Non-Steroidal Anti-inflammatory Drugs (NSAID’s) are a group of pharmacologically active agents widely used in the routine treatment of pain and inflammation. The oldest and probably widest known of these compounds is aspirin (salicylic acid), which has been available commercially and clinically since 1899 and was used extensively throughout the world up until the mid-20th Century. After that the arrival of acetaminophen in 1956 was closely followed by ibuprofen in 1962. Naproxen arrived in 1976, the last of the non-selective NSAIDs before the COX inhibitors at the end of the Century.

Although widely used, aspirin has various well-documented side effects mostly gastro-intestinally related. And as generic versions of the drug became available, the arrival of acetaminophen resulted in aspirins dip in popularity due to a much improved side-effect profile and lack of GI disturbance offered by other options. This situation continued up until the mechanism of the action of aspirin was discovered by British pharmacologist John Vane and his work into the anti-clotting capabilities of aspirin came to light throughout 1960s to 1980s. It’s for these reasons that there was an absolute resurgence in the use of what was then considered as almost a wonder drug for prevention of strokes and heart attacks towards the end of the 20th century. At one point there was almost the suggestion of putting aspirin in drinking water in the same way as flouride to divert occlusive disease, and prevent strokes and heart attacks. Although this was banded around, it was never taken seriously. It is acknowledged that not everyone should take aspirin due to its anti-coagulative properties.

More selective NSAID’s came to market in the early 21st Century and these cyclooxygenase (COX)-1 and COX-2 inhibitors demonstrate an improved side effect profile due to their selective nature. The specificity has allowed them to be used to treat different inflammatory diseases such as osteo-arthritis and rheumatoid arthritis. However, these newer compounds still work with the same mechanism as their earlier cousins.

Aspirin has and does remain the main stay of treatment for secondary prevention of cardiovascular (CV) events and the FDA published updated guidance on this in 2014. The FDA states that “available evidence supports the use of aspirin for preventing another heart attack or stroke in patients who have already had a heart attack, or stroke, or have other evidence of coronary artery disease.” What they also state is that they do not support use in primary prevention and indeed that “there are serious risks associated with the use of aspirin, including increased risk of bleeding in the stomach and the brain.” As a result questions have arisen with regards to the safety of these widely used and available treatments.

For a group of drugs that have been highly advocated as being protective, there is now mounting evidence that people who use high doses of the NSAIDs are actually at greater risk of having heart attacks and other cardiovascular issues. However, such evidence is hard to judge. The most recent study published in the British Medical Journal (BMJ) in May 2017 suggests that there is a direct link between the likes of aspirin and ibuprofen and these heart problems. In the observational study conducted and led by Michele Bally at the University of Montreal Hospital Research Centre 446,763 sets of patient data from Canada, Finland and the UK were analyzed in order to ascertain when heart issues may arise. The authors concluded that taking a NSAID could raise the risk of having a heart attack as early as a week after commencing treatment with the greatest risk being in the first 30 days. This risk is particularly defined if patients are taking high doses, such as over 1200mg ibuprofen a day. However, due to the demographics of the patient population, and the fact that the study was observational, no definitive causal link may be established.

It has been pointed out that due to the fact that patients taking excessively high doses of the non-steroidal therapies are clearly in immense pain from either injury or disease, and having a heart attack a week following initiation of NSAID therapy could not necessarily be attributed to the drug. It is entirely feasible that a myodcardial infarct could be down to either a previously underlying condition of something entirely different.

It is however food for thought that there could be a link and with 61,460 of the patients studied having suffered from a heart attack, the researchers reported an increased risk of 75% with both ibuprofen and naproxen. Furthermore in March 2017 a Danish study group based at the University of Copenhagen published evidence in the European Heart Journal concluding that in their patient cohort taking ibuprofen can increase the risk of MI by 31%.

There has been previously established links between non-steroidals and heart failure whereby in 2016 research published in the BMJ by an Italian research group based at University of Milano-Biocca who presented data from 10 million patient cases from across the UK, Netherlands, Italy and Germany. They concluded that taking this group of medicines could increase the risk of hospitalization due to heart failure by 19%. UK findings suggested that this wasn’t particularly relevant for under-65s, however, the older population should well consider the implications.

In fairness, the use of aspirin around cardiovascular events is reasonably well established and much research time has been invested into this area of study. In general it is also not the treatment of choice for pain relief these days. However, ibuprofen, and naproxen are available over-the-counter in the U.S. and probably sit in most peoples’ handbags or backpacks to relieve that hangover, headache or pulled muscle at the gym. Clearly these medicines have a place in the treatment pathways of many disease areas and are valuable clinical tools. However, as the authors of the BMJ article point out, it has to be worthwhile considering their use and aiming to obtain the lowest possible dose for pain management, for the least possible time. The mounting evidence on the relationship between non-steroids and cardiovascular events presents a tricky balancing act when it comes to their use. It leaves them swinging between friend and foe and we can only hope that more definitive guidance is established in the near future. In the interim there are shouts from researchers for tighter control of medicines and potentially considering returning some from OTC status back to P (pharmacy) status, or some even to Prescription Only Medicine (POM) in order to ensure guidance is supplied at the time of purchase. Some may consider this a step backwards but with growing evidence as to the implications of treatment it surely has the potential to be on the horizon.

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Adele Graham-King
Contributing Editor

Adele is a design consultant who works in product development for medical and healthcare applications. Her background is in pharma, and she has a degree in applied physiology.