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Acetylsalicylic acid - low-dose

Classification: A

Drug products: Acetylsalicylic acid Bluefish, Acetylsalicylsyra Actavis, Acetylsalicylsyra APL, Acetylsalicylsyra G.L. Pharma, Acetylsalicylsyra Orifarm, Acetylsalicylsyra Teva, Amolita, Asasantin Retard, Asasantin® Retard, Diprasorin, Hjertealbyl, Trombyl®

ATC code: B01AC06, B01AC30

Summary

For secondary prevention, low dose acetylsalicylic acid (aspirin) lowers the total risk of cardiovascular disease similarly in men and women. Studies on primary prevention showed aspirin-induced lowered risk of ischemic stroke in women but not in men while the risk of myocardial infarction was slightly more reduced in men compared to women. Due to the risk of bleeding, low dose aspirin is not recommended for primary prevention in low risk patients of either sex. For secondary prevention aspirin seems to be equally effective in men and women.

In our opinion, at present the described differences regarding primary prevention do not motivate differentiated dosing or treatment in men and women. Secondary prevention with aspirin is similarly effective in men and women.

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 the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

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

Cancer risk

The 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.

Updated: 2019-02-26

Date of litterature search: 2018-02-27

References

  1. Capodanno D, Angiolillo DJ. Impact of race and gender on antithrombotic therapy. Thromb Haemost. 2010;104:471-84. PubMed
  2. TROMBYL (acetylsalicylic acid). Summary of Product Characteristics. Medical Products Agency Sweden; 2017.
  3. Patti G, De Caterina R, Abbate R, Andreotti F, Biasucci LM, Calabrò P et al. Platelet function and long-term antiplatelet therapy in women: is there a gender-specificity? A 'state-of-the-art' paper. Eur Heart J. 2014;35(33):2213-23b. PubMed
  4. Rosenkranz B, Frölich JC. Plasma concentrations and anti-platelet effects after low dose acetylsalicylic acid. Prostaglandins Leukot Med. 1985;19(3):289-300. PubMed
  5. Husted SE, Pedersen AK, Petersen T, Geday E. Systemic availability of acetylsalicylic acid in normal men and women and its effect on in vitro platelet aggregability. Eur J Clin Pharmacol. 1983;24:679-82. PubMed
  6. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295:306-13. PubMed
  7. Yerman T, Gan WQ, Sin DD. The influence of gender on the effects of aspirin in preventing myocardial infarction. BMC Med. 2007;5:29. PubMed
  8. Adelman EE, Lisabeth L, Brown DL. Gender differences in the primary prevention of stroke with aspirin. Womens Health (Lond Engl). 2011;7:341-52; quiz 352-3. PubMed
  9. Meyer DM, Eastwood JA, Compton MP, Gylys K, Zivin JA, Ovbiagele B. Sex differences in antiplatelet response in ischemic stroke. Womens Health (Lond Engl). 2011;7:465-74. PubMed
  10. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293-304. PubMed
  11. Xie M, Shan Z, Zhang Y, Chen S, Yang W, Bao W et al. Aspirin for primary prevention of cardiovascular events: meta-analysis of randomized controlled trials and subgroup analysis by sex and diabetes status. PLoS One. 2014;9(10):e90286. PubMed
  12. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849-60. PubMed
  13. Sacco S, Cerone D, Carolei A. Gender and stroke: acute phase treatment and prevention. Funct Neurol. 2009;24:45-52. PubMed
  14. Chiang N, Hurwitz S, Ridker PM, Serhan CN. Aspirin has a gender-dependent impact on antiinflammatory 15-epi-lipoxin A4 formation: a randomized human trial. Arterioscler Thromb Vasc Biol. 2006;26:e14-7. PubMed
  15. Gum PA, Kottke-Marchant K, Poggio ED, Gurm H, Welsh PA, Brooks L et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol. 2001;88:230-5. PubMed
  16. Sadiq PA, Puri A, Dixit M, Ghatak A, Dwivedi SK, Narain VS et al. Profile and prevalence of aspirin resistance in Indian patients with coronary artery disease. Indian Heart J. 2005;57:658-61. PubMed
  17. Kojuri J, Mahmoody Y, Zangbar Sabegh B, Jannati M, Mahboodi A, Khalili A. Dose-related effect of aspirin on laboratory-defined platelet aggregation and clinical outcome after coronary stenting. Cardiovasc Ther. 2010;28:147-52. PubMed
  18. Cao Y, Nishihara R, Wu K, Wang M, Ogino S, Willett WC et al. Population-wide Impact of Long-term Use of Aspirin and the Risk for Cancer. JAMA Oncol. 2016;2(6):762-9. PubMed
  19. Ye X, Fu J, Yang Y, Chen S. Dose-risk and duration-risk relationships between aspirin and colorectal cancer: a meta-analysis of published cohort studies. PLoS One. 2013;8(2):e57578. PubMed
  20. Jiang HY, Huang TB, Xu L, Yu J, Wu Y, Geng J et al. Aspirin use and lung cancer risk: a possible relationship? Evidence from an updated meta-analysis. PLoS One. 2015;10(4):e0122962. PubMed
  21. Li S, Liu Y, Zeng Z, Peng Q, Li R, Xie L et al. Association between non-steroidal anti-inflammatory drug use and melanoma risk: a meta-analysis of 13 studies. Cancer Causes Control. 2013;24(8):1505-16. PubMed
  22. Liu Y, Lu Y, Wang J, Xie L, Li T, He Y et al. Association between nonsteroidal anti-inflammatory drug use and brain tumour risk: a meta-analysis. Br J Clin Pharmacol. 2014;78(1):58-68. PubMed
  23. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2018-04-17.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson