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Abstract

Aims

Cholinesterase inhibitors (ChEIs) have beneficial effects on the heart. Associations between ChEI-use and reduced mortality and cardiovascular events in Alzheimer's disease (AD) have been shown. Whether these associations exist in those with both heart failure (HF) and AD is unknown.

Methods and results

A propensity score (PS) matched cohort with patients with HF and AD was obtained through linking registers for cognitive/dementia disorders, comorbidities, drug prescription, and death, in Sweden, to analyse associations between ChEI-use and risk of mortality or hospitalization for HF, stroke, or myocardial infarction, were examined. In 455 patients with and 455 without ChEI treatment, ChEI use was associated with reductions of mortality and hospitalization due to HF by 21% [0.79; (confidence interval) CI 0.66–0.96] and 47% (0.53; CI 0.38–0.75), respectively. Donepezil and galantamine but not rivastigmine were associated with a lower risk of death compared with non-users. Donepezil was associated with a lower risk of hospitalization due to HF compared with non-users. There was no significant difference in hospitalization for bradycardia, AV block, or implantation of pacemaker between ChEI use and non-use.

Conclusion

This study suggests that in persons with HF and AD, treatment with ChEIs is associated with improved survival and a decreased risk of hospital care for HF, but results due to the type of ChEI vary.

Heart failure, Alzheimer's disease, Cholinesterase inhibitors, Hospitalization, Mortality
Topic:
Issue Section:
Original Article > Heart failure/cardiomyopathy

Introduction

The improved treatment during the last decades of diseases such as cancer and cardiovascular disorders have increased the incidences of chronic diseases as Alzheimer's dementia (AD)1 and heart failure (HF).2

Treatment of vascular risk factors has been associated with a lower incidence of dementia3 and a slower decline in AD.4

Changes in the autonomic nervous system5 (ANS) among patients with AD6,7 and with HF6 have been demonstrated. The parasympathetic activation has been shown to decrease during the development of AD, along with a more dominant role of sympathetic activation, leading to an increase in cardiovascular disorders.6 Also, deficits in central cholinergic function observed in AD could lead to autonomic dysfunction.7 These alterations in the ANS actively contribute to cardiac disease progression.

Inflammation plays a distinct role in AD and has also been suggested to play a key role in cardiac diseases, especially in HF. Murphy8 reported that in HF the strongest associations of inflammatory markers are found in HF with preserved ejection fraction (HFpEF), the most common form of HF in the elderly.

Acetylcholine (ACh) has been shown to have anti-inflammatory properties and the role of cholinergic signalling may be a key regulator of cardiac inflammation.9 Khuanjing et al.10 have in a review article demonstrated improved autonomic and cardiac functions of cholinesterase inhibitors (ChEIs) through various mechanisms including direct action of ACh on anti-arrhythmogenic, anti-apoptotic, anti-oxidative, anti-inflammatory, anti-hypertrophic, and anti-fibrotic processes. In fact, the main cardiovascular effects such as reduction of heart rate, and improved contractility and haemodynamic conditions11 could actively contribute to the positive effects on the heart in treatment with various drugs with heart rate-reducing effects, including beneficial effects on the inflammasome in cardiovascular disease. Inflammasomes, being large intracellular multiprotein complexes, promote inflammatory molecules as cytokines and interleukins with direct effects not only on atherosclerosis but also on HF.12

Still, in elderly patients there may be a fear of negative chronotropic effects when treating patients with ChEIs due to changes in regulatory functions in the vascular system, but it has been reported that none of the three ChEIs were associated with increased negative chronotropic, arrhythmogenic, and hypotensive effects for the elderly patients with AD.13 Isik et al.14 also reported that galantamine was not associated with significantly altered ECG parameters or arterial blood pressure in these elderly patients with AD, and further that donepezil15 or rivastigmine16 were also not associated with increased negative chronotropic, arrhythmogenic, or hypotensive effects among AD patients’.

Moreover, amyloid beta (Aβ) has been found to accumulate in the heart of patients with AD17 and accumulation of Aβ40 in blood has been associated with cardiac dysfunction and cardiovascular mortality.18

ChEIs are approved treatments in AD. The ChEIs reversibly, irreversibly, or pseudo-reversibly act by blocking acetylcholineesterase enzymes (AChE) and butyrylcholinesterase (BuChE) from breaking down ACh, which results in increased ACh levels in the synaptic cleft.19 ChEIs have been shown to be associated with modest cognitive benefits persisting over long-term20 as well as, by our group and others, a longer life expectancy.21,6,20,22

Using national epidemiology data, we have shown that in AD patients, ChEI use is associated with reduced risk for myocardial infarction,21 stroke,23 and death.20,21,23,24 Hsiao25 reported significantly fewer cardiovascular events and a reduction of cardiovascular death among AD patients treated with ChEI compared with non-users. It has further been shown that donepezil and rivastigmine could reduce HF hospitalization26 and that donepezil could reduce natriuretic peptide levels.27

Evidence of a possible risk reduction for cardiovascular events or mortality by ChEIs in persons with both cardiovascular disease and AD is scarce.

One of the most common cardiovascular disorders is HF. In a Swedish dementia population of 27 000 persons, the prevalence of HF was 15%.28 ChEIs have well known pulse reducing effects29 and although the risk for bradycardia must be considered, reducing heart rate is an important target for treatment of HF.

Thus, ChEIs may have beneficial effects on HF via both cardiac innervation and inflammation. However, there is no data on the ChEIs and risk for new HF events and mortality in an AD-population with HF. The aim of this study was therefore to investigate whether treatment with ChEI among persons with HF prior to the AD diagnosis, would be associated with decreased risk for hospitalization due to cardiovascular events or mortality and to investigate whether differences exist between the different ChEIs.

Methods

Study population

This study was based on the Swedish registry of cognitive/dementia disorders; SveDem, www.svedem.se. SveDem is a web-based registry established in 2007 with the aim to register all incident dementia patients in Sweden with annual follow-up. The baseline registration in SveDem is initiated at the time of the dementia diagnosis. For this study, SveDem was record-linked with the National Patient Registry to obtain diagnoses of comorbidities, made in specialist clinics and hospitals, the Prescribed Drug Registry to obtain data on prescribed medications, the Total Population Registry, and the Causes of Death Registry to obtain death dates. We identified 9446 patients registered in SveDem with a dementia diagnosis between 1 January 2008, and 16 October 2018, who had at least one hospitalization with a diagnosis of HF [International Classification of Diseases (ICD)-10 scores I099, I110, I130, I132, I255, I420, I425-429, I43, I50, P290, Supplementary material online, Table S1] prior to the dementia diagnosis. Exclusion criteria were patients who had non-AD dementia (n = 7750), were dead at the diagnosis date (n = 1) or within 3 months thereafter (n = 79) and patients treated with ChEI before the dementia diagnosis date (n = 147). Of 1469 eligible AD patients, 809 were initiated with ChEI within 90 days, and 660 were not (non-ChEI users, Figure 1).

Flowchart of two groups with or without treatment with Cholinesterase inhibitors for comparisons.
Figure 1

Flowchart of two groups with or without treatment with Cholinesterase inhibitors for comparisons.

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Cholinesterase inhibitor exposure

The studied exposure was initiation of ChEIs therapy with donepezil, galantamine, or rivastigmine within 3 months of the dementia diagnosis, vs. no initiation within 3 months. Our primary analysis used an intention-to-treat design and assumed study exposures to be constant until end of follow up. The study index date was set 3 months after the dementia diagnosis date.

Covariates

Study covariates were defined at the date of the study entry (from the diagnosis date and up to 3 months after the dementia diagnosis): age, sex, comorbidities (based on the ICD-10 codes): alcohol abuse, atrial fibrillation, cerebrovascular disease, chronic kidney disease (CKD), chronic pulmonary disease, depression, diabetes, fractures, hearing loss, hypertension, liver disease, myocardial infarction, obesity, peptic ulcer disease, peripheral vascular disease, rheumatic disease, and stroke; and medications in the ATC groups: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), acetylsalicylic acid, antipsychotics, antidepressants, antithrombotics, anxiolytics, beta-blockers, calcium channel blockers, diuretics, aldosterone antagonists, hypnotics, memantine, nonsteroidal anti-inflammatory drugs and statins. For ICD-10 codes and ATC codes please see Supplementary material online, Table S1.

Outcomes

The study outcome was all-cause death confirmed from the Cause of death registry and hospitalization due to composite, or separate events, of HF, stroke, or myocardial infarction (MI) from 3 months after the dementia diagnosis date to death or to the end of the follow-up on 16 October 2018, whichever occurred first, see Supplementary material online, Table S2. We also reported any hospitalization for ChEIsʹ known severe side effects of bradycardia, atrioventricular (AV) block, or need for pacemaker implantation. Patients were followed from the dementia diagnosis date until death, or the end of follow up in 16 October 2018, whichever occurred first. For ICD codes for outcome, please see Supplementary material online, Table S2.

Data analyses

We performed 1:1 propensity score (PS) matching (without replacement) using the nearest-neighbor matching method and with a caliper of 0.01 to balance confounders between patients who used ChEIs and those who did not. We estimated the PS for ChEI using logistic regression models based on age, sex, diagnosis at the memory clinic, living situation (alone or in a nursing home), patient comorbidities, and current medications. The balance of baseline characteristics before and after matching is shown in Tables 1 and 2.

