NSAIDs (non-steroidal anti-inflammatory drugs) are likely the most commonly consumed class of medication in the world. While most people assume these drugs are perfectly safe if taken as directed – like with all medicines, there are always possible downsides.
No drug is 100% benign, 100% of the time, for 100% of the population.
Over the past dozen years or so the evidence linking the use of NSAIDs - both Rx and OTC - to adverse cardiac events has steadily grown.
- In 2004 Vioxx, a COX-2 inhibitor which had been marketed by Merck as being less likely to cause stomach bleeding, was abruptly pulled from the market after a study showed that prolonged use increased one’s chances of having a heart attack or stroke.
- Bextra, another COX-2 inhibitor, was also recalled after it was linked to increased cardiovascular accidents and to several rare, but potentially deadly, skin disorders.
- In 2005, the FDA required the inclusion of a `black box warning’ for prescription NSAIDs and a couple of years later stiffened the labeling requirements on OTC NSAIDs as well.
In 2011 we explored a pair of studies that looked at NSAID use and the increased risk of cardiovascular events (see NSAIDs and Prior Heart Attacks).
- The BMJ published an open access meta-analysis on the safety of NSAIDs called Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis that concluded: Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms.
- The American Heart Association Journal Circulation looked at the risks of NSAID use among those who have previously had a heart attack (Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With Prior Myocardial Infarction) that found that even short duration treatment (1 week) with NSAIDs resulted in a 45% increased risk of death or recurrent M.I. in those who had previously had a heart attack.
And just last year, we saw the FDA Strengthen Warnings Of Cardiovascular Risks With NSAIDs, issuing a communique with the following findings:
- The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.
- The risk appears greater at higher doses.
- It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.
- NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied.
- In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline.
- Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.
- There is an increased risk of heart failure with NSAID use.
It should be noted that while relative risks of having a heart attack, heart failure, or stroke while taking some of these drugs may double, in terms of absolute risk, the numbers go up far less. If your risk of having a heart attack is 1%, and it goes up by 20% by taking the drug, you are still only at a 1.2% chance of a cardiac event.
Like just about everything else in life, the taking of any medicine involves balancing the risks and the rewards.
Last year the FDA recommended that people with heart disease or high blood pressure consult a health care provider before taking NSAIDs, and that everyone try to take the lowest effective dose for the shortest length of time possible.
All of which brings us to a new open-access research article appearing in the BMJ describing a nested case-control study based on almost 10 million NSAID users from 4 European nations.
You'll want to follow the link below to read the full study, as I've only excerpted the main findings.
Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study
BMJ 2016; 354 doi: http://dx.doi.org/10.1136/bmj.i4857 (Published 28 September 2016) Cite this as: BMJ 2016;354:i4857
Results Current use of any NSAID (use in preceding 14 days) was found to be associated with a 19% increase of risk of hospital admission for heart failure (adjusted odds ratio 1.19; 95% confidence interval 1.17 to 1.22), compared with past use of any NSAIDs (use >183 days in the past).
Risk of admission for heart failure increased for seven traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two COX 2 inhibitors (etoricoxib and rofecoxib). Odds ratios ranged from 1.16 (95% confidence interval 1.07 to 1.27) for naproxen to 1.83 (1.66 to 2.02) for ketorolac.
Risk of heart failure doubled for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib used at very high doses (≥2 defined daily dose equivalents), although some confidence intervals were wide. Even medium doses (0.9-1.2 defined daily dose equivalents) of indomethacin and etoricoxib were associated with increased risk. There was no evidence that celecoxib increased the risk of admission for heart failure at commonly used doses.
Conclusions The risk of hospital admission for heart failure associated with current use of NSAIDs appears to vary between individual NSAIDs, and this effect is dose dependent. This risk is associated with the use of a large number of individual NSAIDs reported by this study, which could help to inform both clinicians and health regulators.
What this study adds
- Use of seven individual traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two individual COX 2 selective NSAIDs (etoricoxib and rofecoxib) is associated with and increased risk of hospital admission for heart failure
- Risk of admission for heart failure is doubled for some NSAIDs used at very high doses
- Estimates of the risk of heart failure associated with the use of many individual NSAIDs in this study could help to inform both clinicians and health regulators
This study, despite its size, is subject to a number of limitations (listed in the article), but it provides additional evidence that NSAID use may be linked to higher rates of heart failure.
Statistically, some NSAIDs produced a much greater impact than others, so those who are concerned will want to discuss their options with their health care provider.