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Current Management of Peptic Ulcer Bleeding

Joseph Sung Nat Clin Pract Gastroenterol Hepatol. 2006;3(1):24-32.

Summary and Introduction

Summary

Peptic ulcer bleeding is a common and potentially fatal condition. It is best managed using a multidisciplinary approach by a team with medical, endoscopic and surgical expertise. The management of peptic ulcer bleeding has been revolutionized in the past two decades with the advent of effective endoscopic hemostasis and potent acid-suppressing agents. A prompt initial clinical and endoscopic assessment should allow patients to be triaged effectively into those who require active therapy, versus those who require monitoring and preventative therapy. A combination of pharmacologic and endoscopic therapy (using a combination of injection and thermal coagulation) offers the best chance of hemostasis for those with active bleeding ulcers. Surgery, being the most effective way to control bleeding, should be considered for treatment failures. The choice between surgery and repeat endoscopic therapy should be based on the pre-existing comorbidities of the patient and the characteristics of the ulcer.
Introduction

Peptic ulcer bleeding is a common medical emergency, accounting for more than 300,000 hospital admissions annually in [1] the US. In a population-based UK audit, the incidence of peptic ulcer bleeding was 103 cases per 100,000 adults per [2] year. The condition is seen predominantly among the elderly: 68% of patients are over 60 years of age and 27% are over [3] 80 years of age. Large cohorts have reported that 7-10% of patients die from the disease. This mortality rate has remained unchanged for the past two decades. Death from peptic ulcer bleeding occurs almost exclusively among elderly patients with significant comorbidities. Approximately 80-85% of upper-gastrointestinal bleeding stops spontaneously and supportive therapy only is required. The remaining 15-20% of upper-gastrointestinal bleeding continues or develops into recurrent bleeding; patients with continual or recurrent bleeding constitute a high-risk group with substantially increased morbidity and mortality rates. Early risk-stratification based on clinical and endoscopic criteria facilitates the delivery of the appropriate level of care to patients. Endoscopic therapy is well accepted as the first-line treatment in most management algorithms. The management of patients with peptic ulcer bleeding requires a multidisciplinary approach, cooperation among gastroenterologists who are skilled in endoscopic hemostasis and surgeons who are proficient in ulcer surgery.

Risk Assessment
Several validated risk-stratification schemes have been published; most are composite scoring systems incorporating both clinical and endoscopic parameters. Such a scheme should aid in making clinical decisions, as to both the need for urgent intervention and the prediction of continued or recurrent bleeding in the context of endoscopic therapy. The latter point is important because alternative treatment strategies should be readily available to prevent recurrent bleeding. Each of the published schemes has its own objective and clinical usage. With the data generated from 4,185 admissions in the national UK audit, Rockall et al. derived a scoring scheme based on admission and postendoscopy scores, and validated its ability to predict recurrent bleeding and death using data from 1,625 [4] patients ( ). Their scoring system is based on age, comorbidities, the presence of shock, and endoscopic findings. A total score of three or less is associated with an excellent prognosis, while a score of eight or more is associated with a high risk of death. To date, the Rockall Score is the most widely used method for risk assessment and it has been validated by [5-7] independent studies.
Table 1. The Rockall Risk Score Scheme
[4]

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Score Value 0 1 2 3

Age (years) Shock

<60 No shock (systolic BP 100, pulse <100) No major comorbidity

60-79 Tachycardia (systolic BP 100, pulse 100) --

>80 Hypotension (systolic BP <100) Cardiac failure, ischemic heart disease, any major comorbidity

---

Comorbidity

Renal failure, liver failure, disseminated malignancy --

Diagnosis

Mallory-Weiss tear, no All other diagnoses Malignancy of upper lesion identified and gastrointestinal tract no SRH -Blood in upper gastrointestinal tract, adherent clot, visible or spurting vessel

Major stigmata of None or dark spot only recent hemorrhage

--

Maximum additive score prior to diagnosis = 7, maximum additive score following diagnosis = 11. BP, blood pressure; SRH, stigmata of recent hemorrhage. Blatchford et al. used simple clinical and biochemical parameters to derive a score that predicts the need for intervention to [8] control bleeding ( ). Without incorporating endoscopic parameters, the Blatchford score was modelled on the clinical process rather than treatment outcome. The risk markers -- elevated blood urea nitrogen, reduced hemoglobin, a drop in systolic blood pressure, raised pulse rate, the presence of melena or syncope, and evidence of hepatic or cardiac disease -are assigned numerical values that are easy to remember. The full score can be used to determine the required level of care on admission and to identify those patients who need urgent treatment.
Table 2. Blatchford Admission Risk Markers

