our of Hpatloy 996: 2: 570-575, Printed in Denmark All right seme tunkegantCopnbagen Non-steroidal anti-inflammatory drugs and variceal bleeding: a case-control study Victor de Lédinghen', Paul-Régis Mannant', Juliette Foucher’, Marie-Christine Perault?, Thierry Barrioz', Pierre Ingrand®, Bernard Vandel”, Christine Silvain' and Michel Beauchant! 'Semiced Hepatolosie, Service de Pharmacologie Clinique, Unité de Biolattiques, Centre Hospitalier Universitaire, Potiers, France Background/Aim: The aim of this case-control study was to assess the risk of bleeding from esophageal varices associated with aspirin and non-steroidal anti-inflammatory drug consump- tion, Methods: Between January 1992 and May 1994, patients admitted for bleeding from esophageal or gastric lesions related to portal hypertension were matched with a control patient of the same age and sex, who was free of gastrointestinal bleeding. A structured interview was conducted with the cases and controls to determine drug consumption during the 2 weeks preceding admission. Fifty- nine cases and 59 controls were recruited. Results/Conclusions: Use of aspirin was more prevalent among the cases than the controls (adds IME INCIDENCE of upper gastrointestinal bleeding due to all causes is 40-50/100 000/year (1). ‘There is a recognized association between the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) and both upper and lower gastrointes- tinal bleeding (2-8). Several studies have shown that a person exposed to NSAID has three to four times the risk of upper gastrointestinal bleeding and/or perforation relative to a non-user (9). However, patients with esophageal varices and a history of liver cirrhosis were excluded from these studies (1,10,11). The contribution of aspirin and NSAID consumption to bleeding from esophageal varices thus remained to be explored. The aim of this case-control study was to evaluate the risk of bleeding from esophageal and gastric Received 27 June: revised 25 September: acceped 2 October 1998 Correspondence: Victor de Lédinghen, Service d’ Hepatol- ogie, Centre Hospitalier Universitaire, 33604 Pessac Ce- dex, France. 570 ratio 3.81; 95% confidence interval 1.36-11.64; p=0.004). This difference remained significant in the subgroups of patients with a first episode of variceal bleeding (odds ratio 3.9; 95% confidence interval 1.2-139, p=0.01), but was not significant in the subgroups of patients with a recurrent epi- sode of variceal bleeding. The use of aspirin was associated with a high risk of a first episode of variceal bleeding, suggesting that patients with portal hypertension should avoid taking these drugs. Key words: Esophageal variceal bleeding; Non- steroidal anti-inflammatory drugs; Portal hyper- tension. lesions related to portal hypertension, associated with aspirin and NSAID use. Patients and Methods Case definition Between January 1992 and May 1994, patients, admitted to our unit because of hematemesis, melena or bright red rectal bleeding related to portal hyper- tension were enrolled in this study. The source of bleeding was identified by endoscopy within 12 h of admission. When more than one lesion was present, the endoscopist had to identify the most likely source of bleeding. Selection of controls Each patient was matched with a control of the same sex and age (to within 5 years), who was admitted for the first time to the same department within 1 week after admission of the case. Controls were not included if they had previous or current gastrointesti- nal bleedingData collection The cases and controls had the same structured inter- view administered by a specially trained pharmacolo- gist, to gather information on all medications (pre- scribed or self-administered) taken in the 2 weeks preceding admission, Particular attention was paid to the use of aspirin and NSAID. To ensure that drug histories were as complete as possible, the interview started with an open question on a list of common symptoms often prompting use of aspirin and NSAID, and the patients were then asked to recall the trade names of the most popular aspirin and NSAID- containing medications. Relatives were allowed to accompany the patient and aid him or her in the recall exercise, but only information confirmed by the patient was recorded. Statistical analysis Means (SD) were compared using Student's t-test. A probability (p) value of 0.05 or less was considered ta denote a significant difference. The prevalence of aspirin and NSAID use was compared between the cases and controls by means of the Pearson chi-square test. Differences between cases and controls with respect to a particular risk factor were identified by using odds ratios. The significance of odds ratios was determined by using the chi-square test with continu- ity correction, The confidence interval (CI) was calcu- lated using the Mehta, Patel and Gray algorithm (12). Fisher's exact test was used to analyze categorical data, and the Wilcoxon signed rank sum test was used for analysis of continuous data. The severity of liver disease was evaluated with Child-Pugh's score (13) and the severity of bleeding was assessed in terms of the baseline hemoglobin concentration, transfusion requirements and the length of hospital stay. TABLE 1 Ansi-inflammarory drugs and variceal bleeding Results From January 1992 through May 1994, 59 cases and 59 comectly matched controls were recruited. Data collection was complete for all the patients (Table 1). ‘The source of bleeding was first variceal bleeding in 38 cases (64.4%), recurrent