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American Journal of Gastroenterology C 2008 by Am. Coll. of Gastroenterology Published by Blackwell Publishing ISSN 0002-9270 doi: 10.1111/j.1572-0241.2008.01865.x ORIGINAL CONTRIBUTION Endoscopy CME Predictive Factors of Mortality From Nonvariceal Upper Gastrointestinal Hemorrhage: A Multicenter Study Riccardo Marmo, M.D., Maurizio Koch, M.D., Livio Cipolletta, M.D., Lucio Capurso, M.D., Angelo Pera, M.D., Maria A. Bianco, M.D., Rodolfo Rocca, M.D., Angelo Dezi, M.D., Renato Fasoli, M.D., Sergio Brunati, M.D., Ivano Lorenzini, M.D., Ugo Germani, M.D., Giovanni Di Matteo, M.D., Paolo Giorgio, M.D., Giorgio Imperiali, M.D., Giorgio Minoli, M.D., Fausto Barberani, M.D., Sandro Boschetto, M.D., Marco Martorano, M.D., Giovanni Gatto, M.D., Mariano Amuso, M.D., Alfredo Pastorelli, M.D., Elena S. Torre, M.D., Omero Triossi, M.D., Andrea Buzzi, M.D., Renzo Cestari, M.D., Domenico Della Casa, M.D., Massimo Proietti, M.D., Anna Tanzilli, M.D., Giovanni Aragona, M.D., Francesco Giangregorio, M.D., Luciano Allegretta, M.D., Salvatore Tronci, M.D., Paolo Michetti, M.D., Paola Romagnoli, M.D., Andrea Nucci, M.D., Francesca Rogai, M.D., Walter Piubello, M.D., Maria Tebaldi, M.D., Fabrizio Bonfante, M.D., Alessandro Casadei, M.D., Claudio Cortini, M.D., Giorgio Chiozzini, M.D., Lisa Girardi, M.D., Claudio Leoci, M.D., Giampiero Bagnalasta, M.D., Sergio Segato, M.D., Giuseppe Chianese, M.D., Mario Salvagnini, M.D., Gianluca Rotondano, M.D. – For the Italian Registry on Upper Gastrointestinal Bleeding (Progetto Nazionale Emorragie Digestive – PNED) OBJECTIVES: From an Italian Registry of patients with upper gastrointestinal hemorrhage (UGIH), we assessed the clinical outcomes and explored the roles of clinical, endoscopic, and therapeutic factors on 30-day mortality in a real life setting. METHODS: Prospective analysis of consecutive patients endoscoped for UGIH at 23 community and tertiary care institutions from 2003 to 2004. Covariates and outcomes were defined a priori and 30-day follow-up obtained. Logistic regression analysis identified predictors of mortality. RESULTS: One thousand and twenty patients were included. A total of 46 patients died for an overall 4.5% mortality rate. In all, 85% of deaths were associated with one or more major comorbidity. Sixteen of 46 patients (35%) died within the first 24 h of the onset of bleeding. Of these, eight had been categorized as ASA class 1 or 2 and none of them was operated upon, despite a failure of endoscopic intention to treatment in four. Regression analysis showed advanced age, presence of severe comorbidity, low hemoglobin levels at presentation, and worsening health status as the only independent predictors of 30-day mortality (P < 0.001). The acute use of a PPI exerted a protective effect (OR 0.23, 95% CI 0.09–0.73). Recurrent bleeding was low (3.2%). Rebleeders accounted for only 11% of the total patients deceased (OR 3.27, 95% CI 1.5–11.2). CONCLUSIONS: These results indicate that 30-day mortality for nonvariceal bleeding is low. Deaths occurred predominantly in elderly patients with severe comorbidities or those with failure of endoscopic intention to treatment. (Am J Gastroenterol 2008;103:1639–1647) INTRODUCTION Acute upper gastrointestinal hemorrhage (UGIH) remains a common reason for hospital admission, requiring high levels of assistance and health-care expenditures. The incidence of acute UGIH and hospital-related 30-day mortality vary widely, partly because of the changing epidemiology in western countries, in which a number of factors, such as older age, comorbidites, prescriptions for proton pump inhibitors (PPI), low-dose aspirin, oral anticoagulants, cyclooxygenase-2 inhibitors, are involved (1–6). Risk assessment is mainly based on endoscopic recognition of high-risk stigmata at ulcer base To access a continuing medical education exam for this article, please visit www.acg.gi.org/journalcme. (7, 8) and controversy exists in the literature about the predicting value of clinical, biochemical, or therapeutic variables on the risk of death. The main aim of this prospective multicenter database study was to describe the ultimate outcome of patients with nonvariceal UGIH in a contemporary “real-life” setting. Additional analysis assessed the impact of clinical, endoscopic, or therapeutic factors on the risk of death in this patient population. METHODS The PNED Initiative and Data Collection A dedicated software including an endoscopic reporting system (Cartella Clinica Endoscopia Digestiva, Bracco, Italy) 1639 1640 Marmo et al. linked to a project-specific research database was developed. This software was distributed to 23 participating sites across Italy, establishing a network of centers that received emergency admissions from which source data were collected – the Progetto Nazionale Emorragie Digestive (PNED) study group. Fifteen community hospitals