Management of Nonvariceal Upper Gastrointestinal … · Endoscopy is the cornerstone of management....

232 JCOM May 2013 Vol. 20, No. 5 www.jcomjournal.com

UPPER GASTROINTESTINAL BLEEDING

ABSTRACT• Objective:Toprovideanoverviewofmanagementof

nonvaricealuppergastrointestinalbleeding(NVUGIB).• Methods:Literaturereviewinthecontextofaclinical

case.• Results: NVUGIB is a common condition, with ap-

proximately 30% to 50% of cases attributable topeptic ulcer disease. Endoscopy is the cornerstoneof management. Comprehensive evidence-basedguidelinesexisttodirectappropriatecareforpersonswith NVUGIB. Adherence to these guidelines willpromotethedeliveryofthemostcost-effectivecare,allowing high-risk patients to receive appropriatemanagementtoreducetheriskofrebleedinganditscomplicationsandallowlow-riskpatientstobeman-agedintheoutpatientsetting.

• Conclusion: Improvements in medical and endo-scopic management have led to a decrease in themorbidityandmortalityassociatedwithgastrointesti-nalbleeding.Itishopedthatfurtherresearchwillhelpbetterdifferentiatelow-riskandhigh-riskpatientsandthat further improvements inendoscopic techniquesandpost-endoscopicmedicaltherapymayleadtoafurtherreductioninrebleedingratesandmortality.

Upper gastrointestinal bleeding (UGIB) is a com-mon gastrointestinal emergency and a leading cause of mortality, with patients requiring ad-

mission to a hospital having a mortality rate of 4.5% to 8.2% [1]. It has an annual incidence of 48 to 100 cases per 100,000 adults [2–4] and poses a significant economic burden, costing the United States $2 million per year [5]. The latest research shows geographic variation in UGIB incidence and mortality [6]. UGIB is classically divided into variceal and nonvariceal bleeding (NVUGIB). A recent review article reports 80% to 90% of acute UGIB in Europe and North America as being nonvariceal in etiology [7]. Fortunately, advances in the management of NVUGIB have led to a decrease in mortality in recent

years [3,4]. This review article aims to provide a brief overview of risk factors for NVUGIB, patient assessment, and pre- and post-endoscopic management.

CASE STUDYInitial Presentation and History

An 81-year-old man with a past medical his-tory of type 2 diabetes mellitus, hypertension,

ischemic heart disease (on aspirin), and gastroesopha-geal reflux disease presents to the emergency department with 2 episodes of melena.

Physical ExaminationBlood pressure is 95/63 mm Hg and heart rate is 120 bpm. Hemoglobin has dropped from 79 g/L to 59 g/L, blood urea nitrogen is 20.1 mmol/L, and INR is 1.2.

• WhatclinicalfeaturesareassociatedwithUGIB?

A retrospective analysis of risk predictors of UGIB reports the most common presenting symptom as hemetemesis (59%), followed by melena (29%) [8]. Hematochezia (passage of bright red blood per rectum) has been noted as a less common but more severe presentation of UGIB [9]. A recent review by Srygley et al [1] has shown that having a history of melena, epigastric pain, a positive nasogastric lavage, and melena on exam are strongly predictive of an UGI source, whereas finding clots in the stool is suggestive of the lower GI tract being the site of bleeding [1]. Elevation of the urea/creatinine ratio also is much more common in UGIB, with persons with a urea/creatinine ratio of 30 or greater having 7.5 times increased odds of having an upper GI bleed. Having a

Management of Nonvariceal Upper Gastrointestinal BleedingCase Study and Commentary, Sobia Asad Zuberi, MB, BCh, and Laura E. Targownik, MD, MSHS

From the University of Manitoba, Winnipeg, Manitoba, Canada.

www.jcomjournal.com Vol. 20, No. 5 May 2013 JCOM 233

normal hemoglobin also decreased the likelihood of an upper GI source by 75%.

• WhatareriskfactorsforUGIB?

Approximately 30% to 50% of NVUGIB cases can be at-tributed to peptic ulcer disease [7,10]. Peptic ulcer disease can have up to a 5% to 10% mortality rate, some of which may be credited to its prevalence in the geriatric popula-tion. Other causes of NVUGIB include (in order of de-creasing incidence) erosive gastritis, esophagitis, Mallory-Weiss tear, malignancy, and miscellaneous (Dieulafoy’s lesion, hemobilia, angiodysplasia, vasoenteric fistula, gas-tric antral vascular ectasia) [10].

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (ASA) has been well documented to be a leading cause of NVUGIB [11,12]. Colonization of the gastrointestinal tract with Helico-bacter pylori is another important risk factor that may eventually lead to peptic ulcer disease, which in turn may cause NVUGIB [13]. The use of anticoagulants has also shown to be a cause of NVUGIB [14]. The introduction of acid suppression therapy with pro-ton pump inhibitors (PPIs) and proper eradication of H. pylori with triple therapy has proven to be beneficial in reducing the incidence of NVUGIB [15,16].

