+ MODEL Journal of the Formosan Medical Association (2017) xx,1e10

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Original Article Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use Hsiu-Chi Cheng a,b, Er-Hsiang Yang a,b, Chung-Tai Wu a,b, Wen-Lun Wang c, Po-Jun Chen a,b, Meng-Ying Lin a,b, Bor-Shyang Sheu a,b,d,* a Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, , 70403, b Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70403, Taiwan c Department of Internal Medicine, E-Da Hospital, I-Shou University, 1 Yida Road, Yanchao , , 82445, Taiwan d Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan

Received 29 April 2017; received in revised form 8 June 2017; accepted 7 July 2017

KEYWORDS Background/purpose: Peptic ulcer bleeding remains a deadly disease, and a simple indicator of Hypoalbuminemia; long-term outcomes is crucial. This study validated whether hypoalbuminemia and its related Mortality; factors in patients with peptic ulcer bleeding can indicate long-term mortality and rebleeding Peptic ulcer under proton pump inhibitor use. hemorrhage Methods: The prospective cohort study enrolled 426 patients with peptic ulcer bleeding who had high risk stigmata at endoscopy and had received endoscopic hemostasis. They were divided into 79 patients in the hypoalbuminemia group (Hypo-AG, serum albumin <28 g/L), 135 in the marginal hypoalbuminemia group (Margin-AG, serum albumin 28e34.9 g/L), and 212 in the normal albuminemia group (Normal-AG, serum albumin 35 g/L). Each subject received 72-h of intravenous infusion and then the oral form of proton pump inhibitors and were monitored for 84 days to assess all-cause mortality and recurrent bleeding. Results: The primary outcome of all-cause mortality rates were increased in a stepwise fashion in a trend from Normal-AG, Margin-AG, to Hypo-AG (0e28th day: 1.9%, 2.2%, 12.8%, p < 0.001; 29the84th day: 2.5%, 8.0%, 10.6%, p < 0.01). The secondary outcome of recurrent bleeding rates were also increased in the same fashion (0e28th day: 6.4%, 15.4%, 24.6%, p < 0.001; 29the84th day: 0%, 3.0%, 4.2%, p Z 0.01). Abnormal albuminemia was <30 g/L related to

* Corresponding author. Department of Internal Medicine, National Cheng Kung University Hospital, Tainan Hospital, Ministry of Health & Welfare, 138 Sheng Li Road, Tainan, 70403, Taiwan. Fax: þ886 6 2766175. E-mail addresses: [email protected] (H.-C. Cheng), [email protected] (E.-H. Yang), [email protected] (C.-T. Wu), [email protected] (W.-L. Wang), [email protected] (P.-J. Chen), [email protected] (M.-Y. Lin), [email protected] (B.-S. Sheu). http://dx.doi.org/10.1016/j.jfma.2017.07.006 0929-6646/Copyright ª 2017, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006 + MODEL 2 H.-C. Cheng et al.

hemoglobin levels <70 g/L, nosocomial bleeding, cirrhosis, age 70 years, shock, and ulcer size 1.0 cm independently (p < 0.05). Conclusion: Hypoalbuminemia in patients with peptic ulcer bleeding can be an alarm indicator of all-cause mortality and recurrent bleeding in a long-term follow-up situation under proton pump inhibitor use (NCT01591083). Copyright ª 2017, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/).

Introduction shown in Fig. 1. The work described has been carried out in accordance with declaration of Helsinki. Peptic ulcer bleeding is the most common gastrointes- Eligible participants included patients 20 years who tinal emergency and is a deadly disease. In addition to had undergone gastroscopy due to bleeding peptic ulcers with major stigmata of a recent hemorrhage including rebleeding, comorbidity is also a risk factor leading to 15 mortality.1e4 With advances in endoscopic hemostasis Forrest class Ia, Ib, IIa, and IIb. All of the participants and high potency acid suppression agents, the prognosis were given one or a combination of endoscopic therapies, of peptic ulcer bleeding has been altered in the past including a local injection of diluted epinephrine 1:10000, a couple of decades.5e7 However, the mortality rate still bipolar heated probe, argon plasma coagulation, band e 4,7,8 ligation, or hemoclip therapy until cessation of active remains in a range of approximately 2% 6%. There- 16,17 fore, the use of validated prognostic scales to risk bleeding or achievement of co-aptive coagulation. stratify patients with peptic ulcer bleeding has been Patients were excluded if they had tumors, Dieulafoy advocated.9 There are many scores intended to predict lesions, esophageal ulcers, esophageal varices or mechan- outcomes of peptic ulcer bleeding.4,10e12 However, it is ical factor-related bleeding (e.g., gastrostomy tube induc- crucial to find an easy to obtain score like a simple blood tion), hypersensitivity to esomeprazole or pantoprazole, or test. The AIMS65 score includes the serum albumin level, had previously participated in the study. and it has been shown to be an important predictor of Patients were enrolled after successful endoscopic he- mostasis and immediately received an 80 mg loading dose short-term intra-hospital mortality in upper gastrointes- tinal bleeding.12,13 However, this score is based on of intravenous esomeprazole (Nexium , AstraZeneca AB, analysis of data from both variceal and non-variceal So¨derta¨lje, Sweden). The patients then received three days upper gastrointestinal bleeding. There is no doubt that of continuous high-dose (8 mg/h) intravenous esomeprazole the serum albumin level,14 which is associated with as therapy and then received 40 mg oral esomeprazole once cirrhosis, is one of the parameters that can be used to or twice daily for the first 2 weeks. Subsequently, all pa- tients received an oral proton pump inhibitor once daily for predict mortality after variceal bleeding. Nevertheless, it 5,6 is of importance to validate whether a low serum albumin at least the following 8 weeks. Patients who took clopi- level by itself can be a simple indicator of rebleeding and dogrel received the same dose and duration of intravenous and oral pantoprazole (Pantoloc, Takeda, Singen, Ger- mortality due to peptic ulcer bleeding. Moreover, the 18 reason why a low serum albumin level can be a predictor many) therapy. Patients who took warfarin or anti- platelet therapy discontinued such medication for three has not been well explored as yet. 9,19 In this study, a large-scale comparison of mortality rates days after primary endoscopy. in a long-term follow-up between patients with different In Fig. 1, all enrolled patients were divided into the serum albumin levels was prospectively conducted. It was hypoalbuminemia group (Hypo-AG), the marginal hypo- presumed that our data will be helpful with regard to albuminemia group (Margin-AG), and the normal albu- identifying patients at risk of mortality and rebleeding and minemia group (Normal-AG) based on the serum albumin level on arrival, <28 g/L, 28e34.9 g/L, and 35 g/L, respectively. answering why hypoalbuminemia can be a predictor in 14 cases of peptic ulcer bleeding under contemporary treat- Patients who were lost to follow-up were excluded from the ment strategies. analysis of the primary and secondary outcomes. The AIMS65 score and co-morbidities were evaluated according to relevant studies.10,12,20 Nosocomial bleeding Patients and methods was defined as peptic ulcer bleeding that developed more than 24 h after admission. Ulcer size was estimated with Patients and study design biopsy forceps, with fully opened cups being 6 mm in diameter (FB-25K-1, Olympus, Tokyo, Japan). This prospective observational cohort study was conducted in the inpatient wards of National Cheng Kung University Hospital, a tertiary healthcare center in Tainan City, Outcome measures for all-cause mortality and Taiwan. The research and ethics committee of the hospital rebleeding within 84 days approved the study design (ER-100-008 and trial registra- tion identifier: NCT01591083, ClincalTrials.gov). All All patients except those who expired regularly returned to participants were enrolled after giving written informed out-patient clinics for at least 84 days for a clinical mani- consent. A schematic flow chart of the study protocol is festation review and to monitor outcomes in hospital and

