Abstract

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.

See page 2580 for the editorial comment on this article (doi:10.1093/eurheartj/eht244)

Introduction

Taken together, the various features of cardiovascular disease (CVD) comprise the leading cause of death worldwide, and the World Health Organization estimated in 2008 that 12.6% of all deaths globally were caused by ischaemic heart disease.1 The estimated global cost of CVD was USD 863 billion in 2010, and this cost is expected to rise by 22% in the next 20 years due to populational ageing.2 Although CVD risk factors, such as hypertension, hyperlipidaemia, smoking, and diabetes, are well known and effective drugs are available, the risk of cardiovascular death remains about five-fold greater in individuals with at least two of these risk factors at the age of 55 years than in those with no risk factor.3 These data suggest that the identification of new drugs with modes of action that differ from those of available drugs would be of interest.

Cholinesterase inhibitors (ChEIs) were introduced in the mid-1990s for the treatment of mild-to-moderate Alzheimer's disease (AD). Three ChEIs (donepezil, rivastigmine, and galantamine) are currently available and have shown similar AD treatment effects in randomized-controlled studies.4 These effects have been attributed to the reduced breakdown of acetylcholine, a neurotransmitter that has been associated with memory function, by the blockage of the enzyme acetylcholinesterase. The side effects are primarily affecting the gastrointestinal system. However, vagotonic side effects could also be of interest with respect to the risk of CVD.4,5 Furthermore, experimental studies in mice and humans have suggested that ChEIs also have anti-inflammatory properties.6–8 Given that atherosclerosis, which underlies most forms of CVD, is considered to be an inflammatory disease, such effects could be of interest with respect to CVD.

Thus, the present cohort study investigated the association between ChEI use and the later risk of myocardial infarction (MI) and death in a nationwide cohort of ∼7000 individuals diagnosed with AD.

Methods

Data source and study population

Data used in this study were obtained from the Swedish Dementia Registry (SveDem; www.svedem.se), a web-based registry established in 2007 to improve the quality of dementia diagnosis, treatment, and care in Sweden. This incident-based database here represents ∼90% of all new dementia diagnoses in memory clinics (n = 53) in Sweden. SveDem lists the age, gender, heredity, body mass index, living conditions, cognitive evaluations using the Mini-Mental State Examination (MMSE),9 the content of diagnostic work up, type of dementia diagnosis, drug treatment, and support for each patient by county and municipality.10

A search of SveDem for all patients with newly diagnosed AD (including early-onset, late-onset, and mixed dementia) according to the International Classification of Diseases (ICD) 10 criteria between 1 May 2007 and 31 December 2010 yielded the records of 7073 patients. For these patients, a MMSE was performed in 97.8%, an extended neuropsychological examination was performed in 89.4%, laboratory testing was performed in 96.3%, and a computed tomography scan was performed in 86.9% of the patients, while MRI was performed in an additional 6.5%. The regional human ethics committees in Stockholm and Umeå, and the National Board of Health and Welfare in Sweden approved this study. Data were coded and anonymized before statistical analysis.

Assessment of cardiovascular disease, death, emigration, and cholinesterase inhibitor use

Diagnoses and expedited drugs in the cohort at baseline and during the follow-up were identified by searching the Swedish National Patient Register (NPR) and the national register for prescribed and expedited drugs (NDR), administered by the Centre for Epidemiology at the National Board of Health and Welfare in Sweden. By using NPR, we got information about all diagnoses set during inpatient care in Sweden since 1998 and all outpatient care since 2001. The ICD 10 codes I21.xx (MI), I20.xx (angina pectoris), and I63.xx (ischaemic stroke) were used. Through NDR we got information about all drugs prescribed and expedited in Sweden since July 2005. The Anatomical Therapeutic Chemical Classification (ATC)-codes N06DA (ChEIs), N06A (antidepressants), N05A (neuroleptics), C03, C07, C08, C09 (antihypertensive drugs), and A10 (antidiabetic drugs) were used. Diagnoses and expedited drugs, i.e. drugs that were collected by the patient at the pharmacy, were linked to individuals in the cohort using the unique social security number assigned to each Swedish citizen. A validation study of the NPR including 713 patients with diagnosed MIs between 1987 and 1995 determined that 86% of patients fulfilled the present criteria for MI diagnosis, 9% likely had an MI, and the remaining 5% did not have an MI.11

Information on deaths occurring within the cohort during the study period was obtained through record linkage with the NPR. Information about emigration within the cohort was obtained using the Statistics Sweden database.

Statistical analysis

Baseline differences in the cohort for continuous variables were investigated using Student's t-test for independent samples. Differences in the distribution of living conditions between subjects with and without ChEI use were examined using the χ2 test. Associations between ChEI use and the risk of MI and death were investigated using Cox proportional hazard models, with baseline defined as the date of first expedited ChEI dose, or date of dementia diagnosis in subjects who had never used ChEIs. All the models were adjusted for age, gender, mixed dementia, residency, living with co-resident, home care, MMSE score, expedited antidepressants, neuroleptics, antihypertensives, antidiabetics, and any history of CVD according to Table 1. The study end of the follow-up for the outcome of MI was the date of emigration, date of MI, date of death, or 31 December 2010, whichever came first. The end of follow-up for the outcome of death was the date of emigration, date of death, or 31 December 2010, whichever came first. Kaplan–Meier curves were used to check proportional hazard assumptions.