Table 1
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Baseline characteristics, comorbidities and medication of the total HF-AD cohort stratified by ChEI treatment status within 3 months after diagnosis prior to propensity score matching

Baseline characteristicsHF and AD non-ChEI user n = 660HF and AD ChEI-user n = 809P-value
 AD diagnosis100.0%100.0%
 Age, mean (SD)84.2 (6.3)81.5 (6.5)<0.001***
 Age strata <0.001***
  <702.7%5.3%
  70–7917.3%28.3%
  80–8960.3%58.7%
  ≥9019.7%7.7%
 Female60.3%57.0%0.20
 MMSE baseline, mean (SD)19.4 (5.3)21.5 (4.3)<0.001***
 MMSE strata <0.001***
  0–94.7%0.7%
  10–1938.9%27.6%
  20–2435.6%44.0%
  ≥2515.3%25.8%
 MMSE not recorded/done5.5%1.9%
 Diagnosed in specialist/memory clinic58.0%56.5%0.55
 Living alone49.4%47.7%0.52
 Living in nursing home14.8%6.3%<0.001***
Comorbidities
 CCI, mean (SD)4.0 (1.9)3.9 (1.8)0.17
 Alcohol abuse2.0%1.9%0.87
 Atrial fibrillation57.6%51.7%0.024*
 Cerebrovascular diseases18.6%16.1%0.19
 Chronic kidney disease12.6%6.7%<0.001***
 Chronic pulmonary disease19.5%20.1%0.77
 Depression9.7%7.9%0.23
 Diabetes25.3%26.2%0.69
 Fractures35.0%28.6%0.008**
 Hearing loss14.5%12.5%0.25
 Hypertension70.0%69.5%0.83
 Liver disease1.7%1.1%0.36
 Myocardial Infarction31.8%31.6%0.94
 Peptic ulcers disease7.0%5.7%0.31
 Peripheral vascular disease9.1%12.2%0.054
 Rheumatic diseases8.6%6.7%0.16
 Stroke11.7%8.3%0.030*
Medication
 ACEI/ARB67.3%73.5%0.009**
 Acetylsalicylic acid47.4%50.2%0.29
 Antipsychotics8.0%4.6%0.006**
 Antidepressants30.8%29.3%0.54
 Antithrombotics90.8%90.9%0.95
 Anxiolytics24.2%17.9%0.003**
 Beta-blocker74.5%75.3%0.75
 Calcium channel blocker21.5%23.9%0.29
 ChEI use<0.001***
  Non100.0%0.0%
  Donepezil0.0%61.1%
  Rivastigmine0.0%20.5%
  Galantamine0.0%18.4%
 Diuretics73.6%69.1%0.056
  Aldosterone antagonist17.4%20.1%0.18
 Hypnotics32.1%29.9%0.36
 Memantine39,8%5,2%<0.001***
 NSAID6.2%7.9%0.21
 Statins38.5%50.4%<0.001***
Baseline characteristicsHF and AD non-ChEI user n = 660HF and AD ChEI-user n = 809P-value
 AD diagnosis100.0%100.0%
 Age, mean (SD)84.2 (6.3)81.5 (6.5)<0.001***
 Age strata <0.001***
  <702.7%5.3%
  70–7917.3%28.3%
  80–8960.3%58.7%
  ≥9019.7%7.7%
 Female60.3%57.0%0.20
 MMSE baseline, mean (SD)19.4 (5.3)21.5 (4.3)<0.001***
 MMSE strata <0.001***
  0–94.7%0.7%
  10–1938.9%27.6%
  20–2435.6%44.0%
  ≥2515.3%25.8%
 MMSE not recorded/done5.5%1.9%
 Diagnosed in specialist/memory clinic58.0%56.5%0.55
 Living alone49.4%47.7%0.52
 Living in nursing home14.8%6.3%<0.001***
Comorbidities
 CCI, mean (SD)4.0 (1.9)3.9 (1.8)0.17
 Alcohol abuse2.0%1.9%0.87
 Atrial fibrillation57.6%51.7%0.024*
 Cerebrovascular diseases18.6%16.1%0.19
 Chronic kidney disease12.6%6.7%<0.001***
 Chronic pulmonary disease19.5%20.1%0.77
 Depression9.7%7.9%0.23
 Diabetes25.3%26.2%0.69
 Fractures35.0%28.6%0.008**
 Hearing loss14.5%12.5%0.25
 Hypertension70.0%69.5%0.83
 Liver disease1.7%1.1%0.36
 Myocardial Infarction31.8%31.6%0.94
 Peptic ulcers disease7.0%5.7%0.31
 Peripheral vascular disease9.1%12.2%0.054
 Rheumatic diseases8.6%6.7%0.16
 Stroke11.7%8.3%0.030*
Medication
 ACEI/ARB67.3%73.5%0.009**
 Acetylsalicylic acid47.4%50.2%0.29
 Antipsychotics8.0%4.6%0.006**
 Antidepressants30.8%29.3%0.54
 Antithrombotics90.8%90.9%0.95
 Anxiolytics24.2%17.9%0.003**
 Beta-blocker74.5%75.3%0.75
 Calcium channel blocker21.5%23.9%0.29
 ChEI use<0.001***
  Non100.0%0.0%
  Donepezil0.0%61.1%
  Rivastigmine0.0%20.5%
  Galantamine0.0%18.4%
 Diuretics73.6%69.1%0.056
  Aldosterone antagonist17.4%20.1%0.18
 Hypnotics32.1%29.9%0.36
 Memantine39,8%5,2%<0.001***
 NSAID6.2%7.9%0.21
 Statins38.5%50.4%<0.001***

MMSE, mini-mental state examination; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs.

*P < 0.05, **P < 0.01, ***P < 0.001.

Table 1
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Baseline characteristics, comorbidities and medication of the total HF-AD cohort stratified by ChEI treatment status within 3 months after diagnosis prior to propensity score matching

Baseline characteristicsHF and AD non-ChEI user n = 660HF and AD ChEI-user n = 809P-value
 AD diagnosis100.0%100.0%
 Age, mean (SD)84.2 (6.3)81.5 (6.5)<0.001***
 Age strata <0.001***
  <702.7%5.3%
  70–7917.3%28.3%
  80–8960.3%58.7%
  ≥9019.7%7.7%
 Female60.3%57.0%0.20
 MMSE baseline, mean (SD)19.4 (5.3)21.5 (4.3)<0.001***
 MMSE strata <0.001***
  0–94.7%0.7%
  10–1938.9%27.6%
  20–2435.6%44.0%
  ≥2515.3%25.8%
 MMSE not recorded/done5.5%1.9%
 Diagnosed in specialist/memory clinic58.0%56.5%0.55
 Living alone49.4%47.7%0.52
 Living in nursing home14.8%6.3%<0.001***
Comorbidities
 CCI, mean (SD)4.0 (1.9)3.9 (1.8)0.17
 Alcohol abuse2.0%1.9%0.87
 Atrial fibrillation57.6%51.7%0.024*
 Cerebrovascular diseases18.6%16.1%0.19
 Chronic kidney disease12.6%6.7%<0.001***
 Chronic pulmonary disease19.5%20.1%0.77
 Depression9.7%7.9%0.23
 Diabetes25.3%26.2%0.69
 Fractures35.0%28.6%0.008**
 Hearing loss14.5%12.5%0.25
 Hypertension70.0%69.5%0.83
 Liver disease1.7%1.1%0.36
 Myocardial Infarction31.8%31.6%0.94
 Peptic ulcers disease7.0%5.7%0.31
 Peripheral vascular disease9.1%12.2%0.054
 Rheumatic diseases8.6%6.7%0.16
 Stroke11.7%8.3%0.030*
Medication
 ACEI/ARB67.3%73.5%0.009**
 Acetylsalicylic acid47.4%50.2%0.29
 Antipsychotics8.0%4.6%0.006**
 Antidepressants30.8%29.3%0.54
 Antithrombotics90.8%90.9%0.95
 Anxiolytics24.2%17.9%0.003**
 Beta-blocker74.5%75.3%0.75
 Calcium channel blocker21.5%23.9%0.29
 ChEI use<0.001***
  Non100.0%0.0%
  Donepezil0.0%61.1%
  Rivastigmine0.0%20.5%
  Galantamine0.0%18.4%
 Diuretics73.6%69.1%0.056
  Aldosterone antagonist17.4%20.1%0.18
 Hypnotics32.1%29.9%0.36
 Memantine39,8%5,2%<0.001***
 NSAID6.2%7.9%0.21
 Statins38.5%50.4%<0.001***
Baseline characteristicsHF and AD non-ChEI user n = 660HF and AD ChEI-user n = 809P-value
 AD diagnosis100.0%100.0%
 Age, mean (SD)84.2 (6.3)81.5 (6.5)<0.001***
 Age strata <0.001***
  <702.7%5.3%
  70–7917.3%28.3%
  80–8960.3%58.7%
  ≥9019.7%7.7%
 Female60.3%57.0%0.20
 MMSE baseline, mean (SD)19.4 (5.3)21.5 (4.3)<0.001***
 MMSE strata <0.001***
  0–94.7%0.7%
  10–1938.9%27.6%
  20–2435.6%44.0%
  ≥2515.3%25.8%
 MMSE not recorded/done5.5%1.9%
 Diagnosed in specialist/memory clinic58.0%56.5%0.55
 Living alone49.4%47.7%0.52
 Living in nursing home14.8%6.3%<0.001***
Comorbidities
 CCI, mean (SD)4.0 (1.9)3.9 (1.8)0.17
 Alcohol abuse2.0%1.9%0.87
 Atrial fibrillation57.6%51.7%0.024*
 Cerebrovascular diseases18.6%16.1%0.19
 Chronic kidney disease12.6%6.7%<0.001***
 Chronic pulmonary disease19.5%20.1%0.77
 Depression9.7%7.9%0.23
 Diabetes25.3%26.2%0.69
 Fractures35.0%28.6%0.008**
 Hearing loss14.5%12.5%0.25
 Hypertension70.0%69.5%0.83
 Liver disease1.7%1.1%0.36
 Myocardial Infarction31.8%31.6%0.94
 Peptic ulcers disease7.0%5.7%0.31
 Peripheral vascular disease9.1%12.2%0.054
 Rheumatic diseases8.6%6.7%0.16
 Stroke11.7%8.3%0.030*
Medication
 ACEI/ARB67.3%73.5%0.009**
 Acetylsalicylic acid47.4%50.2%0.29
 Antipsychotics8.0%4.6%0.006**
 Antidepressants30.8%29.3%0.54
 Antithrombotics90.8%90.9%0.95
 Anxiolytics24.2%17.9%0.003**
 Beta-blocker74.5%75.3%0.75
 Calcium channel blocker21.5%23.9%0.29
 ChEI use<0.001***
  Non100.0%0.0%
  Donepezil0.0%61.1%
  Rivastigmine0.0%20.5%
  Galantamine0.0%18.4%
 Diuretics73.6%69.1%0.056
  Aldosterone antagonist17.4%20.1%0.18
 Hypnotics32.1%29.9%0.36
 Memantine39,8%5,2%<0.001***
 NSAID6.2%7.9%0.21
 Statins38.5%50.4%<0.001***