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006 + MODEL Hypoalbuminemia and mortality with peptic ulcer bleeding 3

Figure 1 The schematic flow chart of the study design and the serial case numbers for the enrollment, allocation, and follow up during the study period. during the period between discharge and the follow-up minus the specificity for serum albumin levels. The esti- visit. Otherwise, we prospectively maintained telephone mated mortality rates in patients with normal and abnormal contact to determine the status of outcomes after albuminemia were about 3% and 12%, respectively, and the discharge. The primary outcome was all-cause mortality, number of patients was at a 1:1 ratio. With a two-sided a which was defined as any causes of death. The secondary value of 0.05 and a power of 80% (b Z 0.20), the number of outcomes were bleeding-related mortality and rebleeding. patients required was 134 for each group. Assuming a Bleeding-related mortality was defined as patient deaths screening failure and a dropout rate of 10%, the study was due to 1) uncontrolled bleeding, 2) death within 48 h after closed when the total number of eligible patients was more endoscopy, transarterial embolization for bleeding vessels than 443, and the enrollment period lasted a total of three or surgery for uncontrolled bleeding, or 3) complications years. The areas under receiver operating characteristic related to these therapies. curve (AUROC) for serum albumin levels and AIMS65 scores Rebleeding was defined as: 1) continuous melena, for discriminating all-cause mortality were compared and hematochezia, or the presence of recurrent bloody aspi- tested for equality using the Delong c2 test. The abnormal rates through a nasogastric tube and 2) relapse of hemo- albuminemia was validated in a 10-fold cross validation dynamic instability, including systolic blood pressure strategy with 10 rounds of 10 repetitions.21 Multiple COX <90 mmHg, heart rate >120 beats per minute, or a drop in regression analyses with forward selection at the 0.05 level hemoglobin concentration by more than 20 g/L. The serial were applied to assess independent risk factors related to check-ups of hemoglobin were scheduled on arrival, the 3rd all-cause mortality, bleeding-related mortality, or day, and on the 14th day to evaluate rebleeding. rebleeding. Low variance inflation factor values among the covariates were documented and no potential multi- Statistical analysis collinearity problems were identified. No hazard ratios (HR) which violated the assumption of proportional hazards were found by using Assess statement and ph option of SAS PROC The patient characteristics were compared using either the PHREG. A multivariable logistic regression analysis using a Pearson’s c2 test or the Fisher’s exact test. Continuous selection of variables significant at the 0.10 level was variables were categorized to avoid multiplicative errors. In applied to assess independent risk factors related to the survival analysis, the log-rank test was used to compare abnormal albuminemia. Standard software (SPSS v17.0, SAS KaplaneMeier curves among the study groups. Receiver v9.4, and R v3.3.0) was used for statistical analyses. All operating characteristic (ROC) curves for determining cut- tests were two-tailed, and p values < 0.05 indicated sig- off values that best discriminated between mortality and nificant differences. survival were derived by plotting the sensitivity versus 1

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006 + MODEL 4 H.-C. Cheng et al.