and eight tertiary care institutions were included. At each site, a “lead” consultant represented the project locally. At each hospital, a coordinator identified subjects daily in the accident and emergency department, the wards, the endoscopy unit, the operating theater, and from blood transfusion records and admission data. Specially trained research assistants collected data directly from the patient’s point of care into case report forms. The coordinator was then responsible for checking and returning a completed form for each patient correctly identified. All data were denominalized and downloaded into a central database on a monthly basis. They were reviewed at a single national location for internal logic of patient flow and biological plausibility. All data queries were resolved within 30 days following original data entry. To help assure the internal validity of the registry, there was an independent data validation of a random subset of all information collected; quality of data was validated on a quarterly basis by randomly comparing 5% of all records to the source data recorded in the hospital charts. Personnel from a clinical research organization trained all research staff at a common startup meeting and at each initial on-site visit prior to the first patient entry. On that occasion, all endoscopists participating in the registry were invited to review a wide set of video images of different bleeding stigmata in order to estimate inter-rater variability and find as much agreement as possible on the diagnosis of stigmata. Patient Population Patients were considered for the study if they had clinical evidence of overt UGIH on admission or a history of hematemesis/coffee ground vomiting, melena, hematochezia, or a combination of any of the above within 24 h preceding the admission, or clinical evidence of acute UGIH while hospitalized for any other reason (in-hospital bleeding), independently of their age. UGIH was confirmed only if either hematemesis, melena, or dark, tarry materials on rectal examination was documented and witnessed by nursing or medical staff. Patients were entered in the registry only if an upper GI endoscopy was performed. In case of bleeding from esophago-gastric varices, data were initially computed as patients having an UGIH, but were then excluded from the prospective database. An audit of all patients presenting over a fixed time period, at each participating institution, was performed to rule out any selection bias in the way in which the study population was enrolled. Patients initially assessed at another hospital for the bleeding episode and subsequently transferred to one of the participating centers were excluded from the analysis. Study Variables The following independent variables were included in the electronic form: demographics (age, sex, site, and date of endoscopy); historical data (presenting signs or symptoms, any significant comorbidity, the patient’s physical status on presentation using the American Society of Anesthesiologists [ASA] classification (9), relevant past medical history, any concomitant intake of medications in the 7 days preceding the bleeding episode, time elapsed from the onset of bleeding); physical examination findings and laboratory data (hemodynamic data, rectal exam, nasogastric tube use, complete blood count and coagulation parameters); and resuscitative measures. The endoscopic report included identification of the bleeding lesion, stigmata of recent hemorrhage at ulcer base according to the Forrest classification (active bleeding, visible vessel, or adherent clots were classified as “high-risk,” whereas flat spot and clean based ulcer as “lowrisk”) (8), detailed description of any method of endoscopic hemostasis delivered, number of therapeutic attempts, timing, and negative outcomes of endotherapy. The presence of fresh blood into the stomach in such amount to hamper endoscopic diagnosis of the source of bleeding was annotated and underscored as a “bleeding but source not identified at EGD.” The impossibility to conclude an already started endoscopic procedure with the intention to treat the source of hemorrhage was defined as “failed intention to endoscopic treatment.” Both surgical and angiographic therapies were recorded as well as any pharmacologic therapy administered for hemorrhage (types, amount, and route of administration). The outcomes evaluated were the frequency of death, recurrent bleeding, and need for surgery. Such outcomes were monitored from the admission to the hospital or the onset of bleeding for in-hospital patients up to 30 days after the endoscopic examination. Both investigators and nurses all worked with the same operational definitions of outcome. A priori definitions for all outcomes were adopted according to established definitions (10). Thirty-day mortality was the primary investigated outcome; a “bleeding-related” death was defined as any