Acetylcholinesterase inhibitors and risk of bleeding and acute ischemic events in non‐hypertensive Alzheimer's patients (original) (raw)
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Aspirin in Alzheimer's Disease: Increased Risk of Intracerebral Haemorrhage and no Clinical Benefit
Alzheimer's & Dementia, 2010
Background and Purpose-In a randomized controlled trial in Alzheimer's disease (AD), we found a higher number of intracerebral hemorrhages (ICHs) in patients randomized to aspirin treatment. Here, we evaluate the literature on the risk of ICH as a complication in patients with AD treated with aspirin. Methods-Systematic review and comparison of the occurrence of events over time between the aspirin and control group in each trial using Cox regression analysis. Estimated hazard ratios (HRs) were combined in a pooled HR. Results-Two randomized controlled trials on aspirin for AD were found. In the Evaluation of Vascular Care in Alzheimer's Disease (EVA) trial (conducted in our center), 4.6% of patients in the group receiving a multicomponent treatment that included aspirin had an ICH (3/65; 95% confidence interval [CI], 1.0 to 12.9) versus 0% in the control group (0/58; 95% CI, 0 to 6.2). In the Aspirin in Alzheimer's Disease (AD2000) trial, these proportions were, respectively, 2.6% (4/156; 95% CI, 0.7 to 6.4) and 0% (0/154; 95% CI, 0 to 2.4). The pooled proportion of ICHs in the aspirin group is 3.2% (7/221; 95% CI, 1.3 to 6.4) versus 0% in the control group (0/212; 95% CI, 0 to 1.7). The pooled HR for an ICH in AD patients using aspirin is 7.63 (95% CI, 0.72 to 81.00; Pϭ0.09). Conclusions-Although the number of cases in both trials is small, our findings suggest that aspirin use in AD might pose an increased risk of ICH, whereas it has no effect on cognition. If there is an unequivocal cardiovascular indication for aspirin, it should not be withheld in AD patients. (Stroke. 2010;41:2690-2692.)
Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial
The Lancet Neurology, 2008
AD2000 Collaborative Group* Summary Background Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefi ts of aspirin in patients with AD.
Antihypertensive Medication Use and Incident Alzheimer Disease
Archives of Neurology, 2006
Background: Recent reports suggest that antihypertensive (AH) medications may reduce the risk of dementing illnesses. Objectives: To examine the relationship of AH medication use with incidence of Alzheimer disease (AD) among the elderly population (aged 65 years and older) of Cache County, Utah, and to examine whether the relationship varies with different classes of AH medications. Methods: After an initial (wave 1) multistage assessment (1995 through 1997) to identify prevalent cases of dementia, we used similar methods 3 years later (wave 2) to identify 104 incident cases of AD among the 3308 survivors. At the baseline assessment, we obtained a detailed drug inventory from the study participants. We carried out discrete time survival analyses to examine the association between the use of AH medications (including angiotensin converting enzyme inhibitors, -blockers, calcium channel blockers, and diuretics) at baseline with subsequent risk of AD. Results: Use of any AH medication at baseline was associated with lower incidence of AD (adjusted hazard ratio, 0.64; 95% confidence interval, 0.41-0.98). Examination of medication subclasses showed that use of diuretics (adjusted hazard ratio, 0.57; 95% confidence interval, 0.33-0.94), and specifically potassiumsparing diuretics (adjusted hazard ratio, 0.26; 95% confidence interval, 0.08-0.64), was associated with the greatest reduction in risk of AD. Corresponding analysis with a fully examined subsample controlling for blood pressure measurements did not substantially change our findings. Conclusions: These data suggest that AH medications, and specifically potassium-sparing diuretics, are associated with reduced incidence of AD. Because the latter association is a new finding, it requires confirmation in further study.
Annals of Geriatric Medicine and Research
Epidemiology and Pathophysiology of Alzheimer's Disease Alzheimer's disease (AD) is the most common cause of dementia worldwide, affecting over 40 million people, primarily older adults. 1) The pathophysiology of AD is believed to result from the loss of cholinergic neurons, resulting in atrophy of cholinergic nuclei and reduced levels of the neurotransmitter acetylcholine in the brain. 2) Acetylcholine is involved in brain functions including attention, memory, motivation, and arousal, which are often affected in patients with the disease. The β-amyloid protein plaques found in the brains of patients with AD are also thought to negatively impact cholinergic synapses. 3) Acetylcholine is broken down into acetic acid and choline by acetylcholinesterase enzymes in the synaptic cleft, thereby ending signal transmission and postsynaptic receptor activation. Management of Alzheimer's Disease There are no well established disease-modifying treatments for AD; thus, prevention and behavioral interventions comprise the bedrocks of management. There has been a focus on improving
Comparative cardiovascular safety of dementia medications: a cross-national study
Journal of the American Geriatrics Society, 2012
ObjectivesTo compare the cardiovascular safety of currently marketed dementia medications in new users in the United States and Denmark.To compare the cardiovascular safety of currently marketed dementia medications in new users in the United States and Denmark.DesignRetrospective cohort study.Retrospective cohort study.SettingNationally representative sample of Medicare beneficiaries from 2006 through 2009 and nationwide Danish administrative registries from 1997 through 2007.Nationally representative sample of Medicare beneficiaries from 2006 through 2009 and nationwide Danish administrative registries from 1997 through 2007.ParticipantsIndividuals treated with a dementia medication aged 65 and older.Individuals treated with a dementia medication aged 65 and older.MeasurementsHospitalizations for myocardial infarction (MI), heart failure, and syncope or atrioventricular block in both cohorts; fatal or nonfatal MI and cardiac death in the Danish cohort; and all-cause mortality in sensitivity analyses.Hospitalizations for myocardial infarction (MI), heart failure, and syncope or atrioventricular block in both