Risk Stratification

The first step in managing patients with upper gastrointestinal bleeding is clinical evaluation and risk stratification. The aim is to determine the severity of bleeding and, hence, the priority and timing of different therapies. Patients with exsanguinating hemorrhage and unstable hemodynamics require immediate resuscitation and intensive monitoring. Prompt fluid and red cell replacement can be life saving in this situation. Nevertheless, overzealous transfusion in otherwise stable patients should be avoided, as it can be associated with higher rates of rebleeding and death. In a randomized controlled trial involving 921 patients with severe acute upper gastrointestinal bleeding, patients receiving liberal transfusion at a hemoglobin threshold of 9 g/dL had an increased risk of further bleeding and death, compared with patients receiving transfusion only at a hemoglobin threshold of 7 g/dL. Blood product transfusion also carries a risk of pulmonary edema, transfusion reaction, and blood-borne infection. Apart from the hemodynamic assessment, several risk stratification systems have been developed to predict disease outcomes. These systems include the Rockall score, which combines clinical and endoscopic parameters, and the Glasgow-Blatchford score, which combines clinical and laboratory parameters to predict disease outcomes. Furthermore, a risk stratification score combining albumin, International Normalized Ratio (INR), mental status assessment, systolic blood pressure and age (AIMS65) has been derived and validated in more than 60,000 patients to predict in-hospital mortality, length of stay, and costs. These scores may help to risk stratify patients to different therapeutic strategies and allow some of the patients with lower risk for outpatient management.

Pre-endoscopic Management

The role of preemptive acid suppressive therapy before endoscopy was addressed in several studies. In a randomized study involving 638 patients with upper gastrointestinal bleeding, high-dose proton-pump inhibitor was found to reduce the endoscopic grade of peptic ulcer and, hence, the need for endoscopic therapy. This result was confirmed in a subsequent meta-analysis that showed an almost one-third reduction in the need for endoscopic therapy (odds ration [OR] = 0.68, 95% confidence interval [CI] = 0.50–0.93) ; yet there was no significant difference in blood transfusion, rebleeding, surgery, or death. The use of proton-pump inhibitors should not replace endoscopy in actively bleeding patients. In situations whereby endoscopy may be delayed or contraindicated, proton-pump inhibitor therapy improves clinical outcomes.

Endoscopic Treatment

Endoscopy is now the first-line treatment of upper gastrointestinal bleeding. It has been shown to reduce further bleeding (OR = 0.38, 95% CI = 0.32–0.45), the need for surgery (OR = 0.36, 95% CI = 0.28–0.45), and mortality (OR = 0.55, 95% CI = 0.40–0.76). The benefits of endoscopic therapy seem to be most significant in actively bleeding ulcers and in ulcers with a visible vessel. The endoscopic grade of bleeding ulcers can be classified by the Forrest classification, which predicts the risk of rebleeding and death. This classification can be used to stratify patients and guide management decisions. Peptic ulcers with high-risk features (ie, those with active spurting [IA], active oozing [IB], or nonbleeding visible bleeding vessel [IIA]) have a high risk of further bleeding and warrant endoscopic therapy to control the bleeding. For ulcers with an adherent clot (IIB), endoscopic therapy may be performed by targeting the underlying lesion after clot removal. This strategy has been shown to reduce rebleeding as compared with medical therapy alone, although significant heterogeneity exists among the studies. Endoscopic therapy is generally not recommended for ulcers with a flat pigmented spot (IIC) or a clean base (III). Although a recent study suggested that the Forrest classification may not be accurate in predicting mortality, it remained useful to identify patients at high risk of rebleeding, especially those with Forrest IA peptic ulcers.

Conventional methods of endoscopic hemostasis can be divided into injection, thermal, and mechanical methods. Although endoscopic injection of epinephrine was shown to be effective in achieving initial hemostasis, injection monotherapy is insufficient for definitive hemostasis and should be coupled with a second therapy to reduce rebleeding (OR = 0.59, 95% CI = 0.44–0.80) and surgery (OR = 0.66, 95% CI = 0.49–0.89). Both thermal coagulation and endoscopic clipping were effective in achieving hemostasis (81.2% vs 81.5%, P = .99) with no significant difference in rebleeding, need for surgery, and all-cause mortality. These methods have become the mainstay of endoscopic therapies to treat bleeding peptic ulcers.