MMSE, mini-mental state examination; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs.

*P < 0.05, **P < 0.01, ***P < 0.001.

Table 2
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Baseline characteristics, comorbidities and medication stratified by ChEI treatment within 3 months in the propensity score matched cohort

Baseline characteristicsHF and AD Non-ChEI user n = 455HF and AD ChEI-user n = 455P-value
 Age, mean (SD)83.2 (6.2)83.2 (5.7)0.92
 Age strata0.71
  <702.9%3.3%
  70–7920.7%18.2%
  80–8964.2%67.3%
  ≥9012.3%11.2%
 Female58.5%58.2%0.95
 MMSE baseline, mean (SD)20.5 (4.9)20.5 (4.4)0.80
 MMSE strata0.44
  0–92.4%1.1%
  10–1933.4%35.6%
  20–2441.3%43.1%
  ≥2520.4%17.6%
  MMSE not recorded/not done2.4%2.6%
 Diagnosed in specialist/memory clinic57.8%57.1%0.84
 Living alone49.9%50.8%0.79
 Nursing home10.1%9.2%0.65
Comorbidities
 CCI, mean (SD)3.9 (1.9)3.9 (1.9)0.71
 Alcohol abuse2.0%1.8%0.81
 Atrial fibrillation55.8%57.1%0.69
 Cerebrovascular diseases16.5%18.0%0.54
 Chronic kidney disease7.7%8.8%0.55
 Chronic pulmonary disease21.3%20.7%0.81
 Depression9.2%10.1%0.65
 Diabetes24.6%24.0%0.82
 Fractures30.8%29.2%0.61
 Hearing loss13.8%13.2%0.77
 Hypertension70.0%69.5%0.85
 Liver disease1.8%1.3%0.59
 Myocardial infarction31.0%31.9%0.78
 Peptic ulcer6.2%6.4%0.89
 Peripheral vascular disease10.3%9.7%0.74
 Rheumatic diseases7.9%7.7%0.90
 Stroke9.7%10.1%0.82
Medication
 ACEI/ARB69.5%69.7%0.94
 Acetylsalicylic acid48.1%49.7%0.64
 Antidepressants30.3%28.4%0.51
 Antipsychotics6.8%6.2%0.69
 Antithrombotic91.2%91.6%0.81
 Anxiolytics22.2%23.5%0.64
 Beta-blocker72.5%73.8%0.65
 Calcium channel blocker22.6%22.6%1.00
ChEI use<0.001***
  Non100.0%0.0%
  Donepezil0.0%63.5%
  Rivastigmine0.0%19.3%
  Galantamine0.0%17.1%
 Diuretics70.5%71.2%0.83
  Aldosterone antagonist18.9%18.5%0.86
 Hypnotics31.6%32.3%0.83
 Memantine42.4%5.9%<0.001***
 NSAID7.3%6.8%0.80
 Statins43.1%40.7%0.46
Baseline characteristicsHF and AD Non-ChEI user n = 455HF and AD ChEI-user n = 455P-value
 Age, mean (SD)83.2 (6.2)83.2 (5.7)0.92
 Age strata0.71
  <702.9%3.3%
  70–7920.7%18.2%
  80–8964.2%67.3%
  ≥9012.3%11.2%
 Female58.5%58.2%0.95
 MMSE baseline, mean (SD)20.5 (4.9)20.5 (4.4)0.80
 MMSE strata0.44
  0–92.4%1.1%
  10–1933.4%35.6%
  20–2441.3%43.1%
  ≥2520.4%17.6%
  MMSE not recorded/not done2.4%2.6%
 Diagnosed in specialist/memory clinic57.8%57.1%0.84
 Living alone49.9%50.8%0.79
 Nursing home10.1%9.2%0.65
Comorbidities
 CCI, mean (SD)3.9 (1.9)3.9 (1.9)0.71
 Alcohol abuse2.0%1.8%0.81
 Atrial fibrillation55.8%57.1%0.69
 Cerebrovascular diseases16.5%18.0%0.54
 Chronic kidney disease7.7%8.8%0.55
 Chronic pulmonary disease21.3%20.7%0.81
 Depression9.2%10.1%0.65
 Diabetes24.6%24.0%0.82
 Fractures30.8%29.2%0.61
 Hearing loss13.8%13.2%0.77
 Hypertension70.0%69.5%0.85
 Liver disease1.8%1.3%0.59
 Myocardial infarction31.0%31.9%0.78
 Peptic ulcer6.2%6.4%0.89
 Peripheral vascular disease10.3%9.7%0.74
 Rheumatic diseases7.9%7.7%0.90
 Stroke9.7%10.1%0.82
Medication
 ACEI/ARB69.5%69.7%0.94
 Acetylsalicylic acid48.1%49.7%0.64
 Antidepressants30.3%28.4%0.51
 Antipsychotics6.8%6.2%0.69
 Antithrombotic91.2%91.6%0.81
 Anxiolytics22.2%23.5%0.64
 Beta-blocker72.5%73.8%0.65
 Calcium channel blocker22.6%22.6%1.00
ChEI use<0.001***
  Non100.0%0.0%
  Donepezil0.0%63.5%
  Rivastigmine0.0%19.3%
  Galantamine0.0%17.1%
 Diuretics70.5%71.2%0.83
  Aldosterone antagonist18.9%18.5%0.86
 Hypnotics31.6%32.3%0.83
 Memantine42.4%5.9%<0.001***
 NSAID7.3%6.8%0.80
 Statins43.1%40.7%0.46

MMSE, mini-mental state examination; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs.

***P < 0.001.

Table 2
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Baseline characteristics, comorbidities and medication stratified by ChEI treatment within 3 months in the propensity score matched cohort

