NSAIDs and contraceptives: critical thinking on a harmful drug interaction

As an early career doctor I prescribed diclofenac liberally. It was my go-to anti-inflammatory drug for patients in hospital. My prescribing habit wasn’t influenced by evidence but by learnt behaviour. It was the drug others prescribed. Ibuprofen was one of the other options, and during my stint in rheumatology a consultant had warned me of people taking ibuprofen “like smarties” but being unaware of the risk of renal failure. If not ibuprofen, then diclofenac, or another non-steroidal anti-inflammatory drug. Perhaps the evidence wasn’t then clear about the effects of prescribing NSAIDs to women using hormonal contraception? Perhaps I should have paid more attention? Perhaps I would have been better served by critical appraisal and knowledge synthesis and translation, skills I had barely acquired?

Diclofenac and ibuprofen remain two of the most commonly used NSAIDs, although several Nordic countries have withdrawn availability of diclofenac over the counter because of safety concerns (doi:10.1136/bmj.p1990).1 New research from a nationwide cohort study of two million Danish women indicates that even short term prescription of NSAIDs to women on “high risk” hormonal contraception carries a clear additional risk of venous thromboembolism (doi:10.1136/bmj-2022-074450).2 Editorialist Morten Schmidt believes “these data raise important concerns about using NSAIDs, particularly diclofenac, and high risk hormonal contraception concomitantly” (doi:10.1136/bmj.p1990).1 This is a harmful drug interaction that deserves more attention.

The proposed mechanisms of action linking both oestrogens and NSAIDs to venous thromboembolism are well known. In combination therapy the risks are additive, an extra 23 events a week per 100 000 women on top of four events a week per 100 000 in women taking NSAIDs alone, although the baseline risk in women of reproductive age is low. Quantifying risk is important, however, and this is probably the best attempt in this context. The alternative to this combination is to switch to other analgesia or different hormonal contraceptives.

In my time in hospital medicine I might also have leapt on a trailblazing new trial of the monoclonal antibody treatment donanemab, incidentally called Trailblazer-ALZ 2, that delivered statistically significant improvements and an impressive sounding relative risk reduction for symptoms of Alzheimer’s disease. The results of Trailblazer-ALZ 2 were met “with excitement at the Alzheimer’s Association International Congress in July.” They were a gift for science journalists and headline writers. Yet closer examination shows that statistical significance does not, as is often the case, mean clinical significance (doi:10.1136/bmj.p1852).3 Although we generally encourage larger and better powered studies, in this instance the study size was so large that it allowed the trial to “show statistical significance of small differences between drug and placebo.”

I started medical school with a head full of dreams. I ended it with a head full of facts. The dreams evaporated first, the facts soon after. I might have been better served by a medical curriculum that sacrificed some of the factual cramming for better training in critical appraisal and research methods, knowledge synthesis and translation, and communication skills. With information overload worse than ever, with clinicians more time poor than ever, and with the impossibility of turning this information tide, perhaps patient care would benefit from a radical reform of medical training that produces critical thinkers instead of stochastic parrots.