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Journal of Alzheimer’s Disease 48 (2015) 949–958 949

DOI 10.3233/JAD-150499
IOS Press

Cardiovascular Diseases in ∼30,000 Patients


in the Swedish Dementia Registry
Pavla Cermakovaa,b,∗ , Kristina Johnellc , Johan Fastbomc , Sara Garcia-Ptacekd,e , Lars H. Lundf,g ,
Bengt Winblada,e , Maria Eriksdotterd,e and Dorota Religaa,e
a Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research,
Division for Neurogeriatrics, Huddinge, Sweden
b International Clinical Research Center and St.Anne‘s University Hospital, Brno, Czech Republic
c Karolinska Institutet and Stockholm University, Department of Neurobiology, Care Sciences and Society,

Center for Alzheimer Research, Aging Research Center, Stockholm, Sweden


d Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research,

Division of Clinical Geriatrics, Huddinge, Sweden


e Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
f Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
g Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden

Handling Associate Editor: Sotirios Giannopoulos

Accepted 8 July 2015

Abstract.
Background: Cardiovascular diseases are leading causes of death and patients with dementia are often affected by them.
Objective: Investigate associations of cardiovascular diseases with different dementia disorders and determine their impact on
mortality.
Methods: This study included 29,630 patients from the Swedish Dementia Registry (mean age 79 years, 59% women) diagnosed
with Alzheimer’s disease (AD), mixed dementia, vascular dementia, dementia with Lewy bodies (DLB), Parkinson’s disease
dementia (PDD), frontotemporal dementia (FTD), or unspecified dementia. Records of cardiovascular diseases come from the
Swedish National Patient Register. Multinomial logistic regression and cox proportional hazard models were applied.
Results: Compared to AD, we found a higher burden of all cardiovascular diseases in mixed and vascular dementia. Cere-
brovascular diseases were more associated with DLB than with AD. Diabetes mellitus was less associated with PDD and DLB
than with AD. Ischemic heart disease was less associated with PDD and FTD than AD. All cardiovascular diseases predicted
death in patients with AD, mixed, and vascular dementia. Only ischemic heart disease significantly predicted death in DLB
patients (HR = 1.72; 95% CI = 1.16–2.55). In PDD patients, heart failure and diabetes mellitus were associated with a higher
risk of death (HR = 3.06; 95% CI = 1.74–5.41 and HR = 3.44; 95% CI = 1.31–9.03). In FTD patients, ischemic heart disease and
atrial fibrillation or flutter significantly predicted death (HR = 2.11; 95% CI = 1.08–4.14 and HR = 3.15; 95% CI = 1.60–6.22,
respectively).
Conclusion: Our study highlights differences in the occurrence and prognostic significance of cardiovascular diseases in several
dementia disorders. This has implications for the care and treatment of the different dementia disorders.

Keywords: Alzheimer’s disease, cardiovascular diseases, dementia, mortality

∗ Correspondence to: Pavla Cermakova, MD, Karolinska Insti-


tutet, Centrum for Alzheimer Research, Division for Neurogeri- (8)58589397; Fax: +46 (8)58585470; E-mail: Pavla.Cermakova@
atrics, Novum, Blickagången 6, 141 57 Huddinge, Sweden. Tel.: +46 ki.se.

ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
950 P. Cermakova et al. / Cardiovascular Diseases in Dementia

INTRODUCTION the International Classification of Diseases version 10


(ICD 10) criteria [12] were studied. In addition, McK-
Dementia is characterized by deterioration in eith criteria were used for dementia with Lewy bodies
cognitive and functional capacities [1] and is often (DLB) [13], Lund-Manchester criteria for frontotem-
accompanied by cardiovascular (CV) comorbidities poral dementia (FTD) [14], and Movement Disorder
[2]. The comorbidities may exacerbate the progression Society Task Force criteria for Parkinson’s disease
of dementia and, vice versa, dementia may complicate dementia (PDD) [15]. Patients were registered at the
their management or affect utilization of health care time of the dementia diagnosis and diagnosed with
services [3]. AD, mixed dementia, vascular dementia, DLB, PDD,
CV diseases are the leading causes of death world- FTD, unspecified dementia, or other types of demen-
wide [4]. For the past four decades, the rate of death tia. In this study, patients diagnosed with other types
from CV diseases has declined, likely because of their of dementia were excluded due to the imprecision of
better treatment [5]. Previous research suggests that this group.
CV diseases and their risks, such as hypertension, dia-
betes mellitus, or hyperlipidemia, are linked to the CV diseases
development of dementia and therefore represent logi-
In patients in SveDem, records of diseases that
cal targets for its prevention [6]. The reported decrease
occurred between January 1, 2000 and December 31,
in dementia incidence has been attributed to better
2012 in the Swedish National Patient Register were
management of CV risk factors and prevalent CV dis-
studied. This registry covers all inpatient and outpa-
ease [6]. Furthermore, in individuals with established
tient care encounters in Sweden except for out-patient
dementia, CV comorbidities such as atrial fibrillation,
primary care [16] and contains diagnoses according
hypertension, angina, and cerebrovascular events are
to the ICD 10. The diseases were defined as ischemic
associated with a greater rate of cognitive decline [7,
heart disease (ICD I20–I25), atrial fibrillation and flut-
8]. There is, however, limited evidence as to whether
ter (I48), heart failure (I50), cerebrovascular diseases
established CV diseases predict death in dementia
(I60–I69), and diabetes mellitus (E10–E13) and were
patients [9].
counted if the code was present in any position.
Large studies comparing CV diseases in all differ-
ent dementia disorders are lacking, probably due to CV drugs
insufficient patient material [10]. This study aims to
investigate associations of prevalent CV diseases with Drugs from the Swedish Prescribed Drug Register
specific dementia disorders and determine the impact that were dispensed between July 1, 2005 and August
of CV diseases on mortality of patients with dementia. 31, 2013 were investigated. This registry contains
information on all prescriptions dispensed at Swedish
METHODS pharmacies to the entire Swedish population [17].
Drugs are coded according to the Anatomical Thera-
We performed a cohort study based on the Swedish peutic Chemical (ATC) Classification. The medication
Dementia Registry (SveDem). We obtained the infor- was defined as antidiabetic drugs (A10), antithrom-
mation on CV comorbidities from the Swedish botic drugs (B01), diuretics (C03), beta blockers (C07),
National Patient Register and data on CV drugs from calcium channel blockers (C08), renin-angiotensin
the Swedish Prescribed Drug Register. Patients were system (RAS) antagonists (C09), and lipid modifying
informed of the entry into SveDem and had a possibil- drugs (C10). The prescription of drugs was identified
ity to decline participation. This study complies with at 7 time points; at the date of dementia diagnosis and
the Declaration of Helsinki and was approved by the in one-year intervals 3 years before and after; and was
regional ethical review board in Stockholm, Sweden. counted if the code was present at least once. The total
Data were anonymized before analysis. number of drugs at the time of dementia diagnosis
was extracted from the registry and is considered a
Patients surrogate for overall comorbidity [18].

SveDem (http://www.svedem.se) is a national reg- Mortality


istry that aims to improve the quality of dementia
care in Sweden [11]. Patients diagnosed with dementia Dates of death were obtained from the Swedish Pop-
between May 1, 2007 and December 31, 2012 fulfilling ulation Registry. The patients were followed up from
P. Cermakova et al. / Cardiovascular Diseases in Dementia 951

the time of diagnosis until their death or the end of the took on average 5 drugs at the time when demen-
follow-up in October 2013. tia was diagnosed. The most frequent CV drugs were
antithrombotic agents (dispensed to 60% of the study
Statistical analysis population).

Means, standard deviations, and percentages were CV diseases


used to describe continuous and qualitative variables,
respectively. Analysis of Variance for continuous vari- The most commonly recorded CV disease was
ables and chi square test for dichotomous variables ischemic heart disease, present in 23% of all patients
were applied to analyze differences in clinical char- with dementia, followed by cerebrovascular diseases
acteristics between patients with various dementia (20%), atrial fibrillation or flutter (19%), heart failure
disorders. Multinomial logistic regression was per- (15%), and diabetes mellitus (15%). All CV disorders
formed to find associations of CV diseases with were most frequent in patients diagnosed with vascu-
different dementia disorders with AD as reference; lar dementia and least common in FTD patients, with
odds ratios (ORs) with 95% confidence intervals the exception of cerebrovascular diseases that occurred
(CIs) were calculated. Multivariable Cox regression the least in AD (9%) and diabetes mellitus that had the
hazard models were used to estimate hazard ratios lowest frequency in PDD and DLB patients (9%).
(HRs) and 95% CIs for clinical characteristics with Figure 1A presents ORs for associations between
all-cause mortality as outcome. Multivariable adjust- CV diseases and different dementia disorders in com-
ment in logistic and Cox regressions was performed parison with AD as the reference, adjusted for baseline
when controlling for confounders as follows: base- characteristics and other CV diseases. All CV dis-
line characteristics including age, Mini-Mental State orders were significantly more associated with the
Examination (MMSE) score, gender, living alone, diagnoses of mixed and vascular dementia. The rela-
diagnostic unit, total number of drugs; CV diseases tionship was strongest for cerebrovascular diseases in
including ischemic heart disease, atrial fibrillation and vascular dementia (OR = 5.61; 95% CI = 5.08–6.18).
flutter, heart failure, cerebrovascular disease, and dia- Cerebrovascular diseases were also significantly more
betes mellitus; CV drugs including RAS antagonists, likely in DLB (OR = 1.43; 95% CI = 1.12–1.83), while
beta blockers, diuretics, calcium channel blockers, we found the opposite for diabetes mellitus (OR = 0.59;
antithrombotic drugs, antidiabetic drugs, and lipid 95% CI = 0.44–0.80). Similarly, diabetes mellitus
modifying drugs (Table 1). A two-tailed p-value of was less associated with PDD than AD (OR = 0.40;
<0.05 was considered to be statistically significant. 94% CI = 0.27–0.59). Moreover, ischemic heart dis-
Data were analyzed using the Statistical Package for ease was less associated with PDD (OR = 0.73; 95%
the Social Sciences software version 22 (SPSS; IBM CI = 0.55–0.98) as well as with FTD (OR = 0.66; 95%
Corporation, Armonk, NY, USA). CI = 0.45–0.95) when compared to AD. All stud-
ied CV disorders were associated with unspecified
RESULTS dementia with the exception for ischemic heart dis-
ease.
Characteristics of patients
Impact of CV diseases on mortality
We studied 29 630 patients with newly diagnosed