death occurring within 30 days of the indexbleeding episode. Continued or persistent bleeding was defined as (a) failure to control arterial bleeding endoscopically; (b) presence of bloody nasogastric aspirate; (c) shock with a pulse greater than 100 beats/min, a systolic blood pressure <100 mmHg, or both; and/or (d) the need for substantial replacement of blood or fluid volume (need of more than 4 units of blood in 6 h). Persistent hemorrhage was usually considered an indication for emergency surgery or percutaneous embolization. Nonetheless, the decision as to when to resort to surgery in the individual case was left to the discretion of the local teams. Recurrent bleeding was defined by recurrent vomiting of fresh blood, melena, or both with either shock or a decrease in hemoglobin concentration of at least 2 g/L following initial successful treatment and after initial stabilization of 24 h. Rebleeding had to be confirmed by a second endoscopy (visible bleeding or stigmata of recent hemorrhage). Patient transfer to and from other institutions and any readmission was also noted. All data were recorded for the full duration of the initial medical encounter. To ensure the completeness of follow-up information, the study nurses called all patients or their families at 30 days. Furthermore, after PNED had been Thirty-Day Mortality for Nonvariceal GI Bleeding in Italy completed, administrative databases were consulted and all charts of included patients were reviewed for a full 30 days following admission or onset of bleeding while in hospital. Data Analysis Descriptive data were generated for independent and dependent variables. All categorical data were expressed as proportions, whereas all continuous data were expressed as mean ± standard deviations. Where appropriate, alternate descriptive statistics such as quartile ranges for categorical data and medians with ranges for continuous data are reported. All calculations were performed using the SPSS statistical package version 8.0 (MJ Norusis, Chicago, IL). Variance analysis was used for comparisons of continuous data using discriminant analysis to select the cutoff values that best separated those deceased from those nondeceased. Such cutoff values were used to dichotomize continuous variables. Differences in proportions were analyzed using the χ 2 test and odds ratio with 95% confidence intervals when appropriate. Backwards step-wise logistic regression analysis was performed to determine independent predictors of 30-day mortality. A P value <5% was considered statistically significant. To measure the goodness of fit (i.e., strength of association in a nonlinear regression model), both the Cox and Snell’s R-Square and Nagelkerke’s R-Square were used. Ethics The registry was approved by the Institutional Review Board of all participating centers. In addition, all eligible patients were asked to sign a written informed consent. RESULTS Study Population A total of 1,263 cases were identified and entered in the PNED registry between March 2003 and March 2004 (with data queries collected until April 2004). Thirty-nine patients who were in transfers from other hospitals were excluded. Also excluded were 205 patients whose source of bleeding was esophago-gastric varices. Therefore, 1,020 patients affected with nonvariceal hemorrhage were analyzed. The mean enrolment per site was 53 ± 48 patients. The 450 cases (44% of all PNED population) enrolled by the top five recruiting centers represented 80% of all patients with UGIH seen in those institutions during the study period. Patient characteristics are outlined in Table 1. A recent history of drugs’ consumption was recorded in a high proportion of upper GI bleeders, mostly nonsteroidal anti-inflammatory drugs (34%) and low-dose aspirin (17.5%). One or more comorbidities were recorded at the time of presentation in 60.6% of cases (618/1,020), with 25% (255/1,020) having more than two comorbidities. The median number of comorbid conditions per patient was 1.0 (IQR 0–2.0), mainly cardiovascular diseases affecting almost half of the patients. Mean length of stay was 7.2 ± 6.3 days (median 4.0, IQR 2.0–9.0). Full 30- 1641 Table 1. Characteristics of the Study Population Total Population (N = 1,020) Mean (Median, IQR) Male 62% Age (yr) 68 (70, 53–81) Number of comorbidities 1.0 (1.0, 0–2) ASA score 1–2 42% 3 45% 4 13% In-hospital bleeding 14% Symptoms on presentation Melena 78% Hematemesis 28% Hematochezia 9% Timing of endoscopy (h) 8 (10, 2–14) Medications at presentation NSAIDs 34% Aspirin 17.5% Anticoagulants 8.2% Ca++ -antagonists 7.5% Steroids 6.7% Nitrates 6.3% Coxib 3.3% Initial hemodynamic instability 27% Laboratory results Initial mean hemoglobin (g/dL) 9.6 (9.8, 6.9–11.4) Hematocrit 31 (30, 24–35) INR 1.4 (1.2, 1.0–1.3) Source of bleeding at endoscopy Duodenal ulcer 37.8% Gastric ulcer 28.3% Gastroduodenal erosions 9.1% Neoplasia 5.7% Mallory-Weiss tears 