• Whatare importantcomponentsofpreendo-scopicmanagement?

PreendoscopicTreatmentPre-endoscopic treatment is an essential component of the management of NVUGIB. When patients present with signs and symptoms suggestive of any UGIB, they should be immediately resuscitated to maintain adequate blood pressure. If the patient’s hemoglobin is less than or equal to 70 g/L, it is recommended that they be transfused with packed red blood cells, though transfusion at higher hemoglobin levels should probably be avoided [17]. It is often recommend to correct elevated INRs. If patients are on warfarin, their INR should be corrected with intrave-nous vitamin K (for those on warfarin) or replacement of fresh frozen plasma (for those with liver disease, or other coagulopathies). The use of concentrated clotting factors

(eg, octoplex) can also be considered when coagulopathy is present and bleeding is ongoing and/or leading to hemody-namic instability [18]. However, a high INR does not war-rant the need to delay endoscopic intervention if bleeding is severe [19,20]. There is also little evidence on how to best manage UGIB patients who are using the new oral factor Xa inhibiting anticoagulants, such as dagabatrin and/or rivaroxiban, as the effect of factor Xa inhibitors cannot be reversed with vitamin K or clotting factor replacement [21]. Although guidelines do not exist for patients who develop UGIB in this setting, one should proceed with urgent endoscopy if significant UGI bleeding has occurred.

RiskStratificationRisk stratification is an essential component of the assess-ment of a patient with UGIB, both to determine which pa-tients require a more urgent endoscopic assessment and also to better identify low-risk patients who may be able to be investigated electively. Several pre-endoscopic risk assessment tools have been created to help physicians decide whether

CASE-BASED REVIEW

Table 1.Glasgow-BlatchfordScore

Admissionriskmarker Score

Bloodureanitrogen(mmol/L)

≥6.5–7.9 2

8.0–9.9 3

10.0–24.9 4

≥25 6

Hemoglobin,male(g/L)

>120–130 1

100–119 3

<100 6

Hemoglobin,female(g/L)

≥100–120 1

<100 6

Systolicbloodpressure(mmHg)

100–109 1

90–99 2

<90 3

Others

Pulse>100 1

Melena 1

Syncope 2

Hepaticdisease 2

Cardiacdisease 2



or not the patient needs urgent intervention. The 2 most widely used and evaluated pre-endoscopic risk stratification scoring systems are the Glasgow-Blatchford bleeding score [22] (GBS) and the Rockall pre-endoscopic risk score [23].

Glasgow-Blatchford Score The GBS (Table 1) uses clinical and laboratory data to pre-dict the need for blood transfusion, endoscopy, or surgery. The advantage of this scoring tool is in its simplicity, thus making it popular, even to medical students and junior resi-dents. Using GBS, patients are classified as low risk and can be treated as outpatients if they meet the following criteria: blood urea nitrogen less than 6.5 mmol/L, hemoglobin more than 130 g/L (male) or 120 g/L (female), systolic blood pressure greater than or equal to 110 mm Hg, and pulse less than 100 beats per minute. A recent article validated the use of GBS in successfully identifying low-risk patients and therefore reducing the number of unnecessary admis-sions to hospital, demonstrating that a score of 0 or 1 on admission is associated with a 99% probability of not requir-ing an endoscopic intervention or transfusion [24]. Its main limitation is its poor specificity in identifying low risk patients, as the vast majority of persons with a GBS of 2 or greater will also not require an intervention

Rockall ScoreAnother risk stratification tool that is widely used in clini-cal practice is the pre-endoscopy Rockall score (Table 2).

This is essentially a modified version of the Rockall scoring tool, which requires a diagnosis and endoscopy to predict the risk of rebleeding [25]. The pre-endoscopy Rockall score uses the patient’s age, presence of shock and comor-bidity to determine if a patient is low risk for rebleeding and death, and therefore eligible to be treated as an outpa-tient (similar to the GBS). However, more recent studies have reported this scoring tool as being less accurate than the GBS at predicting the need for intervention [26].

PharmacologicTherapyPharmacologic therapy is often used prior to performance of endoscopy in order to better prepare the upper GI tract for optimal visualization. During large UGIB episodes, parts of the stomach, especially the fundus, may be diffi-cult to optimally evaluate due to the presence of retained blood clots. Therefore, agents that improve gastric emp-tying, specifically erythromycin and metoclopramide, have been evaluated in the pre-endoscopic setting in order to improve visualization of the upper GI tract. Erythromycin, given at a dose of 250 mg 20 minutes prior to endoscopy, has been shown to improve upper GI visualization compared to no therapy [27]. Metoclo-pramide has been less widely evaluated, but appears to also improve gastric visualization compared to placebo [28]. While pro-motility agents are not routinely recommend-ed prior to endoscopy in UGIB, their use should be con-sidered when large volume bleeding is suspected or when

Table 2.RockallRiskScore

Score

0 1 2 3

Age (years)* <60 60–79 ≥80

Shock* SystolicBP ≥100 SystolicBP≥100 SystolicBP<100

Heartrate<100 Heartrate ≥100

Comorbidity* None Ischemicheartdisease,cardiac

failure,othermajorcomorbidity

Renalfailure,hepaticfailure,disseminatedmalignancy

Diagnosis Mallory-Weisstear,nolesion,

ornostigmataofhemorrhage

Allotherdiagnoses

MalignancyofUGItract

Stigmata of hemorrhage None,ordarkspot

BloodinUGItract,adherentclot,visible

orspurtingvessel

*Thesevariablesusedtocalculatepre-endoscopyriskscore.


there are signs of ongoing bleeding and performance of endoscopy is imminent [7,29].

PPIs are also widely used prior to endoscopy. The evidence supporting the use of pre-endoscopic PPI emerged from a large trial where patients who presented with suspected UGIB were randomized to receive 80 mg IV pantoprazole, followed by an 8 mg per hour infusion or placebo [30]. It was determined that patients who received pre-endoscopic PPI therapy were less likely to require endoscopic hemostatic therapy (19.1% vs. 28.4% in the placebo group), more likely to have ulcers with clean bases (120 vs. 90 patients in the placebo group), and had shorter hospital stays. Pre-endoscopic PPI had no effects on rates of rebleeding or mortality. In spite of the lack of a demonstrable benefit on rebleeding rates, PPIs are still routinely recommended prior to endoscopy because of their relatively low cost, limited side-effect profile, and the potential to downgrade high-risk le-sions may lead to cost-savings in prevented hospital admissions [31].

CaseContinuedThe patient was resuscitated with intravenous fluids, transfused 3 units of packed red blood

cells, was given 80 mg IV pantoprazole bolus, and then started on an 8 mg per hour infusion. His aspirin was held. The patient’s Glasgow-Blatchford bleeding score was 10 and pre-endoscopy Rockall score was 6.

• Whatareguidelinesfortheuseofendoscopy?

Endoscopy is the cornerstone of management of patients with NVUGIB. The benefits of endoscopy are twofold. First, it allows direct visualization of the source of bleed-ing, providing a definitive diagnosis. Second, prognostic information of the likelihood of continued bleeding or recurrent bleeding is obtained, which may allow for more intensive therapy for persons at high risk of recurrent bleeding or UGIB-related complications as well as out-patient management of low-risk patients. Furthermore, endoscopy facilitates the delivery of direct therapeutic hemostasis, so that persons with ongoing bleeding or at high-risk of recurrent bleeding can undergo hemostatic treatment to prevent future bleeding episodes.

The time frame during which to perform endoscopy is controversial. Most recent guidelines recommend that pa-

tients with NVUGIB have endoscopy within 24 hours of presentation [32,33]. A recent prospective national audit done in the UK showed a direct correlation between late endoscopy (greater than 24 hours) and increased length of hospital stay and a higher rebleeding rate [34]. Conversely, urgent endoscopy (less than 12 hours) was not associated with decrease in mortality but did show improved effec-tiveness of treatment, and decreased need for surgical in-tervention [35]. On the contrary, other retrospective anal-yses did not demonstrate that endoscopy within 6 hours of presentation was associated with decreased rates of mor-tality or the need for blood transfusions or surgery [36]. It is important to note that most patients undergoing urgent endoscopy are those with severe bleeding. There-fore, the lack of benefit seen with urgent endoscopy may be related to the patient population rather than the pro-cedure itself. A few studies analyzed patients admitted on weekends with NVUGIB; they concluded that these patients are less like to get an endoscopy within 24 hours of presentation and are therefore associated with a higher in-hospital mortality [37,38]. In rare circumstances such as the patient having an acute coronary syndrome, it is rec-ommended to delay endoscopy until the patient has been adequately stabilized [39].

ClassificationofPepticUlcersThe main predictor of the risk of rebleeding is the appearance of the ulcer base at the time of initial endoscopy. The Forrest classification (Table 3) uses the characteristics of the lesion found on endoscopy to place patients into high-, intermediate-, or low-risk groups [40]. Forrest Ia lesions (active arterial spurting) are as-sociated with an 85% to 100% risk of recurrent/ongoing bleeding in the absence of endoscopic hemostasis, where-as only one-quarter of Forrest 1b lesions (arterial oozing) will have recurrent bleeding. Forrest IIa (non-bleeding visible vessels) are associated with a 50% risk of recurrent bleeding if left untreated. All of these lesions should be considered for endoscopic hemostasis in order to decrease the risk of further hemorrhage. Conversely, Forrest IIc (hematin flat spot) and Forrest III (clean based) ulcers do not require application of hemostasis, as only 3% to 5% of these lesions will re-bleed [41]. Persons with Forrest IIb (adherent clots) are at intermediate risk of rebleeding, though it is recommended that clots should be removed after first injecting the surrounding tissue with 1:10000 epinephrine to determine if an underlying non-bleeding visible vessel is present [42].

