Between over-the-counter sales and prescriptions, NSAIDs (non-steroidal anti-inflammatory drugs) are likely the most commonly consumed class of medication in the world. Look in just about any medicine cabinet, and you’ll probably find a bottle of aspirin, naproxen, or ibuprofen.
While these drugs have long been associated with increased risks of gastrointestinal bleeding, it has only been in recent years that cardiovascular concerns have emerged.
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 O-T-C NSAIDs as well.
The controversy over their safety has continued, and earlier this year the BMJ published an open access meta-analysis on the safety of NSAIDs.
Objective To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs.
Design Network meta-analysis.
Data sources Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data.
Study selection All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility.
Data extraction The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data.
Data synthesis 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo.
Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death.
Conclusions Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.
It should be noted that while the risk of developing cardiovascular complications for those on NSAIDs was 2 to 4 times higher than placebo, in absolute terms the number of adverse events detected was fairly low.
Of the seven drugs examined, naproxen appeared to pose the least cardiovascular risk.
Jump ahead to today, and we’ve another study – this time appearing in the American Heart Association Journal Circulation – that looks at the risks of NSAID use among those who have previously had a heart attack.
Researchers 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.
I’ve some excerpts from the abstract below, but follow the link to read it in its entirety.
Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With Prior Myocardial Infarction
A Nationwide Cohort Study
Anne-Marie Schjerning Olsen, MB; Emil L. Fosbøl, MD, PhD; Jesper Lindhardsen, MD; Fredrik Folke, MD, PhD; Mette Charlot, MD; Christian Selmer, MD; Morten Lamberts, MD; Jonas Bjerring Olesen, MD; Lars Køber, MD, DMSc; Peter R. Hansen, MD, PhD, DMSc; Christian Torp-Pedersen, MD, DMSc Gunnar H. Gislason, MD, PhD
Background — Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI).
Conclusions— Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.
The authors write that there were some limitations to this study, most notably:
The main limitation of the study is inherent to the observational design. There is a lack of information about important clinical parameters such as blood pressure, body mass index, smoking habits, lipid levels, and left ventricular ejection fraction. Therefore, the effect of unmeasured confounders cannot be excluded.
While this study looked at the safety of NSAID use among those who have already had a heart attack, more study is needed to determine the overall cardiovascular safety of this class of medications.
The authors conclude by saying:
Further studies, preferably randomized clinical studies, are warranted to establish the cardiovascular safety of NSAIDs, but given the additional evidence from randomized trials and other observational studies of selective COX-2 inhibitors and nonselective NSAIDs, the accumulating evidence suggests that we must limit NSAID use to the absolute minimum in patients with established cardiovascular disease.
The bottom line is, if you have a history of heart problems and wish to take NSAIDs (even those available over-the-counter), you need to talk to your doctor about the risks.
For everyone else, it is important to remember that no drug is 100% safe or benign – even those available O-T-C .
That doesn’t mean we shouldn’t use them, but it does mean we should weigh their risks against their benefits, before we take them.