This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (235)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in JAMA  Topic Collections  • Neurology  • Alzheimer Disease  • Randomized Controlled Trial  • Alert me on articles by topic

A Randomized Controlled Trial

Paul S. Aisen, MD; Kimberly A. Schafer, MS; Michael Grundman, MD, MPH; Eric Pfeiffer, MD; Mary Sano, PhD; Kenneth L. Davis, MD; Martin R. Farlow, MD; Shelia Jin, MPH; Ronald G. Thomas, PhD; Leon J. Thal, MD; for the Alzheimer's Disease Cooperative Study

JAMA. 2003;289:2819-2826.

Context  Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease.

Objective  To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD.

Design  Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications.

Setting  Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium.

Participants  Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled.

Interventions  Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo.

Main Outcome Measures  The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death).

Results  The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group.

Conclusion  The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.

Author Affiliations: Department of Neurology, Georgetown University Medical Center, Washington, DC (Dr Aisen); Department of Neurosciences, University of California, San Diego (Ms Schafer and Drs Grundman, Jin, and Thal); Suncoast Gerontology Center, University of South Florida College of Medicine, Tampa (Dr Pfeiffer); Department of Psychiatry (Dr Sano), Mount Sinai School of Medicine, Mount Sinai Medical Center (Dr Davis), New York, NY; Department of Neurology, School of Medicine, Indiana University, Indianapolis (Dr Farlow); Departments of Family and Preventive Medicine and Neurosciences, University of California, San Diego (Dr Thomas).

RELATED ARTICLE

Nonsteroidal Anti-inflammatory Drugs and Alzheimer Disease: What's Next?
Lenore J. Launer
JAMA. 2003;289(21):2865-2867.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

No advantage of A{beta}42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies
Szekely et al.
Neurology 2008;70:2291-2298.
ABSTRACT | FULL TEXT  

Protective effects of NSAIDs on the development of Alzheimer disease
Vlad et al.
Neurology 2008;70:1672-1677.
ABSTRACT | FULL TEXT  

Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury
Choi et al.
FASEB J. 2008;22:1491-1501.
ABSTRACT | FULL TEXT  

NSAID use and dementia risk in the Cardiovascular Health Study*: Role of APOE and NSAID type
Szekely et al.
Neurology 2008;70:17-24.
ABSTRACT | FULL TEXT  

1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel {gamma}-Secretase Modulator, Reduces Brain beta-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity
Imbimbo et al.
J. Pharmacol. Exp. Ther. 2007;323:822-830.
ABSTRACT | FULL TEXT  

Involvement of Prostaglandin E2 in Production of Amyloid-beta Peptides Both in Vitro and in Vivo
Hoshino et al.
J. Biol. Chem. 2007;282:32676-32688.
ABSTRACT | FULL TEXT  

Disease-modifying therapies for Alzheimer disease: Challenges to early intervention
Cummings et al.
Neurology 2007;69:1622-1634.
ABSTRACT | FULL TEXT  

Dementia and Comorbidities: An Overview of Diagnosis and Management
Swanson and Carnahan
Journal of Pharmacy Practice 2007;20:296-317.
ABSTRACT  

NSAIDs in the prevention of dementia: A Cache-22?
Scharf and Daffner
Neurology 2007;69:235-236.
FULL TEXT  

Does NSAID use modify cognitive trajectories in the elderly?: The Cache County Study
Hayden et al.
Neurology 2007;69:275-282.
ABSTRACT | FULL TEXT  

Inflammatory markers and the risk of Alzheimer disease: The Framingham Study
Tan et al.
Neurology 2007;68:1902-1908.
ABSTRACT | FULL TEXT  

Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial
ADAPT Research Group
Neurology 2007;68:1800-1808.
ABSTRACT | FULL TEXT  

Low dose aspirin and cognitive function in the women's health study cognitive cohort
Kang et al.
BMJ 2007;334:987-987.
ABSTRACT | FULL TEXT  

The effects of commonly prescribed drugs in patients with Alzheimer's disease on the rate of deterioration
Ellul et al.
J. Neurol. Neurosurg. Psychiatry 2007;78:233-239.
ABSTRACT | FULL TEXT  

Behavior-Based Interventions to Enhance Cognitive Functioning and Independence in Older Adults
Shumaker et al.
JAMA 2006;296:2852-2854.
FULL TEXT  

Clinical practice with anti-dementia drugs: a consensus statement from British Association for Psychopharmacology.
Burns and O'Brien
J Psychopharmacol 2006;20:732-755.
ABSTRACT  

Therapeutic approaches to Alzheimer's disease
Klafki et al.
Brain 2006;129:2840-2855.
ABSTRACT | FULL TEXT  