CASE-BASED REVIEW



• What endoscopic treatment modalities areutilized?

There are many different modalities of treatment using endoscopy. It is generally recommended that patients with Forrest Ia and IIa lesions be considered for endo-scopic hemostasis [32]. Forrest IIb lesions may also re-quire endoscopic hemostasis if a visible vessel is apparent following removal of the overlying clot. The common modes of endoscopic hemostasis include epinephrine injection, thermal coaptive coagulation, and application of mechanical clip devices [43]. Endoscopic therapy has been shown to decrease the risk of rebleeding and of mortality in patients with active arterial bleeding and those with non-bleeding visible vessels. The applica-tion of epinephrine in combination with either thermal therapy or mechanical therapy has been shown to be su-perior to epinephrine monotherapy [44,45]. The choice of endoscopic technique is generally left to the discretion of the endoscopist. In the event of recurrent bleeding following performance of endoscopic hemostasis, repeat-ing endoscopy and reapplying hemostatic techniques has been shown to prevent surgery in approximately ¾ of cases [46]. Some studies have suggested that a routine second-look endoscopy may be useful even in the absence of signs of recurrent bleeding to identify occult ongo-ing bleeding and the continuing presence of high-risk lesions amenable to endoscopic therapy. While there is evidence that second-look endoscopy may decrease re-bleeding rates, these studies come from an era where PPI therapy was not routinely used, so it is unclear whether these results are generalizable to patients in the current day [47]. Should initial hemostasis be unsuccessful or if rebleeding occurs after a second attempt at endoscopic

hemostasis, the patient should receive urgent consulta-tion with a surgeon for performance of surgical ligation of the bleeding vessel [48]. Alternatively, angiographic embolization has been shown to be effective in achiev-ing hemostasis in patients with recurrent peptic ulcer bleeding, and can be considered if local expertise is available [49].

• Whatispost-endoscopicmanagement?

The main goal of post-endoscopic management of NVUGIB is to determine which patients are at highest risk of rebleeding and continuing inpatient observation, preventing short-term rebleeding, and decreasing the risk of recurrent bleeding over the long term.

It is now generally accepted that patients who are believed to be at low risk for recurrent bleeding should be discharged immediately following recovery from endoscopy [32]. There are several risk scores and treat-ment algorithms which have been used to better identify patients who are at low risk for recurrent hemorrhage [50–52]. In general, patients with lesions at low risk for rebleeding (esophagitis, Mallory-Weiss tears, and peptic ulcers without high-risk stigmata [Forrest IIc/III]) do not require admission to hospital. However, hospitaliza-tion should be considered for patients with severe con-comitant comorbidities, those with poor social support, and persons who require reinitiation of anticoagulation, even if only low-risk findings are present on endoscopy Moreover, patients who are discharged may be adequately treated using oral PPIs [53].

Persons with higher-risk lesions, and thus at a higher risk of rebleeding in the short term, should be hospital-ized, primarily for close observation and to allow the

Table 3.ForrestClassificationofPepticUlcers

Risk Grade Endoscopic Picture Rebleeding Risk

High Ia Spurtinghemorrhage 85–100%

Intermediate Ib Oozinghemorrhage 10–27%

IIa Visiblevessel 50%

IIb Adherentclot 30–35%

Low IIc Hematincoveredflatspot <8%

III Nosignsofhemorrhage <3%


provision of IV PPI infusions. Continuous infusions of PPI are able to maintain an elevated intragastric pH, which promotes clot stability [54]. The initial evidence supporting the use of IV PPIs following endoscopy comes from the study by Lau et al [55], where persons with peptic ulcers with active bleeding or non-bleeding visible vessel were randomized to receive IV infusion of a placebo or omeprazole given as a 80-mg bolus and then 8 mg/hour infusion which was carried on for a total of 72 hours post endoscopy, followed by oral PPIs at 20 mg daily for the next 8 weeks. Subjects who received IV PPI therapy were significantly less likely to have rebleeding (7% vs. 23%) and also had shorter length of hospital stay following endoscopy. Similar findings have been reported in other studies of IV PPI for high-risk ulcers, including in North American and European populations. Because of the costs associated with IV PPI therapy, attempts have been made to look at the role of high-dose oral PPIs in reducing the risk of recurrent bleeding [56]. While there is some evidence that oral PPIs may be equally efficacious as IV PPIs [57,58], the evidence is not currently strong enough to recommend their routine use. IV H2-receptor antagonists (H2RAs) are likely ineffective for preven-tion of ulcer rebleeding; if IV PPIs are not available, it is preferable to substitute an oral PPI over administering an IV H2RA, as H2RAs have been proven to be inef-fective in preventing recurrent bleeding. Lastly, IV PPIs are not sufficient on their own to prevent rebleeding, and are not a substitute for the performance of prompt endoscopy [59].

