Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease

Alzheimer disease (AD) is a chronic, progressive neurodegenerative disorder that is characterized by a variety of structural and functional neurodegenerative changes. Evidence suggests that β-amyloid (Aβ) and CNS cholesterol play important roles in this multifactorial degenerative process.^1,2 Cholesterol modulates the processing of amyloid precursor protein (APP)-related Aβ production in vitro and in animal model studies,^3–7 and AD neuropathologic lesions are demonstrable in patients who have coronary artery disease and no dementia.⁸ Reducing cholesterol through the use of statins (HMG-CoA reductase inhibitors) appears to affect the processing of APP and the production of Aβ.⁹ However, studies on the effect of statin treatment on serum or CSF Aβ concentrations in human subjects are equivocal.¹⁰

Retrospective case control studies have reported a positive relationship between statin use and reduced risk of developing AD,^11,12 while prospective cohort studies have yielded mixed results.^13,14 Two randomized, controlled cardiovascular prevention trials included cognition as a secondary outcome without significant benefits,^15,16 whereas a proof-of-concept randomized controlled trial (RCT) of atorvastatin indicated a trend for symptomatic benefit in mild to moderate AD.¹⁷

The LEADe study (Lipitor's Effect in Alzheimer's Dementia) is the first reported large-scale RCT evaluating the efficacy and safety of statin therapy in patients with mild to moderate AD receiving background therapy with the acetylcholinesterase inhibitor (AchEI) donepezil.

METHODS

MRI substudy.

A sample size of 100 subjects in each treatment arm was estimated, assuming a 30% difference in volumetric change between the treatments and allowing for a 30% attrition rate.

The primary analysis of efficacy was based on a least-squares mean repeated-measures analysis for both the CGIC and the ADAS-cog total score on the modified intent-to-treat population (MITT), where each patient contributed data for each visit until they either completed the study or dropped out. MITT was used for all efficacy analyses (excepting MRI) and included all randomized patients who took at least 1 dose of study medication and who provided both a baseline assessment and at least 1 postbaseline efficacy assessment. The model used for the analyses of efficacy is based on a repeated-measures-mixed-effects analysis including the ADCS-CGIC score or change from baseline score for all other scores as the dependent variable, treatment as the major factor, visit as the repeated factor, and baseline score (if available) as the covariate plus treatment by visit interaction term in the model with subject nested within treatment as the cluster factor.

In addition to running the primary model on all scores, a last observation carried forward (LOCF) approach was employed as a sensitivity analysis (figure 2). The LOCF approach was from an analysis of covariance (ANCOVA) model that included only the last visit data in the analysis with treatment as the major factor and baseline score (if available) as the covariate.

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Figure 2 ADAS-Cog and ADCS-CGIC results

(A) Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and (B) Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale (ADCS-CGIC) over time (modified intent-to-treat [MITT] population). Repeated-measures analyses were performed (with baseline score as covariate for ADAS-Cog score change from baseline). LS = least-squares; LOCF = last observation carried forward.

The MRI endpoints were evaluated for the patients in the MITT population with available MRI data using the following techniques: least-squares (LS) means and standard error (SE) for each treatment group with LS means differences, 95% confidence interval, and the p values for between-treatment comparison regarding the annualized BSI or whole hippocampus volume are based on ANCOVA model. In the ANCOVA model, the annualized BSI or annualized rate of decrease in whole hippocampus volume is included as the dependent variable with treatment arm as the major factor and baseline whole brain volume or baseline whole hippocampus volume as the covariate.

The safety population consisted of all randomized patients who had taken at least 1 dose of study medication, or for whom it was unknown whether they had taken any study medication but for whom there were postrandomization data. For the safety analysis, all observed AEs were reported, regardless of suspected causal relationship to the study drug. These included adverse drug reactions, illnesses with symptom onset during the study or exacerbations of preexisting illnesses, as well as objective test findings that resulted in a change in the study drug dosage. Rates for adverse events, laboratory abnormalities, and EKG changes were summarized.

All statistical analyses were performed using SAS 8.2.

RESULTS

Figure 1 presents the flow of patients through the study. Of the 1,008 selected for screening assessment, there were 640 patients randomized to the study, with an MITT population of 297 patients in the atorvastatin group and 317 patients in the placebo group. The overall study completion rate was very close to predicated at 70.6% with a dropout rate of 29.4%. A larger proportion of subjects discontinued the study in the atorvastatin group compared with the placebo group.

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Figure 1 Patient disposition

MITT = modified intent to treat.

