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  1. Important errors in "Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review" by Farrimond et al.

    George T. Grossberg, MD, St. Louis University School of Medicine, St Louis, Missouri, USA

    Yvonne Wirth, MD, PhD, Wirth Consulting, Stuttgart, Germany

    Suzanne Hendrix, PhD, Pentara Corporation, Salt Lake City, Utah, USA

    Michael Tocco, PhD, Forest Research Institute, Jersey City, New Jersey, USA

    Stephen M. Graham, PhD, Forest Research Institute, Jersey City, New Jersey, USA

    Dear Dr Groves:

    After careful review of the article titled "Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review" (Farrimond et al, BMJ Open, 2012)[1], we have identified significant inaccuracies that we believe should be addressed.

    Several important errors and inconsistencies occur in Figure 3, some of which are also repeated in Table 2 (Analysis 3, Function). First, the figure shows a numerical advantage for placebo over memantine extended- release (ER) in trial MD-50, which is incorrect: in that trial [2], as well as in trial MD-02 [3] and in the subset of patients from MD-12 with moderate AD [4], the memantine group demonstrated a smaller mean decline on the measure of function than the placebo group. The corrected Figure 3, which properly summarizes the data from these 3 trials, along with the authors' original version, can be found at the following site:

    http://dx.doi.org/10.6084/m9.figshare.95823

    As shown in the figure, for the outcome of function, Farrimond et al calculated a standard mean difference (SMD) [95%CI] of -0.04 [-0.21, 0.13] (P = 0.65), whereas, according to our calculations, the correct overall SMD [95%CI] is -0.11 [-0.21, 0.00] (P = 0.05). Therefore, there is a large discrepancy between their analysis and ours in terms of both the observed effect (-0.04 vs -0.11) and the accompanying P-value (0.65 vs 0.05).

    In addition, our analysis of Cognition (Table 2, Analysis 1b), performed by applying the methodology outlined by the authors to the same published data that they used, resulted in an SMD [95%CI] of -0.23 [-0.47, 0.00] (P= 0.05, significantly in favor of memantine), rather than their published SMD of -0.16 [-0.54, 0.23] (P = 0.43). These corrected values reveal that the TA127 analysis would have indeed demonstrated significant cognitive benefits in favor of memantine/donepezil combination therapy had the data been pooled, contrary to the authors' assertion.

    We also bring to your attention several statements pertaining to published literature or previously reported data. In the introduction, the authors refer to the Patel and Grossberg manuscript [5] as a "company- sponsored" review, which in fact was produced independently of industry support, as stated in the acknowledgments ("no sources of funding were used to assist in the preparation of this review"). Moreover, Table 1, which correctly cites the Forest Clinical Trial Registry website as the reference for the MD-50 study, incorrectly states that "the baseline characteristics of patients in this unpublished study are not given." These data are in fact reported in the summary clinical study report posted on the website, with the exception of the mean NPI score (Placebo + ChEI = 16.8; Memantine + ChEI = 17.2). In reference to the memantine ER formulation (28 mg) used in the MEM-MD-50 study, the authors state in the discussion section that "the dose of 28 mg memantine in this preparation was designed to be equivalent to 20 mg daily of the currently marketed preparation," which is incorrect: the new memantine formulation was designed to provide a 40% increase in the maximum daily dose with a much slower absorption rate (median Tmax of 12 h, compared with 3-7 h observed with the immediate-release formulation)[6].

    The authors also speculate that "the trend for an adverse effect on ADL may account for the fact that [the MD-50 trial] data have not been published in peer review literature." This interpretation may have been influenced by their misperception that placebo treatment was superior to memantine for ADL in that trial (as exemplified by the error in Figure 3). In fact, the manuscript describing this trial has been submitted for publication. As reported previously [2], the trial demonstrated significant benefits in favor of memantine ER on both primary efficacy parameters (SIB and CIBIC-Plus) and two additional parameters (NPI and Verbal Fluency Test), as well as a numerical advantage in favor of memantine on the ADCS-ADL19.

    Furthermore, the authors state that "the fact that clinical data have not been released from the 12-month trial, Lu1011 [2], is disturbing"; however, the trial manuscript, which includes the clinical data, was published --and indexed on PubMed and Embase-- in January, 2012 [7], two months before the manuscript by Farrimond et al was accepted for publication.