Baseline characteristicsHF and AD Non-ChEI user n = 455HF and AD ChEI-user n = 455P-value
 Age, mean (SD)83.2 (6.2)83.2 (5.7)0.92
 Age strata0.71
  <702.9%3.3%
  70–7920.7%18.2%
  80–8964.2%67.3%
  ≥9012.3%11.2%
 Female58.5%58.2%0.95
 MMSE baseline, mean (SD)20.5 (4.9)20.5 (4.4)0.80
 MMSE strata0.44
  0–92.4%1.1%
  10–1933.4%35.6%
  20–2441.3%43.1%
  ≥2520.4%17.6%
  MMSE not recorded/not done2.4%2.6%
 Diagnosed in specialist/memory clinic57.8%57.1%0.84
 Living alone49.9%50.8%0.79
 Nursing home10.1%9.2%0.65
Comorbidities
 CCI, mean (SD)3.9 (1.9)3.9 (1.9)0.71
 Alcohol abuse2.0%1.8%0.81
 Atrial fibrillation55.8%57.1%0.69
 Cerebrovascular diseases16.5%18.0%0.54
 Chronic kidney disease7.7%8.8%0.55
 Chronic pulmonary disease21.3%20.7%0.81
 Depression9.2%10.1%0.65
 Diabetes24.6%24.0%0.82
 Fractures30.8%29.2%0.61
 Hearing loss13.8%13.2%0.77
 Hypertension70.0%69.5%0.85
 Liver disease1.8%1.3%0.59
 Myocardial infarction31.0%31.9%0.78
 Peptic ulcer6.2%6.4%0.89
 Peripheral vascular disease10.3%9.7%0.74
 Rheumatic diseases7.9%7.7%0.90
 Stroke9.7%10.1%0.82
Medication
 ACEI/ARB69.5%69.7%0.94
 Acetylsalicylic acid48.1%49.7%0.64
 Antidepressants30.3%28.4%0.51
 Antipsychotics6.8%6.2%0.69
 Antithrombotic91.2%91.6%0.81
 Anxiolytics22.2%23.5%0.64
 Beta-blocker72.5%73.8%0.65
 Calcium channel blocker22.6%22.6%1.00
ChEI use<0.001***
  Non100.0%0.0%
  Donepezil0.0%63.5%
  Rivastigmine0.0%19.3%
  Galantamine0.0%17.1%
 Diuretics70.5%71.2%0.83
  Aldosterone antagonist18.9%18.5%0.86
 Hypnotics31.6%32.3%0.83
 Memantine42.4%5.9%<0.001***
 NSAID7.3%6.8%0.80
 Statins43.1%40.7%0.46
Baseline characteristicsHF and AD Non-ChEI user n = 455HF and AD ChEI-user n = 455P-value
 Age, mean (SD)83.2 (6.2)83.2 (5.7)0.92
 Age strata0.71
  <702.9%3.3%
  70–7920.7%18.2%
  80–8964.2%67.3%
  ≥9012.3%11.2%
 Female58.5%58.2%0.95
 MMSE baseline, mean (SD)20.5 (4.9)20.5 (4.4)0.80
 MMSE strata0.44
  0–92.4%1.1%
  10–1933.4%35.6%
  20–2441.3%43.1%
  ≥2520.4%17.6%
  MMSE not recorded/not done2.4%2.6%
 Diagnosed in specialist/memory clinic57.8%57.1%0.84
 Living alone49.9%50.8%0.79
 Nursing home10.1%9.2%0.65
Comorbidities
 CCI, mean (SD)3.9 (1.9)3.9 (1.9)0.71
 Alcohol abuse2.0%1.8%0.81
 Atrial fibrillation55.8%57.1%0.69
 Cerebrovascular diseases16.5%18.0%0.54
 Chronic kidney disease7.7%8.8%0.55
 Chronic pulmonary disease21.3%20.7%0.81
 Depression9.2%10.1%0.65
 Diabetes24.6%24.0%0.82
 Fractures30.8%29.2%0.61
 Hearing loss13.8%13.2%0.77
 Hypertension70.0%69.5%0.85
 Liver disease1.8%1.3%0.59
 Myocardial infarction31.0%31.9%0.78
 Peptic ulcer6.2%6.4%0.89
 Peripheral vascular disease10.3%9.7%0.74
 Rheumatic diseases7.9%7.7%0.90
 Stroke9.7%10.1%0.82
Medication
 ACEI/ARB69.5%69.7%0.94
 Acetylsalicylic acid48.1%49.7%0.64
 Antidepressants30.3%28.4%0.51
 Antipsychotics6.8%6.2%0.69
 Antithrombotic91.2%91.6%0.81
 Anxiolytics22.2%23.5%0.64
 Beta-blocker72.5%73.8%0.65
 Calcium channel blocker22.6%22.6%1.00
ChEI use<0.001***
  Non100.0%0.0%
  Donepezil0.0%63.5%
  Rivastigmine0.0%19.3%
  Galantamine0.0%17.1%
 Diuretics70.5%71.2%0.83
  Aldosterone antagonist18.9%18.5%0.86
 Hypnotics31.6%32.3%0.83
 Memantine42.4%5.9%<0.001***
 NSAID7.3%6.8%0.80
 Statins43.1%40.7%0.46

MMSE, mini-mental state examination; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs.

***P < 0.001.

Continuous variables are presented as means with standard deviations (SD), while categorical variables are presented as percentages. We estimated crude incidence rates of study outcomes per 1000 person-years. Cox proportional hazards models were used to estimate the association between ChEI use and clinical outcomes, calculating hazard ratios (HRs) with 95% confidence intervals (CIs). Time since the index date was used as the underlying timescale. Since there is a difference in memantine use between the ChEI treatment and non-use groups, we have further adjusted for memantine in the Cox model.

We also investigated the consistency of the effects of different types of ChEIs (donepezil, galantamine, or rivastigmine) vs. no ChEI on the outcomes.

Study covariates had no missing data except for baseline MMSE which was missing in 2.5 and 3.5% of PS matched cohort and total cohort, respectively. Missing MMSE was grouped into a ‘MMSE not recorded’ category.

All analyses were performed using R 3.4.3 software (The R Project for Statistical Computing, Vienna, Austria) and Stata version 17.0 (Stata Corp, College Station, TX).

Results

Figure 1 shows the flowchart of the patient selection. After exclusion criteria were applied, 1469 patients with HF and AD were eligible, of whom 809 were initiated on ChEI therapy within 90 days, whereas 660 were not. The majority of patients (89%) started ChEI treatment within the first 30 days after the dementia diagnosis. Using PS matching, two groups of patients with HF and AD with similar age, gender, and comorbidities were obtained, where one group started treatment with ChEI, and the other did not (Figure 1).

Patient characteristics

Baseline characteristics of the cohort are shown, prior to (Table 1) and after (Table 2) PS matching.

Before PS matching, the total cohort consisted of 809 users of ChEI and 660 non-users. They differed significantly in several aspects, see Table 1. The non-users were older (84.2 vs. 81.5 years, P < 0.001) and had a lower MMSE score at baseline (19.4 vs. 21.5 points, P < 0.001). The non-users more often lived in a nursing home (14.8% vs. 6.3%, P < 0.001) and more often had CKD (12.6% vs. 6.7%, P < 0.001), history of stroke (11.7% vs. 8.3%, P < 0.030) atrial fibrillation (57.6% vs. 51.7%, P < 0.024), and fractures (35% vs. 28.6%, P < 0.008). The non-users were less often treated with statins (38.5% vs. 50.4%, P < 0.001) and ACEI/ARB (67.3% vs. 73.5%, P < 0.009), and more often with anxiolytics (24.2% vs. 17.9%, P < 0.003), antipsychotics (8.0% vs. 4.6%, P < 0.006) and memantine (39.8% vs. 5.2%, P < 0.001).

After PS matching, both groups were well-balanced with no significant differences in age, gender, MMSE, comorbidities, and medications except for dementia medication use (ChEIs and memantine, Table 2): Patients who were non-users of ChEI had more often memantine (42.4%) than the ChEI-treated group (5.9%).

In the propensity matched cohort, donepezil treated patients were less often diagnosed in specialist settings in comparison with patients treated with rivastigmine or galantamine. Moreover, memantine treatment in the ChEI groups within the first 3 months was low but more prevalent in those on rivastigmine (9,1%) and least used in the galantamine group (2.6%), see Supplementary material online, Table S5. Corresponding data for the whole cohort is found in the Supplementary material online, Table S6.

Use of ChEI and outcome of hospitalizations for cardiovascular events or death

The PS matched cohort showed an association with a significant decrease (35%) in the risk of hospitalization due to composite cardiovascular diseases (CVD) events (HR: 0.65, 95% CI: 0.49, 0.87). When analysing the CVD separately, a significant (47%) decrease in risk of hospitalization due to HF (HR: 0.53, 95% CI: 0.38, 0.75) but not to stroke nor MI, was found (Table 3).

Table 3
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Number of events, incidence rates, and adjusted hazard ratios for the association between ChEI initiation and deaths or hospitalizations for cardiovascular events in the propensity score matched cohort

 Number of patientsEventsIncidence rate per 1000 pyaHRb(95% CI)
Deaths     
 No ChEI455276238.61Ref
 Any ChEI455273210.940.79*0.66, 0.96
Hospitalization due to composite CVD events
 No ChEI455126141.35Ref
 Any ChEI4559995.250.65**0.49, 0.87
Hospitalization due to HF
 No ChEI4559299.25Ref
 Any ChEI4556358.460.53***0.38, 0.75
Hospitalization due to stroke
 No ChEI4552423.52Ref
 Any ChEI4552420.770.920.48, 1.73
Hospitalization due to MI
 No ChEI4552726.50Ref
 Any ChEI4551916.310.680.36, 1.31
 Number of patientsEventsIncidence rate per 1000 pyaHRb(95% CI)
Deaths     
 No ChEI455276238.61Ref
 Any ChEI455273210.940.79*0.66, 0.96
Hospitalization due to composite CVD events
 No ChEI455126141.35Ref
 Any ChEI4559995.250.65**0.49, 0.87
Hospitalization due to HF
 No ChEI4559299.25Ref
 Any ChEI4556358.460.53***0.38, 0.75
Hospitalization due to stroke
 No ChEI4552423.52Ref
 Any ChEI4552420.770.920.48, 1.73
Hospitalization due to MI
 No ChEI4552726.50Ref
 Any ChEI4551916.310.680.36, 1.31

*P < 0.05, **P < 0.01, ***P < 0.001.

a

Incidence rates are presented as number of events per 1000 patient-years in PS matched cohort.

b

Hazard ratio is obtained in PS matched cohort adjusting for the variables listed in Table 1 and further adjusted for memantine.

Table 3
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Number of events, incidence rates, and adjusted hazard ratios for the association between ChEI initiation and deaths or hospitalizations for cardiovascular events in the propensity score matched cohort

 Number of patientsEventsIncidence rate per 1000 pyaHRb(95% CI)
Deaths     
 No ChEI455276238.61Ref
 Any ChEI455273210.940.79*0.66, 0.96
Hospitalization due to composite CVD events
 No ChEI455126141.35Ref
 Any ChEI4559995.250.65**0.49, 0.87
Hospitalization due to HF
 No ChEI4559299.25Ref
 Any ChEI4556358.460.53***0.38, 0.75
Hospitalization due to stroke
 No ChEI4552423.52Ref
 Any ChEI4552420.770.920.48, 1.73
Hospitalization due to MI
 No ChEI4552726.50Ref
 Any ChEI4551916.310.680.36, 1.31
 Number of patientsEventsIncidence rate per 1000 pyaHRb(95% CI)
Deaths     
 No ChEI455276238.61Ref
 Any ChEI455273210.940.79*0.66, 0.96
Hospitalization due to composite CVD events
 No ChEI455126141.35Ref
 Any ChEI4559995.250.65**0.49, 0.87
Hospitalization due to HF
 No ChEI4559299.25Ref
 Any ChEI4556358.460.53***0.38, 0.75
Hospitalization due to stroke
 No ChEI4552423.52Ref
 Any ChEI4552420.770.920.48, 1.73
Hospitalization due to MI
 No ChEI4552726.50Ref
 Any ChEI4551916.310.680.36, 1.31

*P < 0.05, **P < 0.01, ***P < 0.001.

a

Incidence rates are presented as number of events per 1000 patient-years in PS matched cohort.

b

Hazard ratio is obtained in PS matched cohort adjusting for the variables listed in Table 1 and further adjusted for memantine.