4.5% Esophagitis 3.6% Dieulafoy’s lesion 1.4% Other vascular source 2.4% No lesion identified 7.2% SRH at ulcer base (N = 675) Clean base 33.2% Flat spot 22.0% Adherent clot 11.7% Visible vessel 17.7% Active bleeding 15.4% 95% CI/SD 58.8–64.8 ±16 ±1.3 39.2–44.5 42.5–47.3 11.8–15.7 12–16 76.0–81.1 25.0–30.0 7.9–11.5 ±10 31.1–36.9 15.3–20.0 6.7–10.0 6.0–9.2 5.5–7.8 4.9–7.9 2.5–4.0 24.7–30.2 ±2.4 SD ±7 SD ±1.3 SD 34.9–40.9 25.6–31.2 7.4–10.9 4–0–6.9 3.8–5.5 3.0–5.0 0.9–2.4 1.5–3.4 5.7–8.9 29.7–36.8 18.9–25.2 9.4–14.3 15.0–20.8 12.8–18.3 IQR = interquartile range; SD = standard deviation; CI = confidence interval; NSAIDs = nonsteroidal anti-inflammatory drugs; SRH = stigmata of recent hemorrhage. Mean daily dose of aspirin 100 ± 25 mg. ASA score refers to the American Society of Anesthesiologists classification of a patient’s severity and acuity of disease index. day follow-up information was available for 1,008 (98.8%) patients. Endoscopic Data Overall, 1,844 endoscopic procedures were performed with a median of one procedure per patient (range 1–5). Upper GI endoscopy was first performed in 78% of patients within 24 h of presentation to the emergency room or of the onset of bleeding in patients already hospitalized. Peptic ulcers 1642 Marmo et al. Table 2. Endoscopic and/or Medical Treatment and Outcomes in Patients With Nonvariceal Bleeding No endoscopic treatment Endoscopic treatment Injection Thermal coagulation Hemoclips Combined injection + thermal Medical therapy PPI H2 RA PPI and H2 RA Vasoactive drugs (somatostatin or octreotide) Outcome Clinical rebleeding Need for emergency surgery 30-day-mortality No. of Patients Percent (95% CI) 633 387 168 113 74 32 62.0 (58.2–65.3) 38.0 (35.7–41.8) 43.4 (39.8–47.3) 29.2 (25.7–33.7) 19.1 (15.3–22.5) 8.3 (6.8–10.3) 586 194 100 96 57.5 (54.4–60.5) 19.0 (16.2–20.8) 9.8 (8.1–11.7) 9.4 (7.7–11.3) 33 13 46 3.2 (2.2–4.5) 1.3 (0.7–2.2) 4.5 (3.3–6.0) PPI = proton pump inhibitors; H2 RA = histamine-2 receptor antagonists. were by far the most common cause of bleeding, accounting for 66% of the cases (gastric 28%). The distribution of diagnoses was similar for inpatients and emergency admissions except that Mallory-Weiss lesions were more common in those admitted urgently. No lesion could be identified as source of the hemorrhage in 7.2% of the cases (Table 1). No patient received erythromycin or other prokinetic agents to attempt to clean out the gastric blood before endoscopy. On endoscopy, actively bleeding ulcers were found in 15.4% of patients, whereas visible vessels and adherent clots at ulcer base were diagnosed in 17.7% and 11.7% of cases, respectively. Low-risk endoscopic stigmata were detected in 55.2% of ulcer patients (22% pigmented material, 33.2% clean base). Overall, endoscopic treatment was delivered in 387 patients, and all patients with “high-risk stigmata” received endoscopic therapy. Injection therapy alone with diluted epinephrine was performed in 43.4%, isolated thermal probe coagulation in 29.2%, hemoclips in 19.1%, and combined endotherapy with injection followed by thermal coagulation in 8.3% (Table 2). Pharmacotherapy The vast majority of the bleeding patients (67.5%) were given PPIs, either intravenously or orally, during hospitalization or emergency room visit. Among patients with high-risk lesions at endoscopy, the mean daily doses of IV and oral PPI were 212 ± 80 mg and 80 ± 40 mg, respectively. Overall, 19% of UGI bleeders were treated with IV ranitidine. Ten percent of patients received both PPI and H2 -receptor antagonists and 9.4% received vasoactive drugs such as somatostatin or octreotide. Ninety-seven percent of patients undergoing endoscopic hemostasis also received a PPI. Helicobater pylori Management Testing for H. pylori was performed during hospital stay in 62% of patients (all by means of histologic evaluation, as per protocol). Among patients who were tested, H. pylori infection was detected in 44.3% (95% CI 41.3–47.4) of patients overall. Eradication therapy was initiated during hospitalization in less than 10% of cases. Outcomes Recurrent bleeding was recorded in 33 patients (3.2%, [2.2– 4.5]), whereas emergency surgery was deemed necessary in only 13 cases (1.3%, [0.7–2.2]). Overall, 46 patients died with a 30-day mortality rate of 4.5% [3.3–6.0], with no significant differences for the inpatient group compared with emergency admissions (Table 2). The median time to death was 4 days (95% CI 2–6). In the absence of any comorbidity, mortality was 0.7%. It increased to 8.4% if one severe comorbidity was recorded, and to 23.1% if two or more severe comorbidities were present (P < 0.01). The mean age of the patients who died was 76.6 ± 14.0 yr. In all, 85% of deaths (39 out of 46) were associated with one or more severe comorbidities. Sixteen patients (34.8%) died within the first 24 h of the onset of bleeding, with 10 patients deceased within 8 h of the endoscopic