding peptic ulcers. ^[49]

PPIs have a very good safety profile, although attention must continue to be focused on adverse effects, especially with long-term and/or high-dose therapy, such as Clostridium difficile infection, community-acquired pneumonia, hip fracture, and vitamin B12 deficiency. ^[50] Long-term use of PPIs is also associated with decreased absorption of some medications. PPIs impair gastric secretion of acid; thus, absorption of any medication that depends on gastric acidity, such as ketoconazole and iron salt, is impaired with long-term PPI therapy. In addition, achlorhydria (absence of intragastric acidity) may be associated with iron deficiency anemia, because the ferric form of iron must be converted to the ferrous form by gastric acid. Most iron absorbed is in the ferrous form.

Parenteral PPI administration is used after successful endoscopic therapy for ulcers with high-risk signs, such as active bleeding, visible vessels, and adherent clots. Parenteral PPI use before endoscopy is a common practice. Based on intragastric pH data, nonvomiting patients with bleeding ulcers may be treated with oral lansoprazole (120-mg bolus, followed by 30 mg every 3 h). ^[51] When indicated, intravenous pantoprazole or omeprazole is administered as an 80-mg bolus followed by a continuous 8-mg/h infusion for 72 hours. A study by Chan et al determined that intravenous, standard-dose omeprazole was inferior to high-dose omeprazole in preventing rebleeding after endoscopic therapy for peptic ulcer bleeding. ^[52] This treatment is changed to oral PPI therapy after 72 hours if no rebleeding occurs.

In a study by Andriulli et al, standard-dose PPI infusion was found to be as effective as a high-dose regimen in reducing the risk of recurrent bleeding following endoscopic hemostasis of bleeding ulcers. The primary end point was the in-hospital rebleeding rate (determined on repeat endoscopy). Patients with actively bleeding ulcers and those with a nonbleeding visible vessel or an adherent clot were treated with (1) epinephrine injection and/or thermal coagulation, then randomized to receive an intensive regimen of 80-mg PPI bolus, followed by 8 mg/h as continuous infusion for 72 hours, or (2) a standard regimen of a 40-mg PPI bolus daily, followed by saline infusion for 72 hours. After the infusion, all patients were given 20 mg PPI twice daily orally. ^[53]

In the intensive PPI regimen group, rebleeding recurred in 11.8%, whereas in the standard regimen group, rebleeding recurred in 8.1%. Most of the rebleeding episodes occurred during the initial 72-hour infusion. The duration of hospital stay was less than 5 days for 37.0% in the intensive regimen group and 47.0% in the standard group. There were fewer surgical interventions in the standard group. Five patients in each treatment group died. ^[53]

A Canadian database (RUGBE) indicated some benefit from parenteral PPI in decreasing rebleed rates. ^[49] No randomized, controlled trial has provided evidence to support the use of parenteral PPI in this setting, but giving oral PPI both before and after EHT for persons with peptic ulcers with signs of recent hemorrhage can be justified on the grounds of cost-effectiveness. ^[25]

Whether acid suppression improves the therapeutic outcomes of peptic ulcers compared with placebo may be more important than the issues raised above. Many researchers have compared parenteral PPI therapy with placebo, and overall, the results have demonstrated a shorter period of bleeding and a decreased incidence of rebleeding with PPI therapy. Some studies have demonstrated a decreased need for emergency surgery and blood transfusion; however, evidence that parenteral PPI reduces mortality from ulcer bleeding is relatively recent. ^[26]

The 2017 American College of Gastroenterology (ACG) guidelines for the treatment of H pylori infection strongly recommend 10-14 days of quadruple therapy with bismuth, a proton pump inhibitor (PPI), tetracycline, and a nitroimidazole). ^[33] An alternative strongly recommended option is 10-14 days of concomitant PPI, clarithromycin, amoxicillin, and a nitroimidazole. ^[33]  See ACG Guidelines.

In the United States, PPI–based triple therapy was the previous recommendation. ^[1] These regimens result in a cure of infection and ulcer healing in approximately 85-90% of cases. ^[2] Ulcers can recur in the absence of successful H pylori eradication.

Dual therapies, which are alternative regimens for treating H pylori infection, are usually not recommended as first-line therapy, because of a variable cure rate that is significantly less than the cure rate achieved with triple therapy.