Results levels <70 g/L, thrombocytopenia <80 109/L, and pro- thrombin time prolong 4s(P < 0.05), but not according to Clinical characteristics and treatment of the study sex, heart disease, drug use, ulcer characteristics, and the > groups method of gastroscopic therapy (P 0.05). The rate of Helicobacter pylori infection was less in the Hypo-AG group than in the other groups (P < 0.05, Table 1). From August of 2011 to July of 2014, 474 patients with peptic ulcer bleeding were consecutively assessed for eligibility (Fig. 1). Forty-eight patients were excluded Causes of mortality in different study groups because 19 did not meet the inclusion criteria; one declined to participate; 13 had bleeding from cancers, and 15 had Three patients were lost to follow-up (1 in Hypo-AG and 2 in bleeding from esophageal ulcer or others. The 426 Normal-AG). There were 17 patients who expired within 28 remaining patients were divided as follows: 79 were placed days and 22 patients who expired during the 29the84th in the Hypo-AG group; 135 were placed in the Margin-AG day, respectively. The distribution of the major underlying group, and 212 were placed in the Normal-AG group. diseases stratified according to mortality in the study There was an increasing trend in a stepwise fashion from groups is shown in Fig. 2A and B. Within 28 days, there were patients in the Normal-AG and Margin-AG groups to those in ten patients in the Hypo-AG group who died because of the Hypo-AG group according to rates of old age 70 y/o, bleeding (n Z 2), infectious diseases (n Z 5), malignancy in cirrhosis, uremia with maintenance dialysis, malignant the terminal stage (n Z 1), ischemic colitis (n Z 1), and diseases, lung diseases, American Society of Anesthesiology subdural hemorrhage (n Z 1); three patients in the Margin- physical status class III, nosocomial bleeding, shock on AG group died because of bleeding (n Z 2) and infectious arrival, Rockall scores 6, AIMS65 scores 2, hemoglobin diseases (n Z 1), and four patients in the Normal-AG group

Table 1 The differences in clinical demographic features, ulcer characteristics, endoscopic hemostatic modalities, and proton pump inhibitor use among the three groups. Variables, N (%) Hypo-AG (n Z 79) Margin-AG (n Z 135) Normal-AG (n Z 212) P valuea Female 25 (31.6) 36 (26.7) 63 (29.7) 0.92 Age 70 y/o 49 (62.0) 67 (49.6) 78 (36.8) <0.001 Cirrhosis 16 (20.3) 17 (12.6) 9 (4.2) <0.001 End stage renal disease with 12 (15.2) 14 (10.4) 15 (7.1) 0.04 maintenance dialysis Malignant diseases 17 (21.5) 22 (16.3) 21 (9.9) 0.01 Lung diseases 21 (26.6) 21 (15.6) 19 (9.0) <0.001 Heart diseases 19 (24.1) 30 (22.2) 44 (20.8) 0.54 ASA physical status class III 61 (77.2) 88 (65.2) 75 (35.4) <0.001 Nosocomial bleeding 37 (46.8) 23 (17.0) 14 (6.6) <0.001 Shock on arrivalb 24 (30.4) 29 (21.5) 27 (12.7) <0.001 Rockall scores 6 72 (91.1) 104 (77.0) 127 (59.9) <0.001 AIMS65 scores 2 68 (86.1) 38 (28.1) 18 (8.5) <0.001 H. pylori infectionc 17/61 (27.9) 56/117 (47.9) 93/183 (50.8) 0.01 NSAIDs use 39 (49.4) 54 (40.0) 81 (38.2) 0.11 Antiplatelet and/or anticoagulant use 24 (30.4) 49 (36.3) 75 (35.4) 0.52 Ulcer characteristics Gastric ulcer 46 (58.2) 78 (57.8) 99 (46.7) 0.04 Mean ulcer size 1.0 cm 49 (62.0) 81 (60.0) 108 (50.9) 0.05 Forrest classification, Ia or Ib 30 (38.0) 37 (27.4) 74 (34.9) 1.00 Hemoglobin levels < 70 g/L 35 (44.3) 34 (25.2) 15 (7.1) <0.001 Platelet count < 80 109/L 10 (12.7) 11 (8.1) 3 (1.4) <0.001 PT prolong 4 s 21 (26.6) 14 (10.4) 10 (4.7) <0.001 aPTT prolong 1.5-fold 3 (3.8) 2 (1.5) 3 (1.4) 0.25 Gastroscopic combination therapies or 71 (89.9) 114 (84.4) 188 (88.7) 0.92 monotherapy other than diluted epinephrine-injection Abbreviations: aPTT, activated partial thromboplastin time; ASA, American Society of Anesthesiology; CI, confidence interval; H. pylori, Helicobacter pylori; Hypo-AG, the hypoalbuminemia group; Margin-AG, the marginal hypoalbuminemia group; Normal-AG, the normal albuminemia group; NSAID, non-steroidal anti-inflammatory drug; PT, prothrombin time. a The trend test. b Systolic blood pressure <100 mmHg on arrival. c The number of patients who received H. pylori infection survey totaled 361. Activated partial thromboplastin time: normal range 26.0e38.0 s. Hemoglobin: normal range 116e148 g/L. Platelet: normal range: 151e366 109/L. Prothrombin time: normal range 9.40e12.5 s. Serum albumin: normal range 35e50 g/L.

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006 + MODEL Hypoalbuminemia and mortality with peptic ulcer bleeding 5

Figure 2 The distribution of underlying diseases in the hypoalbuminemia group (Hypo-AG), the marginal hypoalbuminemia group (Margin-AG), and the normal albuminemia group (Normal-AG) was stratified according to mortality causes within 28 days (A) and during the 29th84th day. (B) Some patients had two or more underlying diseases, and the cause of mortality was attributed to the most relevant one. AAA: abdominal aortic aneurysm. AMI: acute myocardial infarction. CHF: congestive heart failure.

