Cholinesterase Inhibitors for Dementia and Risk of Pneumonia
Objectives To compare the risk of pneumonia in older adults receiving donepezil, galantamine, or rivastigmine for dementia.
Design Retrospective cohort study.
Setting Nationally representative 5% sample of Medicare databases.
Participants Medicare beneficiaries aged 65 and older who newly initiated cholinesterase inhibitor therapy between 2006 and 2009.
Measurements Pneumonia, defined as the presence of a diagnosis code for pneumonia as the primary diagnosis on an inpatient claim or on an emergency department claim followed by dispensing of appropriate antibiotics. Cox proportional hazards models were used to estimate the risk of pneumonia. Subgroup analyses and sensitivity analyses were conducted using alternative pneumonia definitions and adjustments using high-dimensional propensity scores to test the robustness of the results.
Results The mean age of 35,570 new users of cholinesterase inhibitors (30,174 users of donepezil, 1,176 users of galantamine, 4,220 users of rivastigmine) was 82; 75% were women, and 82% were white. The cumulative incidence of pneumonia was 51.9 per 1,000 person-years. The risk of pneumonia for rivastigmine users was 24% lower than that of donepezil users (hazard ratio (HR) = 0.75, 95% confidence interval (CI) = 0.60–0.93). Risk in galantamine users (HR = 0.87, 95% CI = 0.62–1.23) was not significantly different from risk in donepezil users. Results of subgroup and sensitivity analyses were similar to the primary results.
Conclusion The risk of pneumonia was lower in individuals receiving rivastigmine than in those receiving donepezil. Additional studies are needed to confirm the findings of pneumonia risk between the oral and transdermal forms of rivastigmine and in users of galantamine.
Dementia is a chronic neurodegenerative disorder characterized clinically by deterioration of daily living, behavioral functioning, and global cognitive ability. Cholinesterase inhibitors are the cornerstone of medical therapy and are approved for symptomatic treatment of individuals with mild to moderate dementia. Because pneumonia is a common cause of death in older adults with dementia, concern has been raised about the potential risk of pneumonia associated with cholinesterase inhibitors. Cholinesterase inhibition may lead to overactivation of muscarinic receptors and result in bradycardia, bronchospasm, emesis, and diarrhea. Moreover, overstimulation of nicotinic receptors results in fasciculation, muscle weakness, and paralysis that may increase pneumonia risk. Although there is no direct evidence of greater pneumonia risk associated with cholinesterase inhibitors, results of randomized clinical trials have suggested the possibility. One study found that cholinesterase inhibitor therapy in 183 hospitalized individuals with dementia was associated with nearly twice the risk of pulmonary disorders, mostly pneumonia.
The current study evaluated the comparative risk of pneumonia in older adults receiving donepezil, galantamine, or rivastigmine. Rivastigmine inhibits acetylcholinesterase and butyrylcholinesterase and has greater selectivity for brain tissue than peripheral tissues. Some studies have indicated that rivastigmine has lower affinity for the type 4 globular isoform of acetylcholinesterase than the type 1 isoform, which is a possible safety advantage because the type 4 isoform predominates in the peripheral nervous system. Because the peripheral nervous system regulates involuntary physiological functions such as breathing and digestion, cholinesterase inhibitors with fewer peripheral effects are less likely to cause unintended respiratory outcomes, such as shortness of breath and dyspnea, or unintended digestive outcomes, such as gastroesophageal reflux or esophageal immotility, which may have a negative effect on pneumonia risk, but there is no evidence of the comparative safety of cholinesterase inhibitors with regard to pneumonia risk. It was hypothesized that rivastigmine posed a lower risk than donepezil and galantamine, which are acetylcholinesterase inhibitors without selectivity for the type 4 isoform.
Abstract and Introduction
Abstract
Objectives To compare the risk of pneumonia in older adults receiving donepezil, galantamine, or rivastigmine for dementia.
Design Retrospective cohort study.
Setting Nationally representative 5% sample of Medicare databases.
Participants Medicare beneficiaries aged 65 and older who newly initiated cholinesterase inhibitor therapy between 2006 and 2009.
Measurements Pneumonia, defined as the presence of a diagnosis code for pneumonia as the primary diagnosis on an inpatient claim or on an emergency department claim followed by dispensing of appropriate antibiotics. Cox proportional hazards models were used to estimate the risk of pneumonia. Subgroup analyses and sensitivity analyses were conducted using alternative pneumonia definitions and adjustments using high-dimensional propensity scores to test the robustness of the results.
Results The mean age of 35,570 new users of cholinesterase inhibitors (30,174 users of donepezil, 1,176 users of galantamine, 4,220 users of rivastigmine) was 82; 75% were women, and 82% were white. The cumulative incidence of pneumonia was 51.9 per 1,000 person-years. The risk of pneumonia for rivastigmine users was 24% lower than that of donepezil users (hazard ratio (HR) = 0.75, 95% confidence interval (CI) = 0.60–0.93). Risk in galantamine users (HR = 0.87, 95% CI = 0.62–1.23) was not significantly different from risk in donepezil users. Results of subgroup and sensitivity analyses were similar to the primary results.
Conclusion The risk of pneumonia was lower in individuals receiving rivastigmine than in those receiving donepezil. Additional studies are needed to confirm the findings of pneumonia risk between the oral and transdermal forms of rivastigmine and in users of galantamine.
Introduction
Dementia is a chronic neurodegenerative disorder characterized clinically by deterioration of daily living, behavioral functioning, and global cognitive ability. Cholinesterase inhibitors are the cornerstone of medical therapy and are approved for symptomatic treatment of individuals with mild to moderate dementia. Because pneumonia is a common cause of death in older adults with dementia, concern has been raised about the potential risk of pneumonia associated with cholinesterase inhibitors. Cholinesterase inhibition may lead to overactivation of muscarinic receptors and result in bradycardia, bronchospasm, emesis, and diarrhea. Moreover, overstimulation of nicotinic receptors results in fasciculation, muscle weakness, and paralysis that may increase pneumonia risk. Although there is no direct evidence of greater pneumonia risk associated with cholinesterase inhibitors, results of randomized clinical trials have suggested the possibility. One study found that cholinesterase inhibitor therapy in 183 hospitalized individuals with dementia was associated with nearly twice the risk of pulmonary disorders, mostly pneumonia.
The current study evaluated the comparative risk of pneumonia in older adults receiving donepezil, galantamine, or rivastigmine. Rivastigmine inhibits acetylcholinesterase and butyrylcholinesterase and has greater selectivity for brain tissue than peripheral tissues. Some studies have indicated that rivastigmine has lower affinity for the type 4 globular isoform of acetylcholinesterase than the type 1 isoform, which is a possible safety advantage because the type 4 isoform predominates in the peripheral nervous system. Because the peripheral nervous system regulates involuntary physiological functions such as breathing and digestion, cholinesterase inhibitors with fewer peripheral effects are less likely to cause unintended respiratory outcomes, such as shortness of breath and dyspnea, or unintended digestive outcomes, such as gastroesophageal reflux or esophageal immotility, which may have a negative effect on pneumonia risk, but there is no evidence of the comparative safety of cholinesterase inhibitors with regard to pneumonia risk. It was hypothesized that rivastigmine posed a lower risk than donepezil and galantamine, which are acetylcholinesterase inhibitors without selectivity for the type 4 isoform.
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