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Abstract

Objective:

To determine the effect of treatment gaps on the risk of institutionalization or death among community-dwelling elderly patients treated with cholinesterase inhibitors (ChIs).

Methods:

A survival analysis was conducted among a cohort of community-dwelling elderly patients (age 66+) newly treated with ChIs identified in the Quebec drug claims databases (Régie de l'Assurance Maladie du Québec [RAMQ]) between January 1, 2000, and December 31, 2007. Treatment nonpersistence during the year following ChI initiation was defined as treatment discontinuation or gaps of at least 6 weeks. To account for reverse causality, Cox proportional hazard modeling was conducted only among patients who did not discontinue treatment, in order to assess the association between treatment nonpersistence and institutionalization or death.

Results:

Among the 24,394 elderly ChI users, 4,108 (16.8) experienced a treatment gap during the year following ChI treatment initiation while 596 (2.4%) discontinued their treatment within the first 3 months (early stoppers) and 4,038 (16.6%) after 3 months of treatment (late stoppers). Of all treated patients, 4,409 (18.1%) were institutionalized or died during follow-up. In patients who did not stop their treatment, the risk of institutionalization or death appeared lower in patients who experienced a treatment gap (hazard ratio 0.91; 95% confidence interval 0.86–0.96).

Conclusions:

Our results suggest that, contrary to what was previously reported in clinical trials, treatment gaps do not compromise the outcome of patients treated with ChIs in a real-life setting.

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REFERENCES

1.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Washington, DC: American Psychiatric Association; 1994.
2.
Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112–2117.
3.
Fratiglioni L, Launer LJ, Andersen K, et al. Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts: Neurologic Diseases in the Elderly Research Group. Neurology 2000;54:S10–S15.
4.
Farlow MR, Cummings JL. Effective pharmacologic management of Alzheimer's disease. Am J Med 2007;120:388–397.
5.
Bond J, Stave C, Sganga A, O'Connell B, Stanley RL. Inequalities in dementia care across Europe: key findings of the Facing Dementia Survey. Int J Clin Pract 2005;(suppl):8–14.
6.
Gruber-Baldini AL, Stuart B, Zuckerman IH, Simoni-Wastila L, Miller R. Treatment of dementia in community-dwelling and institutionalized medicare beneficiaries. J Am Geriatr Soc 2007;55:1508–1516.
7.
Herrmann N, Gill SS, Bell CM, et al. A population-based study of cholinesterase inhibitor use for dementia. J Am Geriatr Soc 2007;55:1517–1523.
8.
Pariente A, Helmer C, Fourrier A, Moore N, Dartigues JF. Prevalence of drug treatment in subjects with Alzheimer's disease in Europe. Pharmacoepidemiol Drug Saf 2008;17:655–660.
9.
Feldman HH, Pirttila T, Dartigues JF, et al. Treatment with galantamine and time to nursing home placement in Alzheimer's disease patients with and without cerebrovascular disease. Int J Geriatr Psychiatry 2009;24:479–488.
10.
Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006:CD005593.
11.
Lanctot KL, Herrmann N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003;169:557–564.
12.
Loy C, Schneider L. Galantamine for Alzheimer's disease and mild cognitive impairment. Cochrane Database Syst Rev 2006:CD001747.
13.
Lopez OL, Becker JT, Saxton J, Sweet RA, Klunk W, DeKosky ST. Alteration of a clinically meaningful outcome in the natural history of Alzheimer's disease by cholinesterase inhibition. J Am Geriatr Soc 2005;53:83–87.
14.
Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008;148:379–397.
15.
Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA 2003;289:210–216.
16.
US Food and Drug Administration. Peripheral and Central Nervous System Drugs Advisory Committee Meeting. Rockville, MD: Department of Health and Human Services, Public Health Service; 1989.
17.
European Medicine Evaluation Agency (EMEA). Note for Guidance on Medicinal Products in the Treatment of Alzheimer's Disease. London: EMEA; 1997.
18.
Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005;331:321–327.
19.
Loveman E. Appraisal Consultation Document: Alzheimer's Disease: Donepezil, Rivastigmine, Galantamine and Memantine (review). London: National Institute for Clinical Excellence; 2005.
20.
Greenberg SM, Tennis MK, Brown LB, et al. Donepezil therapy in clinical practice: a randomized crossover study. Arch Neurol 2000;57:94–99.
21.
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease: Donepezil Study Group. Neurology 1998;50:136–145.
22.
Amuah J, Hogan D, Eliasziw M, et al. Persistence of cholinesterase inhibitor therapy in a population-based cohort of patients with Alzheimer's disease. Pharmacoepidemiol Drug Saf 2010; 19:670–679.
23.
Pariente A, Pinet M, Moride Y, Merlière Y, Moore N, Fourrier-Réglat A. Factors associated with persistence of anti-Alzheimer drugs in France. Pharmacoepidemiol Drug Saf 2010;19:680–686.
24.
Hofman A, Ott A, Breteler MM, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 1997;349:151–154.
25.
Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE, Breteler MM. Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia 1996;39:1392–1397.
26.
Raffaitin C, Gin H, Empana JP, et al. Metabolic syndrome and risk for incident Alzheimer's disease or vascular dementia: The Three-City Study. Diabetes Care 2009;32:169–174.
27.
Gamaldo A, Moghekar A, Kilada S, Resnick SM, Zonderman AB, O'Brien R. Effect of a clinical stroke on the risk of dementia in a prospective cohort. Neurology 2006;67:1363–1369.
28.
Launer LJ, Andersen K, Dewey ME, et al. Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses: EURODEM Incidence Research Group and Work Groups European Studies of Dementia. Neurology 1999;52:78–84.
29.
Yoshitake T, Kiyohara Y, Kato I, et al. Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology 1995;45:1161–1168.
30.
AD2000 Collaborative Group Bentham P, Gray R, et al. Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial. Lancet Neurol 2008;7:41–49.
31.
Nilsson SE, Johansson B, Takkinen S, et al. Does aspirin protect against Alzheimer's dementia? A study in a Swedish population-based sample aged > or =80 years. Eur J Clin Pharmacol 2003;59:313–319.
32.
Hayden KM, Zandi PP, Khachaturian AS, et al. Does NSAID use modify cognitive trajectories in the elderly? The Cache County Study. Neurology 2007;69:275–282.
33.
Szekely CA, Breitner JC, Fitzpatrick AL, et al. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology 2008;70:17–24.
34.
Khachaturian AS, Zandi PP, Lyketsos CG, et al. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch Neurol 2006;63:686–692.
35.
Ohrui T, Tomita N, Sato-Nakagawa T, et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology 2004;63:1324–1325.
36.
Rockwood K. Epidemiological and clinical trials evidence about a preventive role for statins in Alzheimer's disease. Acta Neurol Scand Suppl 2006;185:71–77.
37.
Scott HD, Laake K. Statins for the prevention of Alzheimer's disease. Cochrane Database Syst Rev 2001:CD003160.
38.
Winblad B, Jelic V, Kershaw P, Amatniek J. Effects of statins on cognitive function in patients with Alzheimer's disease in galantamine clinical trials. Drugs Aging 2007;24:57–61.
39.
Li NC, Lee A, Whitmer RA, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 2010;340:b5465.
Letters to the Editor
1 October 2012
Effect of treatment gaps in elderly patients with dementia treated with cholinesterase inhibitors: letter to the editor
Erika Droogsma, Geriatric Medicine
N.J.G.M. Veeger2, P.E. van Walderveen1, S.M. Niemarkt1, D.Z.B. van Asselt1 1 Geriatric Medicine, Medical Centre Leeuwarden, PO Box 888 Leeuwarden 8901 BR, the Netherlands, 2 Department of Epid