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006 + MODEL 6 H.-C. Cheng et al. died because of infectious diseases (n Z 1), malignancy in The rebleeding rates during the study period were also the terminal stage (n Z 2), and sudden cardiac death increased in the same trend (0e28th day: 6.4% [12/188], (n Z 1). During the 29the 84th day, the causes of mortality 15.4% [19/123], 24.6% [15/61], P < 0.001; 29the84th day: were diverse in the Hypo-AG group (2 due to rebleeding, 3 0% [0/186], 3.0% [3/99], 4.2% [2/48], P Z 0.01). due to infectious diseases, and 2 due to malignancy in the terminal stage), the Margin-AG group (1 due to rebleeding, The optimal cut-off value of serum albumin to 4 due to infectious diseases, 4 due to malignancy in the terminal stage, and 1 due to acute myocardial infarctions), predict mortality of peptic ulcer bleeding and the Normal-AG group (2 due to infectious diseases, 1 due to malignancy in the terminal stage, and 2 due to The AUROC of AIMS65 used to predict 28-day and 84-day all- e < cardiovascular disorders). The majority of mortalities were cause mortality were 0.77 (95% CI, 0.63 0.90, P 0.001) and e < related to co-morbidity, including 12 (70.6%) within 28 days 0.72 (95% CI, 0.63 0.81, P 0.001), respectively. The AUROC e and 17 (77.3%) during the 29the84th day. of serum albumin levels were 0.76 (95% CI, 0.66 0.86, P < 0.001) and 0.73 (95% CI, 0.65e0.80, P < 0.001) to predict 28-day and 84-day all-cause mortality, respectively. Based Serum albumin levels correlated to all-cause or on the ROC curve, the optimal cut-off value of serum albumin bleeding-related mortality and rebleeding within levels was selected as 30 g/L to predict 28-day (70.6% 84 days sensitivity and 75.6% specificity) and 84-day all-cause mor- tality (59.0% sensitivity and 77.2% specificity). In Table 2, all-cause mortality rates during the two follow- Furthermore, multiple COX regression analyses with up periods were increased in a stepwise fashion in a trend forward selection confirmed that serum albumin <30 g/L from patients in the Normal-AG and Margin-AG groups to (HR [95% CI]: 3.35 [1.79e6.26], P < 0.001), ulcer those in the Hypo-AG group (0e28th day: 1.9% [4/210], 2.2% size 2 cm (HR [95% CI]: 2.99 [1.60e5.59], P Z 0.001), and [3/135],12.8% [10/78], P < 0.001; 29the84th day: 2.5% [5/ end stage renal disease with maintenance dialysis (HR [95% 200], 8.0% [10/125], 10.6% [7/66], P < 0.01). The bleeding- CI]: 2.44 [1.07e5.56], P Z 0.04) were three independent related mortality rates were also increased in the same factors for 84-day recurrent bleeding. Moreover, exclusive fashion (0e28th day: 0% [0/210], 1.5% [2/135], 2.6% [2/78], of the catastrophic co-morbidity with malignant diseases, P Z 0.03; 29the84th day: 0% [0/200], 0.8% [1/125], 3.0% serum albumin <30 g/L (HR [95% CI]: 4.41 [1.03e18.97], [2/66], P Z 0.02). While including lost-to-follow-up pa- P Z 0.046) and nosocomial bleeding (HR [95% CI]: 6.14 tients in the denominator, we tested the assumptions about [1.59e23.70], P Z 0.01) were two independent factors for the outcomes among patients, i.e., none or all of lost-to- 84-day all-cause mortality. follow-up patients had the outcomes and expressed the Accordingly, the relative risks of all-cause mortality (within least or most possible values as ranges (Table 2). In Fig. 3, 28 days: 6.75, 95% CI [2.43e18.72], P < 0.001; 29the84th day: the KaplaneMeier curves show that the cumulative survival 3.12, 95% CI [1.40e6.96], P < 0.01) and all-cause mortality proportions within 28 days and follow-up to 84 days were adjusted for rebleeding (within 28 days: 4.06, 95% CI lower in the Hypo-AG group than in the Margin-AG group [1.79e9.24], P < 0.001; 29the84th day: 1.46, 95% CI (P < 0.01 and 0.01, respectively) as compared to the [1.07e2.00], P Z 0.02) were compared between patients with Normal-AG group (both with P < 0.001). The cumulative abnormal albuminemia <30 g/L and those 30 g/L. Moreover, survival proportion follow-up to 84 days was lower in the abnormal albuminemia <30 g/L was associated with an abso- Margin-AG group than in the Normal-AG group (P Z 0.047). lute risk increase in all-cause mortality of 16.2 in every 100

Table 2 The analysis of all-cause and bleeding-related mortalities and recurrent bleeding in the three groups. Outcomes N, % (range)a Hypo-AG Margin-AG Normal-AG Pb value Primary outcomes All-cause mortality rates 0e28th day 10/78, 12.8 (12.7e13.9) 3/135, 2.2 (2.2e2.2) 4/210, 1.9 (1.9e2.8) <0.001 29the84th day 7/66, 10.6 (10.1e14.5) 10/125, 8.0 (7.6e12.9) 5/200, 2.5 (2.4e6.3) <0.01 Secondary outcomes Bleeding-related mortality rates 0e28th day 2/78, 2.6 (2.5e3.8) 2/135, 1.5 (1.5e1.5) 0/210, 0 (0e0.9) 0.03 29the84th day 2/66, 3.0 (2.9e7.2) 1/125, 0.8 (0.8e6.1) 0/200, 0 (0e3.8) 0.02 Recurrent bleeding rates 0e28th day 15/61, 24.6 (19.0e41.8) 19/123, 15.4 (14.1e23.0) 12/188, 6.4 (5.7e17.0) <0.001 29the84th day 2/48, 4.2 (3.6e17.9) 3/99, 3.0 (2.6e16.5) 0/186, 0 (0e5.6) 0.01 Abbreviations: Hypo-AG, the hypoalbuminemia group; Margin-AG, the marginal hypoalbuminemia group; Normal-AG, the normal albu- minemia group. a The outcomes of all patients excluding those who were lost to follow-up were shown as values. While including lost-to-follow-up patients in the denominator, the least and most possible values were shown as ranges in parentheses according to the assumptions that none or all of the lost-to-follow-up patients had the outcomes, respectively. b The trend test was based on analyses of all patients excluding lost-to-follow-up patients.

