European Journal of Clinical Pharmacology

, Volume 69, Issue 8, pp 1589–1597 | Cite as

Potentially inappropriate medication use among patients with Alzheimer disease in the REAL.FR cohort: be aware of atropinic and benzodiazepine drugs!

  • François Montastruc
  • Virginie Gardette
  • Christelle Cantet
  • Antoine Piau
  • Maryse Lapeyre-Mestre
  • Bruno Vellas
  • Jean-Louis MontastrucEmail author
  • Sandrine Andrieu
  • REAL.FR Group
Pharmacoepidemiology and Prescription



Few studies have investigated potentially inappropriate medication (PIM) use in patients with Alzheimer’s disease (AD). The aim of our study was to assess the prevalence of PIM in community-dwelling patients diagnosed with mild-to-moderate AD and identify the clinical factors associated with PIM prescriptions.


REAL.FR is a 4-year, prospective, multicenter French cohort of AD patients recruited in centers of expertise. We analyzed patient baseline data at entry into the study. PIMs were assessed using the Laroche list. A multivariate logistic regression was conducted to assess factors associated with PIMs.


A total of 684 AD patients were enrolled in the study [mean age 77.9 ± 6.8 years, 486 (71.0 %) females]. According to the Laroche list, 46.8 % [95 % confidence interval (CI) 43.0–50.5 %] of the patients had at least one PIM. “Cerebral vasodilators” were the most widely used class of PIM, accounting for 24.0 % (95 % CI 20.9–27.3 %) of all prescriptions, followed by atropinic drugs (17.0 %, 95 % CI 14.1–19.8 %) and long half-life benzodiazepines (8.5 %, 95 % CI 6.4–10.6 %). Atropinic drugs were associated with cholinesterase inhibitors in 16 % of patients. In the multivariate analysis, only two factors, namely, female gender [odds ratio (OR) 1.5, 95 % CI 1.1–2.2] and polypharmacy (≥5 drugs; OR 3.6, 95 % CI 2.6–4.5) were associated with prescriptions for PIMs.


These results reveal that approximately one out of two community-dwelling patients with mild-to-moderate AD treated by AD specialists use PIMs. They also indicate that the characteristics of the disease and the pharmacodynamic/pharmacokinetic profile of the drugs prescribed are not sufficiently taken into account by physicians when prescribing for AD patients.


Alzheimer’s disease Potentially inappropriate medications Atropinic drugs Benzodiazepines 



This work was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (PHRC No. 98-47N/01-010-01).

REAL.FR Study group:

Principal investigator: Pr. B. Vellas (Toulouse). Associated investigators: Pr. M. Rainfray (Bordeaux), Pr. J.P. Emeriau (Bordeaux), Pr. A. Franco (Grenoble), Pr. F. Pasquier (Lille), Dr. B. Frigard (Lille), Dr. B. Michel (Marseille), Pr. C. Jeandel (Montpellier), Pr. J. Touchon (Montpellier), Pr. P.H. Robert (Nice), Pr. P. Brocker (Nice), Pr. B. Forette (Paris), Dr. L. Lechowski (Paris), Pr. J. Belmin (Paris), Pr. M. Verny (Paris), Pr. F. Forette, Pr. A.S. Rigaud (Paris), Pr. P. Jouanny (Rennes), Dr. S. Belliard (Rennes), Dr. O. Michel (Rennes), Pr. R. Gonthier (Saint Etienne). Study coordinators: S. Gillette-Guyonnet, Pr. F. Nourhashemi, Dr. P.J. Ousset (Toulouse). Epidemiologist: Pr. S. Andrieu (Toulouse). Data Management: C. Cantet (Toulouse).