Following discharge, the goals of therapy are to elimi-nate or mediate the effects of the modifiable risk factors which are associated with the source of NVUGIB. This includes detection and treatment of H. pylori, discontinu-ation of ASA/NSAIDs/anticoagulants when possible, or decreasing the gastrointestinal toxicity of these agents when they cannot be discontinued. Testing for H. pylori is most commonly performed in the acute setting by obtain-ing gastric biopsies at the time of endoscopy, which can then be analyzed for H. pylori histologically or with rapid urease testing [32,60]. However, the false-negative rate for H. pylori has been reported to be high in the setting of an acute bleed, and repeat testing in the outpatient setting is recommended if H. pylori testing is negative, either with urea breath testing or serologic evaluation [61]. Serologic testing for H. pylori is very specific and is not affected by acute bleeding, though patients with prior H. pylori eradication may be falsely positive [62]. Eradication of

H. pylori once detected is of paramount importance as those with proven H. pylori have shown up to a 20% rate of rebleeding, which drops to 2.7% if eradication is under-taken, and 1.1% if eradication is confirmed [63]. Follow-ing treatment, successful eradication should be confirmed either with urea breath testing, stool antigen testing, or via gastric biopsy. Chronic maintenance therapy with oral PPIs is not generally required following H. pylori eradica-tion unless the patient is on chronic ASA, NSAIDs, or anticoagulation [15].

Patients using an NSAID when they developed a NVUGIB should ideally discontinue its use. However, if they need to continue for some reason, the use of COX-2 inhibitors in combination with an oral PPI has been shown to be superior to either a COX-2 inhibitor or PPI as monotherapy [64,65]. However, patients with known cardiovascular disease should not be given COX-2 inhibi-tors as they have been shown to increase the risk of MI [66]. In this case, continued use of an NSAID, preferably naproxen, with a PPI, is acceptable, though ideally the NSAID should be discontinued [67].

Patients who continue ASA following acute NVU-GIB have been shown to have a high rate of recurrent bleeding if there is no co-prescription of a PPI [68]. However, patients at high risk of cardiovascular disease may have an increased risk of coronary events if ASA is discontinued [69,70]. Persons with acute NVUGIB who had ASA discontinued have been shown to have a higher rate of cardiovascular-associated mortality at 8 weeks compared with those in whom ASA was continued, while recurrent gastrointestinal bleeding was nonsignificantly greater among those who continued ASA [71]. As the risk of bleeding was highest in the first few days, it seems reasonable to hold ASA for approximately 3 to 5 days following a bleeding event before restarting [72]. If the patient is on ASA for primary prevention, then it may be discontinued as evidence shows that the risk of recurrent gastrointestinal bleeding outweighs the cardiovascular benefits of continuing the medication.

Clopidogrel, another antiplatelet agent used for cardio-prophylaxis, has been reported to cause higher rebleed-ing rates than those on ASA combined with a PPI [73]. However, clopidogrel is often required for patients with recent coronary stenting and those at high risk of recurrent stroke. The bleeding risk associated with clopidogrel can be reduced through concomitant therapy with a PPI [74]. However, there is controversy as to whether PPIs may in-terfere with the antiplatelet effects of clopidogrel, increas-

CASE-BASED REVIEW



ing the risk of cardiovascular events [75]. The most recent data from well-designed observational trials suggests that although PPIs appear to inhibit clopidogrel action in vitro, the effect on cardiovascular outcomes is no different than those not given PPI [76,77]. Therefore, PPIs should still be used long term in persons who have a history of NVU-GIB who require chronic clopidogrel therapy.

CaseContinuedThe patient was taken for an endoscopy within 24 hours of presentation. Endoscopy revealed an

ulcer in the duodenum and some old blood was seen in the stomach. The ulcer was classified as Forrest Class IIa (non-bleeding visible vessel) and endoscopic hemostasis was performed by injecting the area surrounding the ulcer with 10 cc of 1:10000 epinephrine and applying a hemo-static clip. A biopsy was taken from the antrum and body of the stomach and was sent for H. pylori testing (later came back as negative). The IV pantoprazole infusion was continued for a total of 48 hours after which the patient was started on an oral PPI. He was discharged home 2 days after endoscopy and instructed to continue taking the PPI. Aspirin was restarted a week after due to the patient’s extensive cardiovascular disease.