Spouses and H pylori –positive family members of H pylori –positive persons should be considered for testing and treatment of H pylori infection, ^[54] since mother-to-child transmission may be a major route of H pylori infection. ^[55]

Triple-therapy regimens

PPI-based triple therapy regimens for H pylori consist of a PPI, amoxicillin, and clarithromycin for 7-14 days. A longer duration of treatment (14 d vs 7 d) appears to be more effective and is currently the recommended treatment. Amoxicillin should be replaced with metronidazole in penicillin-allergic patients only, because of the high rate of metronidazole resistance. ^[56] In patients with complicated ulcers caused by H pylori, treatment with a PPI beyond the 14-day course of antibiotics and until the confirmation of the eradication of H pylori is recommended.

Polymorphisms in the host CYP2C19 gene and antibiotic-resistance attributes of H pylori isolates appear to influence the outcome of triple therapy. ^[57] CYP2C19 affects peptic ulcer healing, H pylori eradication, and PPI therapeutic efficacy. When a patient’s CYP2C19 genotype is unknown, H pylori eradication may be achieved with fluoroquinolones/metronidazole/clarithromycin-based triple therapies. ^[57]

PPI-based triple therapies are a 14-day regimen as outlined below.

Omeprazole (Prilosec): 20 mg PO bid

or

Lansoprazole (Prevacid): 30 mg PO bid

or

Rabeprazole (Aciphex): 20 mg PO bid

or

Esomeprazole (Nexium): 40 mg PO qd

Plus

Clarithromycin (Biaxin): 500 mg PO bid

and

Amoxicillin (Amoxil): 1 g PO bid

Alternative triple-therapy regimens

The alternative triple therapies, also administered for 14 days, are as follows:

Omeprazole (Prilosec): 20 mg PO bid

or

Lansoprazole (Prevacid): 30 mg PO bid

or

Rabeprazole (Aciphex): 20 mg PO bid

or

Esomeprazole (Nexium): 40 mg PO qd

Plus

Clarithromycin (Biaxin): 500 mg PO bid

and

Metronidazole (Flagyl): 500 mg PO bid

Quadruple therapy

Quadruple therapies for H pylori infection are generally reserved for patients in whom the standard course of treatment has failed.

Quadruple treatment includes the following drugs, administered for 14 days:

• PPI, standard dose

• Bismuth 525 mg PO qid

• Metronidazole 500 mg PO qid

• Tetracycline 500 mg PO qid

Consider maintenance therapy with half of the standard doses of H2-receptor antagonists at bedtime in patients with recurrent, refractory, or complicated ulcers, particularly if cure of H pylori has not been documented or if an H pylori –negative ulcer is present.

In 2009, the American College of Gastroenterology (ACG) issued a guideline for prevention of nonsteroidal anti-inflammatory agent (NSAID)-related ulcer complications that supports the recommendations in this section. ^[58] According to the ACG guideline, all patients who are beginning long-term NSAID therapy should first be tested for H pylori. NSAIDs should be immediately discontinued in patients with positive H pylori test results if clinically feasible. The 2017 ACG guidelines for the treatment of H pylori infection (HPI) have reaffirmed testing for HPI before initiating NSAID therapy. ^[33]

For patients who must continue with their NSAIDs, PPI maintenance is recommended to prevent recurrences even after eradication of H pylori. ^{[3, 4]} If NSAIDs must be continued, changing to a cyclooxygenase (COX)-2 selective inhibitor is an option. However, the use of a traditional NSAID and once-daily proton pump inhibitor (PPI) is comparable to a selective COX-2 inhibitor with respect to ulcer bleeding in patients with a history of peptic ulcer disease. ^[59] In general, 6-8 weeks of therapy with a PPI is required for complete healing of a duodenal ulcer.

Active ulcers associated with NSAID use are treated with an appropriate course of PPI therapy and the cessation of NSAIDs. ^[60] For patients with a known history of ulcer and in whom NSAID use is unavoidable, the lowest possible dose and duration of the NSAID and co-therapy with a PPI or misoprostol are recommended.