examination. Eight patients had been categorized as severely unstable or moribund (ASA class 3 or 4), whereas eight patients as healthy or moderately healthy (ASA class 1 or 2) and none of them was operated upon. In four of them, there had been a failure of endoscopic intention to treatment. No patient was treated radiologically by means of percutaneous embolization. For the remaining 30 patients, death occurred within 7 days in 50% and within 12 days in 75% of cases. Subgroup analysis according to the health status showed that 3.4% (33/934) of patients categorized as ASA 1 or 2 died versus 25.5% (13/38) of patients categorized as ASA 3 or 4 (P < 0.0001, OR 9.68 [4.7–19.8]). During the first 24 h, 8/960 (0.8%) ASA 1 or 2 patients died versus 9/42 (17.6%) of ASA 3 or 4 patients (P < 0.0001) [OR 29.4 (9.1–96.6)]. Advanced age, hemodynamic instability, hemoglobin concentration, and size of the ulcer(s) were all significantly associated with the risk of death at univariate analysis (Table 3). Diastolic pressure <70 mmHg (OR 2.46), concomitant use of nitrates (OR 1.82), systolic pressure <115 mmHg (OR 1.78), hematemesis (OR 1.66), and active bleeding at endoscopy Table 3. Predictors of 30-Day Mortality at Univariate Analysis (Continuous Variables) Predictors Mean age (± SD) in years Diastolic pressure (mmHg) Heart rate (bpm) Hemoglobin (g/dL) Size of duodenal ulcer (mm) Size of gastric ulcer (mm) bpm = beats per minute. Death (N = 46) 76.6 ± 14.0 66.3 ± 15.2 96.7 ± 18.7 8.2 ± 2.8 12.7 ± 7.3 17.9 ±12.8 No Death (N = 974) P Value 67.5 ± 16.0 <0.001 72.5 ± 11.6 0.001 89.1 ± 14.4 0.001 9.2 ± 2.5 0.001 9.4 ± 5.4 0.04 11.3 ± 6.7 0.003 Thirty-Day Mortality for Nonvariceal GI Bleeding in Italy 1643 Table 4. Predictors of 30-Day Mortality at Univariate Analysis (Categorical Data) Predictors Clinical In-hospital bleeding Hematemesis Renal failure Neoplasia Liver cirrhosis Endoscopic Blood in gastric cavity, source not identified Failed intention to endoscopic treatment Gastric cancer Recurrent bleeding Need for surgery No. of Deaths/No. of Patients With Predictor No. of Deaths/No. of Patients Without Predictor P Value Odds Ratio (95% CI) 10/142 (7.0%) 20/282 (7.1%) 8/71 (11.3%) 14/81 (17.3%) 7/69 (10.1%) 36/878 (4.1%) 26/738 (3.5%) 38/949 (4.1%) 32/939 (3.4%) 39/951 (4.1%) 0.126 0.018 0.011 0.0001 0.03 1.77 (0.8–3.6) 2.0 (1.1–3.8) 3.0 (1.4–6.8) 5.9 (3.0–11.6) 2.6 (1.1–6.1) 5/13 (38.5%) 6/8 (75%) 7/48 (14.6%) 5/33 (15.2%) 2 /13 (15.4%) 41/1,007 (4.1%) 40/1,012 (4%) 39/972 (4.0%) 41/987 (4.2%) 44/1,007 (4.4%) <0.001 <0.001 0.004 0.003 0.057 14.7 (4.6–46.9) 72.9 (14.2–372) 4.0 (1.7–9.7) 4.12 (1.5–11.2) 3.9 (0.85–18.5) EGD = esophago-gastro-duodenoscopy. The following variables were all NOT associated with the risk of death: previous nonvariceal hemorrhage, history of peptic ulcer disease, previous gastric resection, comorbid illnesses such as cardiovascular disease or diabetes, medications (clopidogrel, low-dose aspirin, COX-2 inhibitors, other NSAIDs, anticoagulants, heparin, steroids or antidepressants), syncope or melena on presentation, naso-gastric tube findings of coffee-ground material or bright red blood mixed with clots; type of endoscopic lesions such as Mallory-Weiss tears, Dieulafoy’s ulcers, angiodysplasias, esophagitis, gastro-duodenal erosions; site of either gastric or duodenal ulcer; major endoscopic stigmata of bleeding; type of endoscopic therapy delivered; timing of endoscopy; size of the hospital, community or university affiliation, geographic location (by region). (OR 1.30) were all clinically relevant OR but did not reach statistical significance and were therefore not inserted in the final multivariate model. Similar prognostic impact had the presence of “severe” comorbid illnesses such as renal failure, liver cirrhosis and neoplasia, or the presence of blood in the gastric cavity in such amount to hamper both diagnostic and therapeutic endoscopy (Table 4). A total of 345 patients (33.8%) received one or more transfusions with packet red cells. Thirty-day mortality was 7.5% in patients with transfusion requirements (OR 2.67, 95% CI 1.46–4.85). Thirty-day mortality was 15.2% in patients with recurrent bleeding and recurrent bleeders accounted for 10.9% of the total patients deceased (OR 4.12, 95% CI 1.5–11.2). Resort to emergency surgery was rare; only 13 patients (1.3%) were operated and 2 of them died. Thirty-day mortality was therefore 15.4% in patients needing surgery who accounted for 4.3% of the total deaths (OR 3.97, 95% CI 0.85–18.5) (Table 4). Adjuvant medical therapy with antisecretory drugs is likely to impact on the risk of death after endoscopic treatment. Thirty-day mortality rate was significantly higher in patients treated with H2 -receptor antagonists than in those treated with PPIs (15% vs 4%, P < 0.0001) (OR 4.28 [95% CI 1.36– 11.34]). Conversely, the acute use of a PPI showed a protective effect (OR 0.23, 95% CI 0.09–0.73), with a