Admission risk marker

Score component value

Blood urea (mMol/l) 6.5-8.0 8.0-10.0 10.0-25.0 >25 Hemoglobin (g/l) for men 120-130 100-120 <100 Hemoglobin (g/l) for women 100-120 <100 Systolic blood pressure (mm Hg) 1 6 1 3 6 2 3 4 6

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100-109 90-99 <90 Other markers Pulse >100 per min Presentation with melena Presentation with syncope Hepatic disease Cardiac failure

1 2 3

1 1 2 2 2

Reproduced with permission from reference 8 (2000) Elsevier. The Baylor Group developed and validated the Baylor Bleeding Score to identify patients who might require early surgical [9] intervention. By assessing simple pre-endoscopic (age; number and severity of concurrent medical illnesses) and postendoscopic parameters (site and stigmata of bleeding ulcers), Saeed et al. showed that this scoring system might be able to predict patients at risk of rebleeding after successful endoscopic therapy of bleeding ulcers. In the Canadian Consensus Conference Statement published in 2003, Barkun et al. reviewed studies over the previous [10] decade that used multivariate analyses, and formulated their own risk scoring scheme. Like the authors of most other scoring systems, they concluded that advanced age, poor health status or comorbid illness, continued or recurrent bleeding, fresh hematemesis or hematochezia, and the onset of bleeding in hospitalized patients (i.e. those admitted for reasons other than upper-gastrointestinal bleeding) predicted poor prognosis and death. Endoscopic factors including active bleeding, major stigmata of recent hemorrhage, ulcers greater than 2 cm in diameter, and the location of ulcers in proximity to large arteries, were also identified as factors that predict recurrent bleeding.

Pharmacologic Therapy
Platelet aggregation is impaired in acidic environments, and hence blood clots that form on the surface of peptic ulcers are [11] unstable. In the stomach, an almost complete shutdown of gastric secretion is required to facilitate platelet aggregation and clot formation.
H -Receptor Antagonists
2

With the advent of potent acid-suppressing agents, attempts have been made to halt ulcer bleeding using pharmacologic control. Unfortunately, H -receptor antagonists (H RAs) are relatively weak acid suppressors. No single study has
2 2

convincingly demonstrated an overall benefit of using H RAs in the cessation of acute peptic ulcer bleeding. In a recent
2

meta-analysis, Levine et al. pooled data from 30 randomized studies comprising 3,786 patients. They showed that the use of H RAs was beneficial only in patients with gastric ulcers, giving a modest reduction in the rate of recurrent bleeding,
2

[12]

the need for surgery and in mortality rate. There was no demonstrable benefit even with a high-dose infusion of H RA. These findings are remarkably similar to those reported by Collins and Langman. generally recommended in the management of bleeding peptic ulcers.
Proton-Pump Inhibitors
[13]
2

The use of H RAs is therefore not

2

Proton-pump inhibitors (PPIs) have a more potent acid-suppressing effect in the stomach than H RAs. In the first large-scale
2

study of intravenous omeprazole for the treatment of peptic ulcer bleeding, 1,174 patients with overt signs of uppergastrointestinal bleeding were randomly assigned to receive placebo or omeprazole 80 mg intravenous bolus followed by 40

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[14]