There were no significant differences in demographics, mean baseline scores, and mean lipid levels between treatment arms (table 1). Through the 72-week treatment period there were no significant differences on either the ADAS-cog (figure 2A and table e-1 on the Neurology® Web site at www.neurology.org) or the CGIC (figure 2B and table e-2), or among the secondary endpoints (NPI, ADFACS, CDR-SB, MMSE, and modified ADAS-cog [tables e-3 to e-7]). Since the primary endpoints were not met, the withdrawal phase is not reported.

In the MRI substudy, there were 64 subjects evaluable for longitudinal assessment of hippocampal volumes and 58 evaluable for BSI and whole brain volumes. Atorvastatin therapy was associated with a significant smaller annualized decrease in hippocampal volume, but no significant difference in the annualized boundary shift integral between the treatment groups. Post hoc review of this MRI subsample showed differences in baseline demographics between treatment arms and a significant treatment effect on ADCS-CGIC in favor of atorvastatin.

While lipid values at baseline were similar between the 2 treatment groups, by month 3, mean LDL-C had decreased −72.4 mg/dL (−50.2%) in the atorvastatin group and −1.0 mg/dL (−0.2%) in the placebo group (figure 3). These changes remained constant through month 18. Total cholesterol and serum triglyceride levels demonstrated larger decreases in the atorvastatin group compared with the placebo group while there was little change in HDL-C in either treatment group.

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Figure 3 Changes in lipid levels by treatment group over time

(A) Low-density lipoprotein cholesterol, (B) total cholesterol, (C) triglycerides, and (D) high-density lipoprotein cholesterol.

Treatment with atorvastatin was generally well-tolerated (table 2). The incidence of persistent elevations in AST or ALT levels (3 × upper limits of normal on 2 consecutive measures 4 to 10 days apart) was 2.6% in the atorvastatin group and 0% in the placebo group. There were 60 (19.1%) atorvastatin-treated and 69 (21.2%) placebo-treated patients who experienced serious adverse events (SAEs), with the most common being falls (9 and 13 subjects). Six subjects in the atorvastatin-treated group and 1 subject in the placebo group had SAEs considered treatment related by either the investigator or the sponsor. The SAEs considered treatment related in the atorvastatin group were hepatitis, acute renal failure/rhabdomyolysis/pancreatitis, abdominal pain/nausea/chest discomfort, transaminases elevation, liver disorder, and gastrointestinal hemorrhage. There were 9 deaths (2.9%) in the atorvastatin group and 6 (1.8%) in the placebo group. Causes of death in the atorvastatin group included congestive cardiac failure, pneumonia, acute renal failure/rhabdomyolysis/pancreatitis, gastric perforation, myocardial infarction, sudden cardiac death, complete atrioventricular block, and advancing AD.

DISCUSSION

The LEADe study was a randomized placebo-controlled trial that was designed to evaluate the long-term symptomatic effects of atorvastatin in mild to moderate AD as well as its potential for disease modification. Significantly, it represents one of the largest and longest RCTs testing both the efficacy and safety of a statin in AD. The results of another large recently completed RCT of simvastatin with a similar study design are anticipated (clinicaltrials.gov, NCT00053599).

There is good evidence that these trial results are valid as most of the a priori assumptions were met. In particular, the placebo rate of decline on the primary outcomes was very close to the estimates in the sample size determination, while the actual dropout rate fell within the anticipated range. The cholesterol-lowering effects of atorvastatin followed expectations, with a sharp reduction seen by week 12 on LDL-C, total cholesterol, and triglycerides and with reversal of the reductions in the atorvastatin group randomized to receive placebo during the 8-week randomized withdrawal period of the trial. Despite the successful design and execution, the treatment intervention of adding atorvastatin on a background of donepezil use was not associated with any significant clinical benefits on either cognition or global functioning. Furthermore, there were no apparent benefits on a broader range of secondary outcome measures including neuropsychiatric symptoms, functional disability, disease staging, caregiver burden, and health economics. These results would indicate that cholesterol lowering in patients with mild to moderate AD without elevated LDL-C and at low risk of ischemic events is not associated with better preservation of cognition or function.

