Author response: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease
JohnBreitner, geriatric psychiatrist, Douglas Hospital Research Centre
Pierre-FrancoisMeyer, PhD student, Integrated Program in Neuroscience, McGill University
Submitted June 11, 2019
We thank Dr. Ashford for his comment on our paper “INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.”1 Dr. Ashford raises two important points: whether a gamma-secretase-modifying (GSM) NSAID such as ibuprofen would likely have given different results; and whether the APS outcome was sufficiently precise to reveal efficacy.
A meta-analysis of 6 prospective studies2 compared apparent AD risk modification in 13,499 older persons (70,863 person-years) exposed to various NSAIDs versus unexposed, but showed no appreciable differences in risk modification comparing individuals exposed to GSM versus non-GSM NSAIDs. This analysis specifically suggested no difference in apparent risk reduction with exposure to naproxen versus 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.
The second point relates to statistical power. Our manuscript addressed this issue directly. We acknowledged that INTREPAD lacked an initially estimated degree of power. But we pointed out that the APS 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 lack of apparent benefit on any of the 12 APS components.
Disclosure​
The authors report no relevant disclosures. Contact journal@neurology.org for full disclosures.
References
Meyer PF, Tremblay-Mercier J, Leoutsakos J, et al. INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease. Neurology Epub 2019 Apr 5.
Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001;414:212–216.
Green RC, Schneider LS, Amato DA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009;302:2557–2564.
We thank Dr. Ashford for his comment on our paper “INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.”1 Dr. Ashford raises two important points: whether a gamma-secretase-modifying (GSM) NSAID such as ibuprofen would likely have given different results; and whether the APS outcome was sufficiently precise to reveal efficacy.
A meta-analysis of 6 prospective studies2 compared apparent AD risk modification in 13,499 older persons (70,863 person-years) exposed to various NSAIDs versus unexposed, but showed no appreciable differences in risk modification comparing individuals exposed to GSM versus non-GSM NSAIDs. This analysis specifically suggested no difference in apparent risk reduction with exposure to naproxen versus 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.
The second point relates to statistical power. Our manuscript addressed this issue directly. We acknowledged that INTREPAD lacked an initially estimated degree of power. But we pointed out that the APS 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 lack of apparent benefit on any of the 12 APS components.
Disclosure​
The authors report no relevant disclosures. Contact journal@neurology.org for full disclosures.
References