variceal bleeding in 13 (22.0%), portal hypertensive gastropathy in six (10.2%), and banding ligation induced esophageal ulcer in two (3.4%), Aspirin and NSAID had been taken in the previous 2 weeks by 20 (33.9%) cases and 7 (11.9%) controls (Table 1). The cases had used more aspirin and NSAID than the controls: the odds ratio for the use of aspirin and/or NSAID was 3.81 (95% Cl, 1.36-11.64, p=0.004), The prevalence of aspirin and NSATD use by the cases was significantly higher than among the controls (p < 0.01), a difference that remained signifi- cant in the subgroups of patients with a first variceal bleeding episode (p < 0.02) (Table 2). The time between the last drug intake and bleeding, (250 mg to 1000 mg of aspirin) was less than 3 hin three cases, 3-12 h in eight cases, 12-24 h in six cases, and 2448 h in three cases. There was no sig- nificant difference between the patients who had and had not used aspirin and NSAID, even after correc- tion for age, gender, diabetes, smoking or alcohol consumption (Table 3). Patients, regardless of aspirin and NSAID use, were comparable in terms of the severity of liver disease, bleeding and variceal size (Table 3). Recurrent variceal bleeding and portal hypertensive gastropathy bleeding was not signifi- cantly associated with aspirin and NSAID use. Six patients who had used aspirin and/or NSAID (30%) and six who had not (15.4%) had another gastroduo- denal lesion, but it was considered as an unlikely source of bleeding by the endoscopist. (Characteristics of cases according tothe source of bleeding, together with drug use by the cases and controls Number All cases First variceal n=59 bleeding n= 38 Cases Controls Cases Mean age (years) 5904130 5934129 $9.44136 Range (years) 37-94 398-8 Malesffemales 4613, 46013 299 Aspinin 18 5 5 NSAID 2 2 1 Corticosteroids 3 1 2 1 2 1 1B 4 10 Recurrent variceal Portal hypertensive bleeding n= 13 gastropathy n= 6 Cases Controls Cases Controls 602 GIL 62IEI13 50.3866 48.2855 39484088 20) 1m pn an 4a 4 1 1 2 0 2 1 ° 0 ° 1 o ° 1 0 2 0 ° ° ° 2 3 1 1 1 NSAID: non-steroidal anti inflamma 571V, de Lédinghen etal. ‘TABLE 2 (Odds rato of aspirin snd non seroida! ant inflammatory drugs use according tothe ste of Bleeding Site of bleeding (number of patients) Druguseby Druguety Oddsratio—p 95% confidence cases (7) controls (n) interval ‘All cases (69) 20 381 0.004 136-1164 First variceal bleed (38) 16 6 3.88 oon 118-13.86 Recurrent variceal bleed (13) 2 1 218 Ns 0112-71.09 NS: not significant. ‘TABLE Characteristics ofthe cases according to aspirin and non-steroidal anti-inflammatory drugs use All patients Cases with drug Cases without dig 59 n=20 =39 ‘Mean age (years) 9813.1 oL1z140 3802126 NS Range (years) 31-94 3794 37-84 NS Malesffomales 463 m1 20no NS. Diabetes (n) 4 4 10 NS ‘Tobacco (n) 2 10 1s NS Alcohol (gd) 5118565 42.6853.8 6798595 NS Child's grade (a) A 10 4 6 NS B 25 9 6 NS c 24 7 ” NS. Prothrombin time (%) 55.18180 5934179 SR.08179 NS ‘Albumin (/}) 27685.1 20nt.s 274854 NS. Bilirubin (uot) 50.54479 6254648 4428356 NS Piatelets (Qx1000)(mum?) 14388727 164488.7 1413873 NS. STUN) 85.04893 72168320 91581079 NS ALT), 41.7483.7 38.8422. 4338516 NS. Hemoglobin (g/t) 9241.9 9382.0 perry NS Number of transfusions 45844 3783.0 5.05.0 NS Hospital stay (days) 17-8420.1 1534202 1618204 NS Variceal size (n) 1 4 o 4 NS 2 39 B 6 NS. 3 16 7 9 NS. AST: aspartate aminowansferase. ALT: alanine aminotransferase. NS: not significa. Discussion This case-control study shows that use of aspirin is associated with an increased risk of bleeding in patients with portal hypertension, particularly a first episode of variceal bleeding, independently of the severity of liver disease and the variceal size. Given the relatively small number of patients in this study, we were unable to assess the role of aspirin and NSAID in variceal rebleeding and portal hyperten- sive gastropathy bleeding. An information bias cannot be ruled out, as data on aspirin and NSAID use were based on patient recall and could not be checked. The interviewer was an ‘outside consultant who recruited controls only on the basis of gender, birthdate and date of first admission to the unit, with no knowledge of previous disease 572 except for gastrointestinal bleeding (a criterion of non-inclusion). However, none of the controls had portal hypertension. The prevalence of aspirin and NSAID use in the control group (11.9%) was compa- rable with previous case-control study data, ie. 4% (14), 5% (15), 14% (4), 15% (1), 18% (16) and 23% (11). Previous studies have given relative risks of gastrointestinal bleeding associated with aspirin of between 1.1 and 15 (8.82 in our study) (6-8,10) ‘These differences might partly be explained by meth- codological weaknesses. Indeed, a lack of endoscopic diagnosis in some of the case patients may have led to ‘an underestimation of the risk, while inadequate age- ‘matching of the cases and controls may have led to an overestimation (14). Patients with esophageal varices and those with ahistory of liver cirthosis are often excluded from case-control studies of gastrointestinal bleeding (2,10,11,15). Wileox et al. reported aspirin and NSAID use by 9% of patients with variceal bleeding (17). The precise role of aspirin and NSAID in variceal bleeding remains to be determined, but the two main candidate mechanisms are erosion of the esophageal mucosa through local irritation (18,19), and the inhibitory effect of these drugs on platelet aggregation. 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