{'fraction_non_alphanumeric': 0.035314550366653805, 'fraction_numerical': 0.017657275183326902, 'mean_word_length': 5.001737116386798, 'pattern_counts': {'":': 0, '<': 3, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Angiotensin II receptor blocker prevents upper gastrointestinal bleeding in hypertensive patients with chronic kidney disease not on dialysis

Investigate if angiotensin II receptor blocker (ARB) decreases risk of upper gastrointestinal bleeding (UGIB) in hypertensive patients with chronic kidney disease (CKD) not on dialysis.


Introduction
Overactivity of the renin-angiotensin-aldosterone system (RAAS) is linked to the development of chronic kidney disease (CKD), hypertension (HTN) and cardiovascular disease (1). RAAS may play a regulatory role in upper gastrointestinal injury induced by lowdose aspirin (2). The use of angiotensin II receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEI) is associated with a decreased risk of upper gastrointestinal bleeding (UGIB) in patients who took low dose aspirin (3). Inhibition of RAAS is associated with a protective effect in cold-restraint gastric mucosal damage in animal model (4). It has never been investigated if inhibition of RAAS is associated with a decreased UGIB in human. In this study, we investigate the effect of ARB and ACEI on the risk of UGIB in hypertensive patients with CKD not on dialysis. The hypertensive patients with CKD were selected because ARB or ACEI were most commonly prescribed antihypertensives in hypertensive patients especially in patients with CKD; more importantly, the effect of ARB/ACEI on UGIB can be compared with other antihypertensives. Confounders of UGIB such as aspirin, warfarin, steroid and a history of UGIB were also taken into consideration.

Methods
This observational cohort study was approved by the Internal Review Board of China Medical University Hospital for the review of medical records (DMR 99-IRB-301) and the need for informed consent was waived for the review of medical records. All hypertensive patients with CKD in the outpatient department of China Medical University Hospital from June 2003 to May 2013 were analysed. CKD patients on dialysis or kidney transplant were excluded. All patients were followed from the date of enrolment to the date of first episode of UGIB, patient's death, haemodialysis, peritoneal dialysis, kidney transplant, loss to follow-up, or May 2013. There were 132 (4.8%) patients died, 587 (21.4%) patients receiving haemodialysis, 233 (8.5%) patients receiving peritoneal dialysis, 6 (0.2%) patients receiving kidney transplant, and 335 (12.2%) patients lost to follow-up during the study period. HTN was defined as taking antihypertensives without regard to the actual measurement of blood pressure, or having a systolic blood pressure (SBP) reading greater than 140 mmHg or a diastolic blood pressure (DBP) reading greater than 90 mmHg (5). UGIB was defined as melena, hematemesis, rectorrhagia or emergence of red blood in gastric lavage fluid together with a bleeding lesion or a lesion likely to have bled in the upper digestive tract (6). A history of UGIB was recorded based on a review of medical record at enrolment. Helicobacter pylori infection was defined by the identification of the organism on antral biopsies or a reactive Cumpylobacter-like organism test (7). Coronary artery disease (CAD) was defined as a positive exercise test, angiography showing at least one stenosis of more than 50%, or positive scintigraphy (8). Diabetes mellitus (DM) was defined as use of insulin or a hypoglycaemic agent, a fasting plasma glucose level of 126 mg/dl or more (9). Underlying disease of CKD was diagnosed by the physician in primary care who enrolled the patient. A study nurse performed all reviewing of medical records and the study nurse consulted one physician if any uncertain condition exists in the reviewing. The study nurse and physician were blind to the aim of the study and the analysis was performed by another physician.
Each patient's body mass index, SBP, DBP, haemoglobin, platelet, blood urea nitrogen (BUN) and creatinine were measured at enrolment. Uric acid, sodium, potassium, calcium, phosphorus, albumin, cholesterol, triglyceride and fasting blood glucose were measured within 3 months. An estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (10). Antihypertensives including angiotensin converting enzyme inhibitor (ACEI), ARB, calcium channel blocker (CCB), beta blocker (BB) and diuretics prescribed in recent 3 month were recorded based on a review of medical record at enrolment. Medications related to UGIB including proton pump inhibitor (PPI), nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin and warfarin were also reviewed. Patients reported use of NSAIDs in 3 month at enrolment was taken into consideration.

Statistical analysis
Data are reported as mean AE standard deviation, median (interquartile range) or frequency (%). All continuous variables were tested using skewness test and kurtosis test for their normality. Testing for sta-tistical significance was conducted using Student's t-test for parametric variables, Kolmogorov-Smirnov test for non-parametric variables, and v 2 test for categorical variables. Possible confounders of UGIB were analysed using univariate Cox proportional hazard regression followed by multivariate Cox proportional hazard regression. A hazard ratio (HR) and 95% confidence interval (CI) were calculated. All analysis was performed using Stata version 12 SE (StataCorp, College Station, TX). A p < 0.05 was considered as statistical significant.

