Protecting Hearts and Heads in the NSAID Era

University of South Alabama 
Dr Rutecki is professor of medicine at the University of South Alabama College of Medicine in Mobile.He is also a member of the editorial board of CONSULTANT.


Top Papers of the Month
Articles You Don't Want To Miss


How safe are NSAIDs for patients with cardiovascular risk factors?

The history of NSAID use is not particularly long, but complicated nonetheless. As analgesics, these drugs started out as “the best thing since canned beer.” In the early 1990s, they were prescribed 70 million times in the United States.1 A chink in the NSAID armor began with a host of gastrointestinal complications. Then followed reports of serious renal injury. Lately, certain NSAIDs (selective COX-2 inhibitors) were suspected of aggravating cardiac ischemia. The early 21st century has focused on cardiovascular risks contingent to NSAID use, and the results are disconcerting.


This month’s “Top Paper” is “robust” in its findings.2 Denmark has a nationwide electronic registry of hospitalizations and pharmaceutical dispensing. This registry was used to track patients (30 years of age and older) with a prior first myocardial infarction (MI) from 1997 through 2006. This cohort’s (n = 83,677) risk of
recurrent MI was plotted according to duration and type of NSAID use (35,405 of the original cohort took NSAIDs after their MI) or no use. NSAID use was associated with an increased risk of death or recurrent MI (hazard ratio, 1.45; CI, 1.29 - 1.62) at the beginning of NSAID treatment and persisted throughout the treatment course (hazard ratio, 1.55; CI, 1.46 - 1.64 after 90 days). Diclofenac was the worst offender (hazard ratio, 3.36; CI, 2.57 - 3.86) for increasing the risk of death at days 1 to 7 of NSAID treatment.

Although the numbers are impressive, the major-ity of entrants in the study were Danish. Can the increased cardiovascular risk be generalized to other populations? Another systematic review (17 case-control and 6 cohort studies) from Australia found that rofecoxib and diclofenac increased cardiovascular events (primarily MI).3

A study from Harvard corroborated the risk incurred from MI in patients treated with either rofecoxib or diclofenac.4 A French registry trial (n = 23,728)
demonstrated that NSAID use was associated with an increased risk of stroke (odds ratio, 1.635; CI, 1.239 - 2.159).5 Finally, a Spanish meta-analysis (6 studies reporting stroke incidence) implicated rofecoxib (relative risk, 1.82; CI, 1.09 - 3.04) and diclofenac (RR, 1.20; CI, 0.99 - 1.45) in increasing the risk of stroke in users.6


How should these data change practice? Although certain NSAIDs are considered safer than others, caution should be exercised in general with any NSAID in patients at risk for vascular events. It may be worthwhile to ask whether another class of analgesics can be used. Special vigilance should be applied to rofecoxib (withdrawn from the market) and diclofenac in persons known to have or be at risk for cardiac disease or stroke. The data are from large, well-designed studies and cannot be ignored.



1. Tamblyn R, Berkson L, Dauphinee WD, et al. Unnecessary prescribing of NSAIDs and the management of NSAID-related gastropathy in medical practice. Ann Intern Med. 1997;127:429-438.

2. Olsen AMS, Fosbol EL, Lindhardsen J, et al. Duration of treatment with non-steroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011;123:2226-2235.

3. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006; 296: 1633-1644.

4. Hernandez-Diaz S, Varas-Lorenzo C, Garcia-Rodriguez LA. Non-steroidal antiinflammatory drugs and the risk of acute myocardial infarction. Basic Clin Pharmacol Toxicol. 2006;98:266-272.

5. Barthelemy O, Limbourg T, Collet JP, et al. Impact of non-steroidal anti-inflammatory drugs (NSAIDS) on cardiovascular outcomes in patients with stable atherothrombosis or multiple risk factors. Int J Cardiol. 2011;6-28 [Epub ahead of print]. 

6. Varas-Lorenzo C, Riera-Guardia N, Calingaert B, et al. Stroke risk and NSAIDS: a systematic review of observational studies. Pharmacoepidemiol Drug Saf.2011;20:1225-1236.