mg every 8 hours or placebo. Disappointingly, no differences in recurrent bleeding or mortality rates were observed between the two treatment groups. In this particular trial, patients were randomized on admission and before endoscopic confirmation of the diagnosis; the timing of endoscopy was not standardized. The decision to perform endoscopic therapy and guidelines on how endoscopy was performed were not uniform among participating endoscopists. There were indications, however, that endoscopic stigmata of bleeding were seen less frequently during endoscopy among patients given omeprazole. This study suggests that omeprazole might hasten the resolution of endoscopic stigmata of bleeding. Two multicenter trials from Scandinavia have subsequently evaluated the infusion of high-dose omeprazole (80 mg [15,16] intravenous bolus followed by 8 mg per hour for 72 h) in conjunction with endoscopic treatment. Both trials, however, lacked discrete outcome variables. Instead, they used composite endpoints combining clinical and endoscopic outcomes in the analysis, which makes the interpretation of efficacy difficult. In the trial by Hasselgren et al., the mortality rate at day 21 [16] was, in fact, higher among those receiving active treatment. The first evidence showing a benefit of PPIs for the treatment of peptic ulcer bleeding came from a study performed in [17] India. 220 patients were randomized to receive either oral omeprazole 40 mg twice daily or placebo for 5 days after endoscopic confirmation of the presence of a bleeding peptic ulcer (defined as actively bleeding ulcers or ulcers with [17] non-bleeding visible vessels or clots). Patients whose ulcers had a nonbleeding visible vessel or a clot were less likely to have further bleeding. A reduction in recurrent bleeding was not evident in those patients with ulcers with spurting or oozing hemorrhage who were given oral omeprazole. In ulcers that stopped bleeding spontaneously, acid suppression again seemed to prevent recurrent bleeding. In their study, Lau et al. adopted a policy of early endoscopic triage and enrolled only patients with actively bleeding ulcers or [18] ulcers with nonbleeding visible vessels. In this double-blind, placebo-controlled trial, 240 patients were randomized to receive either a high-dose omeprazole infusion (80 mg intravenous bolus followed by 8 mg per hour for 72 h) or an equivalent placebo. The rate of recurrent bleeding at day 30 was 21.7% and 5.8%, respectively, for those assigned to placebo and omeprazole infusion (RR 3.7, 95% CI 1.68-8.23). The study also demonstrated that there was a reduction in the need for re-treatment and blood transfusion, as well as a trend towards fewer surgeries and deaths among those assigned to omeprazole infusion. This trial provides convincing evidence to support the adjunctive use of high-dose PPI infusion after endoscopic hemostasis. Two studies have further evaluated the use of oral PPIs after endoscopic treatment. Javid et al. enrolled 166 patients with [19] peptic ulcers with signs of recent hemorrhage, confirmed by endoscopy. All patients received endoscopic injection sclerotherapy using 1:10,000 epinephrine and 1% polidocanol, and were randomly assigned to receive omeprazole (40 mg orally) every 12 h for 5 days, or placebo. Recurrent bleeding was reduced, and the hospital stay was shorter for those who received the oral PPI. In a similar study, Kaviani et al. randomized 160 patients with bleeding ulcers after endoscopic [20] injection. The authors also showed that there was a lower rate of recurrent bleeding associated with the use of oral omeprazole. With the accumulation of conflicting data on the use of PPIs for the treatment of peptic ulcer bleeding, the Cochrane [21] Collaboration Group performed a systemic review on the subject. Twenty-one randomized, controlled trials with a total of 2,915 participants were identified in the literature. The pooled data showed that there was no significant difference in mortality rates between patients receiving PPIs and control treatment (5.2% versus 4.6%, OR = 1.11, 95% CI 0.46-0.76). PPI treatment did, however, significantly reduce the rate of recurrent bleeding and surgical intervention compared with control. The result was independent of the route of administration of PPI -- oral or intravenous -- as long as a high dose was given. Post-hoc analysis showed that there was an interesting difference in patient outcome according to the geographic location of trials. For European studies, mortality rates were significantly higher for PPI treatment than for controls, whereas data pooled from Asian trials revealed that the mortality rate was significantly lower with PPI treatment (1.5%) than for controls (4.7%) (OR = 0.35, 95% CI 0.16-0.74, P = 0.006). It is not clear why there is such a difference in outcome among different geographic locations, but a possible explanation is variation in the rate of PPI metabolism and acid secretion capacity among patients of different ethnic groups; these ideas require further investigation. The benefit of PPI therapy has been further confirmed in a study comparing the use of intravenous pantoprazole versus intravenous ranitidine in the prevention of peptic ulcer bleeding. Barkun et al. randomized more than 1,200 patients to [22] receive either of the two pharmacologic therapies for 72 h. Using a composite endpoint, including need for endoscopy,

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surgery and death, they showed that patients who received intravenous PPI had a lower rebleeding risk than those who received an H RA.
2