Results
A total of 2744 CKD stage 1-5 without renal replacement therapy (RRT) patients including 1229 female and 1515 male with an average of 64.9 AE 13.8 years old were analysed. In a median of 1.9 (0.9-3.9) years follow-up, 357 (12.2%) patients developed UGIB and the incidence of UGIB was 4.5 per 100 patient-years. ARB was prescribed in 1438 (52.4%) patients and ACEI was prescribed in 240 (8.8%) patients. As ARB was the most commonly used antihypertensives, patients' characteristics were presented based on the prescription of ARB. Patients' characteristics including age, gender, underlying disease, stage of CKD, H. pylori infection, comorbidity, blood pressure and biochemistry measurements were similar in patients with and without ARB treatment ( Table 1). The prevalence of UGIB (p < 0.001) and RRT (p < 0.001) was lower in patients with ARB.

Discussions
In a cohort consisting of hypertensive patients with CKD and not on dialysis, ARB was associated with decreased risk of UGIB. This finding was supported by the Cox regression which demonstrated a 40% decrease of UGIB risk in patients with ARB treatment (Table 4). Meanwhile, ACEI but not CCB treatment was also associated with a decreased risk of UGIB in univariate Cox regression (Table 3). This finding supported our hypothesis that inhibition of RAAS is associated with a decreased risk of UGIB in hyperten-sive patients with CKD. The association between ARB and lower UGIB may be explained by the reduced mucosal damage (4) through the decrease in inflammatory cytokines such as tumour necrosis factor alpha (11). The renoprotective effect of ARB (12) may also play a role in the lower UGIB risks because lower eGFR was associated with higher UGIB risks (13,14). The risk of UGIB was not significantly lower in patients on ACEI because limited number (8.8%) of patients took ACEI in this study. The effect of ARB on decreasing UGIB risk was independent of the confounders of UGIB. The confounders for UGIB in this study included H. pylori infection, lower renal function (14,15), comorbid diabetes (16), and a low serum albumin (17,18) that had also been reported in the previous studies. Given the strong association between CKD and CAD, antithrombotic (19,20) or antiplatelet medications are commonly used in CKD patients. It is generally believed that antithrombotic or antiplatelet medications may increase the risk of UGIB in CKD patients. The use of aspirin (19,20) and warfarin (21) were analysed, but none of these medications were linked to UGIB. In this study, PPI treatment was associated with an increased UGIB risk (Table 3) because the cost of PPI treatment was covered by the health insurance of Taiwan only after a peptic ulcer was diagnosed using panendoscopy. Since most of the patients receiving PPI treatment had the history of peptic ulcer, these patients were more at risk for developing UGIB.
There are some potential limitations of this study. First, this is not a randomised control trial to investi-  gate the effectiveness of ARB in decreasing UGIB risk. As the basal characteristics of patients with and without ARB were not different at enrollment (Table 1), selection bias did not explain the beneficial effect of ARB on UGIB in this study. Second, the use of ARB or ACEI was recorded at enrolment and the use of these medications in follow-up was not recorded. We were not able to analyse the effect of ARB treatment duration on UGIB. Third, ARB or ACEI should be considered in all CKD patients with/ without HTN based on the KDIGO guideline (4) and there were 50% patients receiving ARB or ACEI in this study. Most of the patients without ARB or ACEI may be treated by clinicians who are not physicians of nephrology, or have contraindication for ARB/ACEI treatment. Fourth, comprehensive suppression of the RAAS by adding spironolactone on ARB or ACEI may further hold the progression of CKD (22). We did not observe a superior benefit in adding spironolactone on ARB or ACEI for the risk of UGIB because spironolactone was prescribed in 0.8% of the patients in this study. Combination of ARB and ACEI was more effective in decreasing proteinuria than monotherapy (23); however, its clinical application can be limited by an increase in hyperkalemia risk (24,25). In this study, there were less than 1% of patients on the combination therapy (ARB + ACEI) and no significant association was found for its effect on UGIB. Despite these limitations, this study presented an extra clinical application for ARB, it not only decreases progression of CKD but also reduces UGIB risk in hypertensive patients with CKD.
In conclusion, ARB is associated with lower risk of UGIB in hypertensive patients with CKD and not on dialysis. Patients' renal function, medical history, H. pylori infection, comorbidity and patients' serum albumin are independently linked to UGIB risks.