relative risk reduction of 76.6% (95% CI 34.5–90.5%) and an absolute risk reduction of 11.5% (95% CI 8.6–14.3). In the logistic regression analysis, independent predictors of 30-day mortality included advanced age (over 80 yr), low hemoglobin levels at presentation (<7 g/dL), presence of severe comorbidity (renal failure, neoplasia, liver cirrhosis), and worsening health status (ASA class 1 or 2 vs ASA class 3 or 4) (Table 5). The Nagelkerke R2 of our final model was 0.79. The interaction between the two major prognostic factors, i.e., advanced age and severe comorbidity, on the risk of 30-day mortality is outlined in Figure 1. DISCUSSION Acute UGIH remains a common medical problem that has significant associated morbidity, 30-day mortality, and health-care resource use. The PNED data indicate that ulcers are by far the most common cause of nonvariceal UGIH, accounting for 66% of all diagnoses. More than a half of the patients in the present study were taking at least one ulcerogenic drug, mainly NSAIDs, whereas the use of low dose aspirin was much lower than reported in North America (11, 12) and this should be taken into account in terms of generalizability of results. An important feature of the PNED study is that it represents a consortium of practice sites that use a structured endoscopy reporting system to collect information in a centralized endoscopic database. Such data are useful because they reflect “real world” endoscopic practice from a wide range of practice settings and minimize patient selection or potential referral bias. Of the 23 participating centers, in fact, only eight Table 5. Independent Predictors of 30-Day Mortality (Logistic Regression Analysis) Predictors Rebleeding ASA class 3 Time to admission∗ Hemoglobin <7 g/dL Age >80 yr ASA class 4 Renal failure Advance neoplasia† Liver cirrhosis Failure of endoscopic intention to treatment ∗ † Odds Ratio 95% CI P Value 3.27 3.32 4.35 4.70 4.70 7.24 5.29 9.81 11.01 11.35 −1.1–7.7 0.56–6.1 −0.1–8.8 2.3–7.0 2.3–7.0 4.0–10.4 2.8–7.8 7.3–12.3 7.5–14.5 −1.4–24.1 0.1166 0.0206 0.0544 0.0004 0.0005 0.0009 0.0004 0.0000 0.0002 0.0616 Time elapsed between patient’s perception of malaise and seeking medical attention; Karnofsky index ≤70. 1644 Marmo et al. Figure 1. The interaction between advanced age and severe comorbidity on the risk of 30-day mortality. were tertiary institutions, unlike the Canadian RUGBE study in which tertiary institutions accounted for two-thirds of the participating centers and 62% of patients were enrolled at six centers (13). All ulcer-bleeding patients with high-risk stigmata had an endoscopic treatment. About 43% of patients who were given endoscopic treatment received epinephrine injection therapy, probably a less than optimal endoscopic therapy according to consensus recommendations (14), although in line with other recent European surveys on this matter (15, 16). Thermal probe coagulation or mechanical securing of hemostasis by means of hemoclips were employed in one-third and one-fifth of the cases, respectively, whereas combination therapy was seldom applied. Outcomes in the PNED registry were comparable to previously published large databases, except the recurrent bleeding rate of 3.2% which is much lower than previously reported (1, 5, 7, 13, 15, 16). Such difference may be possibly explained with the strict definition of “clinically relevant” recurrent bleeding (confirmation endoscopy required), which may in part have reduced the number of patients labeled as such; the relatively high percentage (44%) of nonulcer bleeding; the relatively low proportion of patients with actively bleeding lesions (only 15.4% vs a 27% rate in the RUGBE registry) (13); the fact that all patients with high-risk stigmata were treated endoscopically and the widespread use of PPIs after endoscopic therapy. Also, the mean dosages of adjuvant PPI therapy were sensibly higher than those reported in the Canadian study where most patients may not have received their PPI in the appropriate manner (58% had a mean daily dose ≤100 mg). This may have played a role in preventing rebleeding, particularly in patients with adherent clots (17). Although it is possible that some patients may have rebled and gone to another hospital at that time, such an event is unlikely in the manner in which patients were cared for in the participating institutions. The usual timing of a recurrent bleeding and the mean duration of hospital stay of patients included in PNED make us quite confident that the number of missed negative outcomes is very low. Nonetheless, the inability to identify prognosticators of rebleeding due to its low prevalence should be acknowledged as an important limitation of the present study. Mortality from nonvariceal UGIH is usually in the range of 5–10% in most studies that emphasize prompt resuscitation, early endoscopic diagnosis, and treatment followed by dedicated multidisciplinary