Among 87,680 women, we documented 1537 major gastrointestinal bleeding events over 1,095,193 person-years. Compared to participants who reported no aspirin use, women reporting the highest levels of use were older, had a higher body mass index (BMI), were less apt to exercise, more likely to use non-steroidal anti-inflammatory drugs (NSAIDs), and more likely to have diabetes mellitus, hypercholesteremia, hypertension, coronary artery disease, or osteoarthritis ().
Baseline Characteristics of the Study Cohort in 1990
We found that regular aspirin users (≥ 2 standard [325 mg] tablets/week) had a significantly higher risk of developing gastrointestinal bleeding compared to nonregular users (age-adjusted RR, 1.56 ; 95% CI, 1.41-1.73)(). The relationship remained largely unchanged even after adjusting for other risk factors, (multivariate RR, 1.43; 95% CI, 1.29-1.59). Compared to non-regular use, the number needed to harm (NNH) associated with regular aspirin use was 1,169 for major gastrointestinal bleeding from any site, 2,120 for bleeding from upper tract, 4,210 for bleeding from the lower tract and 6,809 for bleeding from the small bowel or an unknown site. Regular aspirin use was associated with a multivariate RR of bleeding originating from the upper gastrointestinal tract of 1.70 (95% CI, 1.45-2.00). Although regular aspirin use was also significantly associated with risk of bleeding originating from the lower gastrointestinal tract, the effect appeared to be somewhat weaker (multivariate RR, 1.21; 95% CI, 1.03-1.41). Although we did not collect data on the precise etiology of gastrointestinal bleeding in all of the cases, we reviewed medical records in a subsample of 351 cases. The most common causes of upper gastrointestinal bleeding were ulcers (59.5%), inflammation (gastritis/duodenitis) (22.0%), and arteriovenous malformations (6.0%),. The most common causes of lower gastrointestinal bleeding were inflammation (colitis) (47.3%), diverticuli (43.5%), and arteriovenous malformation (3.8%).
Relative Risk of Gastrointestinal Bleeding According to Regular Use of Aspirin†
The apparent hazard associated with aspirin use was substantially greater with increasing dose (). Compared to participants who took no aspirin, women who took >14 tablets/week experienced the greatest risk (multivariate RR, 2.05; 95% CI, 1.53-2.74; Ptrend <.001). Since women who reported regular use of higher doses may have used for longer periods, we further examined the influence of aspirin dose after additionally controlling for years of use. However, adjusted for duration of use, the effect of increasing aspirin dose remained strong (multivariate RR 2.24; 95% CI, 1.66-3.03 for >14 tablets/week; Ptrend <.001). This effect of dose was observed for upper gastrointestinal bleeding (Ptrend <.001) and lower gastrointestinal bleeding (Ptrend =.004). Women who used >14 tablets/week had multivariate RRs of 3.61 (95% CI, 2.32-5.63) for upper and 1.45 (95% CI, 0.86-2.45) for lower gastrointestinal bleeding.
Relative Risk of Gastrointestinal Bleeding According to Dose of Aspirin Use†
We examined whether aspirin dose influenced both short-term (≤5 years) and long-term (>5 years) users (). For both regular short-term and long-term users, increasing dose remained significantly associated with increasing risk of gastrointestinal bleeding. Among women who used >14 tablets/week, the multivariate RRs for gastrointestinal bleeding were 2.17 (95% CI, 1.51-3.12) for short-term users (Ptrend <.001) and 1.94 (95% CI, 1.32-2.87) for long-term users (Ptrend<.001). Duration of aspirin use did not significantly alter the association between aspirin dose and gastrointestinal bleeding risk (Pinteraction=.15).
We also specifically assessed the effect of duration of regular use on risk of gastrointestinal bleeding. We observed a progressively greater risk of gastrointestinal bleeding with longer duration of use, with the highest risk among women who used aspirin > 20 years (multivariate RR, 1.19; 95% CI, 0.86-1.63: Ptrend=0.02) (). However, when we adjusted for the number of tablets/week, the effect of duration was no longer significant (multivariate RR for >20 years of aspirin, 0.79, 95% CI, 0.57-1.11; Ptrend=0.28). We found similar associations for upper gastrointestinal bleeding, with increasing risk associated with longer duration of use. (Ptrend=.004). However, after accounting for dose, the association of duration with risk of upper gastrointestinal bleeding was no longer significant (Ptrend=0.74). For lower gastrointestinal bleeding, duration of use did not appear to be strongly associated with bleeding risk.
Relative Risk of Gastrointestinal Bleeding According to Duration of Regular Aspirin Use†
We considered the possibility that risk of gastrointestinal bleeding may vary according to underlying risk factors for which individuals may take aspirin. At the baseline assessment in 1990, 25,974 women had a history of prior myocardial infarction or coronary artery bypass grafting or had at least 2 cardiac risk factors (BMI ≥30 kg/m2, diabetes mellitus, hypertension, current smoking, hypercholesterolemia). Among such women, regular aspirin use was associated with a multivariate RR of 1.55 (95% CI, 1.31-1.83) for gastrointestinal bleeding. We also did not find significant differences in the influence of aspirin in strata defined by age, body mass index, NSAID use, smoking, or alcohol use (). In particular, the relative risk of bleeding was similar in women over age of 60 compared with younger women; however, the absolute risk of bleeding was higher among women over age 60 with an incidence rate of 1.97 per 1000 person-years compared with an incidence rate of 0.64 per 1000 person-years in the younger women.
Figure 1 Multivariate-adjusted Stratified Analyses of Gastrointestinal Bleeding Risk According to Aspirin Use. Multivariate hazard ratios are adjusted for age (years), NSAID use (yes or no), smoking status (never, past, current), body mass index (<21, (more ...)