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006 + MODEL Hypoalbuminemia and mortality with peptic ulcer bleeding 7

Figure 3 The KaplaneMeier curves showed that the cumulative survival proportion either within 28 days or follow-up to 84 days after peptic ulcer bleeding was lower in the hypoalbuminemia group (Hypo-AG) than in either the marginal hypoalbuminemia group (Margin-AG) (within 28 days, P < 0.01 and follow-up to 84 days, P Z 0.01 by log rank test, respectively) or the normal albuminemia group (Normal-AG) (P < 0.001, log rank test). patients in an 84-day follow-up. The likelihood ratios for a mortality and rebleeding in patients with peptic ulcer positive test and negative test were 2.89 and 0.39 for 28-day all- bleeding. The study further illustrated low hemoglobin cause mortality, and 2.59 and 0.53 for 84-day all-cause mor- <70 g/L, nosocomial ulcer bleeding, cirrhosis, age 70 y/o, tality, respectively. The accuracy, sensitivity, specificity, and shock, and ulcer size 1 cm to be independently related to AUROC of abnormal albuminemia <30 g/L based on 10-fold hypoalbuminemia. cross validation procedures were 68.1%, 64.7%, 31.8%, and About 80% of the total mortality in peptic ulcer bleeding 0.621 for 28-day all-cause mortality and 63.5%, 71.8%, 37.2%, has been shown to be due to concomitant disease exacer- and 0.618 for 84-day all-cause mortality, respectively. The bation.3,8,22,23 Our study reinforced these findings and dis- Nagelkerke R-square scores were 0.124 and 0.107, respectively. closed that 82.1% (32/39) of patients died because of concomitant diseases, most of which, a total of 90.6% (29/ Independent clinical variables related to abnormal 32) were non-gastrointestinal co-morbidities (Fig. 2A and albuminemia <30 g/L B). Therefore, it was clear that there is a need for a simple biomarker that can reflect the status of co-morbidity and thus predict mortality. Because serum albumin levels can In Table 3, abnormal albuminemia <30 g/L is independently be either disease-specific or may indirectly reflect the related to the following variables, which are ranked in nutritional or stress status of patients with poor mucosal order from the highest odds ratio (OR) as hemoglobin healing,24e26 our study shows that peptic ulcer healing levels < 70 g/L (OR [95% CI]: 9.53 [4.74e19.17], P < 0.001), might be delayed and carry an increased rebleeding risk nosocomial bleeding (OR [95% CI]: 6.24 [2.89e13.47], among patients who have hypoalbuminemia (P < 0.001, P < 0.001), cirrhosis (OR [95% CI]: 5.90 [2.13e16.33], Table 2). Additionally, all-cause mortality rates were found P Z 0.001), age 70 y/o (OR [95% CI]: 2.74 [1.44e5.23], to be correlated to serum albumin levels in a dose- P < 0.01, shock on arrival (OR [95% CI]: 2.51 [1.23e5.14], dependent manner either within 28 days or from the 29th P Z 0.01), or mean ulcer size 1.0 cm (OR [95% CI]: 2.12 to 84th day (1.9%, 2.2%, 12.8%, p < 0.001 and 2.5%, 8.0%, [1.09e4.13], P Z 0.03). 10.6%, P < 0.01, respectively, in Table 2). Moreover, the AUROC of serum albumin levels used to predict all-cause Discussion mortality was similar to that of AIMS65 either in the 28- day (0.76 vs. 0.77, P Z 0.92) or 84-day (0.73 vs. 0.72, This prospective cohort study disclosed that serum albumin P Z 0.93) follow-up. The data suggest that hypo- levels correlate to risk of all-cause and bleeding-related albuminemia can be a significant mortality predictor not

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006 + MODEL 8 H.-C. Cheng et al.

