Friday, June 18, 2010

Worrisome Cardiovascular Risks of NSAIDs Reported

NSAIDsIn a large study spanning 9 years researchers examined cardiovascular risks, such as fatal heart attack or stroke, associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) by otherwise healthy persons. Overall, naproxen was found to have the lowest risk of cardiovascular morbidity and mortality; however, such risks could be much greater in persons with chronic pain and other health problems.

In prior posts [here] and [here] we have described the considerable and largely overlooked risks associated with chronic use of NSAID pain-relievers, primarily gastrointestinal complications but, also, cardiovascular safety concerns. Now, new research reported in an upcoming edition of Circulation: Cardiovascular Quality and Outcomes, a journal of the American Heart Association, observes that most NSAIDs carry significant risks of cardiovascular complications [Fosbol et al. 2010].

Investigators studied the safety of NSAID therapy in a very large, nationwide cohort of individuals in Denmark who received at least one NSAID prescription during 1997 to 2005 but had not been hospitalized within the prior 5 years or received major medications, including cardiovascular or analgesic agents, for the previous 2 years; that is, subjects for analysis were presumably “healthy.” The sample included 1,028,437 persons (58% male, all over age 10, median 39 years of age). Three endpoints were tracked — 1) cardiovascular death, 2) a composite of coronary death or nonfatal myocardial infarction (MI), and 3) fatal or nonfatal stroke — for the following NSAIDs, comparing study subjects with a population of Danish residents not using the medications:
  • Ibuprofen was associated with a 52% increased risk of coronary death or nonfatal MI and a 29% greater risk of fatal or nonfatal stroke.

  • Diclofenac demonstrated a 91% increased risk of cardiovascular death, 82% increased risk of coronary death or nonfatal MI (100% increase at higher doses), and 71% increased risk of fatal or nonfatal stroke.

  • Rofecoxib produced a 66% greater risk of cardiovascular death and at higher doses a 200% increased risk of coronary death or nonfatal MI.

  • Celecoxib exhibited a 93% increased risk for coronary death or nonfatal MI; however, analyses were based on relatively few events and the authors considered results for this agent as uncertain.

  • Naproxen was not associated with significant increases in cardiovascular risks.

  • While it was not a primary endpoint, all NSAIDs studied except for celecoxib were found to be associated with a substantially increased risk of gastrointestinal bleeding (at least double the risk).
The authors conclude that individual NSAIDs have different degrees of cardiovascular safety, which must be considered when choosing appropriate treatment. In particular, diclofenac appears to be associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals (rofecoxib, also of great concern, was withdrawn from the market in 2004 for cardiac safety reasons). Celecoxib exhibits the lowest risk of gastrointestinal bleeding complications but may confer some increased cardiovascular risks; further research is needed to confirm this.

Ibuprofen exhibits only moderate, dose-dependent increases in cardiovascular risk; however, naproxen appears to be the NSAID with the safest cardiovascular risk profile. Naproxen’s favorable cardiac safety also would be important for patients taking prophylactic aspirin, since there can be an interaction whereby ibuprofen may abrogate the benefits of aspirin if the two agents are taken simultaneously [see Hudson et al. 2005]. (Note: there still might be concerns about gastrointestinal bleeding with naproxen in susceptible persons.)

CAVEATS/LIMITATIONS: This was a large-scale observational study covering an ample period of data collection time; yet, there is always some question about whether results from a study conducted in one locale (among a Danish population in this case) would apply equally to other populations such as in the United States or elsewhere. Unlike in many other countries, ibuprofen in low doses was the only NSAID that could be purchased over-the-counter (OTC) in Denmark and all others were available exclusively by prescription. In absolute numbers, the frequency of cardiovascular events associated with NSAID use in Denmark was relatively low; eg, deaths during NSAID exposure were only 4% of total all-cause mortality. It is of some concern, however, that the median exposure time to NSAID therapy was only 14 days; so, chronic use of NSAIDs was not necessarily required to manifest harmful cardiovascular events. In countries where OTC access to various NSAIDs is more readily available the exposure times, risks, and consequent incidence of cardiovascular morbidity and mortality might be greater.

Furthermore, the Danish study was purportedly the first to report on increased cardiovascular risks due to NSAIDs among “healthy people” but the authors concede that they had no information about why NSAIDs were prescribed for these persons. Whatever disease or pain condition prompted initiation of NSAID therapy could at the same time have incurred an increased risk of cardiovascular disease or death, and there was no way of controlling for this possible confounder of study results. Still, the doses examined in this study were similar to amounts that individuals are likely to encounter either by OTC purchase or prescription, which should be of concern to healthcare providers and their patients. And, this could be especially worrisome in patients who may already have cardiovascular complications due to the stresses and strains of chronic pain conditions, and who also may be self-medicating with OTC NSAIDs.

> Fosbol EL, Folke F, Jacobsen S, et al. Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals. Circulation: Cardiovascular Quality and Outcomes. 2010(Jun); online before print [
PDF of article available here].
> Hudson M, Baron M, Rahme E, Pilote L. Ibuprofen may abrogate the benefits of aspirin when used for secondary prevention of myocardial infarction. J Rheumatol. 2005;32:1589 –1593 [
abstract here].