Apart from these conventional methods, novel endoscopic tools have been developed for hemostasis in gastrointestinal bleeding. TC-325 (Hemospray; Cook Medical, Bloomington, IN) is a hemostatic inorganic particle that becomes adhesive on contact with moisture, forming a mechanical barrier to achieve hemostasis. The absorbent power also concentrates the clotting factors to enhance clot formation. Early clinical experience in 20 patients with active peptic ulcer bleeding showed that TC-325 is safe and effective, achieving a rate of acute hemostasis in 95% of patients. Out of the 19 patients with successful acute hemostasis, 2 patients (10.5%) developed rebleeding by blood counts but not confirmed by endoscopy. Similar rates of efficacy were reported in several subsequent cohorts. A higher rebleeding rate (38.9%) was observed in one study in which its main use was as a rescue therapy. Although TC-325 seems to be safe and effective, prospective trials are required to determine its efficacy against other hemostatic devices.

The Over-The-Scope Clip (OTSC; Ovesco Endoscopy, Tübingen, Germany) is another novel endoscopic device for hemostasis. It is a large endoscopic clip with a greater jaw width, designed to provide a robust tissue apposition to achieve mechanical hemostasis. It has the advantages of being applicable for large ulcers with deep vessels or for closure of fistulas and perforations. Early experiences in patients with gastrointestinal bleeding showed favorable rates of initial hemostasis, with rebleeding rates ranging from 7.4% to 22.2%. Like TC-325, further studies are needed to determine its role as a primary or rescue hemostatic device in peptic ulcer bleeding.

Postendoscopy Management

Proton-pump inhibitor is effective in reducing rebleeding after endoscopy. In a randomized study of 240 patients with actively bleeding ulcers, high dose intravenous omeprazole after endoscopy treatment reduced early rebleeding within 3 days (relative risk = 4.80). These results were supported by other studies showing a consistent reduction in rebleeding and the need for surgery. Despite some studies showing benefits with a high-dose intravenous regimen, there is now increasing evidence that standard dose or even an oral regimen may be as effective in reducing rebleeding. A larger randomized study will be necessary to determine the equivalency or noninferiority of the two treatments in a heterogeneous patient population.

Risk Factors for Rebleeding

Multiple prospective studies have evaluated the risk factors for rebleeding after initial endoscopic hemostasis. One of the earliest descriptions is the Forrest classification of stigmata of recent hemorrhage, which correlated the endoscopic appearance of the ulcer with the rebleeding rate. Given that this classification system only comprises the endoscopic description, Rockall and colleagues undertook a large prospective audit in 1995 to integrate clinical parameters with endoscopic score to predict disease outcomes, including rebleeding and mortality. Nevertheless, with changing epidemiology and the advent of endoscopic techniques, larger cohorts have been conducted to evaluate the risk factors. A cohort study involving 1144 patients with peptic ulcer bleeding identified several clinical and endoscopic parameters as independent factors predicting rebleeding. These findings were supported by 2 subsequent meta-analyses involving more than 3000 individuals, showing hemodynamic instability, active bleeding at endoscopy, large ulcer size, and ulcer location (posterior duodenal wall or lesser gastric curve) as the most important predictors for rebleeding. These factors may be used to identify patients who are most likely to benefit from intensive monitoring and treatment.

Acute Management of Rebleeding

Repeat endoscopy can be performed in patients with clinical evidence of rebleeding after initial hemostasis ( Fig. 1 ). A randomized trial comparing repeated endoscopic therapy versus surgery revealed that 73% of patients with rebleeding can be treated with a second endoscopy to achieve durable hemostasis with a lower complication rate. It is, therefore, recommended to repeat endoscopy after the first episode of rebleeding. Nevertheless, it remains unknown whether the novel endoscopic devices may provide more secure hemostasis in cases of rebleeding, although initial experiences on their use as a salvage therapy were encouraging with high success rates of hemostasis.