Table 3 The univariable analysis and multivariable logistic regression to validate factors associated with abnormal albu- minemia <30 g/L. Variables, N (%) Univariable analysis Multivariable analysis Odds ratio (95% CI) P valuea Odds ratio (95% CI) P value Female 0.97 (0.60e1.56) 0.88 ee Age 70 y/o 2.31 (1.48e3.59) <0.001 2.74 (1.44e5.23) <0.01 Shock on arrivalb 2.54 (1.53e4.23) <0.001 2.51 (1.23e5.14) 0.01 Cirrhosis 2.89 (1.51e5.52) 0.001 5.90 (2.13e16.33) 0.001 End stage renal disease with 2.71 (1.41e5.23) <0.01 2.10 (0.71e6.19) 0.18 maintenance dialysis Malignant diseases 1.78 (1.00e3.16) 0.05 0.61 (0.24e1.53) 0.29 Lung diseases 3.34 (1.91e5.84) <0.001 1.68 (0.71e3.96) 0.24 Nosocomial bleeding 7.69 (4.46e13.25) <0.001 6.24 (2.89e13.47) <0.001 H. pylori infectionc 0.40 (0.24e0.67) <0.001 0.69 (0.36e1.33) 0.26 Ulcer characteristics Gastric ulcer 1.30 (0.84e2.01) 0.24 ee Mean ulcer size 1.0 cm 1.61 (1.03e2.51) 0.04 2.12 (1.09e4.13) 0.03 Forrest classification, Ia or Ib 1.17 (0.75e1.84) 0.49 ee Hemoglobin levels < 70 g/L 5.79 (3.48e9.65) <0.001 9.53 (4.74e19.17) <0.001 Platelet count < 80 109/L 3.62 (1.57e8.33) 0.001 1.23 (0.27e5.51) 0.79 PT prolong 4 s 3.81 (2.02e7.16) <0.001 1.92 (0.60e6.11) 0.27 aPTT prolong 1.5-fold 1.70 (0.40e7.24) 0.44 ee Abbreviations: aPTT, activated partial thromboplastin time; CI, confidence interval; H. pylori, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PT, prothrombin time. a The Pearson’s chi-square test and the Fisher’s exact test with 2-tailed analysis were used as appropriate. b Systolic blood pressure <100 mmHg on arrival. c The number of patients who received H. pylori infection survey totaled 361. Activated partial thromboplastin time: normal range 26.0e38.0 s. Hemoglobin: normal range 116e148 g/L. Platelet: normal range: 151e366 109/L. Prothrombin time: normal range 9.40e12.5 s. Serum albumin: normal range 35e50 g/L.

only for the intra-hospital course of variceal and non- hypoalbuminemia may not result in a decrease in the variceal upper gastrointestinal bleeding as stated by pharmacologic effect of a proton pump inhibitor.40 Our AIMS65 but also for a 3-month follow-up of peptic ulcer data indirectly indicated that patients with hypo- bleeding. Moreover, it was easier to diagnose hypo- albuminemia had an increased risk of mortality even albuminemia than to obtain the AMIS65 score.12,13 though they were receiving a proton pump inhibitor. The reasons why hypoalbuminemia can be a predictor Therefore, since non-gastrointestinal comorbidities are of mortality remain uncertain. Although hypoalbuminemia the main causes of mortality, hypoalbuminemia should be is rather common in cirrhosis,14 this study further illus- considered to be an indicator by which to identify risk trated that other factors, including low hemoglobin levels, groups in order to provide holistic care rather than merely nosocomial bleeding, senility, shock, and large ulcers, are focusing on hemostasis. A previous pilot study showed that also independently correlated with abnormal albuminemia intravenous albumin supply does not decrease the in- (P < 0.05, Table 3). These data were reasonable because cidences of 28-day rebleeding and mortality41; neverthe- shock and low hemoglobin levels indicate massive less, in the future, we might be able to improve outcomes bleeding. The data also concur with previous articles of peptic ulcer bleeding not only by identifying hypo- showing that massive bleeding, cirrhosis, old age, and albuminemia but also by correcting its related factors. large ulcer are factors related to poor prognosis.2,3,10,27e31 Patients who took warfarin or anti-platelet therapy Moreover, it is beyond doubt that patients with nosocomial resumed such medication early in this study with adherence bleeding have acute illnesses or exacerbated concomitant to consensus guildlines.9,19 Even so, neither the all-cause diseases and thus have worse prognoses than those mortality rate, the bleeding-related mortality rate, nor without.27,32 These findings proposed possible reasons why the rebleeding rate within 28 days was increased in the hypoalbuminemia could be a single parameter to identify warfarin or anti-platelet agent users (users vs. non-users: patients at risk of poor prognosis in cases of peptic ulcer all-cause mortality rate, 1/148 [0.7%] vs. 16/275 [5.8%], bleeding.12,33e36 P Z 0.01; bleeding-related mortality, 1/148 [0.7%] vs. 3/ In critically ill or surgical patients, nearly 77% of 275 [1.1%], P Z 1.0; rebleeding, 15/134 [11.2%] vs. 31/238 hypoalbuminemia is due to an increase in capillary [13.0%], P Z 0.61). Early reintroduction of such medication permeability and albumin re-distribution, but only 18% is did not increase rebleeding and relevant mortality. due to blood loss.37,38 Therefore, either de novo or The current study had limitations. First, this was only existing hypoalbuminemia might reflect acute critical an observation study; thus, the causal relationship be- stress or chronic incurable illness.39 Moreover, tween hypoalbuminemia and mortality remains uncertain.

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006 + MODEL Hypoalbuminemia and mortality with peptic ulcer bleeding 9