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials
Zhang et al.
JAMA 2006;296:1619-1632.
ABSTRACT | FULL TEXT  

Acetylcholinesterase inhibitors for Alzheimer's disease: anti-inflammatories in acetylcholine clothing!
Tabet
Age Ageing 2006;35:336-338.
ABSTRACT | FULL TEXT  

Clinical trials in mild cognitive impairment: lessons for the future
Jelic et al.
J. Neurol. Neurosurg. Psychiatry 2006;77:429-438.
ABSTRACT | FULL TEXT  

Gene expression changes by amyloid {beta} peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes
Walker et al.
J. Leukoc. Biol. 2006;79:596-610.
ABSTRACT | FULL TEXT  

What is the best evidence for determining harms of medical treatment?
Vandenbroucke
CMAJ 2006;174:645-646.
FULL TEXT  

Glia as a Therapeutic Target: Selective Suppression of Human Amyloid-beta-Induced Upregulation of Brain Proinflammatory Cytokine Production Attenuates Neurodegeneration
Ranaivo et al.
J. Neurosci. 2006;26:662-670.
ABSTRACT | FULL TEXT  

SIRT1 Protects against Microglia-dependent Amyloid-{beta} Toxicity through Inhibiting NF-{kappa}B Signaling
Chen et al.
J. Biol. Chem. 2005;280:40364-40374.
ABSTRACT | FULL TEXT  

Curcumin Inhibits the Classical and the Alternate Pathways of Complement Activation
KULKARNI et al.
Ann. N. Y. Acad. Sci. 2005;1056:100-112.
ABSTRACT | FULL TEXT  

Herbal Complement Inhibitors in the Treatment of Neuroinflammation: Future Strategy for Neuroprotection
KULKARNI et al.
Ann. N. Y. Acad. Sci. 2005;1056:413-429.
ABSTRACT | FULL TEXT  

Translational Research on the Way to Effective Therapy for Alzheimer Disease
Rosenberg
Arch Gen Psychiatry 2005;62:1186-1192.
ABSTRACT | FULL TEXT  

Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs
Townsend and Pratico
FASEB J. 2005;19:1592-1601.
ABSTRACT | FULL TEXT  

Microglial Phagocytosis Induced by Fibrillar {beta}-Amyloid and IgGs Are Differentially Regulated by Proinflammatory Cytokines
Koenigsknecht-Talboo and Landreth
J. Neurosci. 2005;25:8240-8249.
ABSTRACT | FULL TEXT  

The Cardiovascular Toxicity of Selective and Nonselective Cyclooxygenase Inhibitors: Comparisons, Contrasts, and Aspirin Confounding
Konstantinopoulos and Lehmann
J Clin Pharmacol 2005;45:742-750.
ABSTRACT | FULL TEXT  

Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment
Petersen et al.
NEJM 2005;352:2379-2388.
ABSTRACT | FULL TEXT  

Acute treatment with the PPAR{gamma} agonist pioglitazone and ibuprofen reduces glial inflammation and A{beta}1-42 levels in APPV717I transgenic mice
Heneka et al.
Brain 2005;128:1442-1453.
ABSTRACT | FULL TEXT  

Clinical effects of A{beta} immunization (AN1792) in patients with AD in an interrupted trial
Gilman et al.
Neurology 2005;64:1553-1562.
ABSTRACT | FULL TEXT  

Cholinesterase inhibitor use in geriatric outpatients with dementia
Linnebur and Ruscin
Am J Health Syst Pharm 2005;62:923-926.
FULL TEXT  

Atorvastatin for the Treatment of Mild to Moderate Alzheimer Disease: Preliminary Results
Sparks et al.
Arch Neurol 2005;62:753-757.
ABSTRACT | FULL TEXT  

Fatty Acid Oxidation in the Pathogenesis of Alzheimer's Disease
Montine and Morrow
Am. J. Pathol. 2005;166:1283-1289.
ABSTRACT | FULL TEXT  

Overexpression of Monocyte Chemotactic Protein-1/CCL2 in {beta}-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse {beta}-Amyloid Deposition
Yamamoto et al.
Am. J. Pathol. 2005;166:1475-1485.
ABSTRACT | FULL TEXT  

Arthritis Medications and Cardiovascular Events
Lehmann
JAMA 2005;293:1976-1976.
FULL TEXT  

William M. Feinberg Lecture: Cognitive Vitality and the Role of Stroke and Cardiovascular Disease Risk Factors
Gorelick
Stroke 2005;36:875-879.
ABSTRACT | FULL TEXT  