Figure 2 shows Kaplan–Meier curves of cumulative events of significantly decreased probability of composite CVD events and of probability of hospitalization with HF.

Patients treated with Cholinesterase inhibitors had lower risks of composite CVD events and lower risk of hospitalization due to HF compared to non-users.
Figure 2

Patients treated with Cholinesterase inhibitors had lower risks of composite CVD events and lower risk of hospitalization due to HF compared to non-users.

Open in new tabDownload slide

The PS matched cohort showed an association with a significant decrease of 21% in all-cause death for patients treated with ChEIs (HR: 0.79; 95% CI: 0.66, 0.96) compared with those without ChEI (Table 3).

Figure 3 shows Kaplan–Meier curves of cumulative events of significantly decreased mortality risk in the propensity matched cohort.

Patients treated with Cholinesterase inhibitors had lower mortality compared to non-users.
Figure 3

Patients treated with Cholinesterase inhibitors had lower mortality compared to non-users.

Open in new tabDownload slide

The results from the whole cohort are shown in Supplementary material online, Table S3 and Figures S1 and S2.

Type of ChEI and risk of hospitalizations for cardiovascular events or death

Table 4 shows the risk of hospitalizations for cardiovascular events in the PS matched score in relation to type of ChEI. A 41% decreased risk of hospitalization due to CVD (0.59, 95% CI: 0.42, 0.82, P < 0.01) and a 52% reduced risk of hospitalization due to HF (HR: 0.48, 95% CI: 0.32, 0.72, P < 0.001), was associated with donepezil treatment but not for galantamine nor rivastigmine.

Table 4
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Number of events, incidence rates, and adjusted hazard ratios for the association between type of ChEIs and deaths or hospitalizations for cardiovascular events in the propensity score matched cohort

 Number of patientsEventsIncidence rate per 1000 pyaHRb(95% CI)
All-cause death     
 Non-use455276238.61Ref
 Donepezil289156204.280.80*0.64, 0.98
 Rivastigmine8865256.990.960.73, 1.28
 Galantamine7852187.320.64**0.47, 0.87
Hospitalization due to composite CVD events
 Non-use455126141.35Ref
 Donepezil2895587.060.59**0.42, 0.82
 Rivastigmine8822113.360.760.48, 1.22
 Galantamine7822103.020.740.46, 1.18
Hospitalization due to HF
 Non-use4559299.25Ref
 Donepezil2893553.960.48***0.32, 0.72
 Rivastigmine881467.090.610.34, 1.08
 Galantamine781463.520.620.35, 1.10
Hospitalization due to stroke
 Non-use4552423.52Ref
 Donepezil2891116.080.710.33, 1.53
 Rivastigmine88836.521.600.68, 3.76
 Galantamine78519.810.870.32, 2.42
Hospitalization due to MI
 Non-use4552726.50Ref
 Donepezil2891116.050.650.31, 1.39
 Rivastigmine8828.780.370.086, 1.61
 Galantamine78623.881.100.43, 2.82
 Number of patientsEventsIncidence rate per 1000 pyaHRb(95% CI)
All-cause death     
 Non-use455276238.61Ref
 Donepezil289156204.280.80*0.64, 0.98
 Rivastigmine8865256.990.960.73, 1.28
 Galantamine7852187.320.64**0.47, 0.87
Hospitalization due to composite CVD events
 Non-use455126141.35Ref
 Donepezil2895587.060.59**0.42, 0.82
 Rivastigmine8822113.360.760.48, 1.22
 Galantamine7822103.020.740.46, 1.18
Hospitalization due to HF
 Non-use4559299.25Ref
 Donepezil2893553.960.48***0.32, 0.72
 Rivastigmine881467.090.610.34, 1.08
 Galantamine781463.520.620.35, 1.10
Hospitalization due to stroke
 Non-use4552423.52Ref
 Donepezil2891116.080.710.33, 1.53
 Rivastigmine88836.521.600.68, 3.76
 Galantamine78519.810.870.32, 2.42
Hospitalization due to MI
 Non-use4552726.50Ref
 Donepezil2891116.050.650.31, 1.39
 Rivastigmine8828.780.370.086, 1.61
 Galantamine78623.881.100.43, 2.82

*P < 0.05, **P < 0.01, ***P < 0.001.

a

Incidence rates are presented as number of events per 1000 patient-years in PS matched cohort.

b

Hazard ratio is obtained in PS matched cohort adjusting for the variables listed in Table 1 and further adjusted for memantine.

Table 4
Open in new tab

Number of events, incidence rates, and adjusted hazard ratios for the association between type of ChEIs and deaths or hospitalizations for cardiovascular events in the propensity score matched cohort

 Number of patientsEventsIncidence rate per 1000 pyaHRb(95% CI)
All-cause death     
 Non-use455276238.61Ref
 Donepezil289156204.280.80*0.64, 0.98
 Rivastigmine8865256.990.960.73, 1.28
 Galantamine7852187.320.64**0.47, 0.87
Hospitalization due to composite CVD events
 Non-use455126141.35Ref
 Donepezil2895587.060.59**0.42, 0.82
 Rivastigmine8822113.360.760.48, 1.22
 Galantamine7822103.020.740.46, 1.18
Hospitalization due to HF
 Non-use4559299.25Ref
 Donepezil2893553.960.48***0.32, 0.72
 Rivastigmine881467.090.610.34, 1.08
 Galantamine781463.520.620.35, 1.10
Hospitalization due to stroke
 Non-use4552423.52Ref
 Donepezil2891116.080.710.33, 1.53
 Rivastigmine88836.521.600.68, 3.76
 Galantamine78519.810.870.32, 2.42
Hospitalization due to MI
 Non-use4552726.50Ref
 Donepezil2891116.050.650.31, 1.39
 Rivastigmine8828.780.370.086, 1.61
 Galantamine78623.881.100.43, 2.82
 Number of patientsEventsIncidence rate per 1000 pyaHRb(95% CI)
All-cause death     
 Non-use455276238.61Ref
 Donepezil289156204.280.80*0.64, 0.98
 Rivastigmine8865256.990.960.73, 1.28
 Galantamine7852187.320.64**0.47, 0.87
Hospitalization due to composite CVD events
 Non-use455126141.35Ref
 Donepezil2895587.060.59**0.42, 0.82
 Rivastigmine8822113.360.760.48, 1.22
 Galantamine7822103.020.740.46, 1.18
Hospitalization due to HF
 Non-use4559299.25Ref
 Donepezil2893553.960.48***0.32, 0.72
 Rivastigmine881467.090.610.34, 1.08
 Galantamine781463.520.620.35, 1.10
Hospitalization due to stroke
 Non-use4552423.52Ref
 Donepezil2891116.080.710.33, 1.53
 Rivastigmine88836.521.600.68, 3.76
 Galantamine78519.810.870.32, 2.42
Hospitalization due to MI
 Non-use4552726.50Ref
 Donepezil2891116.050.650.31, 1.39
 Rivastigmine8828.780.370.086, 1.61
 Galantamine78623.881.100.43, 2.82

*P < 0.05, **P < 0.01, ***P < 0.001.

a

Incidence rates are presented as number of events per 1000 patient-years in PS matched cohort.

b

Hazard ratio is obtained in PS matched cohort adjusting for the variables listed in Table 1 and further adjusted for memantine.

A decrease in all-cause mortality was significantly associated with donepezil (HR: 0.80, 95% CI: 0.64, 0.98) and galantamine (HR: 0.64, 95% CI: 0.47, 0.87), but not with rivastigmine.

The results for the whole cohort are shown in Supplementary material online, Table S4.

Use of ChEI and hospitalizations for ChEI related severe side effects

ChEIs were not associated with significant differences in hospitalizations for severe side effects of bradycardia, AV block, or need for pacemaker implantation in the PS matched cohort (Supplementary material online, Table S5A) or in the total cohort (Supplementary material online, Table S5B).

Discussion

Our main results are the following:

ChEIs were associated with decreased risk of all-cause death and with decreased risk of hospitalization due to composite CVD events. ChEIs were associated with decreased risk of hospitalization due to HF, but not due to only MI or only stroke. There was no significant difference in hospitalization for bradycardia, AV block, or implantation of the pacemaker between ChEI use and non-use.

When comparing the different ChEIs, we found that donepezil and galantamine but not rivastigmine were associated with a lower risk of death compared with non-users. We also found that donepezil and galantamine, but not rivastigmine were associated with lower risk of composite CVD events compared with non-users. Finally, donepezil was associated with a lower risk of hospitalization due to HF compared with non-users.