Nevertheless, our study showed that serum albumin levels Acknowledgements correlate to mortality in a dose-dependent manner. Moreover, after adjustment for rebleeding, abnormal We are grateful to Professor Sheng-Hsiang Lin for providing albuminemia was still a predictor of mortality. Second, statistical consulting services from the Biostatistics this study did not validate the findings in an external Consulting Center, National Cheng Kung University Hospital. cohort. Nevertheless, albuminemia <30 g/L could still be a good predictor based on 10-fold cross validation pro- cedures. Third, our study might lack the appropriate References power to compare AIMS65 and serum albumin levels. In the future, an external and large-scale cohort would be 1. Longstreth GF. Epidemiology of hospitalization for acute upper promising to validate the predictive effect of abnormal gastrointestinal hemorrhage: a population-based study. Am J albuminemia in cases of peptic ulcer bleeding. Fourth, Gastroenterol 1985;90:206e10. hospital care was not standardized and disease charac- 2. Katschinski B, Logan R, Davies J, Faulkner G, Pearson J, teristics were diverse; nevertheless, it was real world Langman M. Prognostic factors in upper gastrointestinal encountered by clinicians. bleeding. Dig Dis Sci 1994;39:706e12. This study was conducted under contemporary stan- 3. Yavorski RT, Wong RK, Maydonovitch C, Battin LS, Furnia A, Amundson DE. Analysis of 3,294 cases of upper gastrointestinal dardization of treatment as far as endoscopic hemostasis bleeding in military medical facilities. Am J Gastroenterol and proton pump inhibitor use and showed that serum al- 1995;90:568e73. bumin levels can be accurate to predict mortality. Only one 4. Marmo R, Koch M, Cipolletta L, et al. Predicting mortality in parameter is needed; thus its use is intuitive. It could be non-variceal upper gastrointestinal bleeders: validation of the generalizable to clinical practice to screen out patients at Italian PNED score and prospective comparison with the risk of mortality. Rockall score. Am J Gastroenterol 2010;105:1284e91. In conclusion, a low serum albumin level can be both a 5. Sung JJ, Barkun A, Kuipers EJ, et al. Intravenous esomeprazole short-term and long-term indicator for mortality and for prevention of recurrent peptic ulcer bleeding: a random- rebleeding after peptic ulcer bleeding under proton pump ized trial. Ann Intern Med 2009;150:455e64. inhibitor use. Low hemoglobin <70 g/L, nosocomial ulcer 6. Cheng HC, Wu CT, Chang WL, Cheng WC, Chen WY, Sheu BS. Double oral esomeprazole after three-day intravenous eso- bleeding, cirrhosis, senility with age 70 y/o, shock on meprazole infusion reduces recurrent peptic ulcer bleeding in arrival, and large ulcers 1 cm are independently related high-risk patients-a randomized controlled study. Gut 2014;63: < to albuminemia 30 g/L and can thus serve as alarms 1864e72. indicating an increased risk of mortality after peptic ulcer 7. Abougergi MS, Travis AC, Saltzman JR. The in-hospital mortal- bleeding. ity rate for upper GI hemorrhage has decreased over 2 decades in the Unites States: a nationwide analysis. Gastrointest Endosc 2015;81:882e8. Funding/support statement 8. Sung JJ, Tsoi KK, Ma TK, Yung MY, Lau JY, Chiu PW. Causes of mortality in patients with peptic ulcer bleeding: a prospective This study was funded in part by research grants from cohort study of 10,428 cases. Am J Gastroenterol 2010;105: Ministry of Science and Technology (National Science 84e9. Council) of Taiwan (NSC 100-2314-B-006-026-MY3), Ministry 9. Sung JJ, Chan FK, Chen M, et al. Asia-Pacific working group of Health and Welfare of Taiwan (MOHW103-TDU-B-211- consensus on non-variceal upper gastrointestinal bleeding. Gut e 113002, MOHW104-TDU-B-211-113002, MOHW105-TDU-B- 2011;60:1170 7. 10. Rockall TA, Logan RFA, Devlin HB, Northfield TC. Risk assess- 211-113002, MOHW106-TDU-B-211-113003), National Cheng ment after acute upper gastrointestinal haemorrhage. Gut Kung University Hospital in Tainan, Taiwan (NCKUH- 1996;38:316e21. 10104002, NCKUH-10405030, and NCKUEDA10207), and E-DA 11. Blatchford O, Murray WR, Blatchford M. A risk score to predict Hospital in Kaohsiung, Taiwan (NCKUEDA10207). need for treatment for upper gastrointestinal haemorrhage. Lancet 2000;356:1318e21. 12. Saltzman JR, Tabak YP, Hyett BH, Sun X, Travis AC, Author’s contribution Johannes RS. A simple risk score accurately predicts in hospital mortality, length of stay, and cost in acute upper GI bleeding. Dr. Cheng HC designed the research study and drafted the Gastrointest Endosc 2011;74:1215e24. manuscript. Dr. Yang EH, Dr. Wu CT, Dr. Wang WL, Dr. Chen 13. Hyett BH, Abougergi MS, Charpentier JP, et al. The AIMS65 PJ, and Dr. Lin MY collected the data. Dr. Cheng HC and Dr. score compared with the Glasgow-Blatchford score in pre- Yang EH analyzed and interpreted the data. Prof. Sheu BS dicting outcomes in upper GI bleeding. Gastrointest Endosc e revised the manuscript critically and gave approval of the 2013;77:551 7. submitted and final versions. All authors approved the final 14. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal vari- version of the article, including the authorship list. ces. Br J Surg 1973;60:646e9. 15. Forrest JA, Finlayson ND, Sherman DJ. Endoscopy in gastroin- Competing interests testinal bleeding. Lancet 1974;2:394e7. 16. Laine L, McQuaid KR. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of ran- The authors declare no financial relationship with any domized controlled trials. Clin Gastroenterol Hepatol 2009;7: company involved in this study. There is no conflict of in- 33e47. terest, consultant, institutional and other relationships 17. Barkun AN, Martel M, Toubouti Y, Rahme E, Bardou M. Endo- involved in this submission. scopic hemostasis in peptic ulcer bleeding for patients with