dementia. Table 1 presents their baseline charac- During the median time of follow-up of 847 days,
teristics, including prevalence of CV comorbidities 7,886 patients died (27%). Table 2 presents haz-
and drugs. The majority of the patients were diag- ard ratios for associations between CV disorders and
nosed by specialists in memory clinics (65%), while all–cause mortality. All CV diseases were indepen-
35% received the dementia diagnosis in primary care. dent predictors of mortality in the whole population of
The most common dementia disorder was AD that dementia patients. In the adjusted analysis in the over-
accounted for 32% of the sample, followed by unspeci- all dementia population, the strongest predictors were
fied dementia (25%), mixed dementia (19%), vascular heart failure (HR = 1.54; 95% CI = 1.44–1.65) and dia-
dementia (19%), DLB (2%), PDD (1.5%), and FTD betes mellitus (HR = 1.45; 95% CI = 1.29–1.62).
(1.5%). The patients were on average 79 years old Figure 1B presents adjusted HRs for associations
at the time of dementia diagnosis and the majority of between CV disorders and all–cause mortality when
the study population were women (59%). The patients stratified by dementia disorders. All CV diseases were
Table 1 952
Description of patients
All patients Alzheimer’s Mixed Vascular Dementia with Parkinson’s Frontotemporal Unspecified p value
(n = 29 630) disease dementia dementia Lewy bodies disease dementia dementia dementia
(n = 9,603) (n = 5,610) (n = 5,504) (n = 653) (n = 447) (n = 487) (n = 7,326)
Baseline characteristics
Age 79.4 ± 7.9 77.6 ± 8.3 81.0 ± 6.6 80.1 ± 7.4 76.6 ± 7.0 75.5 ± 7.2 69.6 ± 9.5 81.1 ± 7.6 <0.001
MMSE score 21.1 ± 5.0 21.5 ± 5.0 20.9 ± 5.0 21.2 ± 4.9 21.5 ± 5.0 20.9 ± 5.1 23.7 ± 5.0 20.5 ± 5.1 <0.001
Female gender 17,596 (59%) 6,251 (65%) 3,328 (59%) 2,804 (51%) 257 (39%) 177 (40%) 264 (54%) 4,515 (62%) <0.001
Living alone 12,964 (44%) 4,027 (42%) 2,728 (49%) 2,477 (45%) 225 (35%) 97 (22%) 157 (32%) 3,252 (44%) <0.001
Diagnosed at memory clinic 19,390 (65%) 7,277 (76%) 4,874 (87%) 3,724 (67%) 614 (94%) 372 (83%) 460 (95%) 2,067 (28%) <0.001
Number of drugs 4.9 ± 3.6 4.1 ± 3.2 5.2 ± 3.5 5.9 ± 3.8 4.9 ± 3.4 6.4 ± 3.7 3.6 ± 3.4 5.0 ± 3.7 <0.001
Cardiovascular diseases
Ischemic heart disease 6,689 (23%) 1,553 (16%) 1,476 (26%) 1,792 (33%) 129 (20%) 76 (17%) 46 (9%) 1,616 (22%) <0.001
Atrial fibrillation and flutter 5,748 (19%) 1,282 (13%) 1,333 (24%) 1,569 (29%) 109 (17%) 66 (15%) 45 (9%) 1,343 (18%) <0.001
Heart failure 4,393 (15%) 911 (10%) 1,045 (19%) 1,226 (22%) 75 (12%) 51 (11%) 28 (6%) 1,055 (14%) <0.001
Cerebrovascular diseases 5,980 (20%) 838 (9%) 1,313 (23%) 2291 (42%) 94 (14%) 53 (12%) 54 (11%) 1,337 (18%) <0.001
Diabetes mellitus 4,336 (15%) 979 (10%) 911 (16%) 1,221 (22%) 57 (9%) 41 (9%) 62 (13%) 1,065 (15%) <0.001
Cardiovascular drugs
RAS antagonists 12,219 (41%) 3,213 (34%) 2,622 (47%) 2,959 (54%) 217 (33%) 118 (26%) 157 (32%) 2,933 (40%) <0.001
Beta blockers 12,456 (42%) 3,176 (33%) 2,665 (48%) 3,024 (55%) 234 (36%) 132 (30%) 134 (28%) 3,092 (42%) <0.001
Diuretics 11,323 (38%) 2,846 (30%) 2,397 (43%) 2,650 (48%) 193 (30%) 133 (30%) 113 (23%) 2,991 (41%) <0.001
Calcium channel blockers 7,999 (27%) 2,077 (22%) 1668 (30%) 1,956 (36%) 156 (24%) 57 (13%) 92 (19%) 1,993 (27%) <0.001
P. Cermakova et al. / Cardiovascular Diseases in Dementia

Antithrombotic drugs 17,724 (60%) 4,273 (45%) 4,030 (72%) 4,462 (81%) 330 (51%) 233 (52%) 165 (34%) 4,231 (58%) <0.001
Antidiabetic drugs 4,071 (14%) 922 (10%) 818 (15%) 1,130 (21%) 53 (8%) 35 (8%) 62 (13%) 1,051 (14%) <0.001
Lipid modifying drugs 10,488 (35%) 2,841 (30%) 2,246 (40%) 2,647 (48%) 203 (31%) 118 (26%) 139 (29%) 2,294 (31%) <0.001
MMSE, Mini-Mental State Exam; RAS, renin-angiotensin system.
P. Cermakova et al. / Cardiovascular Diseases in Dementia 953