Meta-Analysis of Nonsteroidal Antiinflammatory Drug Use and Risk of Dementia
de Craen et al.
Am J Epidemiol 2005;161:114-120.
ABSTRACT | FULL TEXT  

Alcohol, wine and mental health: focus on dementia and stroke
Pinder and Sandler
J Psychopharmacol 2004;18:449-456.
ABSTRACT  

Inflammation and the Degenerative Diseases of Aging
McGEER and McGEER
Ann. N. Y. Acad. Sci. 2004;1035:104-116.
ABSTRACT | FULL TEXT  

Neuroprotection from Complement-Mediated Inflammatory Damage
KULKARNI et al.
Ann. N. Y. Acad. Sci. 2004;1035:147-164.
ABSTRACT | FULL TEXT  

Modulation of Nuclear Factor-{kappa}B Activity by Indomethacin Influences A{beta} Levels but Not A{beta} Precursor Protein Metabolism in a Model of Alzheimer's Disease
Sung et al.
Am. J. Pathol. 2004;165:2197-2206.
ABSTRACT | FULL TEXT  

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia
Bi et al.
J. Biol. Chem. 2004;279:48238-48245.
ABSTRACT | FULL TEXT  

Risk Factors for Vascular Dementia and Alzheimer Disease
Gorelick
Stroke 2004;35:2620-2622.
ABSTRACT | FULL TEXT  

Rofecoxib did not slow progression of dementia in patients with established Alzheimer's disease
Riggs and Holloway
Evid. Based Med. 2004;9:148-148.
FULL TEXT  

Immunotherapy for Alzheimer's Disease
McGeer and McGeer
Sci Aging Knowl Environ 2004;2004:pe29-pe29.
ABSTRACT | FULL TEXT  

Alzheimer's Disease
Cummings
NEJM 2004;351:56-67.
FULL TEXT  

Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic
WARNER and MITCHELL
FASEB J. 2004;18:790-804.
ABSTRACT | FULL TEXT  

Delirium and Dementia
Ajilore and Kumar
Focus 2004;2:210-220.
ABSTRACT | FULL TEXT  

Editorial
Harris and Keady
Dementia 2004;3:5-7.
 

Con: Sleep Apnea Does Not Cause Cardiovascular Disease
Stradling
Am. J. Respir. Crit. Care Med. 2004;169:148-149.
FULL TEXT  

Mild Cognitive Impairment Can Be Distinguished From Alzheimer Disease and Normal Aging for Clinical Trials
Grundman et al.
Arch Neurol 2004;61:59-66.
ABSTRACT | FULL TEXT  

Cyclooxygenase (COX)-2 and COX-1 Potentiate {beta}-Amyloid Peptide Generation through Mechanisms That Involve {gamma}-Secretase Activity
Qin et al.
J. Biol. Chem. 2003;278:50970-50977.
ABSTRACT | FULL TEXT  

Rofecoxib or naproxen do not slow progression of mild to moderate Alzheimer's disease
Jacoby
Evid. Based Ment. Health 2003;6:110-110.
FULL TEXT  

Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of {beta}-Secretase
Sastre et al.
J. Neurosci. 2003;23:9796-9804.
ABSTRACT | FULL TEXT  

Effect of NSAIDs on risk of Alzheimer's disease: Confounding factors were not discussed
Robertson
BMJ 2003;327:751-751.
FULL TEXT  

Effect of NSAIDs on risk of Alzheimer's disease: Author's reply
Etminan
BMJ 2003;327:751-752.
FULL TEXT  

Anti-inflammatories don't slow cognitive decline in Alzheimer's
BMJ 2003;327:0.
FULL TEXT  

No Benefit of (Some) NSAIDs in Alzheimer's Disease Progression
JWatch Neurology 2003;2003:6-6.
FULL TEXT  

No Benefit of (Some) NSAIDs in Alzheimer's Disease Progression
JWatch Psychiatry 2003;2003:10-10.
FULL TEXT  

Anti-inflammatory drugs and Alzheimer's disease
Martyn
BMJ 2003;327:353-354.
FULL TEXT  

Rosack
Psychiatr. News 2003;38:26-26.
FULL TEXT  

No Benefit of (Some) NSAIDs in Alzheimer's Disease Progression
JWatch Gastroenterology 2003;2003:9-9.
FULL TEXT  

No Benefit of (Some) NSAIDs in Alzheimer's Disease Progression
JWatch General 2003;2003:1-1.
FULL TEXT  

Nonsteroidal Anti-inflammatory Drugs and Alzheimer Disease: What's Next?
Launer
JAMA 2003;289:2865-2867.
FULL TEXT