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high-risk lesions: a series of meta-analyses. Gastrointest 29. Provenzale D, Sandler DS, Wood DR, et al. Development of a Endosc 2009;69:786e99. scoring system to predict mortality from upper gastrointestinal 18. Zargar SA, Javid G, Khan BA, et al. Pantoprazole infusion as bleeding. Am J Med Sci 1987;294:26e32. adjuvant therapy to endoscopic treatment in patients with 30. Hsu YC, Lin JT, Chen TT, Wu MS, Wu CY. Long-term risk of peptic ulcer bleeding: prospective randomized controlled trial. recurrent peptic ulcer bleeding in patients with liver cirrhosis: a J Gastroenterol Hepatol 2006;21:716e21. 10-year nationwide cohort study. Hepatology 2012;56:698e705. 19. Gralnek IM, Dumonceau JM, Kuipers EJ, et al. Diagnosis and 31. Elmunzer BJ, Young SD, Inadomi JM, Schoenfeld P, Laine L. management of nonvariceal upper gastrointestinal hemor- Systematic review of the predictors of recurrent hemorrhage rhage: European Society of Gastrointestinal Endoscopy (ESGE) after endoscopic hemostatic therapy for bleeding peptic ul- guideline. Endoscopy 2015;47:a1e46. cers. Am J Gastroenterol 2008;103:2625e32. 20. Silvertstein FE, Gilbert DA, Tedesco FJ, Buenger NK, Persing J. 32. Terdiman JP, Ostroff JW. Gastrointestinal bleeding in the The National ASGE Survey on upper gastrointestinal bleeding. I. hospitalized patient: a case-control study to assess risk fac- Study design and baseline data. Gastrointest Endosc 1981;27: tors, causes, and outcome. Am J Med 1998;104:349e54. 73e9. 33. Cheng HC, Kao AW, Chuang CH, Sheu BS. The efficacy of high 21. Kohavi R. A study of cross-validation and bootstrap for accuracy and low dose intravenous omeprazole in preventing rebleeding estimation and model selection. In: IJCAI’95 Proceedings of the for patients with bleeding peptic ulcers and comorbid ill- 14th international joint conference on artificial intelligence, nesses. Dig Dis Sci 2005;50:1194e201. vol. 2. San Francisco: Morgan Kaufmann; 1995. p. 1137e43. 34. Cheng HC, Chang WL, Yeh YC, Chen WY, Tsai YC, Sheu BS. 22. Crooks CJ, Card TR, West J. Excess long-term mortality Seven-day intravenous low-dose omeprazole infusion reduces following non-variceal upper gastrointestinal bleeding: a peptic ulcer rebleeding for patients with comorbidities. Gas- population-based cohort study. PLoS Med 2013;10:e1001437. trointest Endosc 2009;70:433e9. 23. Laursen SB, Hansen JM, Hallas J, Schaffalitzky de 35. Gonza´lez-Gonza´lez JA, Va´zquez-Elizondo G, Garcı´a- Muckadell OB. The excess long-term mortality in peptic ulcer Compea´n D, et al. Predictors of in-hospital mortality in pa- bleeding is explained by nonspecific comorbidity. Scand J tients with non-variceal upper gastrointestinal bleeding. Rev Gastroenterol 2015;50:145e52. Esp Enferm Dig 2011;103:196e203. 24. Jellinge ME, Henriksen DP, Hallas P, Brabrand M. Hypo- 36. Cheng HC, Wu CT, Chen WY, Yang EH, Chen PJ, Sheu BS. Risk albuminemia is a strong predictor of 30-day all-cause mortality factors determining the need for second-look endoscopy for in acutely admitted medical patients: a prospective, observa- peptic ulcer bleeding after endoscopic hemostasis and proton tional, cohort study. PLoS One 2014;9:e105983. pump inhibitor infusion. Endosc Int Open 2016;4:E255e62. 25. Chojkier M. Inhibition of albumin synthesis in chronic diseases 37. Uhing MR. The albumin controversy. Clin Perinatol 2004;31: molecular mechanisms. J Clin Gastroenterol 2005;39:S143e6. 475e88. 26. Shiraki T, Iida O, Takahara M, et al. Predictors of delayed 38. Smeets HJ, Kievit J, Dulfer FT, Hermans J, Moolenaar AJ. wound healing after endovascular therapy of isolated infra- Analysis of post-operative hypalbuminaemia: a clinical study. popliteal lesions underlying critical limb ischemia in patients Int Surg 1994;79:152e7. with high prevalence of diabetes mellitus and hemodialysis. 39. Reuben DB, Tinetti ME. The hospital-dependent patient. N Engl Eur J Vasc Endovasc Surg 2015;49:565e73. J Med 2014;370:694e7. 27. Wong GL, Wong VW, Chan Y, et al. High incidence of mortality 40. Rega˚rdh CG, Gabrielsson M, Hoffman KJ, Lo¨fberg I, Ska˚nberg I. and recurrent bleeding in patients with Helicobacter pylori- Pharmacokinetics and metabolism of omeprazole in animals negative idiopathic bleeding ulcers. Gastroenterology 2009; and man-an overview. Scand J Gastroenterol 1985;108(Suppl): 137:525e31. 79e94. 28. Theocharis GJ, Arvaniti V, Assimakopoulos SF, et al. Acute 41. Cheng HC, Chang WL, Chen WY, Tsai YC, Yeh YC, Sheu BS. upper gastrointestinal bleeding in octogenarians: clinical Intravenous albumin shortens the duration of hospitalization outcome and factors related to mortality. World J Gastro- for patients with hypoalbuminemia and bleeding peptic ulcers: enterol 2008;14:4047e53. a pilot study. Dig Dis Sci 2013;58:3232e41.

Please cite this article in press as: Cheng H-C, et al., Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use, Journal of the Formosan Medical Association (2017), http://dx.doi.org/10.1016/j.jfma.2017.07.006