NSAID use linked to higher risk of blood clots in women of reproductive age, association stronger in women on high-risk hormonal contraception

By Dr. Liji Thomas, MDReviewed by Danielle Ellis, B.Sc.Sep 8 2023

The use of hormonal contraception (HC) and non-steroidal anti-inflammatory drugs (NSAIDs) is common today. However, with the rising risk of cardiovascular disease, the implications of their use are being re-examined to identify and quantify potential associations of their combined use. A new paper published in The BMJ explores the effect of these drugs used concomitantly on the risk of venous thromboembolism (VTE).

Introduction

Both NSAIDs and HC use are independent risk factors for VTE, but there is a lack of clarity on the risk when both are used together. HC boosts the odds of VTE involving the deep veins of the lower limb and the lung as the primary and secondary sites, respectively. Estrogen upregulates the coagulation factor genes.

At high doses, as with progestin-only contraception, the risk of VTE is high, but the levonorgestrel intrauterine device (LNG-IUD) has a reduced risk due to the minute doses released into the blood.

Accordingly, the current study categorized HC into low-, medium- and high-risk groups. High-risk HC includes the combined estrogen 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 HC comprises all other combined oral contraceptives and depot medroxyprogesterone injections.

No- or low-risk HC includes progestin-only oral contraceptives and implants and the LNG-IUDs.

NSAIDs are also linked to a higher risk of VTE, whether the older ones like ibuprofen and diclofenac or the newer highly selective cyclo-oxygenase inhibitors. NSAIDs cause not only venous but also arterial thrombosis. This adverse effect is linked to the activation of platelet aggregation. Thus, these drugs come with a warning that they increase the risk of strokes and heart attacks.

What did the study show?

The current study was carried out in Denmark on women aged 15-49. All women were free of known arterial or venous thrombotic conditions and did not have cancer, thrombophilia, nor relevant gynecologic conditions such as hysterectomy, bilateral oophorectomy, sterilization, or infertility treatment. The study period extended from 1996 to 2017.

The study included over two million women, for a total of 21 million women-years. about 530,000 women used both HC and NSAIDs simultaneously. Of this number, almost 60% involved high-risk, a quarter medium-risk, and less than a fifth low-risk or no-risk HC.

During this time, there were over 8,000 events of VTE, which were fatal in less than 3% of cases within a month of the event.

The researchers compared the use of NSAIDs in women on various types of HC. They excluded periods during which the women might have been put at higher VTE risk from other causes, including pregnancy and related events, surgeries requiring hospitalization, and the use of other drugs that carry a risk of thrombosis.

The median number of NSAID prescriptions among HC users was two within a year of beginning HC use. The most commonly used was ibuprofen, in 60%, with diclofenac accounting for another 20%.

The risk for VTE increased by four times with high-risk HC compared to non-use of HC and NSAIDs. It increased by 3 for medium-risk HC but not for low-/no-risk HC.

The risk of VTE went up by eight times with the use of NSAIDs compared to non-use of NSAIDs, even without the concomitant use of HC, with diclofenac being the major culprit.

When both NSAIDs and HCs were used during the same period, the risk of VTE was 51 and 26 times higher when high-risk and medium-risk HC was used, compared to 6 with no- or low-risk HC.

This was observed even after adjusting for other potential confounders like migraine, inflammatory disorders, hypertension, and diabetes. In fact, the risk increased to 6 times higher with the use of high-risk HC only and to 4 for medium-risk HC only among these participants.

With the use of NSAIDs, the risk was seven times higher than in non-users, among women who were not on HC. The risk was eight times higher in those on medium-risk HC but 11 times more with high-risk HC. Conversely, the use of low-risk or no-risk HC still increased the risk of VTE by 4.5 times.

Women not on HC experienced four more VTE per 100,000 women over the first week of NSAID use compared to those not on NSAIDs. Those on medium-risk HC and on NSAIDs had 11 more events, that is, almost three times as many.

Those on high-risk HC had 23 extra VTE incidents per 100,000 when on NSAIDs compared to non-NSAID users. In contrast, low-risk or no-risk HC use was linked to 3 extra events comparable to non-use of HC.

What are the implications?

The use of NSAID by women in their reproductive years is linked to a higher risk of VTE. The magnitude of the increased risk depends on whether the woman using NSAIDs is also using HC or not and which type she is on.

The use of NSAIDs by users of HC was associated with a higher risk of VTE, more among those on high-risk HC and less among those on no-risk or low-risk HC. In most cases, women on HC used NSAIDs for a short-term indication.

The possibility of synergism between these drug categories in causing hypercoagulability requires further research. The authors point out that the absolute risk of VTE remains low despite the increase in risk over the first week of NSAID use.

Considering the highly prevalent indications for use of hormonal contraception and of NSAIDs, studying this association further would be of public interest, especially in regular users of NSAIDs, who might benefit from a low/no risk hormonal contraceptive rather than a high/medium risk hormonal contraceptive.”