In 2004, the American Society of Gastrointestinal Endoscopy recommended the use of PPIs in all patients with uppergastrointestinal bleeding that was severe enough to require endoscopic therapy, and in patients with suspected peptic ulcer [23] bleeding associated with hemodynamic instability. The recommendation endorsed systematic use of PPIs in uppergastrointestinal bleeding. The benefit of pre-emptive PPIs in patients with upper-gastrointestinal bleeding is supported by the interim analysis of a [24] large-scale randomized study from Hong Kong. Patients with symptoms and signs of upper-gastrointestinal bleeding who received intravenous PPIs were found to have less active bleeding on endoscopy, and hence were less likely to require endoscopic therapy. This result needs to be confirmed by the final analysis of this study and validated by other clinical trials. Which dose of intravenous PPI to use has been the subject of debate. While a high-dose regimen (80 mg bolus followed by 8 mg/h infusion) has been used in most studies, the optimal dose of PPI to achieve almost complete cessation of acid secretion in the stomach in patients with upper-gastrointestinal bleeding has not been determined. Two studies suggested [25,26] that there might be room to reduce the infusion of intravenous omeprazole to the 'regular' dose of 20-80 mg per day. It worthwhile pointing out that these studies included patients with low-risk ulcers who did not require endoscopic therapy. The relatively small sample sizes might also limit the interpretation of these studies.

Endoscopic Therapy
Since the late 1980s, endoscopic hemostatic therapy has been widely accepted as the first-line therapy for uppergastrointestinal bleeding. Numerous clinical trials and two meta-analyses have confirmed the efficacy of endoscopic therapy [27,28] in this setting. Most clinical trials demonstrated a reduction in both recurrent bleeding and the need for surgical intervention when endoscopic hemostasis was used. Endoscopic therapy can be broadly categorized into injection therapy, thermal coagulation, and mechanical hemostasis. When analyzed separately, injection therapy, thermal-contact devices, and laser treatment all decrease the frequency of recurrent bleeding and rate of surgical intervention.
Injection Therapy

Injection with solutions of diluted epinephrine (1:10,000) is widely used because of its simplicity. All that is required is a sclerotherapy needle, and the technique is simple. The principal mechanism of action by which diluted epinephrine solutions work is a tamponade effect induced by the volume of solution injected. It is, therefore, logical that in a recent study, a large [29] volume (35-45 ml) epinephrine injection appeared to be more effective than a standard volume (15-25 ml) injection. Solutions of agents other than epinephrine, such as polidocanol, saline and even dextrose, can produce the same effect. In spite of the large body of published literature, no single solution for endoscopic injection has been shown to be superior to another in achieving hemostasis. The use of sclerosants (including absolute alcohol) in injection therapy for bleeding ulcers should, however, be discouraged: extensive and uncontrolled tissue necrosis caused by sclerosants injected to the ulcer base can result in ulcer perforation and complications relating to adjacent tissues.
Thermal Devices

Thermal devices can be divided into contact (heater probe, monopolar and bipolar electrocoagulation) and noncontact types (laser treatment, argon plasma coagulation [APC]). While the hemostatic effects of contact probes are well established by clinical trials, the use of APC in the treatment of peptic ulcer bleeding has only recently been reported. There has been only one randomized, controlled study comparing APC with heater-probe coagulation, and it suggested that APC is equally as [30] safe and effective. In both groups of patients, epinephrine injection was administered before thermal treatment. Of 185 cases analyzed, 97 were in the heater-probe group and 88 in the APC group. No significant differences were detected in terms of initial hemostasis at index endoscopy, frequency of recurrent bleeding, requirement for emergency surgery, number of units of blood transfused, length of hospital stay, and mortality rate. To summarize, no single method of endoscopic thermal coagulation therapy is superior to the others.