It is important to consider both the limitations as well as the broader implications of this study. The population in the current trial was restricted to patients who did not have an indication for statin treatment. Current practice guidelines for patients with hypercholesterolemia call for treatment with statins when lipid values are substantially out of range or in patients with lower values who have high vascular risk factor burden.³¹ This precluded the inclusion of patients with AD with significantly elevated LDL-C. It is therefore possible that the AD patient group with higher LDL-C levels with or without cardiovascular risk factors might have responded better to this intervention with atorvastatin. Also unanswered from this study is the question of whether atorvastatin might benefit patients with AD with significant concurrent cardiac, cerebrovascular, or peripheral vascular disease, since these patients were excluded from the current study. Based on the interaction of cerebrovascular lesions with plaque and tangle pathology, one might hypothesize that there would be a more identifiable treatment benefit.³²

A key issue emerging from this study is the question of the optimal timing of treatment with a statin to achieve benefit in AD. This trial enrolled patients with well-established AD across a spectrum of mild to moderate severity. This may have been too far down the pathogenic cascade of AD leaving open to speculation whether the optimal period of early intervention might have been missed. Recently proposed revised research criteria for AD allow for diagnosis at the prodromal stage where treatment response might be different.³³

This trial provides some important safety data on atorvastatin use within an elderly AD population. The safety profile for atorvastatin at a dosage of 80 mg daily was very similar to that in younger patients as reported in prior RCTs.^34,35 The incidence of liver and muscle adverse events were also consistent with the rates reported in its product monograph.³⁶ There were no hemorrhagic strokes encountered in the atorvastatin group and hepatic side effects resolved fully off when treatment was stopped. Contrary to concerns arising from observational studies,^37,38 there were no adverse cognitive effects as measured by the ADAS-cog, MMSE, or CDR-SB; in fact, the numerical advantage favored atorvastatin on the primary cognitive measure, the ADAS-cog.

The primary analyses (repeated-measures models) take into account the time of each score evaluation. However, the LOCF uses the last visit of each patient and treats all those last visits the same way (without adjusting for the timing of those visits). It is notable that the LOCF approach presents a more optimistic picture of the treatment effect. In this trial, in which patients tended to show clinical decline over time, the differential withdrawal pattern (in which subjects on atorvastatin were more likely to discontinue prematurely from the study) created a small efficacy advantage for the subjects in the atorvastatin group when analyzed with the LOCF model. The patients who withdrew early due to reasons other than progression of dementia will appear to have higher efficacy in a LOCF model. This supports the use of a repeated-measures model as a superior choice for primary analysis in the setting of a longer-term clinical trial in AD.³⁹

Treatment arm imbalances, especially the difference in function as measured by the ADCS-CGIC, lead us to conclude that the MRI substudy sample is not representative of the original cohort.

COINVESTIGATORS

LEADe Steering Committee— Howard Feldman (Chair), Vancouver, Canada; Rachelle Doody, Houston, TX; Roy Jones, Bath, UK; Miia Kivipelto, Stockholm, Sweden; David Lawrence Sparks, Sun City, AZ; David Waters, San Francisco, CA. LEADe Investigators— Australia: K. Boundy, H. Brodaty, R. Clarnette, D.S. Crimmins, J. Hecker, M.C. Woodward, M.W. Yates; Austria: P. Dal-Bianco, M. Haushofer, D. Poewe, M. Rainer; Canada: H. Bergman, S.E. Black, M.J. Borrie, R. Bouchard, H. Feldman, S. Gauthier, D.B. Hogan, G. Lacombe, C. Macknight, A.A. Robillard; Denmark: H. Braendgaard, M. Fink, S.G. Hasselbalch, S.A. Jakobsen, L.F. Lauritzen; Germany: K. Hager, R. Horn, H.-O. Karnath, A. Kurz, W. Maier, W. Mattern, H.-J. Moeller, J.B. Schulz, E. Steinhagen-Thiessen; South Africa: P.R. Laban, S. Lipschitz, C.M. Maud, F.C. Potocnik, A. Smuts; Spain: J.L.D. Ayuso, M.A. Barbera, A.F. Garcia, C.F. Garcia, J.L. Molinuevo, J. Peña-Casanova, M.B. Rovira; Sweden: N. Andreasen, M. Karlsson, H. Olofsson, J. Marcusson, S. Syversen; United Kingdom: A. Baldwin, A. Bayer, R.A. Bullock, R. Coles, F. Inglis, R.W. Jones, A.P. Passmore, D. Wilkinson; United States: P.G. Antuono, S.M. Asthana, C.B. Bernick, F.F. Chang, G.E. Cooper, S.T. Dekosky, J.E. De la Gandara, G.M. Dempsey, A.N. Dengiz, R.S. Doody, D.A. Drachman, E.A. Duboff, D.G. Folks, J.N. Goldstein, P.M. Green, P.J. Holland, R.F. Holub, M.S. Ismail, M. Kalafer, J.A. Kaye, C.S. Krishnasastry, K.A. Levin, P.D. Londborg, L.O. Macina, D.I. Margolin, J.A. Mattes, J.A. McCarthy, J.M. McKenney, M.C. Nunez, J.M. Pittard, S.H. Preskorn, W.G. Preston, M.A. Raskind, R.W. Richter, C.H. Sadowsky, B.E. Safirstein, S.P. Salloway, F.W. Schaerf, B.P. Seltzer, D.L. Sparks, L.J. Spikol, S.R. Stark, J.A. Stoukides, J.R. Tomlinson, M.A. Usman, M.F. Weiner, K.L. Wilks, J.L. Winston, M.L. Wolff, P.P. Zolnouni.

