Acetylsalicylic acid - low-dose

Additional information

Pharmacokinetics and dosing

Acetylsalicylic acid (aspirin) is absorbed more quickly in women and is distributed in a larger apparent volume. The bioavailability is larger in women, which may result in diminished clearance, but this difference disappears in women taking oral contraceptives [1]. A small pharmacokinetic study (6 men, 6 women) showed no difference between the sexes in availability or half-life of 1 g acetylsalicylic acid. The effect on platelet aggregation was similar in men and women [2, 3]. For low-dose acetylsalicylic acid, no such studies have been performed. As the effect of low-dose acetylsalicylic acid is dependent on irreversible binding to COX-1 in platelets the free concentration is less relevant for the effect [4]. Pharmacokinetic properties are conflicting but effect seems to be similar in men and women using the same dose [5]. The same dose in men and women has been shown to be effective [2, 6].

Effects

Meta-analyses show that low-dose acetylsalicylic acid in primary prevention reduces the risk of major cardiovascular events similarly in men and women. The types of benefit have been claimed to differ between the sexes in primary prevention [6]. Acetylsalicylic acid therapy for primary prevention of cardiovascular disease reduced the risk primarily by its effect on reducing the risk of ischemic stroke in women and the risk of myocardial infarction (MI) in men. Among women, acetylsalicylic acid had no effect on the risk of MI. For men, acetylsalicylic acid had no effect on the risk of stroke [6-9]. The large Women’s Health Initiative (WHI) study (39 879 women) on which this is mainly based, studied a poorly documented acetylsalicylic acid dosage (100 mg every other day) in women with extremely low risk (10-year risks of stroke or MI of 1% each) [10]. Low risk patients should not be treated with acetylsalicylic acid as there is no net clinical benefit (event reduction vs. risk of suffering serious bleeds) and these results thus have little clinical relevance. These findings are consistent with a more recent sex-specific meta-analysis in patients assigned to acetylsalicylic acid in any dose (75-650 mg/day) where men had a reduced risk of MI and women a reduced risk of ischemic stroke [11].In secondary prevention, on the other hand, acetylsalicylic acid is equally effective in men and women and no sex difference in the pattern of events is obvious [12, 13].The mechanisms behind these sex-dependent benefits are currently not known, but may be due to acetylsalicylic acid's impact on the anti-inflammatory 15-epi-lipoxin A4 formation. Studies have found a positive correlation between age and 15-epi-lipoxin A4 in women and a negative correlation in men [14].

Adverse effects

A sex-specific meta-analysis shows that acetylsalicylic acid treatment is associated with a 70% increased risk of major bleeding events in both men and women. Pooled results confirm an increase in the odds of major bleeding events with acetylsalicylic acid in both men and women (odds ratio 1.72 in men, 1.68 in women). The predominant site of bleeding was the gastrointestinal tract [6]. These findings are consistent with another sex-specific meta-analysis, reporting an increased risk of major bleeding in both men and women (RR 1.79 in men, 1.55 in women) [11].The Anti-Thrombotic Trialists’ collaboration meta-analysis showed that male sex was associated with an increased risk of suffering extracranial (mainly gastrointestinal) major bleeds whereas the risk of suffering hemorrhagic stroke was similar [12].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

There are converging data from smaller studies on ASA resistance and sex differences [6, 15-17].

Cancer riskThe association between acetylsalicylic acid use and incident cancer was evaluated in two large prospective cohort studies (in total 47 881 men, 88 084 women) with a follow-up of 32 years. Regular acetylsalicylic acid use was associated with a lower risk of overall cancer (RR 0.97) and the risk was similar in men and women. The benefit of acetylsalicylic acid appeared to be dose dependent [18]. Other meta-analyses have specifically studied the association of acetylsalicylic acid in various doses with colorectal cancer [19] and lung cancer [20], but no sex differences in risk have been observed.Meta-analyses have evaluated use of NSAIDs (including acetylsalicylic acid) in various doses and risk of melanoma [21] and risk of brain tumour [22]. No differences between men and women have been observed.