The use of hormonal contraception (HC) and the use of non-steroidal anti-inflammatory drugs (NSAIDs) have each independently been associated with an increased risk of venous thromboembolism (VTE).
The use of combined hormonal contraception (CHC) is an acknowledged risk factor for VTE; the magnitude of the increased risk depends on the dose of oestrogen, type of progestin and route of delivery. Lower or no VTE risk is associated with progestin injection, implants and intrauterine devices.
Observational studies and meta-analyses have reported an increased risk of VTE associated with use of NSAIDs (both the traditional NSAIDs [e.g. ibuprofen, diclofenac, naproxen] and the highly selective cyclo-oxygenase-2 inhibitors). In addition, NSAIDs are also associated with an increased risk of arterial thrombosis (the licensed product information of systemic NSAIDs warns of an increased risk of myocardial infarction and strokes).
There is a lack of evidence, however, on the level of VTE risk associated with concomitant use of HC and NSAIDs. A Danish nationwide pharmacoepidemiological analysis of the incidence of VTE in women using concomitant HC and NSAIDs was recently published (British Medical Journal 2023;382:e074450).
The cohort study used national registries to identify all 15 to 49-year-old women living in Denmark between 1996 and 2017; exclusion criteria included history of venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, sterilisation or infertility treatment. Women were followed from 1st January 1996 or from their 15th birthday if occurring after the start of the study. A national registry which holds information on all prescriptions filled by the Danish population since 1995 was used to collect information on purchase of HCs and systemic NSAIDs.
Exposure to HC was defined from the date of the filled prescription; the duration of use of HC was determined by the amount of defined daily doses purchased (for those administered orally, by patch, injection or vaginal ring) and by one year less than the maximum approved usage of intrauterine systems and implants. HC was categorised according to its association with VTE into high risk HC (e.g. combined oestrogen and progestin patch, vaginal ring and tablets containing 50 microgram ethinyl oestradiol, or the progestins desogestrel, gestodene, drospirenone or the anti-androgen cyproterone), medium risk HC (all other CHCs and medroxyprogesterone injection) and low/no risk HC (progestin-only tablets, implants and hormonal intrauterine devices). Exposure to systemic non-aspirin NSAIDs was defined as one week from the date of the filled prescription. National registries were also used to identify the first diagnosis of all primary VTE events. Confounding variables such as pregnancy, surgery and use of tranexamic acid were considered in the analysis. Adjustment was made for age, calendar time, educational level, migraine, systemic connective tissue disorders, inflammatory polyarthropathies, endometriosis, polycystic ovary syndrome, hypertension and diabetes.
The study included 2,029,065 women who were followed for a median of 10 years (interquartile range [IQR] 4.3 to 16.5). There were 8,710 incident VTEs that occurred during a total of 21 million person years. HC and NSAIDs were used concomitantly by 529,704 women.
The study reported that compared with NSAID non-users, the adjusted incidence ratio of VTE in NSAID users was 7.2 (95% confidence interval [CI] 6.0 to 8.5) in those not using HC, 11.0 (95% CI, 9.6 to 12.6) in those concomitantly using high risk HC, 7.9 (95% CI, 5.9 to 10.6) in those concomitantly using medium risk HC and 4.5 (95% CI, 2.6 to 8.1) in those concomitantly using low/no risk HC. Compared with non-use of NSAIDs, the adjusted number of extra VTE events per 100,000 women over the first week of any NSAID treatment was 4 (95% CI, 3 to 5) in women not using HC, 23 (95% CI, 19 to 27) in women concomitantly using high risk HC, 11 (95% CI, 7 to 15) in women concomitantly using medium risk HC and 3 (95% CI, 0 to 5) in women using low/no risk HC.
A limitation of this observational study was the possibility of residual confounding factors such as smoking status and body mass index which were missing for many of the population; the indication for the NSAID could also affect the VTE risk.
The authors of the study conclude that NSAID use was positively associated with the development of VTE in women of reproductive age, and that the influence of NSAID use on VTE risk was greater in women using high risk HC compared to those with no use of HC, and smaller in those using low/no risk HC. The authors advise, however, that further research is needed to clarify whether these findings represent an actual drug interaction, commenting that such research is of public interest in view of the high prevalence of NSAID and HC use in young women. Of note, the authors also highlight that the absolute risk of VTE in the first week after NSAID purchase remained low even in users of high risk HC (0.02%).
[Editor’s note: an accompanying editorial (BMJ 2023;382:p1990) advises that the data raises important concerns about using NSAIDs (especially diclofenac) and high risk HC concomitantly, and that if NSAIDs are needed, agents other than diclofenac seem preferable, along with lower risk HCs (e.g. progestin-only tablets, implants or intrauterine devices). The UK Faculty of Sexual & Reproductive Healthcare of the Royal College of Obstetricians & Gynaecologists Clinical Effectiveness Unit also released a statement in response to the study (7th September 2023), suggesting that when discussing CHC-associated VTE risk, clinicians consider advising CHC users about potential small additional VTE risk if non-aspirin NSAIDs are used alongside CHC.]
Where this study fits: clinicians could consider advising CHC users about a potential small additional VTE risk if non-aspirin NSAIDs are co-administered with CHC
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