Table 1

Characteristics of the study cohort according to cholinesterase inhibitor use

  Total cohort
 
Case-control cohort
 
ChEI (n = 5159) No ChEI (n = 1914) P-value ChEI (n = 1676) No ChEI (n = 1676) P-value 
Female gender, n (%) 3316 (64.3) 1166 (60.9) 0.01 1027 (61.3) 1013 (60.4) 0.62 
Mixed dementia, n (%) 1133 (22.0) 1062 (55.5) <0.001 907 (54.1) 934 (55.7) 0.35 
Mini-Mental State Examination score (0–30) 22.2 ± 4.4 19.5 ± 5.5 <0.001 19.9 ± 5.1 19.5 ± 5.5 0.04 
Age (years) 77.5 ± 7.9 82.5 ± 6.8 <0.001 82.1 ± 6.0 82.4 ± 6.6 0.13 
Weight (kg, n = 5095) 66.8 ± 13.3 65.2 ± 13.7 <0.001    
Height (cm, n = 4804) 165 ± 9 165 ± 9 0.01    

 
Residency, n (%) 
 At home 4862 (96.5) 1683 (89.3)  1589 (94.8) 1566 (93.4)  
 Nursing home 78 (1.5) 97 (5.1) <0.001 87 (5.2) 110 (6.6) 0.11 
Co-resident, n (%) 2188 (42.4) 1042 (57.2) <0.001 920 (54.9) 956 (57.0) 0.21 
Home care, n (%) 1133 (22.0) 799 (43.3) <0.001 698 (41.6) 731 (43.6) 0.25 

 
Cardiovascular disease, n (%) 
 Myocardial infarction 258 (5.0) 175 (9.1) <0.001 128 (7.6) 151 (9.0) 0.15 
 Stroke 209 (4.1) 134 (7.0) <0.001 111 (6.6) 111 (6.6) 1.00 
 Angina pectoris 481 (9.3) 278 (14.5) <0.001 262 (15.6) 252 (15.0) 0.63 

 
Prescribed drugs at baseline, n (%) 
 Antihypertensive 3171 (61.5) 1414 (73.9) <0.001 1241 (74.0) 1248 (74.5) 0.78 
 Antidiabetic 465 (9.0) 234 (12.2) <0.001 198 (11.8) 207 (12.4) 0.63 
 Antidepressants 2018 (39.1) 704 (36.8) 0.07 626 (37.4) 601 (35.9) 0.37 
 Neuroleptics 388 (7.5) 218 (11.4) <0.001 165 (9.8) 164 (9.8) 0.95 
  Total cohort
 
Case-control cohort
 
ChEI (n = 5159) No ChEI (n = 1914) P-value ChEI (n = 1676) No ChEI (n = 1676) P-value 
Female gender, n (%) 3316 (64.3) 1166 (60.9) 0.01 1027 (61.3) 1013 (60.4) 0.62 
Mixed dementia, n (%) 1133 (22.0) 1062 (55.5) <0.001 907 (54.1) 934 (55.7) 0.35 
Mini-Mental State Examination score (0–30) 22.2 ± 4.4 19.5 ± 5.5 <0.001 19.9 ± 5.1 19.5 ± 5.5 0.04 
Age (years) 77.5 ± 7.9 82.5 ± 6.8 <0.001 82.1 ± 6.0 82.4 ± 6.6 0.13 
Weight (kg, n = 5095) 66.8 ± 13.3 65.2 ± 13.7 <0.001    
Height (cm, n = 4804) 165 ± 9 165 ± 9 0.01    

 
Residency, n (%) 
 At home 4862 (96.5) 1683 (89.3)  1589 (94.8) 1566 (93.4)  
 Nursing home 78 (1.5) 97 (5.1) <0.001 87 (5.2) 110 (6.6) 0.11 
Co-resident, n (%) 2188 (42.4) 1042 (57.2) <0.001 920 (54.9) 956 (57.0) 0.21 
Home care, n (%) 1133 (22.0) 799 (43.3) <0.001 698 (41.6) 731 (43.6) 0.25 

 
Cardiovascular disease, n (%) 
 Myocardial infarction 258 (5.0) 175 (9.1) <0.001 128 (7.6) 151 (9.0) 0.15 
 Stroke 209 (4.1) 134 (7.0) <0.001 111 (6.6) 111 (6.6) 1.00 
 Angina pectoris 481 (9.3) 278 (14.5) <0.001 262 (15.6) 252 (15.0) 0.63 

 
Prescribed drugs at baseline, n (%) 
 Antihypertensive 3171 (61.5) 1414 (73.9) <0.001 1241 (74.0) 1248 (74.5) 0.78 
 Antidiabetic 465 (9.0) 234 (12.2) <0.001 198 (11.8) 207 (12.4) 0.63 
 Antidepressants 2018 (39.1) 704 (36.8) 0.07 626 (37.4) 601 (35.9) 0.37 
 Neuroleptics 388 (7.5) 218 (11.4) <0.001 165 (9.8) 164 (9.8) 0.95 

Data for the total cohort and for the case–control cohort that was matched 1:1 for ChEI use based on variables below, except weight and height.