ACKNOWLEDGMENT

The authors acknowledge IXICO Ltd. (London, UK) for performing the atrophy measurement analysis of the image data collected for this study, including semiautomated brain and hippocampal delineations, as well as the boundary shift integral (BSI) technique. No assistance with content development or writing was provided, but editorial support in preparation for submission was provided by UBC Scientific Solutions and was funded by Pfizer Inc.

STUDY FUNDING

The LEADe study was funded by Pfizer. This manuscript was written by the authors on behalf of the LEADe Investigators. Employees of Pfizer contributed to the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and review of the manuscript.

DISCLOSURE

The LEADe study was funded by Pfizer. Dr. Feldman is an employee of Bristol-Myers Squibb. Since January 1, 2009 Dr Feldman is on leave from University of British Columbia (UBC). The research and writing of this paper were undertaken while he was at UBC. Dr. Feldman served on the scientific advisory boards of Astra Zeneca, Bristol-Myers Squibb, Elan, Glia Scientific, Janssen, Pfizer, Merck Serono, Nestle, Novartis, Wyeth, Glaxo Smith Kline, Neuropharma, Servier, Shionogi/GSK, Targacept, Lundbeck, Pharmagenesis, Sanofi Synthelabo, Eli Lilly Boehringer Ingelheim; received travel expenses and/or honoraria for lectures or educational activities not funded by industry; received reimbursement of travel expenses and/or honoraria for lectures or educational activities sponsored by the Academy of Healthcare Education, Alpha Plus, Astra Zeneca, Cadmus Medea, Eisai, Glia Scientific, Janssen, Lundbeck, Medical Decision Point, Informed Direct PLC, MedPlan Communications, Novartis, and Pfizer. During the other years of the LEADe study (2002–2006), he received reimbursement of travel expenses and/or honoraria for lectures or educational activities sponsored by Academy of Healthcare Education, Alpha Plus Communications, Current Medical Directions, Eisai, Pfizer, Astra Zeneca, Janssen, the Memory Fitness Institute, OCC, Precept Medical, Lundbeck, MedPlan Communications, Excerpta Medica, Impact Communication, Shire, Embryon, Fundacion Maria Wolff Alzheimer, Kenes International, Prescott Medical, Alpha Plus Communications, Six Degrees, Hc3 Communications, Insyght, Ketchum, Novartis, Universal CIT, Center for Health Care Education, Glia Scientific, Health LogiX, and American Academy of Neurology; served as a member of the editorial board or an associate editor of Dementia and Geriatric Cognitive Disorders, Journal of Neurological Sciences, and the Canadian Alzheimer Disease Review; holds patent US Serial Number PCT/2007/070008 “Detecting and Treating Dementia” that may accrue revenue; receives royalties from Atlas of Alzheimer's Disease (Informa Health, London, 2007); served as a paid consultant to Novartis for an FDA Advisory Committee; served as a paid consultant for Migenix, Amorfix, United Biosource, and Ipsen; served on Pfizer Speakers Bureau; served as a member of steering committees of clinical trials sponsored by ONO, Elan and Pfizer; served as a member of data safety monitoring boards for clinical trials of Janssen, Myriad, and Novartis; received research funding from Elan, Lundbeck, Myriad, ONO, Servier, Sanofi Synthelabo, Janssen, and Glaxo Smith Kline; received grant-in-aid funding for the ACCORD Study from Eisai, Pfizer, Lilly and Janssen; and grant funding from the Alzheimer Society of Canada; received or receives research funding from the Canadian Institutes of Health Research (00725-000 [CoInvestigator], 179009 [PI], 74580 [PI], 73376 [PI]), Pacific Alzheimer Research Foundation (C06-01 [Coinvestigator]), NIH (U01AG24904 [Coinvestigator]); received travel reimbursement as PhD opponent Karolinska Institute; and holds stock options in BioMarin. Dr. Doody (during the time span from 2002 to present) served on medical and scientific advisory boards of Astellas, Athenagen, Comentis, Medivation, Myriad, Neurochem, Sonexa, and Zapaq and currently serves on such boards for Medivation and Sonexa; served on steering committees for Sanofi-Synthelabo and Ono; served on a data safety monitoring board for Debiopharm; and