Conflict of interest


Sponsors and grants



  1. 1.
    Viktil KK, Blix HS, Moger TA, Reikvam A (2007) Polypharmacy as commonly defined is an indicator of limited value in the assessment of drug-related problems. Br J Clin Pharmacol 63:187–195PubMedCrossRefGoogle Scholar
  2. 2.
    Agence de Sécurité Sanitaire des Produits de Santé (Afssaps) and Réseau Français des Centres Régionaux de Pharmacovigilance (AFCRPV) Etude PEIMA (2011) Prévalence des effets indésirables médicamenteux chez les patients atteints de la maladie d’Alzheimer ou d’un syndrome démentiels. Available at:
  3. 3.
    Onder G, Gambassi G, Scales CJ, Cesari M, Vedova CD, Landi F, Bernabei R (2002) Adverse drug reactions and cognitive function among hospitalized older adults. Eur J Clin Pharmacol 58:371–377PubMedCrossRefGoogle Scholar
  4. 4.
    Ganjavi H, Herrmann N, Rochon PA, Sharma P, Lee M, Cassel D et al (2007) Adverse drug events in cognitively impaired elderly patients. Dement Geriatr Cogn Disord 23:395–400PubMedCrossRefGoogle Scholar
  5. 5.
    Chang CB, Chen JH, Wen CJ, Kuo HK, Lu IS, Chiu LS, Wu SC, Chan DC (2011) Potentially inappropriate medications in geriatric outpatients with polypharmacy: application of six sets of published explicit criteria. Br J Clin Pharmacol 72:482–489PubMedCrossRefGoogle Scholar
  6. 6.
    Beers MH (1997) Explicit criteria for determining potentially inappropriate medication use by the elderly. An update. Arch Intern Med 157:1531–1536PubMedCrossRefGoogle Scholar
  7. 7.
    Laroche ML, Charmes JP, Merle L (2007) Potentially inappropriate medications in the elderly: a French consensus panel list. Eur J Clin Pharmacol 63:725–731PubMedCrossRefGoogle Scholar
  8. 8.
    Holmes HM, Sachs GA, Shega JW, Hougham GW, Cox Hayley D, Dale W (2008) Integrating palliative medicine into the care of persons with advanced dementia: identifying appropriate medication use. J Am Geriatr Soc 56:1306–1311PubMedCrossRefGoogle Scholar
  9. 9.
    Lau DT, Mercaldo ND, Harris AT, Trittschuh E, Shega J, Weintraub S (2010) Polypharmacy and potentially inappropriate medication use among community-dwelling elders with dementia. Alzheimer Dis Assoc Disord 24:56–63PubMedCrossRefGoogle Scholar
  10. 10.
    Zuckerman IH, Hernandez JJ, Gruber-Baldini AL, Hebel JR, Stuart B, Zimmerman S, Magaziner J (2005) Potentially inappropriate prescribing before and after nursing home admission among patients with and without dementia. Am J Geriatr Pharmacother 3:246–254PubMedCrossRefGoogle Scholar
  11. 11.
    Fick D, Kolanowski A, Waller J (2007) High prevalence of central nervous system medications in community-dwelling older adults with dementia over a three-year period. Aging Ment Health 11:588–595PubMedCrossRefGoogle Scholar
  12. 12.
    Gillette-Guyonnet S, Nourhashemi F, Andrieu S, Cantet C, Micas M, Ousset PJ, Vellas B, REAL.FR Group (2003) The REAL.FR research program on Alzheimer’s disease and its management: methods and preliminary results. J Nutr Health Aging 7:91–96PubMedGoogle Scholar
  13. 13.
    Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW (1963) Studies of illness in the aged. The index of ADL: a standardized measure of biological and phychosocial function. JAMA 185:914–919PubMedCrossRefGoogle Scholar
  14. 14.
    Lawton MP, Brody EM (1969) Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9:179–186PubMedCrossRefGoogle Scholar
  15. 15.
    Rosen WG, Mohs RC, Davis KL (1984) A new rating scale for Alzheimer’s disease. Am J Psychiatry 141:1356–1364PubMedGoogle Scholar
  16. 16.
    Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572PubMedCrossRefGoogle Scholar
  17. 17.