A proposed algorithm for the management of acute peptic ulcer bleeding. PPI, proton pump inhibitor; TAE, transarterial angiographic embolization.

If further bleeding recurs after a second endoscopic attempt, transarterial angiographic embolization (TAE) or surgery may be attempted (see Fig. 1 ). A review of 15 case series with 819 intractable bleeding patients undergoing TAE showed a technical success rate of 93%. In a retrospective study comparing TAE with surgery after failed endoscopic hemostasis, TAE was associated with a higher rate of rebleeding (34.4% vs 12.5%, P = .01) but less complications (40.6% vs 67.9%, P = .01). There was no difference in 30-day mortality between the two groups (25.0% vs 30.4%, P = .77), a result consistent with several other retrospective studies. The preliminary results of a randomized study in patients with massive bleeding uncontrolled by endoscopy showed an insignificantly higher failure rate with TAE than surgery (52.9% vs 21.4%, P = .052), despite similar outcomes in terms of hospitalization and mortality between the two groups.

Preemptive Endoscopy or Angiographic Embolization

Second-look endoscopy was one of the strategies to prevent rebleeding. It is generally defined as a routine repeat endoscopy within 24 hours after initial endoscopy, with an aim to identify persistent high-grade stigmata of recent hemorrhage amendable to further therapy. Although a meta-analysis of randomized trials showed a small but significant reduction in rebleeding with second-look endoscopy, most of these early studies did not use proton-pump inhibitors, which subsequently became the standard of care. This benefit, thus, becomes questionable with the addition of intensive proton-pump inhibitor therapy after endoscopy. Besides, further endoscopic treatment can result in perforation, especially when thermal coagulation is repeatedly applied. Two cost-effectiveness analyses suggested that selective instead of routine second-look endoscopy is more cost-effective. Routine second-look endoscopy is not recommended in most international guidelines.

An alternative approach is to provide preemptive treatment to patients with a high risk of rebleeding. In a preliminary study of 222 patients with high-risk ulcers, early postendoscopy TAE to patients with large peptic ulcers (≥1.5 cm in size) reduced rebleeding (OR = 0.18, 95% CI = 0.02–0.92) compared with patients who did not receive TAE. There was no mortality at 30 days in the TAE group (0% vs 4.5%, P = .065). A preemptive approach in selected cases of high-risk ulcer bleeding using TAE should be considered in preventing rebleeding.

Therapeutic Management of Recurrent Ulcer Disease

Peptic ulcer has a high rate of recurrence, especially if the causative agent or cause is not eliminated. Early studies before the discovery of H pylori and proton-pump inhibitor reported relapse rates of up to 74% during a 12-month follow-up period. Approximately 25% to 40% of the ulcer recurrences were asymptomatic, whereas others may present with rebleeding. Definitive treatment and preventive measures are required to reduce ulcer recurrence and its complications.

Helicobacter Pylori Ulcers

Untreated H pylori –associated peptic ulcers tend to recur. It is, therefore, important to ensure complete eradication of the bacterium. An early study comparing eradication therapy (bismuth, metronidazole, and tetracycline) with acid-suppression therapy (omeprazole) showed similar rates of gastric ulcer healing but a significantly lower rate of ulcer recurrence in the eradication group (4.5% vs 53.2%, P <.01). This study establishes the efficacy of eradication therapy in healing H pylori ulcers and preventing their recurrence. A subsequent review confirmed the efficacy and revealed a recurrence rate of 0.75% per patient-year after H pylori eradication.

Despite the importance of eradication, persistent H pylori may occur because of poor drug compliance or emergency of resistant organisms. The importance of the eradication therapy, as well as its common side effects, should be explained to patients to enhance compliance. The local resistance pattern should be recognized in choosing an eradication regimen, and confirmation of successful eradication should be performed no sooner than 4 weeks after therapy.