currently serves on a data safety monitoring board for GlaxoSmithKline; served on Pfizer Scholars selection committee; received reimbursement for travel to and from advisory board and consulting meetings for those that took place out of town; serves on the editorial boards of Alzheimer's Disease and Associated Disorders, Dementia and Geriatric Cognitive Disorders, and Alzheimer's Research and Therapy (a Biomedical Central journal); receives royalties from Alzheimer's Dementia (Carma Publishing, 2008); received honoraria for academic lectures from Eisai, Lundbeck, Pfizer; Forest (2002–2007 only); attended one or more ad hoc consultation meetings with Abbott, Allon, Amgen, Astellas, AstraZeneca, BristolMeyersSquibb, Dainippon, Eisai, Epix, Forest, Fujisawa, GlaxoSmithKline, Janssen, Lilly, MerckSerono, Merz, Novartis, Noven, Ocera, Pfizer, Saegis, Sanofi-Synthelabo, ScheringPlough, Suven, Takeda, Teva, Transition, Varinel, Voyager; received research funding from Eisai, Elan (now Jannsen Immunotherapy), Forest, GlaxoSmithKline, Myriad, Pfizer, Sanofi- Synthelabo, Teva, and Wyeth (now Pfizer); received research funding from NIH Alzheimer's Disease Cooperative Study Clinical trials (Site PI), NIDDK IR21DK062098 (Coinvestigator), and NIH/NCRR P20 RR020626 (Coinvestigator); received Zenith Award, Alzheimer's Association (PI); holds stock options in Medivation and Sonexa; acted as a consultant to a firm representing Eisai in a patent challenge case and to a firm representing Forest in a patent challenge case. Dr. Kivipelto served on the scientific advisory board for Pfizer and Elan; served as an editor for Journal of Alzheimer's Disease; was reimbursed for meetings organized by Pfizer, Novartis, and Jansen; received honoraria for lectures from Pfizer, Novartis, Jansen, Lundbeck and Merz.; received research support from Academy of Finland 120676 (PI) and 117 458 (PI). Dr. Sparks serves on the scientific advisory board (LEADe steering committee) for Pfizer; received funding from Pfizer to attend LEADe steering committee meetings; serves on the LEADe steering committee, Pfizer; served as a consultant for Resverlogix Pharma; received research support from Resverlogix Pharmaceuticals (0432-03-17607 [ICA]) and Pfizer (140015 [PI]); and receives research support from AZ Biomedical Research (0008-07 [PI]). Dr. Waters served on the scientific advisory board of Pfizer; served on steering committees for Pfizer; served on data safety monitoring boards for Pfizer, Oxigene and Merck Schering-Plough; served on advisory boards of Atherogenics, Merck Schering-Plough, Cortria, Aegerion; served on the endpoint committee of Biosante; served as an associate editor of Journal of the American College of Cardiology; received royalties from publishing Cardiology, Crawford and DiMarco, second edition (Harcourt Publishers, 2004); received honoraria for lectures from Pfizer and Merck; served as a consultant for Anthera; received research funding from Merck Schering-Plough; and held stock options in Anthera. Dr. Jones served on the scientific advisory board of Lundbeck, Pfizer/Medivation, Nutricia, Elan/Wyeth, Lilly, and Glaxo; received funding for travel from Lundbeck, Pfizer/Eisai, Shire, Merz, and Elan; received royalties from publishing Drug Treatment in Dementia, Blackwell (2001-2009); received research funding from Eisai/Pfizer, Lundbeck, Myriad, and Elan; received research funding from the Medical Research Council (grant 2007-001172-36 [Coinvestigator]); received research funding from BRACE (Bristol Research into Alzheimer's and Care of the Elderly [PI]); the Alzheimer's Research Trust (grant ART/NCG2005/1 [Coapplicant]); and served as a witness for the judicial Eisai appeal against NICE (The National Institute for Health and Clinical Excellence) in the UK. Dr. Schwam is an employee of Pfizer; and owns equity/ownership in Pfizer. Dr. Schindler is an employee of Pfizer; and owns equity/ownership in Pfizer. Dr. Hey-Hadavi is an employee of Pfizer; and owns equity/ownership in Pfizer. Dr. DeMicco is an employee of Pfizer; and owns equity/ownership in Pfizer. Dr. Breazna is an employee of Pfizer and he and his wife have equity/ownership interests in Pfizer.