Naproxen and celecoxib are “associated with a substantial and highly significant increase” in the risk that elderly people will develop hypertension, according to the results of the ADAPT study published in PLoS Clinical Trials.

The analysis also suggests that naproxen increases the risk of cardiovascular events by approximately 60% compared to placebo, while celecoxib – sold as Celebrex by Pfizer - showed no significant difference. One of the authors suggests that the study makes “an important contribution” to the understanding of NSAIDs’ tolerability.

Epidemiological studies suggest that NSAIDs may delay or prevent Alzheimer’s disease (AD): a recent meta-analysis suggested that the risk reduction was 58% after at least two years sustained treatment with NSAIDs. The ADAPT study aimed to investigate NSAIDs’ effects on the risk of developing AD and cognitive decline.

However, in December 2004, researchers terminated the APC study early after safety analyses linked celecoxib with 2.3 and 3.4 fold (for the 200 and 400 twice daily doses respectively) increases in the risk of myocardial infarction, cardiovascular death, heart failure and stroke compared to placebo. In response, the researchers terminated ADAPT.

ADAPT enrolled 2528 people aged at least 70 years with a family history of AD. The volunteers received celecoxib (200 mg twice daily), naproxen (220 mg twice daily) or placebo. The paper reports a post hoc analysis that determined the incidence of a composite endpoint of deaths, non-fatal myocardial infarctions, strokes, congestive heart failure and transient ischaemic attacks. Researchers also collected data on antihypertensive use.

Three years after randomisation, 5.5% of the celecoxib group and 5.7% of the placebo arm showed the composite endpoint. This compared to 8.3% of the naproxen group, a hazard ratio of 1.63. ADAPT did not confirm the statistically significant increase that APC associated with celecoxib. Furthermore, 34.1% of the placebo group had started antihypertensives. This compared to 47.4% of the celecoxib group and 45.0% of the naproxen arm. The hazard ratios for antihypertensive use were 1.56 and 1.40 for celecoxib and naproxen compared to placebo respectively.

The paper notes, however, that the link between NSAIDs and cardiovascular endpoints is not conclusive. “These results must be interpreted in the context of a trial that was stopped early, with small numbers of events that were not originally intended as specific outcomes,” they comment.

An accompanying editorial commentary calls for the inclusion of these data in future meta-analysis. Against a background where the cardiovascular safety of conventional NSAIDs’ and COX-2 inhibitors is “intensely debated,” future meta-analyses, they suggest, “will give a more rigorous and reliable assessment” of the safety of conventional NSAIDs and COX-2 inhibitors.

“Because ADAPT stands alone as a large, long-term, placebo-controlled trial of NSAIDs in the elderly, we believe the data are an important contribution to the medical literature,” comments Barbara Martin from the John Hopkins Bloomberg School of Public Health and an author of the study. “Particularly for safety data, 'truth' may come in small doses.”

Mark Greener