We thank Dr. Ashford for his comment on our article “INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.”1 Dr. Ashford raises 2 important points: whether a gamma-secretase-modifying (GSM) NSAID such as ibuprofen would likely have given different results and whether the Alzheimer progression score outcome was sufficiently precise to reveal efficacy.
A meta-analysis of 6 prospective studies2 compared apparent Alzheimer disease (AD) risk modification in 13,499 older persons (70,863 person-years) exposed to various NSAIDs vs unexposed but showed no appreciable differences in risk modification comparing individuals exposed to GSM vs non-GSM NSAIDs. This analysis specifically suggested no difference in apparent risk reduction with exposure to naproxen vs ibuprofen. Considering these results, together with those of the flurbiprofen trials, we doubt that naproxen's lack of GSM activity explains the results of INTREPAD.3
The second point relates to statistical power. Our study addressed this issue directly. We acknowledged that INTREPAD lacked an initially estimated degree of power. But we pointed out that the Alzheimer progression score revealed a significant progression of apparent AD signs over the trial interval. The estimated confidence interval around the treatment-related change rate ratio suggested <5% likelihood that naproxen reduced AD progression by more than 36%. This conclusion was bolstered by the lack of apparent benefit on any of the 12 APS components.
Footnotes
Author disclosures are available upon request (journal{at}neurology.org).
- © 2020 American Academy of Neurology
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