In their interesting article, Pariente et al. conclude that "Treatment gaps do not compromise the outcome of patients treated with cholinesterase inhibitors in a real-life setting." [1] However, their conclusion is based on the effect of treatment gaps on risk of institutionalization and death, rather than on disease-specific endpoints. It has been shown that the beneficial effect of cholinesterase inhibitors on cognition, an important disease-specific endpoint, disappears within 3 weeks of discontinuation. [2,3] In addition, as mentioned by Patiente et al., treatment gaps are likely to occur in patients in whom re-initiation of treatment is worthy. From this, we infer that selection may have played a role, consequently limiting the generalizability of the study to a 'real life setting'. [4] This study is welcome because the authors address an important issue. However, because of these caveats, we feel that clinicians should not discontinue treatment too readily, as discontinuation of treatment does effect cognition, thereby compromising the outcome of patients.

1. Patiente A, Fourrier-R?glat, Bazin F, et al. Effect of treatment gaps in elderly patients with dementia treated with cholinesterase inhibitors. Neurology 2012;78:957-963.

2. Greenberg SM, Tennis MK, Brown LB, et al. Donepezil therapy in clinical practice. A randomized crossover study. Arch Neurol 2000;57:94- 99.

3. Gaudig M, Richarz U, Han J, et al. Effects of galantamine in Alzheimer's disease: double-blind withdrawal studies evaluating sustained versus interrupted treatment. Current Alzheimer Research 2011;8:771-780.

4. Stang A. Appropriate epidemiologic methods as a prerequisite for valid study results. Eur J Epidemiol 2008;23:761-765.

