NSAIDs up VTE risk in women using hormonal contraception

Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) appears to increase the risk of venous thromboembolism (VTE) in women using hormonal contraception, reveals a study.

“The number of extra venous thromboembolic events with NSAID use compared with nonuse was significantly larger with concomitant use of high/medium-risk hormonal contraception compared with concomitant use of low/no-risk hormonal contraception,” the researchers said.

“Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly,” they added.

Using national registries, researchers identified and assessed a total of 2,029,065 women of reproductive age (14‒49 years old) in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilization, or infertility treatment.

Overall, 8,710 VTE events occurred among these women, who were followed for 21.0 million person-years. [BMJ 2023;382:e074450]

The adjusted incidence rate ratio of VTE for NSAID use, compared with nonuse, was 7.2 (95 percent confidence interval [CI], 6.0‒8.5) in women not using hormonal contraception, 11.0 (95 percent CI, 9.6‒12.6) in those using high-risk hormonal contraception, 7.9 (95 percent CI, 5.9‒10.6) in users of medium-risk hormonal contraception, and 4.5 (95 percent CI, 2.6‒8.1) in women using low/no-risk contraception.

The corresponding numbers of extra VTE events per 100,000 women over the first week of NSAID use, compared with nonuse, were 4 (95 percent CI, 3‒5) in women not using hormonal contraception, 23 (95 percent CI, 19‒27) in those using high-risk hormonal contraception, 11 (95 percent CI, 7‒15) in users of medium-risk hormonal contraception, and 3 (95 percent CI, 0‒5) in users of low/no-risk contraception.

“[W]e found the influence of NSAID use on VTE risk to be significantly greater in women using high-risk hormonal contraception compared with no use of hormonal contraception and smaller in women using low/no-risk hormonal contraception,” the researchers said.

“However, further research is needed to clarify whether these findings represent an actual drug interaction,” they added.

Diclofenac, ibuprofen, naproxen

In a meta-analysis of 280 trials of NSAIDs vs placebo and 474 trials of one NSAID vs another NSAID, use of diclofenac correlated with an increased cardiovascular risk and showed a similar cardiovascular risk profile to the withdrawn cyclo-oxygenase-2 inhibitor rofecoxib. [Lancet 2013;382:769-779]

In the present study, a stronger association with VTE risk was observed for diclofenac than for ibuprofen or naproxen. Diclofenac, a common NSAID, has similar affinity to new cyclo-oxygenase-2 inhibitors for cyclo-oxygenase-2, which has been shown to stimulate platelet aggregation and activation of coagulation when inhibited. [Antiinflamm Antiallergy Agents Med Chem 2012;11:52-64]

“As the pharmacodynamics of both hormonal contraception and NSAIDs include an effect on the coagulation system, the observed superadditive joint effect between high/medium-risk hormonal contraception and NSAIDs could represent a synergistic drug interaction between the drug classes,” the researchers said. [Thromb Haemost 2002;88:186-193; Thromb Res 2010;126:5-11]

“However, further research is warranted to determine the potential existence and mechanism of such drug interaction,” they added.