In 2004, a recently approved painkiller belonging to the widely used non-steroidal anti-inflammatory drug (NSAID) class was pulled from the market after investigators revealed that the drug induced an unacceptably high number of heart attacks and stroke-causing blood clots.
Ever since then, medical researchers have remained on high alert; wondering if any other drugs in this class – which includes aspirin, ibuprofen (Advil), and naproxen (Aleve) – should be abandoned due to their cardiovascular risks. Risks that were overlooked or unapparent during safety studies that occurred years to decades ago.
Now, a team from Denmark has uncovered evidence that people who use diclofenac, one of the most commonly used NSAIDs and one often available without a prescription, experience significantly more serious adverse events than those taking other NSAIDs or paracetamol (aka acetaminophen).
“In our study, we found that diclofenac initiators were at increased risk of major adverse cardiovascular events – both compared with no NSAID initiation, initiation of paracetamol as an analgesic alternative to NSAIDs, as well as initiation of other traditional NSAIDs,” the authors wrote in the British Medical Journal.
“While NSAID use previously was considered risk-neutral in short treatment periods and low doses, the risks were apparent even within 30 days and also for low doses of diclofenac.”
The authors drew their data from nationwide medical records and prescription registries, choosing adult patients who had not redeemed a prescription for an NSAID for at least one year (in Denmark low-dose ibuprofen and aspirin are the only NSAIDs available over the counter) when they presented to a hospital between 1996 and 2006. The authors then compared the documented health issues that arose within 30 days in individuals given a course of diclofenac (1.3 million people) to those of 3.8 million people given ibuprofen, 291,490 given naproxen, 764,781 people given the non-NSAID pain reliever paracetamol, and 1.3 million people not prescribed any drug at all.
All subjects who were not taking diclofenac were matched by propensity score to diclofenac users, meaning that the groups were designed to mitigate influences from factors like age and pre-existing diseases. None had experienced prior cardiovascular issues.
An analysis of this massive dataset revealed that diclofenac initiators had a 50 percent greater rate of atrial fibrillation or flutter, ischaemic stroke, heart failure, heart attack, or heart-related death in the 30 days following their prescription fill compared with those who did not receive NSAIDs. The diclofenac users’ rates were 20 percent higher than those of paracetamol or ibuprofen users and 30 percent higher than naproxen users.
Diclofenac initiators were also 2.5 times more likely to experience bleeding in the stomach and intestines, a known risk for many NSAIDS, than ibuprofen or paracetamol initiators, and 4.5 times more likely than non-initiators.
Because the study is observational, rather than a randomized control trial, the authors note that no firm conclusions about cause and effect can be determined. Yet, they argue that their impressive sample size and the consistency between their results and those of similar investigations together provide strong enough evidence that physicians and regulators should take heed.
“Treatment of pain and inflammation with NSAIDs may be worthwhile for some patients to improve quality of life despite potential side effects. Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” they wrote. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”