    Vellas B, Guigoz Y, Garry PJ, Nourhashemi F, Bennahum D, Lauque S, Albarede JL (1999) The Mini Nutritional Assessment (MNA) and its use in grading the nutritional state of elderly patients. Nutrition 15:116–122PubMedCrossRefGoogle Scholar
  18. 18.
    Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J (1994) The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 44:2308–2314PubMedCrossRefGoogle Scholar
  19. 19.
    Zarit SH, Reever KE, Bach-Peterson J (1980) Relatives of the impaired elderly: correlates of feelings of burden. Gerontologist 20:649–655PubMedCrossRefGoogle Scholar
  20. 20.
    WHO Collaborating Centre for Drug Statistics Methodology. Available at:
  21. 21.
    Jyrkkä J, Enlund H, Korhonen MJ, Sulkava R, Hartikainen S (2009) Polypharmacy status as an indicator of mortality in an elderly population. Drugs Aging 26:1039–1048PubMedCrossRefGoogle Scholar
  22. 22.
    Onder G, Liperoti R, Fialova D, Topinkova E, Tosato M, Danese P, Gallo PF, Carpenter I, Finne-Soveri H, Gindin J, Bernabei R, Landi F, SHELTER Project (2012) Polypharmacy in nursing home in Europe: results from the SHELTER study. J Gerontol A Biol Sci Med Sci 67:698–704PubMedCrossRefGoogle Scholar
  23. 23.
    Rédaction Prescrire (2001) Eviter les effets indésirables par interactions medicamenteuses: comprendre et décider. Rev Prescr 31:416Google Scholar
  24. 24.
    Boustani MA, Campbell NL, Munger S, Maidment I, Fox GC (2008) Impact of anticholinergics on the aging brain: a review and practical application. Aging Health 4:311–320CrossRefGoogle Scholar
  25. 25.
    Campbell N, Boustani M, Limbil T, Ott C et al (2009) The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging 4:225–233PubMedGoogle Scholar
  26. 26.
    Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH (2003) Updating the beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Arch Intern Med 163:2716–2724PubMedCrossRefGoogle Scholar
  27. 27.
    StataCorp (2009) Stata statistical software: Release 11. StataCorp LP, College StationGoogle Scholar
  28. 28.
    Colloca G, Tosato M, Vetrano DL, Topinkova E, Fialova D, Gindin J, van der Roest HG, Landi F, Liperoti R, Bernabei R, Onder G, SHELTER project (2012) Inappropriate drugs in elderly patients with severe cognitive impairment: results from the shelter study. PLoS One 7:e46669PubMedCrossRefGoogle Scholar
  29. 29.
    Laroche ML, Charmes JP, Bouthier F, Merle L (2009) Inappropriate medications in the elderly. Clin Pharmacol Ther 85:94–97PubMedCrossRefGoogle Scholar
  30. 30.
    Bongue B, Naudin F, Laroche ML, Galteau MM, Guy C, Guéguen R, Convers JP, Colvez A, Maarouf N (2009) Trends of the potentially inappropriate medication consumption over 10 years in older adults in the East of France. Pharmacoepidemiol Drug Saf 18:1125–1133PubMedCrossRefGoogle Scholar
  31. 31.
    Laroche ML, Charmes JP, Nouaille Y, Fourrier A, Merle L (2006) Impact of hospitalization in an acute medical geriatric unit on potentially inappropriate medication use. Drugs Aging 23:49–59PubMedCrossRefGoogle Scholar
  32. 32.
    Bouvenot G (1999) Consumption and prescription of “cerebral vasodilators” in community AFSSAPS Saint Denis. Available at:
  33. 33.
    Nagaraja D, Jayashree S (2001) Randomized study of the dopamine receptor agonist piribedil in the treatment of mild cognitive impairment. Am J Psychiatry 158:1517–1519PubMedCrossRefGoogle Scholar
  34. 34.
    Tavassoli N, Sommet A, Lapeyre-Mestre MP, Bagheri H, Montrastruc JL (2007) Drug interactions with cholinesterase inhibitors: an analysis of the French pharmacovigilance database and a comparison of two national drug formulary (Vidal, British National Formulary). Drug Saf 30:1063–1071PubMedCrossRefGoogle Scholar
  35. 35.