Fig. 1. A) Independent associations of cardiovascular diseases with dementia disorders using Alzheimer’s disease as a comparison group, odds
ratios with 95% confidence intervals. Adjusted for baseline characteristics (age, Mini-Mental State Examination score, living alone, diagnostic
unit, total number of drugs) and cardiovascular diseases (ischemic heart disease, atrial fibrillation and flutter, heart failure, cerebrovascular
diseases, diabetes mellitus). B) Impact of cardiovascular diseases on all-cause mortality, hazard ratios with 95% confidence intervals. Adjusted
for baseline characteristics (age, Mini-Mental State Exam, living alone, diagnostic unit, total number of drugs), cardiovascular diseases (ischemic
heart disease, atrial fibrillation and flutter, heart failure, cerebrovascular diseases, diabetes mellitus), and cardiovascular drugs (renin-angiotensin
system antagonists, beta blockers, diuretics, calcium channel blockers, antithrombotic drugs, antidiabetic drugs, lipid modifying drugs).

linked to a higher risk of death in patients diag- DISCUSSION


nosed with AD, mixed and vascular dementia. In DLB
patients, ischemic heart disease was a significant pre- We performed a cohort study and investigated CV
dictor of all–cause mortality (adjusted HR = 1.72; 95% comorbidities in ∼30,000 dementia patients, their
CI = 1.16–2.55), while there were no significant asso- treatment and impact on mortality. We found that 23%
ciations between the other CV disorders and death. of the patients were affected with ischemic heart dis-
On the other hand, in PDD patients, heart failure and ease and 20% suffered from cerebrovascular diseases.
diabetes mellitus were associated with a significantly Heart failure had the strongest prognostic impact on
higher risk of death (HR = 3.06; 95% CI = 1.74–5.41 death. Moreover, we observed differences in the bur-
and HR = 3.44; 95% CI = 1.31–9.03). In FTD patients, den of CV diseases and impact on mortality among
ischemic heart disease and atrial fibrillation or flut- different dementia disorders.
ter significantly predicted death (HR = 2.11; 95%
CI = 1.08–4.14 and HR = 3.15; 95% CI = 1.60–6.22, CV diseases in different dementia disorders
respectively). All studied CV diseases were linked to
an increased risk of death in patients with unspecified Although CV risk factors are primarily associated
dementia except for ischemic heart disease. with vascular dementia, they are also important risk
954 P. Cermakova et al. / Cardiovascular Diseases in Dementia

Table 2
Impact of cardiovascular diseases on mortality in the whole population, hazard ratios with 95% confidence intervals
All patients (n = 29 630)
Crude analysis
Ischemic heart disease 1.65 (1.58–1.73)×
Atrial fibrillation and flutter 2.04 (1.94–2.14)×
Heart failure 2.52 (2.40–2.65)×
Cerebrovascular diseases 1.71 (1.63–1.80)×
Diabetes mellitus 1.35 (1.27–1.43)×
Adjusted for age, gender, MMSE, and type of dementia disorder
Ischemic heart disease 1.41 (1.34–1.48)×
Atrial fibrillation and flutter 1.69 (1.60–1.78)×
Heart failure 1.98 (1.87–2.09)×
Cerebrovascular diseases 1.40 (1.33–1.48)×
Diabetes mellitus 1.35 (1.27–1.44)×
Complete adjustment∗
Ischemic heart disease 1.28 (1.20–1.36)×
Atrial fibrillation and flutter 1.35 (1.27–1.44)×
Heart failure 1.54 (1.44–1.65)×
Cerebrovascular diseases 1.33 (1.25–1.41)×
Diabetes mellitus 1.45 (1.29–1.62)×
∗ Adjusted for baseline characteristics (age, MMSE, gender, living alone, diagnostic unit, total number of drugs), cardiovascular disease (ischemic

heart disease, atrial fibrillation and flutter, heart failure, cerebrovascular diseases and diabetes mellitus), cardiovascular drugs (RAS antagonists,
beta blockers, diuretics, calcium channel blockers, antithrombotic drugs, antidiabetic drugs, lipid modifying drugs), and type of dementia
disorder.× Statistically significant at the level of p < 0.05. MMSE, MiniMental State Exam.