Our results, showing associations with a 21% decrease in all-cause death in AD patients, are in line with previous findings from our group21,20,23,30 and others (Hsieh et al.6). The positive effect on mortality among patients treated with ChEI is plausible, considering earlier reported enhanced effects on ACh signalling in the heart by ChEI, thereby reducing inflammation and reducing the sympathetic influence in the heart.9 Also direct effects of ChEIs on cardiomyocytes through increased parasympathetic activity with reduced heart rate, increased heart rate variability, and lowered myocardial oxygen demand, as well as indirect effects through anti-inflammatory pathways involving the modulation of nitric oxide signalling, regulation of redox states, improvement in mitochondrial function, calcium regulation, and protection against hypoxia-induced apoptosis and endothelial dysfunction have been reported.10,31,32 Moreover, the cholinergic alpha-7-nicotinic receptor (α7-nAChR) has been shown to be involved in reducing inflammatory neurotoxicity in stroke, AMI, sepsis, and AD.33,34 Li et al.35 reported that peripheral blockade of the α7-nAChR significantly increased the cardioprotective effects of donepezil in HF rats, whereas central blockade did not, suggesting that the peripheral activation of the α7-nAChR plays an important role in cholinergic pharmacotherapy for HF. Further, Vang et al.36 showed that α7-nAChR mediates ventricular fibrosis and diastolic dysfunction, relevant for HF.

Nordstrom et al.21 showed a decrease in all-cause death of a similar range as in our study among AD patients treated with ChEI, but also a decrease in risk of myocardial infarction. The latter was not found in this study. A reason for this discrepancy could be that our cohort included only patients with both HF and AD, while the Nordström study included AD patients irrespective of cardiovascular comorbidities.

If ChEI has disease-modulating effects on HF, a reduction in risk of hospitalization in this group would be expected. There was no reduction in hospitalization for MI or stroke, which makes it plausible that the reduction in risk of hospitalization due to HF was the main driver behind the reduced risk for hospitalization due to composite CVD events. Due to the character of HF, where patients are often recurrently hospitalized during deterioration of their HF, the risk of hospitalization due to HF is likely to be higher than the risk of other CVD events. Further, elderly patients with HF often have HFpEF,2 which is characterized by other aetiologies than myocardial infarction. HFpEF is more associated with inflammation which could strengthen a possible effect of ChEIs on hospitalization due to HF.

We found that galantamine had the strongest association with mortality reduction among the ChEIs (36%). Galantamine is the only ChEI which acts as an allosteric nicotinic modulator.37 Its dual effect as a modulator of α7-nAChR and an acetylcholinesterase inhibitor may at least partially explain this finding.

Our findings that reduction of all-cause death was associated with donepezil and galantamine, and that the risk for hospitalization due to HF was associated with donepezil, but not with rivastigmine need to be discussed. Rivastigmine has previously been reported to have a higher risk of mortality compared with donepezil.38

In our dataset, 86% of patients were using the rivastigmine patch, so the difference between rivastigmine, galantamine, and donepezil on the outcomes cannot be explained by the shorter half-life of rivastigmine.39 The difference may be attributed to several factors: (i) Molecular structure: Rivastigmine differs from donepezil and galantamine in that it inhibits both AChE and BuChE, while the others only inhibit AChE.40 This broader activity may affect the drug's impact on cardiovascular outcomes. (ii) Tissue selectivity: Rivastigmine has greater selectivity for the central nervous system over peripheral tissues, including the heart, which might explain its weaker effects on cardiovascular outcomes compared with donepezil and galantamine.19 (iii) Metabolism differences: Donepezil and galantamine are primarily metabolized by cytochrome P450 in the liver, whereas rivastigmine is metabolized by esterases.41 The cytochrome P450 pathway may lead to more active cardiovascular effects, potentially explaining the superior cardiovascular outcomes with donepezil and galantamine. (iv) Patient characteristics: Rivastigmine may be prescribed to more frail or cognitively impaired patients where the patch administration may be preferred over a pill, which may contribute to its association with worse outcomes. Our data show that rivastigmine was more commonly used in patients with lower MMSE scores and a higher use of antipsychotics, indicating more advanced Alzheimer's disease. These factors combined likely explain why rivastigmine shows different outcomes compared with donepezil and galantamine in terms of mortality and cardiovascular events. Information on frailty is, however, not available in our cohort.

When showing that ChEI-users had a better outcome, in terms of lower all-cause death and lower risk of hospitalization due to HF, it is of interest to discuss possible reasons for physicians to refrain from treatment with ChEIs, as our results suggest. Baseline characteristics prior to PS matching showed that non-users were older, had lower MMSE results, more often CKD and more fractures, atrial fibrillation, and strokes. The fear of cardiovascular side effects by the ChEIs may be one reason why the physicians refrain from prescribing ChEIs to this group. Increased rates of syncope and bradycardia in the presence of ChEI use have been reported by Hernandez.29 However, in the present study, there were no significant associations between ChEIs and the risk of bradycardia, AV block, or pacemaker implantation. A recent meta-analysis which did not find any significant associations between ChEI treatment and hospitalization due to bradycardia-induced events22 support our findings.

Non-ChEI users were also to a higher extent treated with antipsychotics and anxiolytics. The almost double use of antipsychotics suggests a presence of neuropsychiatric symptoms. Memantine is also reported to have a calming and small sedative effect, which may explain the higher use of memantine in this group.

Our data showed that memantine use was lower in the ChEI group compared with the non-user group, which prompted us to further adjust for memantine in our analysis. Additionally, previous studies have shown that memantine can have a beneficial effect on mortality,42 further supporting the advantage of ChEIs in clinical outcomes in our study.

Strengths and limitations

One strength is the use of real-world clinical data in a cohort of HF with AD, treated or not with different ChEIs and the long follow-up. In addition to previous data on the positive effect of ChEIs on all-cause death for AD patients with risk for cardiovascular events, we have here also shown a similar association with reduced risk of mortality and of worsening of HF using the proxy of hospitalizations of HF in patients with both chronic HF and AD.

A limitation of this study is that, although we used PS matching to account for confounding by indication, we were only able to adjust for observed covariates and not for unmeasured or latent characteristics, which may be prevalent in the study population. In addition, before PS matching, the ChEI non-user group appeared to be in worse clinical condition, with a higher prevalence of CKD, stroke, and more patients living in nursing homes. These factors may have influenced the decision not to treat with ChEIs. Another limitation is that no laboratory samples in this cohort were collected and thus no information on inflammatory and other biomarkers is available.

Also, the patients were considered exposed throughout the whole follow-up period based on treatment status at study entry, according to the intention-to-treat design. We should note that despite the recommendation of chronic use, some patients may have discontinued treatment over an extended period. Consequently, we opted for this approach considering that the effects of ChEI on negative clinical outcomes are not instantaneous. Another limitation is the possibility that the attitudes towards ChEIs may have changed over the investigated years. During the first years of the studied period, the hesitation to use ChEIs due to the risk of bradycardia may have been more pronounced than later. However, ChEIs were not associated with adverse outcomes of bradycardia, AV block or pacemaker implantation in our analysis. Finally, lack of information on ejection fraction makes it not possible to relate our findings to the type of HF.

Conclusions

This study supports the hypothesis that treatment with ChEIs is associated with a reduced risk of hospitalization due to HF as well as reduced mortality risk in patients with HF and AD, strengthening the recommendations for the use of ChEI in patients with HF and AD. However, among the ChEIs, varying patterns were observed, suggesting that further studies of different ChEIs are needed.

Acknowledgements

The authors are grateful to the Swedish Dementia Registry (SveDem, www.svedem.se) for providing data for this study. We thank all patients, caregivers, reporting units, and coordinators in SveDem as well as the SveDem steering committee. SveDem is supported financially by the Swedish Associations of Local Authorities and Regions.

Funding

This study was supported by grants from the regional agreement on medical training and clinical research between the Stockholm County council and Karolinska Institutet (ALF, grants FoUI 975207), Swedish medical research council (grants # 2020-02014, 2022-01428), Johanniterorden (Swedish Order of St John), the Strategic Research program in Neuroscience at Karolinska Institutet, Centre for Innovative Medicine (CIMED , FoUI 963369 and FoUI 1002840), Åke Wibergs stiftelse (M22-0170 and M24-0221), and Swedish research council grant (#2022-01428 and 2022-01425), Stockholms Sjukhem and the Erling-Persson foundation.

Conflict of interest

M.E. has served as speaker and/or consultant on dementia on sporadic advisory board meetings for Biogen, Bioarctic, Roche, and Eli Lilly.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

References

1.

Zhang
 
XX
,
Tian
 
Y
,
Wang
 
ZT
,
Ma
 
YH
,
Tan
 
L
,
Yu
 
JT
.
The epidemiology of Alzheimer's disease modifiable risk factors and prevention
.
J Prev Alzheimers Dis
 
2021
;
8
:
313
–
321
.
10.14283/jpad.2021.15

Google Scholar

Crossref
Search ADS

 
2.

Bui
 
AL
,
Horwich
 
TB
,
Fonarow
 
GC
.
Epidemiology and risk profile of heart failure
.
Nat Rev Cardiol
 
2011
;
8
:
30
–
41
.
10.1038/nrcardio.2010.165

Google Scholar

Crossref
Search ADS

 
3.