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Mechanical Devices

Mechanical devices have been used for the treatment of variceal hemorrhage, but rarely in the treatment of peptic ulcer disease. Hemoclips have gained popularity in the past few years. Initial enthusiasm for the use of hemoclips was generated [31] by a study by Cipolleta and colleagues, in which they compared hemoclips with heater probe thermocoagulation. They reported a significantly lower rate of recurrent bleeding with the use of hemoclips (1.8% versus 21%). The deployment of hemoclips on fibrotic ulcer floors can be difficult, however, particularly when they are used tangentially or with the endoscope in a retroflexed position. Indeed, two subsequent trials yielded conflicting results on the use of hemoclips. Lin and colleagues [32] compared hemoclips with heater probe coagulation, and in 6 out of 40 patients the hemoclips could not be applied. [33] Gevers et al. randomly assigned patients with bleeding ulcers to treatment with hemoclips, injection, or both. They reported a failure rate of 13 out of 35 patients with the hemoclips compared with 5 out of 34 patients with injection and 8 out of 32 patients with combined therapy. The efficacy of hemoclips seems to be limited by difficulty of successful application. With improvements in design, this technical problem might be overcome. More studies are required to give a fair verdict on the effectiveness of hemoclips.
Combined Therapy

Many endoscopists favor combined therapy, in which the injection of diluted epinephrine precedes thermal coagulation. In actively bleeding ulcers, an injection can diminish or even stop bleeding, allowing a clear view of the bleeding vessel, which in turn facilitates accurate thermal coagulation. The cessation of blood flow can also prevent dissipation of thermal energy, so that tissue injury can be minimized. In theory, this all sounds very promising. In a prospective randomized trial, 134 patients with actively bleeding ulcers who received epinephrine alone were compared [34] with 136 patients who received the combined therapy of epinephrine injection followed by heater-probe coagulation. There was no difference in the outcome of the two treatment strategies as measured by rebleeding, the need for surgery, requirement for repeated endoscopic hemostasis, length of hospital stay, mortality rate, or healing at 4 weeks. When the subgroup of patients with spurting ulcers was analyzed separately, however, there was less rebleeding in the combined group. A lesser need for surgery was seen in the combined treatment group (8 out of 27 patients versus 2 out of 31 patients in the injection group, P = 0.03). For the severe form of spurting hemorrhage, combined therapy therefore seems to be beneficial. The benefit of combination therapy has been evaluated in many trials and confirmed by meta-analysis. In a systematic review that aimed to determine whether the addition of a second hemostatic procedure immediately after epinephrine injection improves efficacy of hemostasis or patient outcomes, a total of 16 randomized studies involving 1,673 patients were [35] analyzed. The addition of a second procedure reduced the rate of recurrent bleeding from 18.4% to 10.6% (OR 0.53, 95% CI 0.40-0.69) and that of emergency surgery from 11.3% to 7.6% (OR 0.64, 95% CI 0.46-0.90). The mortality rate fell from 5.1% to 2.6% (OR 0.51, 95% CI 0.31-0.84). Eleven studies used injected substances (such as a sclerosant, tissue adhesive, or thrombin), two studies added hemoclips, and three studies evaluated the added use of thermal coagulation devices. Pooled data revealed that combined therapy is the treatment of choice for high-risk bleeding peptic ulcers. The meta-analysis also confirmed a greater risk of the significant complications of perforation and gastric-wall necrosis in the combined therapy group (6 out of 558 patients) than in the epinephrine alone group (1 out of 560 patients). Furthermore, improvement in prognosis seems to be more evident in those with active bleeding. The caveat of this meta-analysis is that some of the studies included are relatively old, and acid suppression therapy using a high-dose PPI was not included. Currently, the standard therapy most widely used is injection with diluted epinephrine, followed by thermocoagulation with a 3.2 mm heater probe.

Second-Look Endoscopy
Despite the effectiveness of endoscopic hemostasis, rebleeding occurs in 10-25% of cases, irrespective of the method of treatment. The benefit of a routine 'second-look' endoscopy after the initial hemostasis is disputed. In a meta-analysis of four studies comparing systematic second-look endoscopy and re-treatment versus expectant treatment, Marmo et al. showed that the risk of recurrent bleeding with the former approach was reduced by 6.2%, but risk reductions for surgery and [36] mortality were insignificant. The authors concluded that appropriate selection of patients for second-look endoscopy is crucial. The selective use of second-look endoscopy and re-treatment has been supported by a single-center trial that

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included only Forrest I and IIa ulcers; patients were treated by a standardized endoscopic therapy in combination with [37] intravenous omeprazole. A scheduled second-look endoscopy the day after initial endoscopic hemostasis was found to prevent recurrent bleeding (relative risk 0.33, 95% CI 0.1-0.96).