postoperative care (13, 15). The 4.5% 30-day mortality rate recorded in the PNED study is very similar to the 5.4% death rate reported in the wellconducted RUGBE study, which ran similar analysis of prognostication of death (13). Nonetheless, one or more severe or life-threatening comorbidity was present in 85% of the patients who died, a figure comparing favorably with other reports (13, 15). Risk stratification in patients with UGIH is essential for optimal management of bleeders, both for triage of those at high risk to inpatient care and for identification of patients at low risk of adverse outcome who can be safely managed as outpatients (14, 18, 19). The Rockall score, prospectively and externally validated as effective in different patient populations, was selected for use by the investigators involved in the PNED initiative. However, as pointed out in a recent review on the topic by Das and Wong (20), at present there is not an Thirty-Day Mortality for Nonvariceal GI Bleeding in Italy ideal risk score. For acute bleeders, urgent EGD should not be an essential part of the initial risk score; however, EGD should be an important component of the risk score at a subsequent point in patient care. Hence, the need to categorize the patient’s risk profile with the aid of accurate and userfriendly clinical predictors that are typically available during initial patient triage. Our study identified a number of prognostic clinical factors independently associated with the risk of 30-day mortality after an acute UGI bleed. The most relevant predictors were advanced age, liver cirrhosis, chronic renal failure and advanced neoplasia, and the low hemoglobin level at presentation. In the presence of any of these prognosticators, emergency physicians as well as managing gastroenterologists should pursue a high level of care to prevent death, because about 30% of deaths occur within the first 24 h of admission to hospital, and part of this mortality within the first 8 h. Interestingly, the same RUGBE investigators recently reported that a modified clinical risk score including hemoglobin level, hemodynamic instability, presence of liver disease, or cardiac failure was significant in multivariate analysis for rebleeding and mortality (21). The impossibility, for whatever reason, to perform endoscopic therapy should be considered as a strong predictor of negative outcome, which was recorded in 6 out of 8 ASA 1 or 2 patients who died within the first 24 h. The absence of statistical significance is clearly due to a high standard error related to the small number of patients in which endoscopic therapy could not be performed. Patients who fail endoscopic therapy are best served with immediate surgery or considered for percutaneous embolization. A surprising and somewhat awkward finding was that half of those who died within the first 24 h were not operated upon despite being at good surgical risk nor did they go for an angiogram instead, and in four of them there was a failure at endoscopic control of hemorrhage. Whether surgeons were reluctant to bring such persistent bleeders to the operation theater or gastroenterologists unwisely insisted on attempts at hemostasis needs to be verified, and clear-cut management protocols should be shared in this setting. The main strength of the PNED registry is that it focused on the most relevant outcome measure, i.e., death. Previous studies have noted that a large proportion of deaths occur in those with severe comorbidity in whom even minor hemorrhage is poorly tolerated, independently of any effective endoscopic intervention (5, 12, 14–16, 22). Furthermore, we identified in detail that advanced age, low hemoglobin levels at presentation, chronic renal failure, neoplasia, and liver cirrhosis were all powerful independent predictors of death. It is difficult to establish what is and what is not a preventable death; however, the identification of potential risk factors may help us select those elements that need to be closely monitored in an attempt to further reduce 30-day mortality. The fact that most deaths occur in elderly patients with severe comorbidities should prompt us to switch our focus to improve management of this selected high-risk subgroup, to be 1645 included into specifically designed trials. Furthermore, major preventive steps should be taken in order to reduce the risk of NSAIDs’ related hemorrhage, particularly in the highest risk population. There are several limitations to the present registry. The adopted study design is not an experimental one, and therefore not as rigorous as that of a randomized controlled trial. The demonstrated associations should be seen as suggestive, but require prospective independent validation, which is actually under way. One specific limitation may be the robustness of our final model, given that multiple covariates for only 46 events were analyzed. Some important clinical variables