Rofecoxib in Patients with Mild Cognitive Impairment: Further Analyses of Data from a Randomized, Double-Blind, Trial

Abstract

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib. 1) Neuropathological hypothesis: Of the 189 incident cases of possible or probable AD, 154 were probable AD. In probable AD patients, the treatment hazard ratio was reduced compared to the primary analysis -- a concordant finding would have strengthened a conclusion that rofecoxib accelerated the underlying neuropathology of AD. The treatment hazard ratio was increased in the remaining 35 patients with less certain diagnoses, but there was no single predominant reason for the reduced certainty of diagnosis. 2) Cardiovascular hypothesis: Neither cardiovascular risk status nor mean arterial blood pressure had an overall effect on AD diagnosis or modified the treatment difference. 3) Cognitive side-effects hypothesis: The percentages of patients with non-specific NSAID-type central nervous system adverse events were similar between the treatment groups. In summary, the present analyses are limited by their post hoc nature but provided little support for any of the possible explanations explored. The significance of the observation that rofecoxib increased the rate of conversion from MCI to AD remains uncertain.

Inflammation and Alzheimer’s disease

“…Investigations conducted with a COX-2 selective inhibitor, rofecoxib (25 mg daily) and naproxen (220 mg twice-daily) in mild to moderate AD patients did not show any cognitive improvement after 12 months of treatment (Aisen et al, 2003). In addition, other researcher investigated the effects of rofecoxib (25 mg daily) in mild AD patients, but the result did not show any significant treatment benefits nor did it accelerate the neuropathological progression of AD (Aisen et al, 2008). Similarly, a double-blind, multicentered trial was done on 692 patients with mild or moderate AD and who were 50 years or older.…”

Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes

“…Cox-2-deficient mice are protected against brain ischemia (2), and inhibition of COX-2 provides beneficial effects against ischemic damage and neuronal death (3)(4)(5)(6), suggesting a detrimental effect of COX-2 in stroke. In contrast, in neurodegenerative diseases, COX-2 inhibitors are not protective in mouse models of Alzheimer disease (7) and did not show benefits in clinical trials in Alzheimer disease patients (8) or in patients with mild cognitive impairment (9). Furthermore, COX-2 inhibitors increase the risk of cardiovascular and cerebrovascular pathology (10), and Cox-2-deficient mice show exacerbated brain inflammation, leukocyte infiltration, and blood-brain barrier damage after exposure to the bacterial lipopolysaccharide (LPS) (11)(12)(13)(14)(15), suggesting some beneficial action of COX-2 in inflammation.…”

Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer's Disease

“…So far, only one large multicenter study on the efficacy of the COX-II inhibitor rofecoxib (25 mg / day taken by people with MCI until the onset of dementia) has been completed. A sample of 1457 subjects with MCI participated, half of whom were given rofecoxib and the other half a placebo over a period of up to 4 years [26, 27]. Since the conversion rate to dementia over the course of the study turned out to be much lower than expected (6.4% in the rofecoxib group versus 4.5% in the placebo group; expected rate of 10-15% per year), the study was discontinued.…”