Thus, the 2009 ACG guideline recommends that patients who are treated with NSAIDs and also require low-dose aspirin therapy for cardiovascular disease be treated with naproxen plus misoprostol or a PPI. Patients at moderate risk for gastrointestinal complications and at high risk for cardiovascular disease should avoid NSAIDs or COX-2 inhibitors entirely and receive alternative therapy. ^[58]

Deterrence and prevention

Primary prevention of NSAID-induced ulcers includes the following:

• Avoid unnecessary use of NSAIDs

• Use acetaminophen or nonacetylated salicylates when possible

• Use the lowest effective dose of an NSAID and switch to less toxic NSAIDs, such as the newer NSAIDs or COX-2 inhibitors, in high-risk patients without cardiovascular disease

Consider prophylactic or preventive therapy for the following patients:

• Patients with NSAID-induced ulcers who require chronic, daily NSAID therapy

• Patients older than 60 years

• Patients with a history of peptic ulcer disease or a complication such as gastrointestinal bleeding

• Patients taking concomitant steroids or anticoagulants or patients with significant comorbid medical illnesses

Prophylactic regimens that have been shown to dramatically reduce the risk of NSAID-induced gastric and duodenal ulcers include the use of a prostaglandin analog or a PPI according to the following regimens:

• Misoprostol 100-200 mcg PO 4 times per day

• Omeprazole 20-40 mg PO every day

• Lansoprazole 15-30 mg PO every day

A 2005 study showed that in patients with aspirin-induced ulcer, contrary to popular belief, aspirin plus esomeprazole (Nexium) was superior to clopidogrel (Plavix) in preventing recurrent gastric ulcer bleeding. ^[61] This was further confirmed in a double-blind randomized study in 2006 by Lai and colleagues. ^[62]

In a study by Hsu et al, combining esomeprazole and clopidogrel reduced the recurrence of peptic ulcers in patients with atherosclerosis and a history of peptic ulcers more than the use of clopidogrel alone. ^[63] This combination did not influence the action of clopidogrel on platelet aggregation.

Presentations of peptic ulcer disease and gastritis usually are indistinguishable in the emergency department (ED) and, thus, the management is generally the same. Treatment goals in the acute setting are the relief of discomfort and protection of the gastric mucosal barrier to promote healing. Administer supportive therapy as needed. Most patients with gastritis or peptic ulcer disease do not require acute interventions.

High-risk patients include those with the following characteristics:

• Bleeding with hemodynamic instability

• Repeated hematemesis or any hematochezia

• Failure to clear with gastric lavage

• Coagulopathy

• Comorbid disease (especially cardiac, pulmonary, or renal)

• Advanced age

Drug treatments

Antacids or a gastrointestinal (GI) cocktail (typically an antacid with an anesthetic such as viscous lidocaine and/or an antispasmodic) may be used as symptomatic therapy; however, relief of symptoms with a GI cocktail is not a diagnostic indicator.

Empiric treatment of H pylori is not recommended. Therapy is indicated only after confirmation of infection. These tests are not performed in the ED. Empiric trial of acid suppression in patients younger than 55 years without alarm features may be initiated with a proton pump inhibitor (PPI) for 4-8 weeks. Appropriate follow-up is required to assess response in 2-4 weeks. ^[64]

Anticholinergic agents are contraindicated.

Bleeding

Massive gastric bleeds are the most difficult complication to treat. Mainstays of resuscitation include the following:

• Establishment of adequate intravenous (IV) access and volume replacement, initially with a crystalloid; in the face of continued hypotension after 2 L, consider blood transfusion.

• A central venous catheter to monitor such resuscitation may be considered.

• Airway protection with intubation should be considered in the case of massive bleeding.

• Nasogastric suction helps to keep the stomach empty and contracted.

• IV PPI has been shown to reduce mortality in upper GI bleeds and reduces the incidence of rebleeding and the need for surgical intervention ^[65] ; emergent surgical or endoscopic intervention may be required

Patients with significant or potentially significant hemorrhage require admission, usually to the intensive care unit.