did not reach statistical significance at univariate analysis despite having clinically relevant odds ratio values. A beta-error cannot be excluded and with larger number of events also other variables (e.g., recurrent bleeding) may likely provide additional information. We attempted to address other possible shortcomings such as completeness of follow-up, ascertainment of outcomes, possible patient selection bias and inadequate adjustment for confounders by establishing conservative and a priori definitions for all study variables including outcomes, by training all research staff in a standardized fashion, by enforcing strict data verification and validation protocols and by ensuring complete 30-day follow-up. Although defining all 30-day mortalities to be “bleeding-related” could be considered a weakness of the study, any death within this time frame can be logically related to the bleeding episode, acting as either determining or precipitating event for the negative outcome. In conclusion, death after an acute nonvariceal UGIH occurs mostly among elderly patients with severe comorbidity or those with failure of endoscopic intention to treatment. These factors should be taken into account in a struggle toward a further reduction of overall 30-day mortality. Future studies should reconsider early resort to surgery, especially for young and surgically fit patients, to reduce the risk of death during the first 24 h of the bleeding episode. Also, the use of preventive strategies to reduce the bleeding risk especially in patients with advanced age, neoplasia, renal failure, and liver cirrhosis deserves appropriate investigation. Improving the ultimate outcome of patients with nonvariceal UGIH will take an integrated approach by a team focused on treating the patient and not just the source of bleeding. ACKNOWLEDGMENTS The PNED initiative was a collaborative effort supported by the Italian Society for Digestive Endoscopy (SIED) and the Italian Association of Hospital Gastroenterologists (AIGO). We acknowledge the great deal of work performed by medical and nursing staff in each of the participating units. APPENDIX The PNED investigators’ group includes Riccardo Marmo, Ospedale Curto, Polla; Livio Cipolletta, Gianluca Rotondano, 1646 Marmo et al. and Maria A. Bianco, Ospedale Maresca, Torre del Greco; Lucio Capurso, Maurizio Koch and Angelo Dezi, ACO San Filippo Neri, Rome; Angelo Pera and Rodolfo Rocca, Ospedale Mauriziano Umberto I, Torino; Fausto Barberani and Sandro Boschetto, Ospedale San Camillo De Lellis, Rieti; Alfredo Pastorelli and Elena Sanz Torre, Ospedale Bel Colle, Viterbo; Sergio Brunati and Renato Fasoli, Ospedale Cantù, Abbiategrasso; Ivano Lorenzini and Ugo Germani, AO Umberto I, Ancona; Giorgio Minoli and Giorgio Imperiali, Ospedale Valduce, Como; Giovanni Gatto and Mariano Amuso, AO Villa Sofia, Palermo; Massimo Proietti and Anna Tanzilli, Ospedale Del Prete, Pontecorvo; Walter Piubello, Maria Tebaldi and Fabrizio Bonfante, Ospedale di Desenzano, Desenzano del Garda; Renzo Cestari and Domenico Della Casa, AO Ospedali Civili, University of Brescia, Brescia; Paolo Michetti and Paola Romagnoli, Ospedali Galliera, Genova; Omero Triossi and Andrea Buzzi, Ospedale Santa Maria delle Croci, Ravenna; Alessandro Casadei and Claudio Cortini, AO Morgagni, Forlı̀; Giorgio Chiozzini and Lisa Girardi, Ospedale Umberto I, Mestre; Luciano Allegretta and Salvatore Tronci, Ospedale Santa Caterina Novella, Galatina; Giovanni Aragona and Francesco Giangregorio, Ospedale Civile, Piacenza; Sergio Segato and Giuseppe Chianese, AO Ospedale Circolo e Fondazione Macchi, Varese; Andrea Nucci and Francesca Rogai, AO Ospedale Careggi, Firenze; Giampiero Bagnalasta and Claudio Leoci, Ospedale Civile, Manerbio; Giovanni Di Matteo and Paolo Giorgio, IRCCS Ospedale De Bellis, Castellana Grotte; Marco Martorano, Ospedale dell’Immacolata, Sapri; Mario Salvagnini, Ospedale San Bortolo, Vicenza. STUDY HIGHLIGHTS What Is Current Knowledge r Mortality for nonvariceal upper GI bleeding varies widely and has been reported from 5% to 14%. Predictors of recurrent bleeding and mortality have been identified in previous registries, showing endoscopic intervention and adjuvant proton pump inhibitor (PPI) therapy to exert a protective effect. What Is New Here r In this Italian multicenter registry, 30-day mortality was low (4.5%). Mortality occurred in 30% of cases within the first 24 h of the index bleeding. Recurrent bleeding was infrequent and had a lower impact on the risk of mortality. Multivariate logistic regression identified advanced age, presence of severe comorbidities, and low hemoglobin levels at presentation as major clinical predictors of poor outcome. All these parameters can be used pre-endoscopy to identify a subset of highrisk patients in which a high level of care is warranted to prevent negative outcomes. 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