Nonsteroidal Antiinflammatory Drug–Induced Peptic Ulcers

Nonsteroidal antiinflammatory drugs (NSAIDs) have emerged as a major cause of recurrent peptic ulcer disease as the incidence of H pylori –associated ulcers decline. It is estimated that up to 25% of long-term NSAID users will develop peptic ulcer, of which 2% to 4% will have complications, such as bleeding or perforation. Several studies have been performed to prevent ulcer bleeding in patients starting NSAIDs. Two studies have showed that test and eradication of H pylori infection can substantially reduce peptic ulcers (12.1% vs 34.4% at 6 months, P <.01) and the complications, suggesting that there may be synergistic effects between H pylori and NSAIDs in ulcerogenesis. As for a protective strategy, a systematic review showed that proton-pump inhibitor, high-dose histamine-2 receptor antagonist, and misoprostol were all effective in the prevention of long-term NSAID-related peptic ulcers. For high-risk patients with a history of ulcer bleeding, long-term prophylactic use of a proton-pump inhibitor could significantly lower the risk of recurrent ulcer bleeding (4.4% vs 18.8% at 6 months, P <.01).

Selective cyclooxygenase-2 (COX-2) inhibitors were originally developed to be a less toxic alternative of NSAIDs. Despite early studies showing fewer gastroduodenal ulcers and complications compared with nonselective NSAIDs, COX-2 inhibitors have not adequately reduced the risk of ulcer recurrence in very-high-risk patients. In a randomized study of 287 patients, celecoxib usage in patients with an ulcer bleeding history had a risk of rebleeding of 4.9% over 6 months, compared with 6.4% in patients receiving diclofenac plus omeprazole. Nevertheless, the risk can be lowered by adding a proton-pump inhibitor to a COX-2 inhibitor, which was found to have significantly fewer rebleeding episodes than a COX-2 inhibitor alone (0% vs 8.9% at 13 months, P <.01). However, the increased cardiovascular risk associated with COX-2 inhibitors should be considered and balanced against the gastrointestinal risk.

Antiplatelet-Induced Peptic Ulcers

Acetylsalicylic acid is an independent risk factor for ulcer bleeding, with an estimated OR of 2.07. Because of the cardiovascular diseases pandemic, acetylsalicylic acid and other antiplatelet agents are being increasingly consumed worldwide and have, thus, become an important cause of peptic ulcers.

The strategies for reducing rebleeding in acetylsalicylic acid users include elimination of risk factors and administration of a gastroprotective agent. H pylori infection is an independent risk factor for ulcer bleeding (OR = 4.7, 95% CI = 2.0–10.9). There is now good evidence that H pylori eradication could reduce rebleeding in high-risk acetylsalicylic acid users, although the evidence for average-risk patients is less definite. Despite claims of clopidogrel being less toxic to the gastrointestinal tract, a randomized study showed that the addition of a proton-pump inhibitor to acetylsalicylic acid was preferred to clopidogrel, with a 10-fold difference in ulcer bleeding risk (0.7% vs 8.6%, P <.01). Therefore, adding a proton-pump inhibitor as a gastroprotective agent to low-dose acetylsalicylic acid should be preferred over clopidogrel in situations when either drug can be prescribed.

Another important question in managing peptic ulcer bleeding is the resumption of an antiplatelet agent after hemostasis. In a randomized controlled trial involving 156 patients with established cardiovascular disease, early resumption of acetylsalicylic acid after endoscopic hemostasis resulted in almost 10-fold reduction in all-cause mortality (1.3% vs 12.9%) despite a higher risk for rebleeding (10.3% vs 5.4%). This may be accounted by the fact that the major causes of death in these patients were cardiovascular diseases related rather than gastrointestinal bleeding. Early resumption of acetylsalicylic acid with proton-pump inhibitor in patients with established cardiovascular diseases, preferably within 1 to 3 days, should be considered to minimize the overall mortality and morbidity.