Surgical care for perforated peptic ulcer

With the success of medical therapy, surgery has a very limited role in the management of peptic ulcer disease. Elective peptic ulcer surgery has been virtually abandoned. In the 1980s, the number of elective operations for peptic ulcer disease dropped more than 70%, and emergent operations accounted for more than 80%. ^[66] In general, 5% of bleeding ulcers eventually require operative management. The indications for urgent surgery include the following:

• Failure to achieve hemostasis endoscopically

• Recurrent bleeding despite endoscopic attempts at achieving hemostasis (many advocate surgery after two failed endoscopic attempts)

• Perforation

The appropriate surgical procedure depends on the location and nature of the ulcer. Many authorities recommend simple oversewing of the ulcer with treatment of the underlying H pylori infection or cessation of NSAIDs for bleeding peptic ulcer disease. Additional surgical options for refractory or complicated peptic ulcer disease include vagotomy and pyloroplasty, vagotomy and antrectomy with gastroduodenal reconstruction (Billroth I) or gastrojejunal reconstruction (Billroth II), or a highly selective vagotomy.

Only one prospective randomized trial has compared laparoscopic surgery with open surgery for perforated ulcer. The study found that the only difference between the two groups was reduced need for analgesia and an increased operative time in the laparoscopic group. Contraindications for laparoscopic repair for perforated peptic ulcer include large perforations, a posterior location of the perforation, and a poor general state of health. ^[49]

Surgical complications include pneumonia (30%), wound infection, abdominal abscess (15%), cardiac problems (especially in those >70 y), diarrhea (30% after vagotomy), and dumping syndromes (10% after vagotomy and drainage procedures).

See Surgical Treatment of Perforated Peptic Ulcer for more information.

A special diet is not indicated for patients with duodenal ulcers. It is a common-sense approach to avoid any food or beverages that may aggravate symptoms. Although the link between duodenal ulcers and alcohol is inconclusive, moderation of alcohol intake may be recommended for other health reasons.

Refractory, symptomatic peptic ulcers, though rare after eradication of H pylori infection and the appropriate use of antisecretory therapy, are a potential complication of peptic ulcer disease. Obstruction is particularly likely to complicate peptic ulcer disease in cases refractory to aggressive antisecretory therapy, H pylori eradication, or avoidance of NSAIDs. Obstruction may persist or recur despite endoscopic balloon dilation. Perforation is also a possibility. Penetration, particularly if not walled off or if a gastrocolic fistula develops, is a potential complication. In addition, ulcer bleeding, particularly in patients with a history of massive hemorrhage and hemodynamic instability, recurrent bleeding on medical therapy, and failure of therapeutic endoscopy to control bleeding is a serious complication.

Patients with gastric ulcers are also at risk of developing gastric malignancy. The risk is approximately 2% in the initial 3 years. One of the important risk factors is related to H pylori infection. H pylori is associated with atrophic gastritis, which, in turn, predisposes to gastric cancer. H pylori infection is associated with gastric lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma. Normal gastric mucosa is devoid of organized lymphoid tissue. H pylori infection promotes acquisition of lymphocytic infiltration and often the formation of lymphocytic aggregates and follicles from which MALT lymphoma develops. Eradication of H pylori is very important in this group of patients because eradication of H pylori has been shown to cause a remission of MALT lymphoma.

Malignancy should be strongly considered in the case of a persistent nonhealing gastric ulcer. Endoscopic ultrasound examination may be helpful for assessing mucosal invasion or detecting associated adenopathy in such patients. Surgical resection should be considered if evidence of cancerous transformation is present.

Surgical consultation is recommended for all patients with bleeding ulcers, especially those patients who are at a high risk of significant bleeding. Such ulcers include those that have caused hemodynamic instability, those that are actively bleeding, and those that show a visible vessel on endoscopy.

Maintenance therapy with antisecretory medications (eg, H2 blockers, PPIs) for 1 year is indicated in high-risk patients. High-risk patients include those with recurrent ulcers and those with complicated or giant ulcers. If H pylori eradication is not achieved despite repeat treatment, maintenance antisecretory therapy should be recommended.

Consider maintenance therapy with half of the standard doses of H2-receptor antagonists at bedtime in patients with recurrent, refractory, or complicated ulcers, particularly if cure of H pylori has not been documented or if an H pylori –negative ulcer is present.

Patients with refractory ulcers may continue receiving once-daily PPI therapy indefinitely. In this setting, if H pylori is absent, consider a secondary cause of duodenal ulcer, such as Zollinger-Ellison syndrome.

Peptic ulcer rebleeding is extremely rare after H pylori eradication. The use of maintenance antisecretory therapy is not necessary if H pylori eradication has been achieved. However, NSAID use may cause rebleeding even in patients in whom H pylori has been eradicated. ^[67]