    Fox C, Richardson K, Maidment ID, Savva GM, Matthews FE, Smithard D, Coulton S, Katona C, Boustani MA, Brayne C (2011) Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc 59:1477–1483PubMedCrossRefGoogle Scholar
  36. 36.
    Wu CS, Ting TT, Wang SC, Chang IS, Lin KM (2011) Effect of benzodiazepine discontinuation on dementia risk. Am J Geriatr Psychiatry 19:151–159PubMedCrossRefGoogle Scholar
  37. 37.
    Boeuf-Cazou O, Bongue B, Ansiau D, Marquié JC, Lapeyre-Mestre M (2011) Impact of long-term benzodiazepine use on cognitive functioning in young adults: the VISAT cohort. Eur J Clin Pharmacol 67:1045–1052PubMedCrossRefGoogle Scholar
  38. 38.
    Billioti de Gage S, Bégaud B, Bazin F, Verdoux H, Dartigues JF, Pérès K, Kurth T, Pariente A (2012) Benzodiazepine use and risk of dementia: prospective population based study. Br Med J 345:e6231. doi: 10.1136/bmj.e6231 CrossRefGoogle Scholar
  39. 39.
    Özdemir V, Fourie J, Busto U, Naranjo CA (1996) Pharmacokinetic changes in the elderly: do they contribute to drug abuse and dependence? Clin Pharmacokinet 31:372–385PubMedCrossRefGoogle Scholar
  40. 40.
    Ruggiero C, Dell’Aquila G, Gasperini B, Onder G, Lattanzio F, Volpato S, Corsonello A, Maraldi C, Bernabei R, Cherubini A, ULISSE Study Group (2010) Potentially inappropriate drug prescriptions and risk of hospitalization among older, Italian, nursing home residents: the ULISSE project. Drugs Aging 27:747–758PubMedCrossRefGoogle Scholar
  41. 41.
    Weston AL, Weinstein AM, Barton C, Yaffe K (2010) Potentially inappropriate medication use in older adults with mild cognitive impairment. J Gerontol A Biol Sci Med Sci 65:318–321PubMedCrossRefGoogle Scholar
  42. 42.
    Lapeyre-Mestre M, Chastan E, Louis A, Montastruc JL (1999) Drug consumption in workers in France: a comparative study at a 10-year interval (1996 versus 1986). J Clin Epidemiol 52:471–478PubMedCrossRefGoogle Scholar
  43. 43.
    Fialová D, Topinková E, Gambassi G, Finne-Soveri H, Jónsson PV, Carpenter I, Schroll M, Onder G, Sørbye LW, Wagner C, Reissigová J, Bernabei R, AdHOC Project Research Group (2005) Potentially inappropriate medication use among elderly home care patients in Europe. JAMA 293:1348–1358PubMedCrossRefGoogle Scholar
  44. 44.
    Reynish E, Cortes F, Andrieu S, Cantet C, Olde Rikkert M, Melis R, Froelich L, Frisoni GB, Jönsson L, Visser PJ, Ousset PJ, Vellas B, ICTUS Study Group (2007) The ICTUS Study: a prospective longitudinal observational study of 1,380 AD patients in Europe. Study design and baseline characteristics of the cohort. Neuroepidemiology 29:29–38PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • François Montastruc
    • 1
    • 2
    • 3
    • 4
  • Virginie Gardette
    • 2
    • 3
    • 5
  • Christelle Cantet
    • 3
    • 5
  • Antoine Piau
    • 6
  • Maryse Lapeyre-Mestre
    • 1
    • 4
    • 5
  • Bruno Vellas
    • 5
    • 6
  • Jean-Louis Montastruc
    • 1
    • 4
    • 5
    Email author
  • Sandrine Andrieu
    • 2
    • 3
    • 5
  • REAL.FR Group
  1. 1.Laboratoire de Pharmacologie Médicale et Clinique, Faculté de MédecineUniversité de ToulouseToulouseFrance
  2. 2.Laboratoire de Santé Publique et d’Economie de la Santé, Faculté de MédecineUniversité de ToulouseToulouseFrance
  3. 3.Département d’Epidémiologie, d’Economie de la Santé et de Santé PubliqueCentre Hospitalier Universitaire (CHU) ToulouseToulouseFrance
  4. 4.Service de Pharmacologie Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d’Informations sur le MédicamentCHU ToulouseToulouseFrance
  5. 5.INSERM UMR 1027ToulouseFrance
  6. 6.Département de Médecine Interne et de Gériatrie, CHU Toulouse Purpan, Gérontopôle de ToulouseUniversité de ToulouseToulouseFrance

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