This meta-analysis has shown that the risk of AEs from ASA was low at the doses and durations commonly consumed as OTC medication for the relief of pain, fever, or colds. In particular, there was a virtual absence of major GI (e.g. bleeding or perforation) and non-GI complications (e.g. cerebral hemorrhage). The use of ASA was associated with a small increase of the risk of dyspepsia when compared with placebo and with a non-significant increase in comparison with ibuprofen, another OTC drug also commonly used for the treatment of colds or acute pain. There was an increased risk of dyspepsia with ASA versus acetaminophen when considering the ‘dyspepsia’ MedDRA term, but not when the broader, combined dyspepsia terms defined a priori by the academic authors were used ().
It is important to emphasize that the conclusions obtained from this study on the safety of this therapeutic approach with ASA apply only to very short-term treatment. The majority of patients included in these trials took a single dose of 500–1000 mg in 1 day and were relatively young. Nonetheless, the data reported are clinically valuable. First, previous information on the safety of ASA at OTC doses has relied on a small number of observational studies, since many investigations do not report on OTC use. Second, the data we report here are valid for typical OTC ASA use in the general population. According to some surveys on consumer use of analgesics,[3
] 92.4% of ASA users take one to two tablets (500 mg tablet equivalent) in a 4-week period.
Our meta-analysis agrees with two other studies reported by Edwards et al.,[23
] and Steiner and Voelker.[24
] The former study was not a pooled analysis of individual patient data and was just focused on the efficacy of single-dose ASA for the relief of postoperative pain. Nevertheless, they found risks of AEs with ASA use (13%) and placebo (11%) similar to those reported here. They also found a significantly higher incidence of drowsiness and what they describe as ‘gastric irritation,’ with ASA 600–650 mg than with placebo. The latter study[24
] used pooled individual patient data from 1581 patients treated with ASA and 1271 patients treated with placebo in nine randomized, double-blind, placebo-controlled clinical trials, and these were included in our study. They were chosen because all patients used single doses of ASA 1000 mg for the treatment of acute migraine attacks, episodic tension-type headache, and dental pain. The reported AE rates for ASA and placebo were 14.9% and 11.1%, respectively; this included 5.9% of patients experiencing GI events with ASA and 3.5% experiencing them with placebo. One additional study[11
] reported side effects arising from ASA, acetaminophen, codeine, or placebo therapy in a retrospective analysis of 54 single-dose, double-blind studies involving 4346 patients with postsurgical dental pain. Both the overall and the GI AEs were low for all treatments, but codeine was associated with a higher incidence of nausea, drowsiness, and dizziness than acetaminophen, ASA, or placebo.
Available observational studies reporting on the GI safety of non-cardiovascular ASA, taken for the treatment of pain, fever, or colds, indicate that its use is associated with an increased risk of major GI complications, similar to other nonselective NSAIDs.[6
] In contrast, in our data and in those of Edwards et al.,[23
] no serious GI complications were associated with ASA use or active comparators. This should not necessarily be seen as contradictory, since it is reasonable to assume that the populations and type of drug use studied are different. Clinical trials usually exclude patients with known GI risk factors, whereas observational studies include patients with various levels of risk. This meta-analysis probably included a population that was healthier and younger than that reported in observational studies. Furthermore, it is possible that observational studies report on patients with longer exposure to ASA use, whereas our study basically applies to those taking a single tablet or using ASA doses no higher than 1000 mg/day for the relief of pain, fever, or colds. The same considerations may apply to the absence of GI bleeding events with ibuprofen in this study, where the doses used were low (200–400 mg/day).
ASA use has been associated with other non-GI AEs, both serious and less serious.[11
] No cases of serious non-GI AEs were reported and no significant differences were found between ASA and placebo or between ASA and ibuprofen or acetaminophen for less-serious non-GI AEs in this meta-analysis.
We did not find statistically significant heterogeneity in the ORs in our analysis, suggesting that these statistics are probably generalizable, at least to the sort of patient included in the studies. However, as might be expected with relatively constant ORs and differing background rates of AEs, there was heterogeneity in the risk differences. This finding suggests that the risk differences cannot be directly applied in other clinical contexts.
The data presented in this study have several limitations. The way ASA is used may vary among different populations and therefore the data reported may not be applicable to them. The report from Curhan et al.[2
] from the Nurses’ Health Study showed that ASA was used daily by 25.4% of women >51 years of age, and that 40.1% used ASA ≥1 day/week. Since it is now widely known that ASA protects against cardiovascular events and colon cancer,[1
] some may take this compound very often or on a daily basis for these purposes. In any case, multiple-day exposure to ASA is not uncommon in clinical practice, and the data provided here, although focused on short-term use of ASA for the treatment of acute pain, fever, or colds, suggest an increased risk of AEs with increasing dose and multiple doses.
Another limitation of this study is that the safety data reported here may not be valid for the entire population with access to OTC ASA for the relief of pain, fever, or colds. The risk factors for GI complications in NSAID and ASA users are well defined and include older age (>65 years old), patients with ulcer history, and patients with concomitant use of other NSAIDs, corticosteroids, or anticoagulants. Patients at risk (elderly patients or those with an ulcer history) were excluded in these clinical trials.
Finally, the very low incidence of serious AEs in our study population limited our ability to investigate differences between ASA and placebo or other comparators in this regard. Much larger studies would be required to generate enough events to make such an analysis feasible.