cohorts; fatal or nonfatal MI and cardiac death in the Danish cohort; and all-cause mortality in sensitivity analyses.ResultsIn 46,737 Medicare beneficiaries and 29,496 Danish participants, donepezil was the most frequently used medication. There were no substantial differences in the risk of MI or heart failure between participants using donepezil and those using other cholinesterase inhibitors (all hazard ratios (HR) crossing 1). In the Danish cohort, memantine was associated with fatal or nonfatal MI (HR = 1.33, 95% confidence interval (CI) = 1.08–1.63), cardiac death (HR = 1.31, 95% CI = 1.12–1.53), and a trend toward higher rates of hospitalization for MI (HR = 1.31, 95% CI = 0.98–1.76). Memantine was also associated with greater risk of all-cause mortality in the Medicare (HR = 1.20, 95% CI = 1.13–1.28) and Danish (HR = 1.83, 95% CI = 1.73–1.94) cohorts, suggesting that sicker individuals were selected for memantine therapy.In 46,737 Medicare beneficiaries and 29,496 Danish participants, donepezil was the most frequently used medication. There were no substantial differences in the risk of MI or heart failure between participants using donepezil and those using other cholinesterase inhibitors (all hazard ratios (HR) crossing 1). In the Danish cohort, memantine was associated with fatal or nonfatal MI (HR = 1.33, 95% confidence interval (CI) = 1.08–1.63), cardiac death (HR = 1.31, 95% CI = 1.12–1.53), and a trend toward higher rates of hospitalization for MI (HR = 1.31, 95% CI = 0.98–1.76). Memantine was also associated with greater risk of all-cause mortality in the Medicare (HR = 1.20, 95% CI = 1.13–1.28) and Danish (HR = 1.83, 95% CI = 1.73–1.94) cohorts, suggesting that sicker individuals were selected for memantine therapy.ConclusionCholinesterase inhibitors have similar cardiovascular risk profiles. Associations between memantine and fatal outcomes in Denmark may be related, in part, to selection of sicker individuals for memantine therapy.Cholinesterase inhibitors have similar cardiovascular risk profiles. Associations between memantine and fatal outcomes in Denmark may be related, in part, to selection of sicker individuals for memantine therapy.
European Heart Journal
Background Oral anticoagulation (OAC) is key in preventing stroke in patients with atrial fibrillation (AF). However, patients with AF and dementia pose practical therapeutic challenges, such as compliance and haemorrhagic complications, resulting in possible underuse of cardiovascular (CV) treatment. Purpose The aim of this study is two-fold: a) to determine whether AF patients with dementia are undertreated for stroke prevention with OAC and for their CV comorbidities and b) to assess the risks and benefits of OAC in AF patients with dementia. Methods Analyses were conducted in newly diagnosed AF patients enrolled in GARFIELD-AF, the largest multinational prospective AF registry. Medical history of dementia was recorded at enrolment. Guideline-directed medical therapy (GDMT), defined according to ESC guidelines, was explored for coronary artery disease (CAD), diabetes, heart failure (HF), hypertension, and peripheral vascular disease (PVD). Propensity score weighting was applied t...
European Heart Journal, 2013
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.
NSAID use and dementia risk in the Cardiovascular Health Study*: Role of APOE and NSAID type
Neurology, 2007
Background: Epidemiologic and laboratory studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) reduce risk of Alzheimer dementia (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD. Methods: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident allcause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one ε4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid-beta peptide variant Aβ 42. Results: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% confidence interval or CI 0.60-0.96), and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE ε4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce Aβ 42. Conclusions: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE ε4 allele, and there was no advantage for Aβ 42 lowering NSAIDs.
Journal of the American Geriatrics Society, 2005
al. report that ''cholinesterase inhibitor (CEI) use had a clinically meaningful effect on the natural history of Alzheimer Disease (AD),'' slowing disease progression and lowering risk of nursing home admission after 2 years. 1 The design of the study is worrisome. Of 1,139 patients who enrolled in the AD Research Center over 7 years, 270 were selected; 135 began taking CEIs ''immediately after enrollment, and continued to take them throughout the following 12 months,'' and 135 never took the drug. How these individuals were selected is not otherwise described. They were matched on a few characteristics, such as age, Mini-Mental State Examination score, and education. This study resembles a study by Dr. Geldmacher et al. that showed that patients who took a CEI faithfully (80% of pills or more) had a significant delay in nursing home placement (NHP). 2 Both of these nonrandomized studies failed to report important baseline characteristics of the groups being studied. In the Geldmacher article, for example, nonadherent patients were far less likely to have a spouse caregiver than faithful users, 3 yet the authors, who claimed it was the donepezil that ''resulted in significant delays in NHP,'' omitted this fact. 2 Both papers are easily distinguished from AD 2000, 4 a properly randomized, controlled trial with the largest number of placebo-controlled patient-years of any cholinesterase study. 5 In AD 2000, ''no significant benefits were seen with donepezil compared with placebo in institutionalization or progression of disability. .. [or] in behavioral and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events, or death or between 5 mg and 10 mg of donepezil.'' 4 In the United Kingdom, the National Institute for Clinical Excellence Appraisal Committee has recently issued the following preliminary recommendation: ''Donepezil, rivastigmine and galantamine are not recommended for use in the treatment of mild to moderate Alzheimer's disease (AD).'' 6 Would Dr. Lopez modify the discussion of his paper, where he emphasizes the important benefits of donepezil, in view of the results from AD 2000, a larger, better-designed trial that failed to show any meaningful difference at all?