ROLE OF NON STEROIDAL ANTI-INFLAMMATORY DRUGS IN ACUTE UPPER GASTROINTESTINAL BLEEDING

Objectives: Many patients presented to the causality with upper gastrointestinal bleeding, which is a serious condition associated with significant morbidity and mortality especially in elderly patients and those with coexisting medical diseases. The purpose of the study was to assess the general use of NSAIDs and their relation to upper gastrointestinal bleeding. Methods: Cross sectional study on patients who were referred for endoscopy for upper gastrointestinal bleeding in Sulaimany Teaching Hospital during the period from January to December 2016. All of them had been exposed to full history taking regarding age, gender, smoking, alcohol and medication used in addition to thorough physical examination and upper gastrointestinal endoscopic examination with biopsy when indicated. Results: This study enrolled 100 patients with upper GIT bleeding and showed that 48% of those with upper GIT bleeding were using NSAIDs, with male to female ratio of approximately 2:1, and 37 patients (77.1%) of those who were taken NSAIDs, did not use PPI concomitantly. Conclusion: The study also revealed that elderly patients taking NSAIDs were at higher risk of developing upper GIT bleeding.


INTRODUCTION
Approximately 50 non-steroidal anti-inflammatory drugs (NSAIDs) are in use throughout the world, the oldest and best known is aspirin. NSAIDs are popular because of their versatile effectiveness as analgesics, antipyretics, and (by definition) as anti-inflammatory agents 1 . Aspirin is also widely used as an antithrombotic agent. Unfortunately, aspirin and most other NSAIDs can injure the gastric and duodenal mucosa, with considerable morbidity and mortality 2 . UGI bleeding commonly presents with hematemesis (vomiting of blood or coffee-ground like material) and/or melena (black, tarry stools). A nasogastric tube lavage which yields blood or coffee-ground like material confirms this clinical diagnosis. However, lavage may not be positive if bleeding has ceased or arises beyond a closed pylorus. Gastroduodenal ulcer disease remains a common cause of UGI bleeding. There are four major risk factors for bleeding peptic ulcers 3 . Helicobacter pylori infection, nonsteroidal antiinflammatory drugs (NSAIDs) stress, gastric acid. Reduction or elimination of these risk factors reduces ulcer recurrence and rebleeding rates 4,5,6,7 . NSAIDs are a common cause of gastrointestinal ulceration 8,9,10, 11 . However, all patients with a prior history of bleeding ulcer disease are at increased risk for recurrent ulcer and complications 12,13,14 . NSAIDs also have been implicated as an important factor for non-healing ulcers 15 . Endoscopy is the preferred investigative procedure for upper gastrointestinal bleeding because of its accuracy, low rate of complications and potential for therapeutic intervention 16 . Pathology acute hemorrhagic and erosive gastropathy appears as multiple petechial hemorrhages and small red or black erosions on endoscopy 17,18 . Stress-related lesions (Curling's ulcers) usually appear in the fundus near the gastroesophageal junction and spread distally, but remain confined to the fundus and body 18 . In contrast, gastropathy due to NSAIDs and alcohol involves the entire stomach from the start, although it may be most evident in the antrum 18 . The healthy gastric and duodenal mucosae constitutively use COX-to produce its mucosal protective PGs 18 . Many NSAIDs block COX-1 and COX-2 more or less equally (i.e. are non-selective) and thus impair gastric PG production at low (<1µM) concentrations, examples include aspirin, indomethacin, ibuprofen, and naproxen. Most drugs that spare COX-1 and selectively inhibit COX-2 have less suppressive effects on gastric PG synthesis, examples include celecoxib and etodolac. As a result, selective inhibitors of COX-2, and also COX-3 inhibitors such as acetaminophen, preserve PGmediated GI mucosal protection 19,20,21 . However, COX-2 selective inhibitors can lose their specificity for COX-2 at high doses and have the potential to also block COX-1 in the stomach and duodenum and cause damage. American College of Gastroenterology recommendations-A committee appointed by the American College of Gastroenterology has critically reviewed the data regarding the risk factors for NSAID toxicity, and identified the five most important variables that place patients at risk for NSAID related gastrointestinal complications 22.
1. Prior history of an adverse GI event (ulcer, hemorrhage) increases risk four to five fold. 2. Age >60 increases risk five-to six fold . 3. High dosage of a NSAID increases risk 10-fold. 4. Concurrent use of glucocorticoids increases risk four to five fold. 5. Concurrent use of anticoagulants increases risk 10to 15-fold. Patients with several risk factors are at highest risk for NSAID-induced GI toxicity (up to 9 percent after six months) 2324 , Assessment of these risk factors is recommended for identifying patients who should be considered for prophylaxis if it is felt that an NSAID must be given. Aim of the study includes-1. To determine the overall causes of upper GIT bleeding. 2. To determine the frequency of NSAIDs induced upper GIT bleeding. 3. To assess local practice in using prophylaxis against NSAIDs induced upper GIT bleeding.