factors for AD, and overlap in clinical presentation and in a recent meta-analysis that individuals with diabetes
pathology is common [6]. However, clinicians aware may have a decreased incidence of Parkinson’s disease
of CV comorbidity may be more likely to classify [23].
dementia patients with AD characteristics into mixed FTD patients are the youngest persons in the
dementia. For this reason it is not surprising that all CV dementia population, but after taking confounders into
diseases were associated with the diagnoses of mixed account, they seem to have a similar CV profile as
and vascular dementia in the present study. AD patients [10]. However, our data shows that FTD
DLB and PDD share some neuropathological and patients were less likely to suffer from ischemic heart
clinical characteristics, and some have considered disease. This is in line with a study by Kalkonde and
them as different aspects of one disease entity [19]. colleagues who found a decreased risk of developing
However, there has been insufficient knowledge on FTD in a population of veterans that suffered from
the CV profile of these groups of patients. In this heart disease [24].
study, we found a higher burden of cerebrovascular The diagnosis of unspecified dementia is often
diseases in DLB patients compared to AD. This is in set in a primary care setting, where more exten-
line with our previous study on SveDem in which we sive investigations needed to reveal the etiology of
reported that DLB patients were more likely to suf- dementia, such as lumbar puncture or an extensive
fer cerebral infarctions and speculated that this could cognitive testing, are not available. According to the
be explained by the use of antipsychotic drugs [20], national guidelines for dementia care established by
which is considered high in DLB patients in Sweden the Swedish National Board of Health and Welfare
[21]. On the other hand, both DLB and PDD patients in 2010 [25], a basal dementia work-up shall be
suffered less from diabetes mellitus than AD patients. performed in primary care and if more extensive
PDD patients were also less likely to have ischemic evaluations are needed, patients should be referred
heart disease. These findings are in line with previous to specialist care. Patients diagnosed with unspec-
studies. It has been suggested that Parkinson’s disease ified dementia are the oldest individuals with the
patients may have less CV risks and comorbidities [22]. lowest cognitive status at the time of the dementia
Sciliano and colleagues suggested that hypoglycemia diagnosis. After adjustment for variables including
in Parkinson’s disease patients could be a result of the diagnostic setting, we found a higher burden of
sympathetic denervation, reduced catecholamine and CV diseases in these patients compared to patients
cortisol production and therefore an impaired reaction who had received the diagnosis of AD. We specu-
to stress [22]. Moreover, Lu and colleagues concluded late that the presence of CV comorbidities may have
P. Cermakova et al. / Cardiovascular Diseases in Dementia 955

played a role in a physicians’ decision not to have the quality of treatment of CV diseases in larger groups
the patient examined to obtain the specific dementia of FTD patients.
diagnosis.

Impact of CV diseases on mortality Limitations and strengths

Despite their different CV profile, we found a similar This study has several limitations. The accuracy of
pattern of the influence of CV diseases on mortal- dementia diagnoses in SveDem has not been indepen-
ity risks in AD patients as in individuals with mixed, dently examined and autopsy records are not available.
vascular, and unspecified dementia. Our study there- However, these clinical diagnoses are the ones posed
fore highlights clinical significance of CV diseases in in actual clinical practice and represent the reality of
AD and stresses the importance of an interdisciplinary most patients with dementia in Sweden. Moreover, less
approach toward these patients. than 5% of the diagnoses in SveDem are changed after
In spite of the lower occurrence of diabetes mellitus the yearly follow-up [33]. The quality and recommen-
in PDD, our data demonstrate that diabetes was a strong dations for the diagnostic work-up may differ between
predictor of death in this group. Previous research sug- institutions, as both physicians with specialist compe-
gests that diabetes mellitus in Parkinson’s disease is tences for dementia and general practitioners report to
associated with more severe symptoms [26], reduced SveDem.
efficacy of levodopa therapy [26], and dementia [27]. There may be a selection bias in the groups of
One explanation for the high risk of death could be that DLB and PDD patients which could have influenced
the dysfunction of the autonomic nervous system that our results. These patients are primarily assessed and
is present in Parkinson’s disease as well as individ- treated by neurologists and we speculate that only those
uals with diabetes mellitus [28] may be exacerbated with severe cognitive problems are referred to mem-
when the two conditions co-occur. It may be specu- ory clinics and registered in SveDem. Therefore, DLB
lated that the failure to recognize hypoglycemia due and PDD patients registered in SveDem may not be as
to a low sympathetic response may mediate the higher representative [34].
mortality risk. Patients registered in SveDem and not included in
We show that heart failure was associated with a these analyses (Supplementary Figure 1) had a slightly
three times higher risk of death in PDD patients. There lower MMSE score at baseline (20.6 versus 21.1,
is evidence that heart failure is a common cause of p < 0.001, t-test), but did not differ in age of demen-
death in Parkinson’s disease patients [29]. The func- tia diagnosis (79.5 years versus 79.4, p = 0.4, t-test)
tional and prognostic significance of the sympathetic and gender (females 59.6% versus 59.4%, p = 0.8, chi
denervation in this group of patients is not clear, and square test). We cannot rule out the possibility of
it may be speculated that the autonomic dysfunction residual confounding, such as smoking, alcohol con-
could contribute to the onset of heart failure [30, 31]. sumption, or exercise. Another limitation is that this
Of note is the emerging evidence that some dopamine study lacks measurements of blood pressure and labo-
agonists used to treat Parkinson’s disease increase the ratory values such as cholesterolemia or glycemia. We
risk of heart failure [32], but may also cause ankle did not include metabolic syndrome, hypertension, and
edema leading to heart failure overdiagnosis [31]. dyslipidemia as separate entities as ICD codes may not
Surprisingly, the profile of mortality risk was differ- be the appropriate sources of these diagnoses.
ent in DLB than in PDD. Only ischemic heart disease The strength of this study is its large sample size and
was associated with a higher risk of death in DLB good quality of data on the analyzed CV diseases and
patients. Future studies on a larger sample of DLB drugs. The Swedish National Patient Register has an
patients should investigate causes of death in this dis- almost 100% coverage in the inpatient sector. Hospital-
order. based outpatient care is covered from about 80% and
Despite the previously discussed lower occurrence outpatient specialized public caregivers from almost
of ischemic heart diseases in FTD patients, we found 100%; however, primary care data are not included.
that it was associated with a doubled risk of death in this The positive predictive value of diagnoses in this reg-
group of patients. Moreover, atrial fibrillation or flutter ister is about 85–95% [16]. The Swedish Prescribed
were linked to a three times increased mortality risk. Drug Register covers all prescribed drugs dispensed in
Our findings therefore imply a clinical significance of Swedish pharmacies, but does not contain information
CV diseases in FTD. Future studies should investigate on prescriptions during hospitalizations.
956 P. Cermakova et al. / Cardiovascular Diseases in Dementia

CONCLUSIONS Benjamin EJ, Bennett D, Bernabe E, Bhalla K, Bhandari B,


Bikbov B, Bin Abdulhak A, Birbeck G, Black JA, Blencowe
H, Blore JD, Blyth F, Bolliger I, Bonaventure A, Boufous S,
The results of this study demonstrate differences in Bourne R, Boussinesq M, Braithwaite T, Brayne C, Bridgett L,
the burden and prognostic significance of CV diseases Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello
in specific dementia disorders. This has implications C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney
for the care and treatment of the different dementia P, Burstein R, Calabria B, Campbell B, Canter CE, Cara-
bin H, Carapetis J, Carmona L, Cella C, Charlson F, Chen
disorders. Additional research is needed to evaluate if H, Cheng AT, Chou D, Chugh SS, Coffeng LE, Colan SD,
the treatment of CV diseases should differ in patients Colquhoun S, Colson KE, Condon J, Connor MD, Cooper
with versus without dementia and based on the specific LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W,
dementia disorder. Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya M,
Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo
D, Degenhardt L, Dellavalle R, Delossantos A, Denenberg J,
ACKNOWLEDGMENTS Derrett S, Des Jarlais DC, Dharmaratne SD, Dherani M, Diaz-
Torne C, Dolk H, Dorsey ER, Driscoll T, Duber H, Ebel B,
Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ, Espindola P,
The authors are grateful to SveDem for providing Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT, Ferrari A,
data for this study as well as many thanks to all the Ferri CP, Fevre EM, Finucane MM, Flaxman S, Flood L, Fore-
participants (patients, caregivers, and staff). This study man K, Forouzanfar MH, Fowkes FG, Fransen M, Freeman
MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra HA, Garcia
was supported by the Swedish Brain Power, Swedish
B, Gaspari F, Gillum RF, Gmel G, Gonzalez-Medina D, Gos-
Association of Local Authorities and Regions, the selin R, Grainger R, Grant B, Groeger J, Guillemin F, Gunnell
Swedish Research Council [2012-2291, 2013-23897- D, Gupta R, Haagsma J, Hagan H, Halasa YA, Hall W, Har-
104604-23], Alzheimerfonden, Stiftelsen Dementia, ing D, Haro JM, Harrison JE, Havmoeller R, Hay RJ, Higashi
H, Hill C, Hoen B, Hoffman H, Hotez PJ, Hoy D, Huang JJ,
the Swedish Heart Lung Foundation [20080409 Ibeanusi SE, Jacobsen KH, James SL, Jarvis D, Jasrasaria R,
and 20100419], and the Stockholm County Council Jayaraman S, Johns N, Jonas JB, Karthikeyan G, Kassebaum
[20090556 and 20110120]. The funding source had no N, Kawakami N, Keren A, Khoo JP, King CH, Knowlton LM,
role in the design and conduct of the study; collection, Kobusingye O, Koranteng A, Krishnamurthi R, Laden F, Lal-
loo R, Laslett LL, Lathlean T, Leasher JL, Lee YY, Leigh
management, analysis, and interpretation of the data; J, Levinson D, Lim SS, Limb E, Lin JK, Lipnick M, Lip-
preparation, review, or approval of the manuscript; and shultz SE, Liu W, Loane M, Ohno SL, Lyons R, Mabweijano
the decision to submit the manuscript for publication. J, MacIntyre MF, Malekzadeh R, Mallinger L, Manivannan
Authors’ disclosures available online (http://j- S, Marcenes W, March L, Margolis DJ, Marks GB, Marks R,
Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH,
alz.com/manuscript-disclosures/15-0499r1). McDermott MM, McGill N, McGrath J, Medina-Mora ME,
Meltzer M, Mensah GA, Merriman TR, Meyer AC, Miglioli
SUPPLEMENTARY MATERIAL V, Miller M, Miller TR, Mitchell PB, Mock C, Mocumbi AO,
Moffitt TE, Mokdad AA, Monasta L, Montico M, Moradi-
Lakeh M, Moran A, Morawska L, Mori R, Murdoch ME,
The supplementary material is available in the Mwaniki MK, Naidoo K, Nair MN, Naldi L, Narayan KM,
electronic version of this article: http://dx.doi.org/ Nelson PK, Nelson RG, Nevitt MC, Newton CR, Nolte S,
10.3233/JAD-150499. Norman P, Norman R, O’Donnell M, O’Hanlon S, Olives
C, Omer SB, Ortblad K, Osborne R, Ozgediz D, Page A,
Pahari B, Pandian JD, Rivero AP, Patten SB, Pearce N, Padilla
REFERENCES RP, Perez-Ruiz F, Perico N, Pesudovs K, Phillips D, Phillips
MR, Pierce K, Pion S, Polanczyk GV, Polinder S, Pope CA,
3rd, Popova S, Porrini E, Pourmalek F, Prince M, Pullan RL,
[1] Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri
Ramaiah KD, Ranganathan D, Razavi H, Regan M, Rehm JT,
CP (2013) The global prevalence of dementia: A systematic
Rein DB, Remuzzi G, Richardson K, Rivara FP, Roberts T,
review and metaanalysis. Alzheimers Dement 9, 63-75 e62.
Robinson C, De Leon FR, Ronfani L, Room R, Rosenfeld LC,
[2] Smith T, Maidment I, Hebding J, Madzima T, Cheater F, Cross
Rushton L, Sacco RL, Saha S, Sampson U, Sanchez-Riera L,
J, Poland F, White J, Young J, Fox C (2014) Systematic review
Sanman E, Schwebel DC, Scott JG, Segui-Gomez M, Shahraz
investigating the reporting of comorbidities and medication
S, Shepard DS, Shin H, Shivakoti R, Singh D, Singh GM,
in randomized controlled trials of people with dementia. Age
Singh JA, Singleton J, Sleet DA, Sliwa K, Smith E, Smith JL,
Ageing 43, 868-872.
Stapelberg NJ, Steer A, Steiner T, Stolk WA, Stovner LJ, Sud-
[3] Bunn F, Burn AM, Goodman C, Rait G, Norton S, Robinson
feld C, Syed S, Tamburlini G, Tavakkoli M, Taylor HR, Taylor
L, Schoeman J, Brayne C (2014) Comorbidity and dementia:
JA, Taylor WJ, Thomas B, Thomson WM, Thurston GD, Tley-
A scoping review of the literature. BMC Med 12, 192.
jeh IM, Tonelli M, Towbin JA, Truelsen T, Tsilimbaris MK,
[4] Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD,
Ubeda C, Undurraga EA, van der Werf MJ, van Os J, Vavi-
Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S,
lala MS, Venketasubramanian N, Wang M, Wang W, Watt K,
Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY,
Weatherall DJ, Weinstock MA, Weintraub R, Weisskopf MG,
Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews
Weissman MM, White RA, Whiteford H, Wiebe N, Wiersma
KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S,
ST, Wilkinson JD, Williams HC, Williams SR, Witt E, Wolfe
Barrero LH, Bartels DH, Basanez MG, Baxter A, Bell ML,
P. Cermakova et al. / Cardiovascular Diseases in Dementia 957

F, Woolf AD, Wulf S, Yeh PH, Zaidi AK, Zheng ZJ, Zonies nal review and validation of the Swedish national inpatient
D, Lopez AD, AlMazroa MA, Memish ZA (2012) Disability- register. BMC Public Health 11, 450.
adjusted life years (DALYs) for 291 diseases and injuries in [17] Wettermark B, Hammar N, Fored CM, Leimanis A, Otterblad
21 regions, 1990-2010: A systematic analysis for the Global Olausson P, Bergman U, Persson I, Sundstrom A, West-
Burden of Disease Study 2010. Lancet 380, 2197-2223. erholm B, Rosen M (2007) The new Swedish Prescribed
[5] O’Flaherty M, Buchan I, Capewell S (2013) Contributions of Drug Register–opportunities for pharmacoepidemiological
treatment and lifestyle to declining CVD mortality: Why have research and experience from the first six months. Pharma-
CVD mortality rates declined so much since the 1960s? Heart coepidemiol Drug Saf 16, 726-735.
99, 159-162. [18] Schneeweiss S, Seeger JD, Maclure M, Wang PS, Avorn J,
[6] Cermakova P, Eriksdotter M, Lund LH, Winblad B, Religa Glynn RJ (2001) Performance of comorbidity scores to con-
P, Religa D (2015) Heart failure and Alzheimer’s disease. J trol for confounding in epidemiologic studies using claims
Intern Med 277, 406-425. data. Am J Epidemiol 154, 854-864.
[7] Mielke MM, Rosenberg PB, Tschanz J, Cook L, Corcoran [19] Aarsland D, Londos E, Ballard C (2009) Parkinson’s disease
C, Hayden KM, Norton M, Rabins PV, Green RC, Welsh- dementia and dementia with Lewy bodies: Different aspects
Bohmer KA, Breitner JC, Munger R, Lyketsos CG (2007) of one entity. Int Psychogeriatr 21, 216-219.
Vascular factors predict rate of progression in Alzheimer dis- [20] Fereshtehnejad SM, Damangir S, Cermakova P, Aarsland
ease. Neurology 69, 1850-1858. D, Eriksdotter M, Religa D (2014) Comorbidity profile in
[8] Regan C, Katona C, Walker Z, Hooper J, Donovan J, dementia with Lewy bodies versus Alzheimer’s disease: A
Livingston G (2006) Relationship of vascular risk to the pro- linkage study between the Swedish Dementia Registry and
gression of Alzheimer disease. Neurology 67, 1357-1362. the Swedish National Patient Registry. Alzheimers Res Ther
[9] Batty GD, Russ TC, Starr JM, Stamatakis E, Kivimaki 6, 65.
M (2014) Modifiable cardiovascular disease risk factors [21] Johnell K, Religa D, Eriksdotter M (2013) Differences in
as predictors of dementia death: Pooling of ten general drug therapy between dementia disorders in the Swedish
population-based cohort studies. J Negat Results Biomed dementia registry: A nationwide study of over 7,000 patients.
13, 8. Dement Geriatr Cogn Disord 35, 239-248.
[10] Cermakova P, Fereshtehnejad SM, Johnell K, Winblad B, [22] Scigliano G, Musicco M, Soliveri P, Piccolo I, Ronchetti G,
Eriksdotter M, Religa D (2014) Cardiovascular medica- Girotti F (2006) Reduced risk factors for vascular disorders in
tion burden in dementia disorders: A nationwide study of Parkinson disease patients: A case-control study. Stroke 37,
19,743 dementia patients in the Swedish Dementia Registry. 1184-1188.
Alzheimers Res Ther 6, 34. [23] Lu L, Fu DL, Li HQ, Liu AJ, Li JH, Zheng GQ (2014) Diabetes
[11] Religa D, Fereshtehnejad SM, Cermakova P, Edlund AK, and risk of Parkinson’s disease: An updated meta-analysis of
Garcia-Ptacek S, Granqvist N, Hallback A, Kawe K, Farah- case-control studies. PLoS One 9, e85781.
mand B, Kilander L, Mattsson UB, Nagga K, Nordstrom P, [24] Kalkonde YV, Jawaid A, Qureshi SU, Shirani P, Wheaton M,
Wijk H, Wimo A, Winblad B, Eriksdotter M (2015) SveDem, Pinto-Patarroyo GP, Schulz PE (2012) Medical and environ-
the Swedish Dementia Registry - A tool for improving the mental risk factors associated with frontotemporal dementia:
quality of diagnostics, treatment and care of dementia patients A case-control study in a veteran population. Alzheimers
in clinical practice. PLoS One 10, e0116538. Dement 8, 204-210.
[12] World Health, Organization (1993) The ICD-10 Classification [25] Socialstyrelsen (2010) National Guidelines for Care in cases
of Mental and Behavioral Disorders: Diagnostic Criteria for of Dementia. The National Board of Health and Welfare.
Research, World Health Organization, Geneva. [26] Cereda E, Barichella M, Cassani E, Caccialanza R, Pezzoli
[13] McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, G (2012) Clinical features of Parkinson disease when onset
Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aars- of diabetes came first: A case-control study. Neurology 78,
land D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del 1507-1511.
Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez- [27] Sandyk R, Awerbuch GI (1992) The association of diabetes
Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, mellitus with dementia in Parkinson’s disease. Int J Neurosci
Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, 64, 209-212.
Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima [28] Kanjwal K, George A, Figueredo VM, Grubb BP (2015)
S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier Orthostatic hypotension: Definition, diagnosis and manage-
F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Consor- ment. J Cardiovasc Med (Hagerstown) 16, 75-81.
tium on DLB (2005) Diagnosis and management of dementia [29] Fernandez HH, Lapane KL (2002) Predictors of mortality
with Lewy bodies: Third report of the DLB Consortium. among nursing home residents with a diagnosis of Parkinson’s
Neurology 65, 1863-1872. disease. Med Sci Monit 8, CR241-CR246.
[14] (1994) Clinical and neuropathological criteria for frontotem- [30] Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon
poral dementia. The Lund and Manchester Groups. J Neurol RO, 3rd (2000) Cardiac sympathetic denervation in Parkinson
Neurosurg Psychiatry 57, 416-418. disease. Ann Intern Med 133, 338-347.
[15] Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, [31] Zesiewicz TA, Strom JA, Borenstein AR, Hauser RA, Cimino
Mizuno Y, Broe GA, Cummings J, Dickson DW, Gau- CR, Fontanet HL, Cintron GB, Staffetti JF, Dunne PB, Sulli-
thier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy van KL (2004) Heart failure in Parkinson’s disease: Analysis
R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, of the United States medicare current beneficiary survey.
Sampaio C, Tolosa E, Dubois B (2007) Clinical diagnostic Parkinsonism Relat Disord 10, 417-420.
criteria for dementia associated with Parkinson’s disease. [32] Perez-Lloret S, Rey MV, Crispo J, Krewski D, Lapeyre-
Mov Disord 22, 1689-1707; quiz 1837. Mestre M, Montastruc JL, Rascol O (2014) Risk of heart
[16] Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim failure following treatment with dopamine agonists in Parkin-
JL, Reuterwall C, Heurgren M, Olausson PO (2011) Exter- son’s disease patients. Expert Opin Drug Saf 13, 351-360.
958 P. Cermakova et al. / Cardiovascular Diseases in Dementia

[33] Garcia-Ptacek S, Farahmand B, Kareholt I, Religa D, [34] Fereshtehnejad SM, Religa D, Westman E, Aarsland D, Lokk
Cuadrado ML, Eriksdotter M (2014) Mortality risk after J, Eriksdotter M (2013) Demography, diagnostics, and medi-
dementia diagnosis by dementia type and underlying factors: cation in dementia with Lewy bodies and Parkinson’s disease
A cohort of 15,209 patients based on the Swedish Dementia with dementia: Data from the swedish dementia quality reg-
Registry. J Alzheimers Dis 41, 467-477. istry (SveDem). Neuropsychiatr Dis Treat 9, 927-935.