    Finally, the authors state that "since the impact on clinical global impression depends on exactly which studies are included, and there is no benefit on function, the clinical relevance of combination therapy is not robustly demonstrated." We believe that this statement is unfounded, for the following reasons: (1) As demonstrated above (see the corrected Figure 3), there is a significant benefit on function when all three studies are included in the meta-analysis. (2) In our opinion, the authors' observation that study selection determines the overall effect on the clinical global impression measure (CIBIC-Plus) contradicts the purpose of conducting a meta-analysis. No relevant data set should be excluded from a meta-analysis without a compelling reason - for example, significant heterogeneity. Indeed, the authors' own analysis of global clinical impression for all 3 datasets (Figure 1) demonstrates a significant overall effect of memantine (p<0.001) without evidence of significant heterogeneity, suggesting no reasons for excluding any of the trials. Incidentally, if one data set were to be excluded, the most reasonable choice would be the moderate subset from the MD-12 trial, due to its higher baseline mean MMSE score (15, compared with a mean MMSE score of 10 for both MD-02 and MD-50). In that case, pooling of MD-02 and MD-50 data would yield a significant overall treatment effect for cognition (SIB; p<0.001), function (ADCS-ADL19; p=0.03), behavior (NPI; p<0.001), and clinical global impression (CIBIC-plus; p<0.001).

    In short, we believe that the conclusions in this manuscript are not supported by the data, which, when pooled across all 3 trials, demonstrate significant benefits of adding memantine to ChEIs on cognitive, functional, behavioral, and global clinical outcome measures.

    We strongly urge the authors to reassess and correct the analysis and presentation of data in this manuscript (particularly Figure 3), and to revise the discussion and conclusions so that they are consistent with the corrected data. We respectfully suggest that an appropriate response would be to withdraw the original publication and replace it with a corrected version in BMJ Open.

    Sincerely,

    George T. Grossberg, MD; Co-author of manuscripts from trials MD-02 [3], MD-12 [8], and MD-50 (submitted) and the Patel and Grossberg 2011 review [5]

    Yvonne Wirth, MD PhD; Statistical consultant and co-author of meta-analysis [4] that was the source for MD-12 data for patients with moderate AD

    Suzanne Hendrix, PhD; Statistical consultant

    Michael Tocco, PhD; Medical Affairs, Forest Research Institute

    Stephen M. Graham, PhD; Co-author of manuscripts from trials MD-02 [3] and MD-50 (submitted)

    References

    [1] Farrimond LE, Roberts E, McShane R. Memantine and cholinesterase inhibitor combination therapy for alzheimer's disease: A systematic review. BMJ Open 2012;2(3).

    [2] Grossberg G, Manes F, Allegri R, Miguel L, Robledo L, Gloger S, et al. A multinational, randomized, double-blind, placebo-controlled, parallel-group trial of memantine extended-release capsule (28 mg, once daily) in patients with moderate to severe alzheimer's disease [abstract]. Alzheimers Dement 2008;4(4)(suppl 2):T793.

    [3] Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe alzheimer disease already receiving donepezil: A randomized controlled trial. JAMA 2004;291(3):317-24.

    [4] Winblad B, Jones RW, Wirth Y, Stoffler A, Mobius HJ. Memantine in moderate to severe alzheimer's disease: A meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord 2007;24(1):20-7.

    [5] Patel L, Grossberg GT. Combination therapy for alzheimer's disease. Drugs Aging 2011;28(7):539-46.

    [6] Periclou A, Hu Y. Extended-release (er) memantine capsule (28 mg, once daily): A multiple-dose, open-label study evaluating steady-state pharmacokinetics in healthy volunteers [abstract]. Alzheimers Dement 2008;4(4 (suppl 2)):T792.

    [7] Wilkinson D, Fox NC, Barkhof F, Phul R, Lemming O, Scheltens P. Memantine and brain atrophy in alzheimer's disease: A 1-year randomized controlled trial. J Alzheimers Dis 2012;29(2):459-69.

    [8] Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT. Memantine treatment in patients with mild to moderate alzheimer's disease already receiving a cholinesterase inhibitor: A randomized, double-blind, placebo- controlled trial. Curr Alzheimer Res 2008;5(1):83-9.

    Conflict of Interest:

    Dr. George T. Grossberg has received consulting fees from Avanir Pharmaceuticals, Baxter Bioscience, Forest Laboratories, Eli Lilly, Lundbeck, Novartis Pharmaceuticals, and Otsuka Pharmaceutical; his department also receives research funds from Abbott Laboratories, Baxter, Forest, Janssen Pharmaceuticals, Novartis, and Pfizer Pharmaceuticals, as well as data safety monitoring committee fees from Abbott, Merck, and Schering-Plough. Dr. Yvonne Wirth is employed by Wirth Consulting, a statistical consultant of Merz, Inc. Dr. Suzanne Hendrix is employed by Pentara Corporation, a statistical consultant of Forest Research Institute, Inc. Drs. Michael Tocco and Stephen Graham are employed by Forest Research Institute. Medical writing and editorial assistance was provided by Drs. Vojislav Pejovic and Michael L. Miller from Prescott Medical Communications Group, Chicago, IL

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