Nonbleeding Ulcers With an Adherent Clot or Protuberant Vessel

The role of pharmacologic and endoscopic treatments for nonbleeding peptic ulcers with adherent clots is not well defined. One concern with endoscopic manipulation is the possibility of provoking bleeding while elevating the clot. Two recent randomized, controlled studies supported the lifting of clots overlying an ulcer floor, followed by endoscopic therapy. Jensen et al. randomized 32 patients (17 to medical treatment and 15 to endoscopic therapy) and found that endoscopic therapy [38] completely abolished recurrent bleeding, whereas 35.3% of patients on medical therapy alone experienced rebleeding. [39] Bleau et al. randomized 56 patients (35 to medical therapy and 21 to endoscopic therapy) and reported similar results. It is worth emphasizing, however, that both trials recruited only small numbers of patients. These trials also differed in their definition of an adherent clot. Jensen et al. defined an adherent clot as greater than 6 mm in diameter, red in color, and amorphous in its texture. By contrast, Bleau et al. defined an adherent clot as a red, maroon, or black protuberance greater than 3 mm in diameter, that could not be dislodged by forceful irrigation with water. Combined endoscopic treatment and the adjunctive use of PPI infusion has been compared with the use of PPI infusion [40] alone in the treatment of ulcers with nonbleeding visible vessels or clots. In those assigned to the combined treatment, recurrent bleeding was seen in 1 out of 70 patients, which occurred on day 14 after treatment. In those given an intravenous PPI infusion alone, the rate of recurrent bleeding was 11% at day 30. While the results clearly showed that combined therapy was superior in the control of bleeding, the low rate of recurrent bleeding in the PPI infusion alone group would suggest that acid suppression does have a therapeutic role in the treatment of ulcers with nonbleeding visible vessels and clots.

Recurrent Bleeding After Initial Hemostasis

At the time of recurrent bleeding, the dilemma often faced by physicians is whether to repeat endoscopic treatment or to refer the patient directly to surgery. Lau et al. conducted a randomized trial in patients who experienced recurrent bleeding [41] after initial endoscopic control of their bleeding ulcers. Of 48 patients who underwent endoscopic re-treatment, long-term hemostasis was achieved in 35 patients. Ulcer perforation occurred in two patients, in association with repeated thermal coagulation. Of 44 patients assigned to surgery, 22 underwent gastrectomy, which was associated with greater morbidity. The two groups did not, however, differ in regard to mortality rate. In a logistic regression analysis, ulcers larger than 2 cm in diameter and hypotension at the time of rebleeding were two independent factors that predicted failure of endoscopic retreatment. The findings of Lau et al. suggest that, in the management of patients with recurrent bleeding after initial endoscopic control, a selective approach can be adopted based on the local characteristics of the ulcer and the pre-existing comorbidities of the patients. Large chronic ulcers should probably be treated by expeditious surgery if recurrent bleeding ensues. Those who are poor surgical candidates might benefit from repeated endoscopic treatment.

Eradication of Helicobacter Pylori

There is ample evidence to prove that, for bleeding related to Helicobacter pylori infection, when patient is not using aspirin or nonsteroidal anti-inflammatory drugs, curing the infection with a 1 or 2 week course of triple therapy obviates the risk of ulcer recurrence and ulcer rebleeding. This therapy is even more reliable than maintenance therapy with H RA because the compliance of patients for taking long-term medication will no longer be required. especially in young ulcer patients, cannot be over-emphasized.
[42-44]
2

The economic impact of this strategy,

Conclusions
Peptic ulcer bleeding is best managed using a multidisciplinary approach, as outlined in Figure 1. A prompt initial clinical and endoscopic assessment should allow the effective triaging of patients who require active therapy versus those who need monitoring and preventive therapy. A combination of pharmacologic and endoscopic therapy (i.e. injection and thermal coagulation) offers the best method of hemostasis to those with active bleeding ulcers. Those patients with an adherent clot and/or a protuberant vessel should probably receive the same therapy to reduce the risk of recurrent bleeding. Rebleeding

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despite initial hemostasis can be effectively handled by repeating endoscopic therapy or surgery. The choice between the two options should be made at the discretion of the physician, based on the pre-existing comorbidities of the patient.

Figure 1.

Clinical algorithm for the management of peptic ulcer bleeding adopted at the Prince of Wales Hospital, Hong Kong.

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