The robustness of the results for the outcomes of death and MI was tested in several sensitivity analyses. Since there were relevant differences in many of the variables assessed at baseline for those who used ChEI and the rest of the cohort, the associations between ChEI and the outcomes were tested according to subgroups of different gender, age, previous CVD, cognitive function, use of antihypertensives and diagnosis of mixed dementia at baseline. The robustness of the results was also tested in a matched case–control cohort based on the total study cohort (n = 7073). Each control (never used ChEI) was then matched against one case (used ChEI at least once) based on propensity scores. These scores were derived from the variables gender, age, diagnosis of mixed dementia, cognitive function, residency, living with co-resident, home care, previous MI, stroke and angina pectoris, use of antihypertensives, antidepressants, neuroleptics, and antidiabetic medication at baseline. As shown in Table 1 matching based on these variables gave a case–control cohort with similar background data. The association between ChEI use with the outcomes death and MI was then investigated in this cohort by using Cox proportional hazard models adjusting for the propensity scores. In a final sensitivity analysis, we evaluated whether the associations found were restricted to the use of ChEI or applied also to other drugs used in the treatment of dementia. For these, analyses tested whether memantine was associated with the outcomes death and MI in the total cohort using Cox regression. Memantine is a partial N-methyl-d-aspartate (NMDA) receptor antagonist with the indication moderate-to-severe AD.12

All statistical tests were two-sided and P < 0.05 was considered significant. The SPSS software with the R essentials application was used for all statistical analyses (ver. 20.0 for PC; SPSS, Inc., Chicago, IL, USA).

Results

The study cohort consisted of 7073 men and women with a mean age of 78.9 (range 41–99) years at baseline. Of these subjects, 5159 (72.9%) subjects received expedited ChEIs at least once (Table 1). The mean interval between the first and last time ChEI was expedited was 495 (range 0–2008) days. Compared with the rest of the cohort, these subjects were younger and female, had higher MMSE scores, and lived at home alone with no home care. In addition, fewer of these subjects had a history of CVD than those who had never been prescribed ChEIs. Only 10 subjects were expedited ChEI once. In the matched case–control cohort based on all variables in Table 1, there were marginal differences in the baseline variables between subjects using and not using ChEI.

In those prescribed ChEI at least once (n = 5159), 74 subjects suffered an MI and 427 subjects died during a mean follow-up period of 571 (range 0–2009) days. In the rest of the cohort (n = 1914), 42 subjects suffered an MI and 329 subjects died during a mean follow-up period of 392 (range 2–1333) days. Figure 1 presents cumulative survival curves of the cohort according to occurrence of MI or death during the follow-up, adjusted for the influences of age, gender, mixed dementia, MMSE score, living conditions, history of CVD and use of antidepressants, antihypertensive drugs, antidiabetics, and neuroleptics (all confounders). After adjustment for all confounders, subjects who used ChEIs had a 34% lower risk for the composite outcome of MI or death during the follow-up than those who did not [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.56–0.78, Table 2]. After adjustment for all confounders, use of ChEI was also associated with a reduced risk of MI (HR: 0.62, 95% CI: 0.40–0.95), death (HR: 0.64, 95% CI: 0.54–0.76) (Table 2), and death from cardiovascular causes (n = 307) (HR: 0.74, 95% CI: 0.57–0.97). Other protective factors with respect to MI or death in these analyses included younger age, female gender, higher MMSE score, living at home without home care, absence of CVD and stroke, and no antihypertensive medication at baseline (P < 0.05; for all). Further adjustment of for weight and height in a subcohort of 4841 subjects did not change the risk (HR: 0.68 before and after adjustment) for the combined outcome of MI or death. Weight and height was not considered to be confounders in later analyses.

Table 2

Associations between cholinesterase inhibitor use at baseline and the risks of myocardial infarction and death during the follow-up

Outcomes Composite of MI or death (n = 831)
 
Death (n = 756)
 
MI (n = 116)
 