PATIENTS AND METHODS
This study is a cross sectional study. One hundred patients with upper GIT bleeding had been included in this study. They were randomly selected from those who were referred for GIT centre at Sulaimany Teaching Hospital during the period from January to December 2016. All of them had been exposed to full history taking regarding age, gender, smoking, alcohol intake and medication used, in addition to thorough physical examination and upper gastrointestinal endoscopy with biopsy when indicated. We excluded those patients with history of upper GIT bleeding with no endoscopic evidence of bleeding. All of the collected data had been analyzed using Microsoft Excel and Statistical Package for Social Sciences (SPSS) software. The data had been tabulated in form of frequency distribution tables and figures. Student's ttest and Chi-square test had been used for testing the level of significant association or difference between different quantitative and qualitative groups, respectively. A value of less than 0.05 had been selected as the P value required determining the significant association or difference.

RESULTS
This study enrolled 100 patients with upper GIT bleeding. The sample included 66 male (66% of the sample) and 34 female patients (34% of the sample). The mean age of the patients was 49.33± 14.9 year old (range: 20-80 year old). The mean age of male patients was 50.26±13.7 year old (range:  year old) and the mean age of the female patients was 47.5±17.1 year old (range 20-70 year old). Twenty nine patients (29% of the sample) were 60 years or older. 49 male patients were younger than 60 years (74.3% of male patients) compared to 22 females patients (64.7% of female patients) were within the same age group.   It can be seen clearly from the Figure 1 that approximately half of those with upper GIT bleeding were taking NSAID, while steroids 3% of the sample, alcohol 3% and 16 % of patients were smokers. Figure  2  usage of NSAID. It had been shown that there was a significant association between the use of NSAIDs in all of their types and the development of upper GIT bleeding (X 2 =5.6, p value=0.001). On the other hand no statistically significant association had been observed between use of COX-2 inhibitors and the development of upper GIT bleeding (X 2 =1.43, p value > 0.05).

Figure 2: Frequency of different NSAIDs usage
It can be seen from Table 3 that the majority of patients who use NSAIDs (77.1%) do not use PPI concomitantly, compared to (22.9%) who were using PPI.  26 . In a study from one large health maintenance organization, the annual incidence of hospitalization for acute upper GIT bleeding was 102 per 100 000; the incidence was twice as common in males as in females and increased with age 26 . Similar findings were observed in this study which indicated that overall male to female ratio in all age groups was 1.9:1. Furthermore, this phenomenon of higher frequency of upper GIT bleeding was most prominent and evident among those whose age ranged between 40 and 59 year-old with a frequency of upper GIT bleeding among male patients 3 times its frequency among female patients. COX2 inhibitors are the least frequent risk factor for upper GI bleeding in our sample (6.25% of the sample). This finding is similar to the finding of two large trials that studied the effect of COX2 inhibitors to reduce the gastrointestinal complications. The first trial is the CLASS study which involved 8059 patients and found that over the initial six months of therapy, COX2 inhibitors were associated with significantly fewer symptomatic ulcers and ulcer complications than ibuprofen or diclofenac 35 . A second trial (the SUCCE-SS-I study) included a total of 13, 274 patients with osteoarthritis from 39 countries and found that there was a reduction in gastrointestinal complications only in patients not taking concomitant aspirin i.e. COX2 inhibitors only 36 . The cornerstone in approaching the problem of NSAIDs induced gastrointestinal toxicity is the primary prevention of such a catastrophic adverse effect aiming to reduce the associated high mortality and morbidity 32 . Proton pump inhibitors (PPIs) are useful for the prevention of NSAIDs induced ulcers 37,38, 39 . In an illustrative study, the combined incidence of gastric and duodenal ulcers detected endoscopically was reduced in patients who were also treated with 20 mg omeprazole per day (3.6% versus 16.5% with placebo at 6 months) 40 . Unfortunately, our study only 11 out of 48 patients using NSAIDs (22.9%) were taking PPIs for the prevention of NSAIDs induced GIT bleeding. This means that the remaining 37 patients (77.1%) had been deprived from the protecting effect of PPIs use despite their history of NSAIDs intake. This study revealed that NSAIDs use was more frequently associated with gastric mucosal injury. Twenty three out of 34 patients (67.6%), diagnosed endoscopically as having a gastric mucosal injury in the form of either erosive gastritis (13 patients) or gastric ulcer (10 patients), were using NSAIDs. This higher frequency of gastric mucosal injury in association with NSAIDs use in comparison to less frequent injuries to other parts of GI tract, can be related to the fact that gastric mucosa, not the duodenal or esophageal mucosa, is dependent on COX-1 (which would be inhibited by NSAIDs) to generate mucosal-protective prostaglandins. This protective mechanism can be inhibited by a very low dose of aspirin or other NSAIDs. Cryer et al., found that aspirin doses as low as 10 mg/day can inhibit gastric prostaglandin generation considerably and can damage the stomach 18 . In contrast, some studies showed that aspirin doses as low as 325mg/day every other day increase the risk of duodenal ulcer 42 . Although the risk of gastric mucosal injury is increased with increasing dose of NSAIDs depending on the finding of several epidemiological and placebo controlled studies 43,44,45 , but lower doses of NSAIDs are required to initiate gastric mucosal injury compared to the high doses required for creating the same degree of injury in the mucosa of other parts of GIT.

CONCLUSION
Elderly patients who were taken NSAIDs associated with significant upper GIT bleeding, and their uses were without prophylactic PPI cover in high risk individuals.

RECOMMENDATIONS
1. We have to increase public and physician awareness of NSAIDs side effects, and limit its usage whenever possible 2. To cover NDAIDs usage with prophylactic PPI in high risk groups.