The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer's disease.

AIMS Cholinesterase inhibitors (ChEIs) are used for symptomatic treatment of Alzheimer's disease. These drugs have vagotonic and anti-inflammatory properties that could be of interest also with respect to cardiovascular disease. This study evaluated the use of ChEIs and the later risk of myocardial infarction and death. METHODS AND RESULTS The cohort consisted of 7073 subjects (mean age 79 years) from the Swedish Dementia Registry with the diagnoses of Alzheimer's dementia or Alzheimer's mixed dementia since 2007. Cholinesterase inhibitor use was linked to diagnosed myocardial infarctions (MIs) and death using national registers. During a mean follow-up period of 503 (range 0-2009) days, 831 subjects in the cohort suffered MI or died. After adjustment for confounders, subjects who used ChEIs had a 34% lower risk for this composite endpoint during the follow-up than those who did not [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.56-0.78]. Cholinesterase inhibitor use was also associated with a lower risk of death (HR: 0.64, 95% CI: 0.54-0.76) and MI (HR: 0.62, 95% CI: 0.40-0.95) when analysed separately. Subjects taking the highest recommended ChEI doses (donepezil 10 mg, rivastigmine >6 mg, galantamine 24 mg) had the lowest risk of MI (HR: 0.35, 95% CI: 0.19-0.64), or death (HR: 0.54, 95% CI: 0.43-0.67) compared with those who had never used ChEIs. CONCLUSION Cholinesterase inhibitor use was associated with a reduced risk of MI and death in a nationwide cohort of subjects diagnosed with Alzheimer's dementia. These associations were stronger with increasing ChEI dose.

[1]  Hisashi Adachi,et al.  Inflammation, atherosclerosis, and coronary artery disease. , 2005, The New England journal of medicine.

[2]  Which Cholinesterase Inhibitor is the Safest for the Heart in Elderly Patients With Alzheimer’s Disease? , 2012, American journal of Alzheimer's disease and other dementias.

[3]  B. Winblad,et al.  Dementia Diagnosis Differs in Men and Women and Depends on Age and Dementia Severity: Data from SveDem, the Swedish Dementia Quality Registry , 2012, Dementia and Geriatric Cognitive Disorders.

[4]  M. Burtscher.  Lifetime risks of cardiovascular disease. , 2012, The New England journal of medicine.

[5]  A. Khera,et al.  Forecasting the Future of Cardiovascular Disease in the United States: A Policy Statement From the American Heart Association , 2011, Circulation.

[6]  K. Sunagawa,et al.  Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E-knockout mice. , 2010, Atherosclerosis.

[7]  A. Laupacis,et al.  Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study , 2009, PLoS medicine.

[8]  K. Tracey,et al.  Cholinergic control of inflammation , 2009, Journal of internal medicine.

[9]  V. Pavlov,et al.  Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway , 2009, Brain, Behavior, and Immunity.

[10]  M. Sugimachi,et al.  Effect of the cholinesterase inhibitor donepezil on cardiac remodeling and autonomic balance in rats with heart failure , 2009, The Journal of Physiological Sciences.

[11]  Roy W Jones,et al.  Memantine in Moderate to Severe Alzheimer’s Disease: a Meta-Analysis of Randomised Clinical Trials , 2007, Dementia and Geriatric Cognitive Disorders.

[12]  Christopher J Czura,et al.  Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Touchon,et al.  Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period , 2005, Current medical research and opinion.

[14]  H. Soreq,et al.  Acetylcholinesterase inhibitors reduce brain and blood interleukin‐1β production , 2005, Annals of neurology.

[15]  D. Gambi,et al.  Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1β and interleukin-6 release from lymphocytes of Alzheimer's disease patients , 2005, Experimental Gerontology.

[16]  B. Seltzer,et al.  Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. , 2004, Archives of neurology.

[17]  D. Gambi,et al.  Treatment with an acetylcholinesterase inhibitor in Alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines , 2004, Journal of Neuroimmunology.

[18]  Masaru Sugimachi,et al.  Vagal Nerve Stimulation Markedly Improves Long-Term Survival After Chronic Heart Failure in Rats , 2003, Circulation.

[19]  Bruno Vellas,et al.  Efficacy of Donepezil on Maintenance of Activities of Daily Living in Patients with Moderate to Severe Alzheimer's Disease and the Effect on Caregiver Burden , 2003, Journal of the American Geriatrics Society.

[20]  P. Tariot,et al.  GETTING DONEPEZIL INTO THE NURSING HOME ‐ Response to the Editor , 2003 .

[21]  T. Finucane.  GETTING DONEPEZIL INTO THE NURSING HOME ‐ (Letter referred to the authors of the original paper , 2003, Journal of the American Geriatrics Society.

[22]  B. Winblad,et al.  An Economic Evaluation of Donepezil in Mild to Moderate Alzheimer’s Disease: Results of a 1-Year, Double-Blind, Randomized Trial , 2002, Dementia and Geriatric Cognitive Disorders.

[23]  M Rosén,et al.  A national record linkage to study acute myocardial infarction incidence and case fatality in Sweden. , 2001, International journal of epidemiology.

[24]  A. Hake,et al.  Response of patients with Alzheimer disease to rivastigmine treatment is predicted by the rate of disease progression. , 2001, Archives of neurology.

[25]  G. Wilcock,et al.  Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial , 2000, BMJ : British Medical Journal.

[26]  L. Wilkins.  Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension , 2000, Neurology.

[27]  E. Peskind,et al.  Galantamine in AD , 2000, Neurology.

[28]  P. Tariot,et al.  A 5-month, randomized, placebo-controlled trial of galantamine in AD , 2000, Neurology.

[29]  G. Wilcock,et al.  Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. , 2000, BMJ.

[30]  H.-J. Möller,et al.  The Effects of Donepezil in Alzheimer’s Disease – Results from a Multinational Trial1 , 1999, Dementia and Geriatric Cognitive Disorders.

[31]  P Dal-Bianco,et al.  Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. , 1999, BMJ.

[32]  Y. Agid,et al.  Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trialCommentary: Another piece of the Alzheimer's jigsaw , 1999 .

[33]  R. Mohs,et al.  A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease , 1998, Neurology.

[34]  Rachelle S. Doody,et al.  DONEPEZIL STUDY GROUP. A 24-WEEK, DOUBLE BLIND, PLACEBO-CONTROLLED TRIAL OF DONEPEZIL IN PATIENTS WITH ALZHEIMER'S DIS-EASE , 1998 .

[35]  K. Davis.  Cholinesterase Inhibitors in Alzheimer's Disease , 1994, Neuropsychopharmacology.

[36]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.