For disclosures, please contact the editorial office at [email protected].

Information & Authors

Information

Published In

Neurology®
Volume 78Number 13March 27, 2012
Pages: 957-963
PubMed: 22422894

Publication History

Received: April 19, 2009
Accepted: November 14, 2011
Published online: March 14, 2012
Published in print: March 27, 2012

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Disclosure

Dr. Pariente receives research support from the French government and the European Commission. Dr. Fourrier-Réglat has received research support from the French government, the European Commission, Merck & Co, Merck KgAa, Pfizer Inc, UCB, sanofi-aventis, Novartis, and Roche. Dr. Bazin and T. Ducruet report no disclosures. Dr. Dartigues serves on a scientific advisory board for and has received funding for travel from Janssen; received a gift worth more than US $500 from Novartis; holds a corporate appointment with Merck Serono; and has received research support from Novartis and Ipsen. Dr. Dragomir reports no disclosures. Dr. Perrault is a National Research Scholar who receives financial support from the Fonds de recherche en santé du Québec. Dr. Moore serves on scientific boards for and has received funding for travel and honoraria from Johnson & Johnson, Lundbeck, Inc., Servier, Proctor & Gamble, Reckitt-Benciser, CHU de Bordeaux, Takeda Pharmaceutical Company Limited, sanofi-aventis, ADDS, and Warner Chilcott; serves on the editorial board of Pharmacoepidemiology and Drug Safety, Drug Safety, Inflammopharmacology, and Expert Opinion in Drug Safety; has served as a consultant for Aptalys (Axcan Pharma), sanofi-aventis, Eli Lilly & Company, Lundbeck, Inc., Roche, Cephalon, Inc., Nycomed, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Celgene, GEnopharm, and Servier; and has received research support or participated to the conduct of studies that are supported by the French government, the European Commission, Merck & Co, Merck KgAa, Pfizer Inc, UCB, sanofi-aventis, Novartis, Roche, Abbott, Aptalis, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Eugénie les Bains, Génévrier, GlaxoSmithKline, Helsinn, Janssen, Lundbeck, Inc., Merck Chibret, Merck Serono, Nycomed, Pierre Fabre, Schering-Plough Corp, and Vivatech. Dr. Moride serves on scientific advisory boards for Johnson & Johnson and sanofi-aventis; serves as a consultant for Pfizer Inc, Pierre Fabre Médicament, Millennium Pharmaceuticals, Inc., AstraZeneca, sanofi-aventis, Bayer Schering Pharma, Valeant Pharmaceuticals International, and Bristol-Myers Squibb; and receives research support from AstraZeneca, Elli Lilly, Lundbeck, Sanofi Aventis, CIHR, and FRSQ.

Authors

Affiliations & Disclosures

A. Pariente, MD-PhD
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.
A. Fourrier-Réglat, PharmD-PhD
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.
F. Bazin, PhD
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.
T. Ducruet, MSc
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.
J.F. Dartigues, MD-PhD
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.
A. Dragomir, PhD
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.
S. Perreault, BPharm, PhD
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.
N. Moore, MD-PhD, FISPE
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.
Y. Moride, PhD, FISPE
From the University Bordeaux Segalen (A.P., A.F.-R., F.B., J.F.D., N.M., Y.M.), Bordeaux; INSERM, U657 (A.P., A.F.-R., N.M.), Bordeaux, France; Faculty of Pharmacy (A.P., T.D., A.D., S.P., Y.M.), Université de Montréal, Montreal, Canada; INSERM, U897 (J.F.D.), ISPED, Bordeaux; Service de Neurologie (J.F.D.), CHU de Bordeaux, Bordeaux, France; and Research Center (Y.M.), University of Montreal Hospital Center (CRCHUM), Montreal, Canada.

Notes

Study funding: This study was funded by the Fonds de la Recherche en Santé du Québec (FRSQ).
Correspondence & reprint requests to Dr. Moride: [email protected].

Author Contributions

Dr. Pariente: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, statistical analysis. Dr. Fourrier-Réglat: drafting/revising the manuscript, study concept or design, analysis or interpretation of data. Dr. Bazin: analysis or interpretation of data, statistical analysis. T. Ducruet: analysis or interpretation of data, statistical analysis. Dr. Dartigues: drafting/revising the manuscript. Dr. Dragomir: drafting/revising the manuscript, analysis or interpretation of data. Dr. Perrault: drafting/revising the manuscript, study concept or design, analysis or interpretation of data. Dr. Moore: drafting/revising the manuscript, study concept or design, analysis or interpretation of data. Dr. Moride: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision, obtaining funding.

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