Gottesman
 
RF
,
Albert
 
MS
,
Alonso
 
A
,
Coker
 
LH
,
Coresh
 
J
,
Davis
 
SM
,
Deal
 
JA
,
Mckhann
 
GM
,
Mosley
 
TH
,
Sharrett
 
AR
,
Schneider
 
ALC
,
Windham
 
BG
,
Wruck
 
LM
,
Knopman
 
DS
.
Associations between midlife vascular risk factors and 25-year incident dementia in the atherosclerosis risk in communities (ARIC) cohort
.
JAMA Neurol
 
2017
;
74
:
1246
–
1254
.
10.1001/jamaneurol.2017.1658

Google Scholar

Crossref
Search ADS

 
4.

Deschaintre
 
Y
,
Richard
 
F
,
Leys
 
D
,
Pasquier
 
F
.
Treatment of vascular risk factors is associated with slower decline in Alzheimer disease
.
Neurology
 
2009
;
73
:
674
–
680
.
10.1212/WNL.0b013e3181b59bf3

Google Scholar

Crossref
Search ADS

 
5.

Appenzeller
 
O
.
Aging and the autonomic nervous system
.
Curr Opin Neurol Neurosurg
 
1992
;
5
:
464
–
467
.

Google Scholar

OpenURL Placeholder Text

 
6.

Hsieh
 
M-J
,
Chen
 
D-Y
,
Lee
 
C-H
,
Wu
 
C-L
,
Chen
 
Y-J
,
Huang
 
Y-T
,
Chang
 
S-H
.
Association between cholinesterase inhibitors and new-onset heart failure in patients with Alzheimer's disease: a nationwide propensity score matching study
.
Front Cardiovasc Med
 
2022
;
9
:
831730
.
10.3389/fcvm.2022.831730

Google Scholar

Crossref
Search ADS

 
7.

Femminella
 
GD
,
Rengo
 
G
,
Komici
 
K
,
Iacotucci
 
P
,
Petraglia
 
L
,
Pagano
 
G
,
De Lucia
 
C
,
Canonico
 
V
,
Bonaduce
 
D
,
Leosco
 
D
,
Ferrara
 
N
.
Autonomic dysfunction in Alzheimer's disease: tools for assessment and review of the literature
.
J Alzheimers Dis
 
2014
;
42
:
369
–
377
.
10.3233/jad-140513

Google Scholar

Crossref
Search ADS

 
8.

Murphy
 
SP
,
Kakkar
 
R
,
McCarthy
 
CP
,
Januzzi
 
JL
 Jr.
Inflammation in heart failure: JACC state-of-the-art review
.
J Am Coll Cardiol
 
2020
;
75
:
1324
–
1340
.
10.1016/j.jacc.2020.01.014

Google Scholar

Crossref
Search ADS

 
9.

Rocha-Resende
 
C
,
da Silva
 
AM
,
Prado
 
MAM
,
Guatimosim
 
S
.
Protective and anti-inflammatory effects of acetylcholine in the heart
.
Am J Physiol Cell Physiol
 
2021
;
320
:
C155
–
c161
.
10.1152/ajpcell.00315.2020

Google Scholar

Crossref
Search ADS

 
10.

Khuanjing
 
T
,
Palee
 
S
,
Chattipakorn
 
SC
,
Chattipakorn
 
N
.
The effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure: from cells to patient reports
.
Acta Physiol (Oxf)
 
2020
;
228
:
e13396
.
10.1111/apha.13396

Google Scholar

Crossref
Search ADS

 
11.

Böhm
 
M
,
Swedberg
 
K
,
Komajda
 
M
,
Borer
 
JS
,
Ford
 
I
,
Dubost-Brama
 
A
,
Lerebours
 
G
,
Tavazzi
 
L
.
Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial
.
Lancet
 
2010
;
376
:
886
–
894
.
10.1016/s0140-6736(10)61259-7

Google Scholar

Crossref
Search ADS

 
12.

Olsen
 
MB
,
Gregersen
 
I
,
Sandanger
 
Ø
,
Yang
 
K
,
Sokolova
 
M
,
Halvorsen
 
BE
,
Gullestad
 
L
,
Broch
 
K
,
Aukrust
 
P
,
Louwe
 
MC
.
Targeting the inflammasome in cardiovascular disease
.
JACC Basic Transl Sci
 
2022
;
7
:
84
–
98
.
10.1016/j.jacbts.2021.08.006

Google Scholar

Crossref
Search ADS

 
13.

Isik
 
AT
,
Bozoglu
 
E
,
Yay
 
A
,
Soysal
 
P
,
Ateskan
 
U
.
Which cholinesterase inhibitor is the safest for the heart in elderly patients with Alzheimer's disease?
 
Am J Alzheimers Dis Other Demen
 
2012
;
27
:
171
–
174
.
10.1177/1533317512442999

Google Scholar

Crossref
Search ADS

 
14.

Isik
 
AT
,
Bozoglu
 
E
,
Naharci
 
MI
,
Kilic
 
S
.
Evaluation of the effects of galantamine on cardiac function in elderly patients with Alzheimer's disease
.
Am J Geriatr Pharmacother
 
2010
;
8
:
454
–
459
.
10.1016/j.amjopharm.2010.09.001

Google Scholar

Crossref
Search ADS

 
15.

Isik
 
AT
,
Babacan Yildiz
 
G
,
Bozoglu
 
E
,
Yay
 
A
,
Aydemir
 
E
.
Cardiac safety of donepezil in elderly patients with Alzheimer disease
.
Intern Med
 
2012
;
51
:
575
–
578
.
10.2169/internalmedicine.51.6671

Google Scholar

Crossref
Search ADS

 
16.

Isik
 
AT
,
Soysal
 
P
,
Yay
 
A
.
Which rivastigmine formula is better for heart in elderly patients with Alzheimer's disease: oral or patch?
 
Am J Alzheimers Dis Other Demen
 
2014
;
29
:
735
–
738
.
10.1177/1533317514536598

Google Scholar

Crossref
Search ADS

 
17.

Troncone
 
L
,
Luciani
 
M
,
Coggins
 
M
,
Wilker
 
EH
,
Ho
 
C-Y
,
Codispoti
 
KE
,
Frosch
 
MP
,
Kayed
 
R
,
Del Monte
 
F
.
Abeta amyloid pathology affects the hearts of patients with Alzheimer's Disease: mind the heart
.
J Am Coll Cardiol
 
2016
;
68
:
2395
–
2407
.
10.1016/j.jacc.2016.08.073

Google Scholar

Crossref
Search ADS

 
18.

Stellos
 
K
,
Bigalke
 
B
,
Borst
 
O
,
Pfaff
 
F
,
Elskamp
 
A
,
Sachsenmaier
 
S
,
Zachmann
 
R
,
Stamatelopoulos
 
K
,
Schonberger
 
T
,
Geisler
 
T
,
Langer
 
H
,
Gawaz
 
M
.
Circulating platelet-progenitor cell coaggregate formation is increased in patients with acute coronary syndromes and augments recruitment of CD34+ cells in the ischaemic microcirculation
.
Eur Heart J
 
2013
;
34
:
2548
–
2556
.
10.1093/eurheartj/eht131

Google Scholar

Crossref
Search ADS

 
19.

Eldufani
 
J
,
Blaise
 
G
.
The role of acetylcholinesterase inhibitors such as neostigmine and rivastigmine on chronic pain and cognitive function in aging: a review of recent clinical applications
.
Alzheimers Dement (N Y)
 
2019
;
5
:
175
–
183
.
10.1016/j.trci.2019.03.004

Google Scholar

Crossref
Search ADS

 
20.

Xu
 
H
,
Garcia-Ptacek
 
S
,
Jönsson
 
L
,
Wimo
 
A
,
Nordström
 
P
,
Eriksdotter
 
M
.
Long-term effects of cholinesterase inhibitors on cognitive decline and mortality
.
Neurology
 
2021
;
96
:
e2220
–
e2230
.
10.1212/WNL.0000000000011832

Google Scholar

Crossref
Search ADS

 
21.

Nordström
 
P
,
Religa
 
D
,
Wimo
 
A
,
Winblad
 
B
,
Eriksdotter
 
M
.
The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer's disease
.
Eur Heart J
 
2013
;
34
:
2585
–
2591
.
10.1093/eurheartj/eht182

Google Scholar

Crossref
Search ADS

 
22.

Isik
 
AT
,
Soysal
 
P
,
Stubbs
 
B
,
Solmi
 
M
,
Basso
 
C
,
Maggi
 
S
,
Schofield
 
P
,
Veronese
 
N
,
Mueller
 
C
.
Cardiovascular outcomes of cholinesterase inhibitors in individuals with dementia: a meta-analysis and systematic review
.
J Am Geriatr Soc
 
2018
;
66
:
1805
–
1811
.
10.1111/jgs.15415

Google Scholar

Crossref
Search ADS

 
23.

Tan
 
ECK
,
Johnell
 
K
,
Garcia‐Ptacek
 
S
,
Haaksma
 
ML
,
Fastbom
 
J
,
Bell
 
JS
,
Eriksdotter
 
M
.
Acetylcholinesterase inhibitors and risk of stroke and death in people with dementia
.
Alzheimers Dement
 
2018
;
14
:
944
–
951
.
10.1016/j.jalz.2018.02.011

Google Scholar

Crossref
Search ADS

 
24.

Truong
 
C
,
Recto
 
C
,
Lafont
 
C
,
Canoui-Poitrine
 
F
,
Belmin
 
JB
,
Lafuente-Lafuente
 
C
.
Effect of cholinesterase inhibitors on mortality in patients with dementia: a systematic review of randomized and nonrandomized trials
.
Neurology
 
2022
;
10.1212/wnl.0000000000201161

Google Scholar

OpenURL Placeholder Text

Crossref

 
25.

