Non-steroidal anti-inflammatory drugs (NSAIDs) and venous thromboembolism (VTE)

Non-steroidal anti-inflammatory drugs (NSAIDs) and venous thromboembolism (VTE)

Selective or non-selective NSAIDs two-fold or greater increase the risk of venous thromboembolism (1)

• NSAIDs increase the risk of not only venous but also arterial thromboembolism (1)
  • PGI2 inhibition, which has an antithrombotic effect with COX-2 inhibition, may increase the thrombosis risk
  • both use of traditional NSAIDs, such as ibuprofen, diclofenac, and naproxen, and use of newer highly selective cyclo-oxygenase-2 inhibitors have been linked to an increased risk of both arterial and venous thromboses (2)
  • thrombosis tendency is higher in COX-2 selective inhibitors
    • via their targeted inhibition of cyclo-oxygenase enzymes, NSAIDs promote platelet aggregation, which contributes to activation of the coagulation system and thereby potentially to the formation of a venous thrombosis (2)
    • COX-2 suppression disrupts thromboxane A2/PGI2 balance in favor of thromboxane A2
    • by suppressing COX-1 over 95%, an antithrombotic effect occurs
      
• Meaidi et al undertook a study to assess the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism
  • analysis of Danish registry data (2.0 million women followed for 21.0 -million-person years) found NSAID use linked to venous thromboembolism, the risk of which was significantly larger with concomitant use of high/medium risk vs. low/no risk hormonal contraception
  • NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age
    • number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception
    • authors state that "...women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly..."
      
• in a study among patients with knee osteoarthritis, the authors found:
  • among NSAIDs, the degree of VTE (venous thromboembolism) risk was dependent on the specific NSAID (3)
    • as compared with the 63% increase in the risk among current diclofenac users and 49% increase in current ibuprofen users, the risk was not increased at all among current naproxen users

VTE risk with concomitant use of hormonal contraception and NSAID

A large Danish cohort study concluded (4):

• NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age
  • number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception
    • in the study, definitions of the risk of hormonal contraception were:
      • high-risk hormonal contraceptives
        • included combined oestrogen and progestin patch, vaginal ring, and tablets containing 50 µg ethinyl oestradiol, or the progestins desogestrel, gestodene, drospirenone, or the anti-androgen cyproterone
      • medium-risk hormonal contraception included all other combined oral contraceptives as well as the medroxyprogesterone injection.
      • low risk/no-risk hormonal contraceptives were considered as progestin-only tablets, implants, and hormone intrauterine devices
    • numbers of extra venous thromboembolic events per 100,000 women over the first week of NSAID treatment compared with non-use of NSAIDs were:
      • 4 (3 to 5) in women not using hormonal contraception,
      • 23 (19 to 27) in women using high-risk hormonal contraception,
      • 11 (7 to 15) in those using medium-risk hormonal contraception, and
      • 3 (0 to 5) in users of low/no risk hormonal contraception
  • women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly

Reference:

1. Cumhur Cure M, Kucuk A, Cure E. NSAIDs may increase the risk of thrombosis and acute renal failure in patients with COVID-19 infection. Therapie. 2020 Jul-Aug;75(4):387-388. doi: 10.1016/j.therap.2020.06.012. Epub 2020 Jun 27. PMID: 32636031; PMCID: PMC7320673
2. Meaidi A, Mascolo A, Sessa M, Toft-Petersen A P, Skals R, Gerds T A et al. Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study BMJ 2023; 382:e074450 doi:10.1136/bmj-2022-074450
3. Lee T, Lu N, Felson DT, Choi HK, Dalal DS, Zhang Y, Dubreuil M. Use of non-steroidal anti-inflammatory drugs correlates with the risk of venous thromboembolism in knee osteoarthritis patients: a UK population-based case-control study. Rheumatology (Oxford). 2016 Jun;55(6):1099-105
4. Meaidi A, Mascolo A, Sessa M, Toft-Petersen A P, Skals R, Gerds T A et al. Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study. BMJ 2023; 382:e074450