HR 95% CI HR 95% CI HR 95% CI 
Total cohort (n = 7073) 
 Ever using ChEI (n = 5159) 0.66 0.56–0.78 0.64 0.54–0.76 0.62 0.40–0.95 
 Ever using memantine (n = 1747) 1.16 0.97–1.38 1.15 0.95–1.38 1.22 0.76–1.97 
Subgroup analyses based on ever using ChEI 
 Female gender (n = 4482) 0.67 0.53–0.83 0.62 0.49–0.78 0.68 0.39–1.17 
 Male gender (n = 2591) 0.65 0.51–0.83 0.65 0.50–0.84 0.58 0.29–1.15 
 Age < 80 years (n = 3584) 0.53 0.38–0.72 0.52 0.37–0.73 0.43 0.20–0.95 
 Age ≥ 80 years (n = 3489) 0.72 0.60–0.87 0.69 0.56–0.84 0.71 0.43–1.17 
 CVD at baseline (n = 1251) 0.52 0.38–0.72 0.50 0.36–0.70 0.61 0.29–1.28 
 No CVD at baseline (n = 5822) 0.73 0.60–0.88 0.69 0.56–0.86 0.69 0.40–1.18 
 Use of anti-hypertensives (n = 4585) 0.69 0.57–0.83 0.68 0.56–0.83 0.59 0.37–0.96 
 No anti-hypertensives (n = 2488) 0.56 0.40–0.79 0.51 0.36–0.72 0.73 0.28–1.93 
 Mixed-dementia (n = 2696) 0.67 0.54–0.84 0.66 0.52–0.83 0.57 0.31–1.07 
 Alzheimer's disease (n = 4377) 0.55 0.51–0.83 0.62 0.48–0.80 0.67 0.37–1.22 
 MMSE-score less than 22 (n = 2978) 0.65 0.53–0.80 0.64 0.51–0.79 0.55 0.30–1.02 
 MMSE-score of 22 or more (n = 3665) 0.68 0.51–0.90 0.64 0.47–0.86 0.69 0.38–1.27 
Matched case–control cohort 1:1 (n = 3352) based on ever using ChEIa 0.66 0.55–0.79 0.60 0.50–0.72 0.52 0.32–0.86 
Outcomes Composite of MI or death (n = 831)
 
Death (n = 756)
 
MI (n = 116)
 
HR 95% CI HR 95% CI HR 95% CI 
Total cohort (n = 7073) 
 Ever using ChEI (n = 5159) 0.66 0.56–0.78 0.64 0.54–0.76 0.62 0.40–0.95 
 Ever using memantine (n = 1747) 1.16 0.97–1.38 1.15 0.95–1.38 1.22 0.76–1.97 
Subgroup analyses based on ever using ChEI 
 Female gender (n = 4482) 0.67 0.53–0.83 0.62 0.49–0.78 0.68 0.39–1.17 
 Male gender (n = 2591) 0.65 0.51–0.83 0.65 0.50–0.84 0.58 0.29–1.15 
 Age < 80 years (n = 3584) 0.53 0.38–0.72 0.52 0.37–0.73 0.43 0.20–0.95 
 Age ≥ 80 years (n = 3489) 0.72 0.60–0.87 0.69 0.56–0.84 0.71 0.43–1.17 
 CVD at baseline (n = 1251) 0.52 0.38–0.72 0.50 0.36–0.70 0.61 0.29–1.28 
 No CVD at baseline (n = 5822) 0.73 0.60–0.88 0.69 0.56–0.86 0.69 0.40–1.18 
 Use of anti-hypertensives (n = 4585) 0.69 0.57–0.83 0.68 0.56–0.83 0.59 0.37–0.96 
 No anti-hypertensives (n = 2488) 0.56 0.40–0.79 0.51 0.36–0.72 0.73 0.28–1.93 
 Mixed-dementia (n = 2696) 0.67 0.54–0.84 0.66 0.52–0.83 0.57 0.31–1.07 
 Alzheimer's disease (n = 4377) 0.55 0.51–0.83 0.62 0.48–0.80 0.67 0.37–1.22 
 MMSE-score less than 22 (n = 2978) 0.65 0.53–0.80 0.64 0.51–0.79 0.55 0.30–1.02 
 MMSE-score of 22 or more (n = 3665) 0.68 0.51–0.90 0.64 0.47–0.86 0.69 0.38–1.27 
Matched case–control cohort 1:1 (n = 3352) based on ever using ChEIa 0.66 0.55–0.79 0.60 0.50–0.72 0.52 0.32–0.86 

Hazards are also presented in separate analyses for subjects according to gender, age at baseline, cardiovascular disease or stroke (CVD) at baseline, the use of anti-hypertensive drugs, diagnosis of mixed dementia, and Mini-Mental State Examination (MMSE) score at baseline. In a separate analysis, hazards are presented for all outcomes also based on ever using memantine. Hazard ratios (HR) and 95% confidence intervals (95% CIs) are presented adjusted all variables in Table 1, except weight and height. Finally, hazards are presented for ever using ChEI in a matched case–control cohort.

aThe propensity scores used for matching were based all variables in Table 1, except weight and height. The hazard ratios presented were adjusted for the propensity scores.

Figure 1

Risk of myocardial infarction and death during the follow-up based on whether the subjects were on acetyl cholinesterase inhibitors. The survival curves were adjusted for gender, type of dementia, age, residency, Mini-Mental State Examination Score, co-resident, home care, use of antihypertensives, antidiabetics, antidepressants, neuroleptics, previous cardiovascular disease and stroke. The follow-up time was terminated at 750 days.

Figure 1

Risk of myocardial infarction and death during the follow-up based on whether the subjects were on acetyl cholinesterase inhibitors. The survival curves were adjusted for gender, type of dementia, age, residency, Mini-Mental State Examination Score, co-resident, home care, use of antihypertensives, antidiabetics, antidepressants, neuroleptics, previous cardiovascular disease and stroke. The follow-up time was terminated at 750 days.

Based on the last date of expedited ChEI, the dose was categorized as low (donepezil 5 mg, rivastigmine 3 mg or less, galantamine 8 mg), moderate (rivastigmine 4.5–6 mg, galantamine 16 mg), or high (donepezil 10 mg, rivastigmine 6 mg or more, galantamine 24 mg). Using subjects who had never been prescribed ChEIs as the reference and adjusting for all confounders, we found that the risk of the composite outcome of MI or death decreased with increasing ChEI dose (P for trend <0.001), and those receiving the highest ChEI doses had the lowest risk compared with the reference (HR: 0.52, 95% CI: 0.42–0.65; Figure 2). The highest dose of ChEI was also associated with the highest risk reduction for MI (HR: 0.35, 95% CI: 0.19–0.64) and death (HR: 0.54, 95% CI: 0.43–0.67), when evaluated separately, or MI in a cohort with previous CVD (HR: 0.29, 95% CI: 0.09–0.94, Figure 2).

Figure 2

(AC) The association between low, medium, and high dose of cholinesterase inhibitors in relation to the risk of myocardial infarction (A and B) and death (C). The risk of myocardial infarction was analysed for the total cohort (n = 7073) (A) and for those with a history of cardiovascular disease or stroke (n = 1251) (B). The risks (hazard ratios, HRs) were adjusted for gender, type of dementia, age, residency, Mini-Mental State Examination Score, co-resident, home care, use of antihypertensives, antidiabetics, antidepressants, neuroleptics, previous cardiovascular disease, and stroke.

Figure 2

(AC) The association between low, medium, and high dose of cholinesterase inhibitors in relation to the risk of myocardial infarction (A and B) and death (C). The risk of myocardial infarction was analysed for the total cohort (n = 7073) (A) and for those with a history of cardiovascular disease or stroke (n = 1251) (B). The risks (hazard ratios, HRs) were adjusted for gender, type of dementia, age, residency, Mini-Mental State Examination Score, co-resident, home care, use of antihypertensives, antidiabetics, antidepressants, neuroleptics, previous cardiovascular disease, and stroke.

In a first set of sensitivity analyses, the associations between ChEI use and the composite outcome of MI or death remained significant for subgroups according to different gender, age, CVD at baseline, use of hypertensive drugs, mixed dementia, Alzheimer's dementia, and cognitive function (Table 2). These associations were also similar in the subgroups for the outcome of death and MI when analysed separately (Table 2). Secondly, we analysed ChEI use in the matched case–control cohort. After adjustment for the propensity scores, the use of ChEI was associated with a decreased risk for the composite outcome of MI or death (HR: 0.66, 95% CI: 0.55–0.79), death (HR: 0.60, 95% CI: 0.50–0.72), and MI (HR: 0.52, 95% CI: 0.32–0.86). In a third set of analyses, the association between memantine, a selective NMDA-receptor antagonist, and the different outcomes was analysed (Table 2). After adjustment for all confounders, the use of memantine (n = 1747) was not associated with the composite outcome of MI or death (HR: 1.16, 95% CI: 0.97–1.38), death (HR: 1.15, 95% CI: 0.95–1.38), or MI (HR: 1.22, 95% CI: 0.76–1.97) analysed separately (Table 2). Finally, exclusion of all subjects that died within 90 days did only slightly attenuate the associations between ChEI use and the composite outcome of MI or death (HR: 0.71, 95% CI: 0.60–0.85), MI (HR: 0.70, 95% CI: 0.45–1.10), or death (HR: 0.69, 95% CI: 0.57–0.82) in the total cohort after adjustment for all confounder.

Discussion

In the present observational study, ChEI use was associated with ∼35% reduced risk of MI or death in a cohort of subjects with diagnosed AD. This risk reduction was similar in subcohorts of subjects according to different age, gender and cognitive function, presence of CVD or not, and diagnosis of Alzheimer's dementia or Alzheimer's mixed dementia. This risk reduction was also similar in case–control cohorts that were matched based on all potential confounders. The risk of both MI and death decreased with an increasing dose of ChEI. However, given that this is an observational study, it would be of value if the findings could be confirmed in a randomized controlled trial.

To our knowledge, no previous clinical study has linked the use of ChEIs to a reduced risk of CVD in general or MI in particular. Furthermore, the incidence of MIs has not been reported in high-quality randomized controlled trials with durations of at least 5 months investigating the effects of ChEIs in subjects with AD.13–24 The small numbers of participants and relatively short follow-up periods (1 year or more in only two trials) in these trials may have influenced the absence of CVD in these studies.18,19 Because MIs are rare, pooling of safety data from previous randomized controlled studies would be necessary to create a sufficiently large cohort. Such an effort could be of great value, given the results of the present observational study.

The survival curve for MI or death in the present study cohort indicates that the treatment effects associated with ChEIs may appear in the early stages following onset use. This early effect could admittedly be related to the possibility that ChEI treatment is not typically considered in AD subjects with CVD. For this reason, the primary analysis was adjusted for previous CVD and one of the sensitivity analyses examined a subcohort of subjects with known CVD at baseline. The risk reduction associated with ChEI use was similar in both cohorts, although the estimated treatment effects only reached statistical significance for the highest ChEI doses in the subcohort with previous CVD.

Given that CVD is the major cause of death in Sweden and worldwide,1 we also tested the hypothesis that ChEI use was related to a reduced risk of death in subjects with AD. In the primary analysis, ChEI use was associated with a reduced risk of death of ∼35%, as for MI. This result should be interpreted with caution, given the risk that critically ill patients are not typically prescribed ChEIs at the time of diagnosis. However, the exclusion of subjects that died within 3 months attenuated the treatment effect results with respect to death only slightly. As for MIs, the treatment effect with respect to death increased with higher ChEI doses.

Since the study design of the present study was observational, we can only speculate about the mechanisms of action underlying the cardiovascular effects found. It is of interest that atherosclerosis, which underlies most MIs, is considered to be an inflammatory disease.25 Within the atherosclerotic plaque immune cells produce cytokines that decreases the stability of the plaque, increasing the risk of plaque rupture, and a subsequent MI. Therefore, the documentation of anti-inflammatory properties of ChEIs due to reduced acetylcholine breakdown is of interest.26–28 Treatment with ChEIs has been shown to reduce peripheral cytokine production in experimental studies6 and in humans.7 However, there are also other, and perhaps more likely mechanisms that may contribute to the associations found in the present study. In an experimental model in rats, vagal nerve stimulation after MI resulted in an improved cardiac function and survival.5 In two later studies,29,30 donepezil treatment resulted in favourable effects after MI and reduced atherosclerosis in animal models. In humans, ChEI treatment was also associated with an increased risk of hospitalization for bradycardia through an increased vagal tone.31 In contrast, in a recent study negative chronotropic effects of ChEI treatment were not found in subjects recently diagnosed with AD.32 With respect to our results, effects on the cardiac system from ChEI use, such as those found in some of the studies above, could reduce oxygen demands, improve cardiac function, and thereby reduce the risk of MI and death.

Limitations

The major limitation of the present study is its observational design. Marked differences in many examined factors were present at baseline between ChEI users and the rest of the cohort, increasing the risk of confounding by indication. Thus, it is likely that subjects that were generally healthier at baseline would be more often prescribed ChEI, and perhaps also higher doses of ChEI. Therefore, all the analyses were adjusted to correct for these differences, and the results were also similar in the matched case–control cohort. Nevertheless, there could be other confounders, that we did not have access to, that would influence the associations found, e.g. use of statins. Furthermore, although hypothetically, subjects that are prescribed ChEI may be subjected to a more advanced and comprehensive health care concerning their dementia. However, in the present study, the positive treatment effects were restricted to the use of ChEI and did not apply to memantine, a drug that is also prescribed to subjects with Alzheimer's dementia.12 In the present study, the diagnoses of MI collected from the Swedish NPR were not validated. However, MI data obtained from NPR have been validated previously, and have shown high sensitivity (94%) and a high positive predictive value (86%).11 Although the accuracy of dementia diagnoses registered in SveDem has not been validated, this database reports the diagnostic tools used in each case. Furthermore, >95% of patients in this cohort were diagnosed and treated at memory clinics by physicians specializing in dementia disorders. Finally, although there may be cases of misclassification, the treatment effects of ChEI with respect to the outcomes were similar in patients diagnosed with Alzheimer's dementia and Alzheimer's mixed dementia.

Conclusions

In summary, ChEI use was found to be associated with reduced risks of MI and death in subjects with AD. These associations were stronger with higher ChEI doses. Given that this was an observational study, it would be of value if the results could be confirmed in a study with higher evidence.

Funding

This work was supported by the Swedish research council, the Swedish Brain Power consortium, the Swedish Society of Medicine and Foundation for Geriatric Diseases at Karolinska Institutet, the Swedish Dementia Foundation, and the Swedish Association of Local Authorities and Regions.

Conflict of interest: None declared.

Acknowledgements

The authors are grateful to the national Swedish Dementia Registry (SveDem, www.svedem.se) for providing data for this study and thank all patients, caregivers, and reporting units for providing information.

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Supplementary data

Comments

3 Comments
Cholinesterase inhibitor use and reduced risk of myocardial infarction and death. What about the baroreceptor reflex as possible link?
16 June 2013
Joep Lagro (with Aisha S.S. Meel-van Abeelen, Jurgen A.H.R. Claassen)

To the Editor: With great interest we have read the article by Nordstrom et al.(1) In their well designed prospective cohort study they demonstrate the association of cholinesterase inhibitor use with a reduced risk of myocardial infarction and death in a large cohort of subjects with Alzheimer's dementia or Alzheimer's mixed dementia.

Nordstrom et al.(1) speculate about the mechanisms of action underlying the cardiovascular effects found. They point at the anti- inflammatory properties of cholinesterase inhibitors as a possible explanation. We want to point at the baroreceptor reflex as a possible link between cholinesterase inhibitor use and reduced myocardial infarction and mortality. The baroreceptor reflex is reduced in Alzheimer's disease compared to patients with mild cognitive impairment and healthy controls.(2) The baroreceptor reflex operates via the autonomic nervous system to restore sudden changes in blood pressure by changing heart rate and vascular tone. A clinical example is the drop in blood pressure upon standing, which the baroreceptor reflex corrects by a rapid increase in heart rate (parasympathetic inhibition) followed by peripheral arterial vasoconstriction (sympathetic activation). An impaired baroreceptor reflex function is a strong and independent risk factor for mortality and major cardiovascular events in hypertensive patients and in post myocardial patients.(3,4)With an impaired baroreceptor reflex the correction of the drop in blood pressure upon standing might also be impaired, resulting more frequently in orthostatic hypotension. A profound diastolic blood pressure drop after standing is a powerful independent predictor of mortality in geriatric patients, possibly due to less perfusion of the myocardium during diastole.(5) Moreover, the baroreceptor reflex improves substantially with 66% in patients with Alzheimer's disease after treatment with cholinesterase inhibitor. This improvement of the baroreceptor reflex might be the cause of the reduction in mortality and myocardial infarctions found in patients with Alzheimer's disease treated with acetylcholinesterase inhibitor.

However, we agree strongly with Nordstrom et al.(1) that these results should be replicated and confirmed in a randomized controlled trial. In our opinion, in such a trial not only markers of inflammation, but also baroreceptor reflex functioning should be determined to study the association and interaction with mortality and major cardiovascular events in patients with Alzheimer's disease.

In conclusion, Nordstrom et al.(1) provide convincing evidence for the association of cholinesterase inhibitor use with a reduced risk of myocardial infarction and death in subjects with Alzheimer's dementia. Besides the anti-inflammatory properties of cholinesterase inhibitors, we think that also improvement of the baroreceptor reflex function by cholinesterase inhibitors might play an important role in this association, but further research to establish this is necessary.

Reference List

(1) Nordstrom 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 June 4.

(2) Meel-van den Abeelen AS, Lagro J, Gommer ED, Reulen JP, Claassen JA. Baroreflex function is reduced in Alzheimer's disease: a candidate biomarker? Neurobiol Aging 2013 April;34(4):1170-6.

(3) La Rovere MT, Bigger JT, Jr., Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998 February 14;351(9101):478-84.

(4) Ormezzano O, Cracowski JL, Quesada JL, Pierre H, Mallion JM, Baguet JP. EVAluation of the prognostic value of BARoreflex sensitivity in hypertensive patients: the EVABAR study. J Hypertens 2008 July;26(7):1373- 8.

(5) Lagro J, Laurenssen NC, Schalk BW, Schoon Y, Claassen JA, Olde Rikkert MG. Diastolic blood pressure drop after standing as a clinical sign for increased mortality in older falls clinic patients. J Hypertens 2012 June;30(6):1195-202.

Conflict of Interest:

None declared

Submitted on 16/06/2013 8:00 PM GMT
Response to the comment by Lagro et al.
16 June 2013
Peter Nordstrom (with Maria Eriksdotter)

Lagro et al. has written an interesting comment in response to our recently published article in the European Heart Journal.1 They propose that also an improved baroreceptor reflex (BRR) may underlie the associations found between the use of cholinesterase inhibitors (ChEI) and myocardial infarctions. In their comment, the authors point to the fact that an impaired BRR is found in patients with Alzheimer's disease, and that a compromised BRR is a risk factor for cardiac mortality,2 and also an increased the risk of life-threating arrhythmias.3 With respect to the association found in our study, it is of interest that these authors recently found that an impaired BRR is largely restored in patients with Alzheimer's disease after treatment with ChEI.4 We agree with the authors that also an improved BRR from ChEI use may underlie the associations found in our study. However, it should be noted that based on previous studies the effects of ChEI on the cardiovascular system are complex. As indicated in our original publication, ChEI use was associated with a doubled risk of hospitalization for bradycardia in a recent observational study.5 Furthermore, in that study, 11% of the patients hospitalized required pace maker while 4% died prior to discharge. In contrast, no effects of the ChEI rivastigmine were found on any parameter assessed by electrocardiographs in an analysis of four placebo controlled studies, including about 2800 patients with Alzheimer's dementia.6

Finally, we would to again emphasize the fact that our study was observational, and the associations found are no proof of a beneficial effect from ChEI use. Thus, these results must be confirmed in a randomized controlled trial before any clinical recommendations can be done.

For the authors

Peter Nordstrom, Department of Community Medicine and Rehabilitation, Geriatrics, Umea University

Maria Eriksdotter, Department Neurobiology, Care Sciences and Society, div Clinical Geriatrics, Karolinska Institutet and Dept Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden

References

1. Nordstrom 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. European heart journal 2013.

2. La Rovere MT, Bigger JT, Jr., Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998;351(9101):478-84.

3. La Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R, Bigger JT, Jr., Camm AJ, Schwartz PJ. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life- threatening arrhythmias: implications for clinical trials. Circulation 2001;103(16):2072-7.

4. Meel-van den Abeelen AS, Lagro J, Gommer ED, Reulen JP, Claassen JA. Baroreflex function is reduced in Alzheimer's disease: a candidate biomarker? Neurobiology of aging 2013;34(4):1170-6.

5. Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A, Juurlink DN. Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study. PLoS medicine 2009;6(9):e1000157.

6. Morganroth J, Graham S, Hartman R, Anand R. Electrocardiographic effects of rivastigmine. Journal of clinical pharmacology 2002;42(5):558- 68.

Conflict of Interest:

None declared

Submitted on 16/06/2013 8:00 PM GMT
Beneficial effects of cholinesterase inhibitors on cardiovascular disease
21 July 2013
Toru Kubo (with Hiroaki Kitaoka, Yoshihiko Kakinuma, Takayuki Sato)

To the Editor:

The prevalence of cardiovascular disease (CVD) such as myocardial infarction (MI) and heart failure (HF) has been increasing with advancing life span, and the prognosis of patients with CVD is still poor despite the establishment of various treatments. In this regard, a recent article by Nordstrom and colleagues showing that cholinesterase inhibitor (ChEI) use was associated with a reduced risk of MI and death in a Swedish nationwide cohort of subjects diagnosed with Alzheimer's dementia adds a notable contribution.(1)

Prior to Nordstrom et al, we also reported that patients with Alzheimer's disease who were treated with donepezil, a ChEI, had a lower risk of cardiovascular death than did untreated patients.(2) Furthermore, our recent prospective study, named DOCTER (DOnepezil Cardiac TEst Regisrty) Study, to evaluate clinical events and cardiovascular responses occurring before and after donepezil treatment in dementia patients showed that usual doses of donepezil significantly decreased plasma brain natriuretic peptide levels in patients with subclinical HF.(3)

The previous study showed that electrical vagal nerve stimulation markedly improved long-term survival in rats with HF after large myocardial infarctions,(4) suggesting a bradycardiac effect of vagal stimulation is of importance. However, in recent animal(5) and clinical(3) studies, we demonstrated that donepezil exhibits its cardioprotective actions, independent of a heart rate-slowing mechanism. As a mechanism for the beneficial effects of donepezil, we proposed its direct action on cardiac and endothelial cells. Our recent studies revealed that donepezil activates acetylcholine synthesis in those nonneuronal cells, and then acetylcholine upregulates angiogenic and anti-apoptotic factors including hypoxia-inducible factor-1 alpha and vascular endothelial growth factor.(6,7)

Finally, although the current observational study by Nordstrom et al(1) encouraged us to clarify the clinical usefulness of donepezil as a cardioprotective drug, the number of patients was not enough both in the Swedish Dementia Registry(1) and in our previous studies(2,3), and there has been little information on detailed clinical findings such as echocardiographic data in regard to the effects of ChEI. To establish a novel therapeutic strategy against CVD with ChEI, mechanistic studies and large-scale clinical trials with ChEI are required.

References list

1. Nordstrom P, Religa D, Wimo A, Winblad B, and 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 Epub ahead of print.

2. Sato K, Urbano R, Yu C, Yamasaki F, Sato T, Jordan J, Robertson D, Diedrich A. The effect of donepezil treatment on cardiovascular mortality. Clin Pharmacol Ther 2010;88:335-338.

3. Toru Kubo, Takayuki Sato, Tatsuya Noguchi, Hiroaki Kitaoka, Fumiyasu Yamasaki, Naoto Kamimura, Shinji Shimodera, Tatsuo Iiyama, Naoko Kumagai, Yoshihiko Kakinuma, Andr? Diedrich, Jens Jordan, David Robertson, Yoshinori L. Doi. 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.

4. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal neve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 2004;109:120-124.

5. Handa T, Katare RG, Kakinuma Y, Arikawa M, Ando M, Sasaguri S, Yamasaki F, Sato T. Anti-Alzheimer's drug, donepezil, markedly improves long-term survival after chronic heart failure in mice. J Cardiac Fail 2009;15:805- 811.

6. Kakinuma Y, Akiyama T, Sato T. Cholinoceptive and cholinergic properties of cardiomyocytes involving an amplification mechanism for vagal efferent effects in sparsely innervated ventricular myocardium. FEBS J 2009;276:5111-5125.

7. Kakinuma Y, Akiyama T, Okazaki K, Arikawa M, Noguchi T, Sato T. A non- neuronal cardiac cholinergic system plays a protective role in myocardium salvage during ischemic insults. PLoS One 2012;7:e50761.

Conflict of Interest:

None declared

Submitted on 21/07/2013 8:00 PM GMT