CONCLUSION

NVUGIB is a common problem that health care profes-sionals encounter every day. Comprehensive evidence-based guidelines exist to direct appropriate care for per-sons with NVUGIB, and it has been demonstrated that improvements in the medical and endoscopic management have led to a decrease in the morbidity and mortality associated with gastrointestinal bleeding. Adherence to these guidelines will promote the delivery of the most cost-effective care of these patients, allowing high-risk patients to receive appropriate management to reduce the risk of rebleeding and its complications, and allow low-risk patients to be managed in the outpatient setting, limiting the use of scarce healthcare resources. It is hoped that further research will help better differentiate low-risk and high-risk patients, and that further improvements in endoscopic techniques and post-endoscopic medical therapy may lead to a further reduction in rebleeding rates and mortality. Finally, greater efforts are required on the part of caregivers to better identify patients at risk of NVUGIB so that risk factors may be eliminated or their effects reduced through the preventative use of PPIs.

Corresponding author: Laura E. Targownik, MD, MSHS, Uni-versity of Manitoba, 805G-715 McDermot Ave., Winnipeg, MB Canada, [email protected].

Financial disclosures: Dr. Targownik has consulted for Pfizer Canada and Takeda Canada.

REFERENCES1. Srygley FD, Gerardo CJ, Tran T, et al. Does this pa-

tient have a severe upper gastrointestinal bleed? JAMA 2012;307:1072–9.

2. Lanas A, Garcia-Rodriguez LA, Polo-Tomas M, et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastro-enterol 2009;104:1633–41.

3. Laine L, Yang H, Chang SC, et al. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am J Gastroenterol 2012;107:1190-5; quiz 1196.

4. Targownik LE, Nabalamba A. Trends in management and outcomes of acute nonvariceal upper gastrointesti-nal bleeding: 1993-2003. Clin Gastroenterol Hepatol 2006;4:1459–66.

5. Gralnek IM, Barkun AN, Bardou M. Management of acute bleeding from a peptic ulcer. N Engl J Med 2008;359:928–37.

6. Holster IL, Kuipers EJ. Management of acute nonvariceal upper gastrointestinal bleeding: current policies and future perspectives. World J Gastroenterol 2012;18:1202–7.

7. Bardou M, Benhaberou-Brun D, Le Ray I, et al. Diagno-sis and management of nonvariceal upper gastrointestinal bleeding. Nat Rev Gastroenterol Hepatol 2012;9:97–104.

8. Lahiff C, Shields W, Cretu I, et al. Upper gastrointestinal bleeding: predictors of risk in a mixed patient group includ-ing variceal and nonvariceal haemorrhage. Eur J Gastroen-terol Hepatol 2012;24:149–54.

9. Huang CS, Lichtenstein DR. Nonvariceal upper gas-trointestinal bleeding. Gastroenterol Clin North Am 2003;32:1053–78.

10. Ferguson CB, Mitchell RM. Nonvariceal upper gastrointes-tinal bleeding: standard and new treatment. Gastroenterol Clin North Am 2005;34:607–21.

11. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-ste-roidal anti-inflammatory drugs. Lancet 1994;343:769–72.

12. Sorensen HT, Mellemkjaer L, Blot WJ, et al. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol 2000;95:2218–24.

13. DeCross AJ, Marshall BJ. The role of Helicobacter pylori in acid-peptic disease. Am J Med Sci 1993;306:381–92.

14. Shorr RI, Ray WA, Daugherty JR, et al. Concurrent use of nonsteroidal anti-inflammatory drugs and oral antico-agulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993;153:1665–70.

15. Gisbert JP, Calvet X, Cosme A, et al. Long-term follow-up of 1,000 patients cured of Helicobacter pylori infection


following an episode of peptic ulcer bleeding. Am J Gas-troenterol 2012;107:1197–204.

16. Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleed-ing associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol 2007;102:507–15.

17. Villanueva C, Colomo A, Bosch A, et al. Transfusion strat-egies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11–21.

18. Lavenne-Pardonge E, Itegwa MA, Kalaai M, et al. Emer-gency reversal of oral anticoagulation through PPSB-SD: the fastest procedure in Belgium. Acta Anaesthesiol Belg 2006;57:121–5.

19. Wolf AT, Wasan SK, Saltzman JR. Impact of anticoagula-tion on rebleeding following endoscopic therapy for non-variceal upper gastrointestinal hemorrhage. Am J Gastroen-terol 2007;102:290–6.

20. Choudari CP, Rajgopal C, Palmer KR. Acute gastrointesti-nal haemorrhage in anticoagulated patients: diagnoses and response to endoscopic treatment. Gut 1994;35:464–6.

21. Harinstein LM, Morgan JW, Russo N. Treatment of Dabi-gatran-Associated Bleeding: Case Report and Review of the Literature. J Pharm Pract 2012.

22. Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haem-orrhage. Lancet 2000;356:1318–21.

23. Rockall TA, Logan RF, Devlin HB, et al. Risk assess-ment after acute upper gastrointestinal haemorrhage. Gut 1996;38:316–21.

24. Stanley AJ, Ashley D, Dalton HR, et al. Outpatient man-agement of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective evalu-ation. Lancet 2009;373:42–7.

25. Rockall TA, Logan RF, Devlin HB, et al. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haem-orrhage. BMJ 1995;311:222–6.

26. Stanley AJ, Dalton HR, Blatchford O, et al. Multicen-tre comparison of the Glasgow Blatchford and Rockall Scores in the prediction of clinical end-points after upper gastrointestinal haemorrhage. Aliment Pharmacol Ther 2011;34:470–5.

27. Frossard JL, Spahr L, Queneau PE, et al. Erythromycin intravenous bolus infusion in acute upper gastrointestinal bleeding: a randomized, controlled, double-blind trial. Gastroenterology 2002;123:17–23.

28. Barkun AN, Bardou M, Martel M, et al. Prokinetics in acute upper GI bleeding: a meta-analysis. Gastrointest En-dosc 2010;72:1138–45.

29. Winstead NS, Wilcox CM. Erythromycin prior to en-doscopy for acute upper gastrointestinal haemorrhage: a cost-effectiveness analysis. Aliment Pharmacol Ther 2007;26:1371–7.

30. Lau JY, Leung WK, Wu JC, et al. Omeprazole before en-doscopy in patients with gastrointestinal bleeding. N Engl

J Med 2007;356:1631–40.31. Tsoi KK, Lau JY, Sung JJ. Cost-effectiveness analysis of high-

dose omeprazole infusion before endoscopy for patients with upper-GI bleeding. Gastrointest Endosc 2008;67:1056–63.

32. Barkun AN, Bardou M, Kuipers EJ, et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010;152:101–13.

33. Cooper GS, Kou TD, Wong RC. Use and impact of early endoscopy in elderly patients with peptic ulcer hemor-rhage: a population-based analysis. Gastrointest Endosc 2009;70:229–35.

34. Hearnshaw SA, Logan RF, Lowe D, et al. Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit. Gut 2010;59:1022–9.

35. Lim LG, Ho KY, Chan YH, et al. Urgent endoscopy is associated with lower mortality in high-risk but not low-risk nonvariceal upper gastrointestinal bleeding. Endoscopy 2011;43:300–6.

36. Targownik LE, Murthy S, Keyvani L, et al. The role of rapid endoscopy for high-risk patients with acute nonvari-ceal upper gastrointestinal bleeding. Can J Gastroenterol 2007;21:425–9.

37. Haas JM, Gundrum JD, Rathgaber SW. Comparison of time to endoscopy and outcome between weekend/week-day hospital admissions in patients with upper GI hemor-rhage. WMJ 2012;111:161–5.

38. Ananthakrishnan AN, McGinley EL, Saeian K. Outcomes of weekend admissions for upper gastrointestinal hemor-rhage: a nationwide analysis. Clin Gastroenterol Hepatol 2009;7:296–302e1.

39. Cappell MS, Iacovone FM, Jr. Safety and efficacy of esopha-gogastroduodenoscopy after myocardial infarction. Am J Med 1999;106:29–35.

40. Forrest JA, Finlayson ND, Shearman DJ. Endoscopy in gastrointestinal bleeding. Lancet 1974;2:394–7.

41. Katschinski B, Logan R, Davies J, et al. Prognostic factors in upper gastrointestinal bleeding. Dig Dis Sci 1994;39:706–12.

42. Kahi CJ, Jensen DM, Sung JJ, et al. Endoscopic therapy ver-sus medical therapy for bleeding peptic ulcer with adherent clot: a meta-analysis. Gastroenterology 2005;129:855–62.

43. Laine L, McQuaid KR. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials. Clin Gastroenterol Hepa-tol 2009;7:33–47.

44. Marmo R, Rotondano G, Piscopo R, et al. Dual therapy versus monotherapy in the endoscopic treatment of high-risk bleeding ulcers: a meta-analysis of controlled trials. Am J Gastroenterol 2007;102:279–89.

45. Sung JJ, Tsoi KK, Lai LH, et al. Endoscopic clipping versus injection and thermo-coagulation in the treatment of non-variceal upper gastrointestinal bleeding: a meta-analysis. Gut 2007;56:1364–73.

