Hemostasis and Thrombosis Issues

Charles H. Brown, MSPharm, RPh, CACP
Published Online: Monday, May 16, 2011

All NSAIDS Have Cardiovascular Risks— But Are Some Better Than Others?

This question has been debated by many clinicians without a clear resolution. This leaves patients wondering and asking, are nonsteroidal anti-inflammatory drugs (NSAIDs) safe or not?

In the United States, an estimated 5% of all visits to a physician are related to prescription anti-inflammatories, and they are among the most commonly used medications.

Regulatory agencies early on pointed to cardiovascular signs associated with NSAID use, but these concerns were based mainly on observational evidence. Data from recent studies provide evidence of what was already suspected— none of the NSAIDs currently available should be considered “safe,” especially for anyone who has high cardiovascular risks.

New Evidence Emerges 

A new study funded by the Swiss National Science Foundation provides a comprehensive analysis of all randomized controlled trials of NSAIDs. Earlier metaanalyses were unable to resolve the debate over risk because they failed to include all randomized evidence in 1 study. This new meta-analysis, published by BMJ online on January 11, 2011, includes all available evidence.

Selected Study Highlights

The meta-analysis encompassed 31 trials and 116,429 patients taking naproxen, ibuprofen, diclofenac, celecoxib, rofecoxib, etoricoxib, lumiracoxib, acetaminophen, or placebo. Only drugs that are or were available in the United States are included in this column (Table).

• Celecoxib was the most studied NSAID (15 trials), and ibuprofen was the least studied (2 trials).

• The primary study outcome was myocardial infarction. Researchers also examined rates of stroke, cardiovascular death, and all-cause mortality.

• Trials focusing on patients with cancer were excluded from the current analysis. All included research had at least 100 patient years of follow-up.

• Compared with placebo, rofecoxib was associated with a significantly higher risk for myocardial infarction. Meanwhile, ibuprofen and celecoxib demonstrated a trend toward increasing the risk for myocardial infarction.

• All NSAIDs were associated with some increased risk for stroke. Ibuprofen and diclofenac were associated with significant increases in stroke risk.

• All NSAIDs except naproxen demonstrated some increase in the risk for cardiovascular death. Diclofenac was associated with statistically significant increase in the risk for cardiovascular death.

• Naproxen and diclofenac did not appear to significantly affect the risk for myocardial infarction.

• NSAIDs were associated with a 24% higher rate of clinical response vs acetaminophen, but were also 35% more likely to promote gastrointestinal discomfort. Some patients required a proton pump inhibitor concurrently to protect the stomach.

Evaluating Risk

The researchers indicated that an increase in myocardial infarction, stroke, and cardiovascular death in studied patients suggests the lack of a clear association between specificity of cyclooxygenase-2 inhibitors and cardiovascular risk, which implies that other mechanisms are likely responsible. Multiple effects most probably contribute to the increased risk of cardiovascular events. The most commonly proposed hypothesis is an imbalance between prostacyclin and thromboxane A2 synthesis that leads to an increased risk for thrombosis.

In an interesting twist, investigators found no clear relation between specificity of cyclooxygenase-2 inhibitors and risk for cardiovascular events. This contrasts with previous claims that increased selectivity for cyclooxygnease-2 inhibitors is associated with cardiovascular risk.

Final Thought

Of all the NSAIDs, naproxen seemed least harmful in this study. The finding is in agreement with recommendations made by regulatory agencies when rofecoxib was first removed from the market in 2004.

The ongoing PRECISION trial, otherwise known as the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen, will eventually provide more information on the relative cardiovascular safety of these options.

Overall, naproxyn appeared to be associated with a relatively low risk for cardiovascular events compared with other NSAIDs. PT

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, West Lafayette, Indiana. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different patient populations.

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