Hsiao
 
SH
,
Hwang
 
TJ
,
Lin
 
FJ
,
Sheu
 
JJ
,
Wu
 
CH
.
The Association between the use of cholinesterase inhibitors and cardiovascular events among older patients with Alzheimer disease
.
Mayo Clin Proc
 
2021
;
96
:
350
–
362
.
10.1016/j.mayocp.2020.05.048

Google Scholar

Crossref
Search ADS

 
26.

Rampa
 
L
,
Santangelo
 
R
,
Gaspardone
 
C
,
Cerutti
 
A
,
Magnani
 
G
,
Piscazzi
 
F
,
Sgherzi
 
G
,
Fiore
 
G
,
Filippi
 
M
,
Agosta
 
F
,
Margonato
 
A
,
Fragasso
 
G
.
Potential cardiologic protective effects of acetylcholinesterase inhibitors in patients with mild to moderate dementia
.
Am J Cardiol
 
2023
;
200
:
162
–
170
.
10.1016/j.amjcard.2023.05.041

Google Scholar

Crossref
Search ADS

 
27.

Kubo
 
T
,
Sato
 
T
,
Noguchi
 
T
,
Kitaoka
 
H
,
Yamasaki
 
F
,
Kamimura
 
N
,
Shimodera
 
S
,
Iiyama
 
T
,
Kumagai
 
N
,
Kakinuma
 
Y
,
Diedrich
 
A
,
Jordan
 
J
,
Robertson
 
D
,
Doi
 
YL
.
Influences of donepezil on cardiovascular system—possible therapeutic benefits for heart failure—donepezil cardiac test registry (DOCTER) study
.
J Cardiovasc Pharmacol
 
2012
;
60
:
310
–
314
.
10.1097/FJC.0b013e3182609a74

Google Scholar

Crossref
Search ADS

 
28.

Cermakova
 
P
,
Lund
 
LH
,
Fereshtehnejad
 
S‐M
,
Johnell
 
K
,
Winblad
 
B
,
Dahlström
 
U
,
Eriksdotter
 
M
,
Religa
 
D
.
Heart failure and dementia: survival in relation to types of heart failure and different dementia disorders
.
Eur J Heart Fail
 
2015
;
17
:
612
–
619
.
10.1002/ejhf.222

Google Scholar

Crossref
Search ADS

 
29.

Hernandez
 
RK
,
Farwell
 
W
,
Cantor
 
MD
,
Lawler
 
EV
.
Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs new England healthcare system
.
J Am Geriatr Soc
 
2009
;
57
:
1997
–
2003
.
10.1111/j.1532-5415.2009.02488.x

Google Scholar

Crossref
Search ADS

 
30.

Xu
 
H
,
Garcia-Ptacek
 
S
,
Bruchfeld
 
A
,
Fu
 
EL
,
Shori
 
TD
,
Lindholm
 
B
,
Eriksdotter
 
M
,
Carrero
 
JJ
.
Association between cholinesterase inhibitors and kidney function decline in patients with Alzheimer's dementia
.
Kidney Int
 
2023
;
103
:
166
–
176
.
10.1016/j.kint.2022.09.022

Google Scholar

Crossref
Search ADS

 
31.

Tarnawski
 
L
,
Shavva
 
VS
,
Kort
 
EJ
,
Zhuge
 
Z
,
Nilsson
 
I
,
Gallina
 
AL
,
Martínez-Enguita
 
D
,
Heller Sahlgren
 
B
,
Weiland
 
M
,
Caravaca
 
AS
,
Schmidt
 
S
,
Chen
 
P
,
Abbas
 
K
,
Wang
 
F-H
,
Ahmed
 
O
,
Eberhardson
 
M
,
Färnert
 
A
,
Weitzberg
 
E
,
Gustafsson
 
M
,
Kehr
 
J
,
Malin
 
SG
,
Hult
 
H
,
Carlström
 
M
,
Jovinge
 
S
,
Olofsson
 
PS
.
Cholinergic regulation of vascular endothelial function by human ChAT(+) T cells
.
Proc Natl Acad Sci USA
 
2023
;
120
:
e2212476120
.
10.1073/pnas.2212476120

Google Scholar

Crossref
Search ADS

 
32.

Olofsson
 
PS
,
Steinberg
 
BE
,
Sobbi
 
R
,
Cox
 
MA
,
Ahmed
 
MN
,
Oswald
 
M
,
Szekeres
 
F
,
Hanes
 
WM
,
Introini
 
A
,
Liu
 
SF
,
Holodick
 
NE
,
Rothstein
 
TL
,
Lövdahl
 
C
,
Chavan
 
SS
,
Yang
 
H
,
Pavlov
 
VA
,
Broliden
 
K
,
Andersson
 
U
,
Diamond
 
B
,
Miller
 
EJ
,
Arner
 
A
,
Gregersen
 
PK
,
Backx
 
PH
,
Mak
 
TW
,
Tracey
 
KJ
.
Blood pressure regulation by CD4(+) lymphocytes expressing choline acetyltransferase
.
Nat Biotechnol
 
2016
;
34
:
1066
–
1071
.
10.1038/nbt.3663

Google Scholar

Crossref
Search ADS

 
33.

Tracey
 
KJ
.
Physiology and immunology of the cholinergic antiinflammatory pathway
.
J Clin Invest
 
2007
;
117
:
289
–
296
.
10.1172/JCI30555

Google Scholar

Crossref
Search ADS

 
34.

Norman
 
GJ
,
Morris
 
JS
,
Karelina
 
K
,
Weil
 
ZM
,
Zhang
 
N
,
Al-Abed
 
Y
,
Brothers
 
HM
,
Wenk
 
GL
,
Pavlov
 
VA
,
Tracey
 
KJ
,
Devries
 
AC
.
Cardiopulmonary arrest and resuscitation disrupts cholinergic anti-inflammatory processes: a role for cholinergic alpha7 nicotinic receptors
.
J Neurosci
 
2011
;
31
:
3446
–
3452
.
10.1523/JNEUROSCI.4558-10.2011

Google Scholar

Crossref
Search ADS

 
35.

Li
 
M
,
Zheng
 
C
,
Kawada
 
T
,
Inagaki
 
M
,
Uemura
 
K
,
Akiyama
 
T
,
Sugimachi
 
M
.
Impact of peripheral α7-nicotinic acetylcholine receptors on cardioprotective effects of Donepezil in chronic heart failure rats
.
Cardiovasc Drugs Ther
 
2021
;
35
:
877
–
888
.
10.1007/s10557-020-07062-1

Google Scholar

Crossref
Search ADS

 
36.

Vang
 
A
,
da Silva Gonçalves Bos
 
D
,
Fernandez-Nicolas
 
A
,
Zhang
 
P
,
Morrison
 
AR
,
Mancini
 
TJ
,
Clements
 
RT
,
Polina
 
I
,
Cypress
 
MW
,
Jhun
 
BS
,
Hawrot
 
E
,
Mende
 
U
,
O-Uchi
 
J
,
Choudhary
 
G
.
Alpha7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension
.
JCI Insight
 
2021
;
6
:1–17.
10.1172/jci.insight.142945

Google Scholar

OpenURL Placeholder Text

Crossref

 
37.

Darreh-Shori
 
T
,
Soininen
 
H
.
Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimer's disease: a review of recent clinical studies
.
Curr Alzheimer Res
 
2010
;
7
:
67
–
73
.
10.2174/156720510790274455

Google Scholar

Crossref
Search ADS

 
38.

Kazmierski
 
J
,
Messini-Zachou
 
C
,
Gkioka
 
M
,
Tsolaki
 
M
.
The impact of a long-term rivastigmine and Donepezil treatment on all-cause mortality in patients with Alzheimer's disease
.
Am J Alzheimers Dis Other Demen
 
2018
;
33
:
385
–
393
.
10.1177/1533317518775044

Google Scholar

Crossref
Search ADS

 
39.

Jann
 
MW
.
Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease
.
Pharmacotherapy
 
2000
;
20
:
1
–
12
.
10.1592/phco.20.1.1.34664

Google Scholar

Crossref
Search ADS

 
40.

Uzairu
 
SM
,
Tijani
 
Y
,
Gadaka
 
MA
,
Modu
 
B
,
Watafua
 
M
,
Ahmad
 
HA
,
Zakariya
 
UA
,
Ibrahim
 
A
,
Daja
 
A
,
Zanna
 
H
,
Sallau
 
AB
.
Kinetics and computational study of butyrylcholinesterase inhibition by methylrosmarinate: relevance to Alzheimer's disease treatment
.
Heliyon
 
2022
;
8
:
e10613
.
10.1016/j.heliyon.2022.e10613

Google Scholar

Crossref
Search ADS

 
41.

Noetzli
 
M
,
Eap
 
CB
.
Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease
.
Clin Pharmacokinet
 
2013
;
52
:
225
–
241
.
10.1007/s40262-013-0038-9

Google Scholar

Crossref
Search ADS

 
42.

Hager
 
K
,
Baseman
 
AS
,
Nye
 
JS
,
Brashear
 
HR
,
Han
 
J
,
Sano
 
M
,
Davis
 
B
,
Richards
 
HM
.
Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer's disease: post-hoc analysis of a randomized placebo-controlled study
.
Alzheimers Res Ther
 
2016
;
8
:
47
.
10.1186/s13195-016-0214-x

Google Scholar

Crossref
Search ADS

 
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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