46. Lau JY, Sung JJ, Lam YH, et al. Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J

CASE-BASED REVIEW



Med 1999;340:751–6.47. El Ouali S, Barkun AN, Wyse J, et al. Is routine second-

look endoscopy effective after endoscopic hemostasis in acute peptic ulcer bleeding? A meta-analysis. Gastrointest Endosc 2012;76:283–92.

48. Smith BR, Stabile BE. Emerging trends in peptic ulcer dis-ease and damage control surgery in the H. pylori era. Am Surg 2005;71:797–801.

49. Wong TC, Wong KT, Chiu PW, et al. A comparison of angiographic embolization with surgery after failed endo-scopic hemostasis to bleeding peptic ulcers. Gastrointest Endosc 2011;73:900–8.

50. Longstreth GF, Feitelberg SP. Successful outpatient man-agement of acute upper gastrointestinal hemorrhage: use of practice guidelines in a large patient series. Gastrointest Endosc 1998;47:219–22.

51. Lee JG, Turnipseed S, Romano PS, et al. Endoscopy-based triage significantly reduces hospitalization rates and costs of treating upper GI bleeding: a randomized controlled trial. Gastrointest Endosc 1999;50:755–61.

52. Cipolletta L, Bianco MA, Rotondano G, et al. Outpatient management for low-risk nonvariceal upper GI bleeding: a ran-domized controlled trial. Gastrointest Endosc 2002;55:1–5.

53. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibi-tors. Pharmacology and rationale for use in gastrointestinal disorders. Drugs 1998;56:307–35.

54. Ghassemi KA, Kovacs TO, Jensen DM. Gastric acid inhi-bition in the treatment of peptic ulcer hemorrhage. Curr Gastroenterol Rep 2009;11:462–9.

55. Lau JY, Sung JJ, Lee KK, et al. Effect of intrave-nous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000;343:310–6.

56. Khuroo MS, Yattoo GN, Javid G, et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med 1997;336:1054–8.

57. Bajaj JS, Dua KS, Hanson K, et al. Prospective, randomized trial comparing effect of oral versus intravenous pantopra-zole on rebleeding after nonvariceal upper gastrointestinal bleeding: a pilot study. Dig Dis Sci 2007;52:2190–4.

58. Yen HH, Yang CW, Su WW, et al. Oral versus intravenous proton pump inhibitors in preventing rebleeding for pa-tients with peptic ulcer bleeding after successful endoscopic therapy. BMC Gastroenterol 2012;12:66.

59. Sung JJ, Chan FK, Lau JY, et al. The effect of endoscopic therapy in patients receiving omeprazole for bleeding ulcers with nonbleeding visible vessels or adherent clots: a ran-domized comparison. Ann Intern Med 2003;139:237–43.

60. Laine L, Lewin D, Naritoku W, et al. Prospective comparison of commercially available rapid urease tests for the diagnosis of Helicobacter pylori. Gastrointest Endosc 1996;44:523–6.

61. Gisbert JP, Abraira V. Accuracy of Helicobacter pylori diagnostic tests in patients with bleeding peptic ulcer: a systematic review and meta-analysis. Am J Gastroenterol 2006;101:848–63.

62. Feldman M, Cryer B, Lee E, et al. Role of seroconversion in confirming cure of Helicobacter pylori infection. JAMA

1998;280:363–5.63. Gisbert JP, Khorrami S, Carballo F, et al. H. pylori eradica-

tion therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Cochrane Database Syst Rev 2004:CD004062.

64. Chan FK, Wong VW, Suen BY, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet 2007;369:1621–6.

65. Targownik LE, Metge CJ, Leung S, et al. The relative ef-ficacies of gastroprotective strategies in chronic users of nonsteroidal anti-inflammatory drugs. Gastroenterology 2008;134:937–44.

66. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008;52:1502–17.

67. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086.

68. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002;346:2033–8.

69. Collet JP, Montalescot G, Blanchet B, et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004;110:2361–7.

70. Rodriguez LA, Cea-Soriano L, Martin-Merino E, et al. Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care. BMJ 2011;343:d4094.

71. Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med 2010;152:1–9.

72. Sung JJ, Chan FK, Chen M, et al. Asia-Pacific Working Group consensus on non-variceal upper gastrointestinal bleeding. Gut 2011;60:1170–7.

73. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleed-ing. N Engl J Med 2005;352:238–44.

74. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909–17.

75. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibi-tors and clopidogrel. CMAJ 2009;180:713–8.

76. O’Donoghue ML, Braunwald E, Antman EM, et al. Phar-macodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analy-sis of two randomised trials. Lancet 2009;374:989–97.

77. Douglas I, Evans S, Hingorani A, et al. Clopidogrel and the interaction with proton pump inhibitors: A comparison between cohort and within person study designs. BMJ 2012;345:e4388.

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Management of Nonvariceal Upper Gastrointestinal … · Endoscopy is the cornerstone of management....

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