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Antipsychotic Treatment Associated With

Increased Mortality Risk in Patients With

Dementia. A Registry-Based Observational

Cohort Study

Emilia Schwertner, Juraj Secnik, Sara Garcia-Ptacek, Bjorn Johansson, Katarina

Nägga, Maria Eriksdotter, Bengt Winblad and Dorota Religa

The self-archived postprint version of this journal article is available at Linköping

University Institutional Repository (DiVA):

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-155561

N.B.: When citing this work, cite the original publication.

Schwertner, E., Secnik, J., Garcia-Ptacek, S., Johansson, B., Nägga, K., Eriksdotter, M., Winblad, B.,

Religa, D., (2019), Antipsychotic Treatment Associated With Increased Mortality Risk in Patients With

Dementia. A Registry-Based Observational Cohort Study, Journal of the American Medical Directors

Association, 20(3), 323-329.e2. https://doi.org/10.1016/j.jamda.2018.12.019

Original publication available at:

https://doi.org/10.1016/j.jamda.2018.12.019

Copyright: Elsevier

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Antipsychotic Treatment Associated With Increased Mortality Risk in Patients

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Original Study

Antipsychotic Treatment Associated With Increased Mortality Risk

in Patients With Dementia. A Registry-Based Observational Cohort

Study

Emilia Schwertner MSc

a

, Juraj Secnik MD

a

, Sara Garcia-Ptacek PhD

a,b

,

Björn Johansson PhD

c,d

, Katarina Nagga PhD

e,f

, Maria Eriksdotter PhD

a,d

,

Bengt Winblad PhD

d,g

, Dorota Religa PhD

a,d,

*

aCenter for Alzheimer Research, Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge,

Sweden

bDepartment of Internal Medicine, Section for Neurology, Södersjukhuset, Stockholm, Sweden cDepartment of Molecular Medicine and Surgery Stockholm, Karolinska Institutet, Sweden dTheme Aging, Karolinska University Hospital, Huddinge, Sweden

eClinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden fDepartment of Acute Internal Medicine and Geriatrics, Linköping University, Linköping, Sweden

gCenter for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge,

Sweden Keywords: Antipsychotics dementia mortality Alzheimer vascular dementia mixed dementia

a b s t r a c t

Objective: To assess all-cause mortality patients with dementia treated with typical and atypical anti-psychotic drugs (APDs).

Design: Registry-based cohort study.

Setting and participants: A total of 58,412 patients diagnosed with dementia and registered in the Swedish Dementia Registry were included in the study. Of the study sample, 2526 of the patients were prescribed APDs. Of these, 602 patients were prescribed typical APDs and 1833 patients were prescribed atypical APDs. Ninety-one patients were prescribed both typical and atypical APDs.

Measurements: All-cause mortality based on Swedish Cause of Death Register. Adjusted hazard ratios of mortality were calculated according to class of APDs (typical or atypical) prescribed. Final models were adjusted for age at dementia diagnosis, sex, Charlson comorbidity index, living arrangement, and Mini-Mental State Examination.

Results: In the adjusted models, use of APDs at the time of dementia diagnosis was associated with

increased mortality risk in the total cohort (hazard ratio¼ 1.4; 95% confidence interval 1.3e1.5). After

stratifying for dementia types, increased mortality risks associated with APDs were found in patients with Alzheimer’s disease, mixed dementia, unspecified dementia, and vascular dementia. Higher risk for mortality was found with typical APDs in patients with mixed and vascular dementia and with atypical APDs in patients with Alzheimer’s disease, mixed, unspecified, and vascular dementia. Furthermore, in patients with Alzheimer’s disease who had typical APDs, use lower risk of death emerged in comparison with patients with atypical APDs.

Conclusions/Implications: Both the use of atypical and typical APDs increased the risk of death in patients with dementia even after adjusting for differences in basic characteristics between groups. Although we

SveDem is supportedfinancially by the Swedish Brain Power network (http://

swedishbrainpower.se), the Swedish Associations of Local Authorities and

Re-gions, Gun och Bertil Stohnes Stiftelse, CIMED grant, Alzheimerfonden, and Swedish Research Council (Drn 2012-2291 and Drn 2016-02317), and by grants provided by the Stockholm County Council (ALF project). None of the sponsors had any involvement in the design of the study, the data collection and analysis, the writing of the report, or the decision to submit the paper for publication.

All authors have completed the ICMJE uniform disclosure form atwww.icmje. org/coi_disclosure.pdfand declare: no support from any organization for the sub-mitted work, nofinancial relationships with any organizations that might have an

interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

This study was approved by the regional ethical review board in Stockholm, Sweden. Ethical Number: 2015/2232-31/5.

The authors declare no conflicts of interest.

* Address correspondence to Dorota Religa, PhD, Department of Neurobiology, Care Sciences and Society (NVS), H1, Division of Clinical geriatrics, Sektionen För Klinisk Geriatrik, Plan 7 141 83 Huddinge, Sweden.

E-mail address:dorota.religa@ki.se(D. Religa).

https://doi.org/10.1016/j.jamda.2018.12.019

1525-8610/Ó 2018 Published by Elsevier Inc. on behalf of AMDA e The Society for Post-Acute and Long-Term Care Medicine.

JAMDA

j o u r n a l h o m e p a g e : w w w . j a m d a . c o m

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cannot rule out the influence of residual confounding, these results would seem to add to studies suggesting caution in APD prescription for patients with dementia.

Ó 2018 Published by Elsevier Inc. on behalf of AMDA e The Society for Post-Acute and Long-Term Care Medicine.

Dementia is a general term for a clinical syndrome caused by

neurodegeneration.1Survival time after dementia diagnosis has been

reported to range between 1.1 and 8.5 years2and interactions of many

different factors influence survival of a patient. In a previous study, it

was shown that patients with other dementia diagnoses had a higher

risk of death compared with patients with Alzheimer’s disease (AD).3

Other risk factors are older age, functional impairment, male sex, low body mass index, severity of dementia, institutionalization, and higher

number of medications.3e5Previous studies have also raised concerns

about the use of antipsychotic drugs (APDs), which are mainly pre-scribed to treat behavioral and psychological symptoms of dementia

(BPSD).6,7Approximately 80% of patients with dementia will suffer

from at least 1 symptom during the course of disease,8 and this

significantly decreases the quality of life of both the patients and their

carers,9often underlying the decision for institutionalization10,11and

contributing to the progression of dementia.12

Both atypical and typical APDs are used in the management of BPSD. There are numerous studies showing that APD treatment in patients with dementia may lead to serious side effects including death. A meta-analysis of 15 randomized controlled trials (RCTs) showed that short-term treatment with atypical APDs increases the

risk of death 1.54 times compared with placebo treatment.13

Subse-quently, observational studies found that typical APDs may convey

similar14or even higher risk of death relative to atypical APDs.15On

the other hand, other studies suggest that this association does not

persist when adjusting for BPSD,16use of restraints,17or other clinical

factors like severity of dementia.18 Similarly, no difference in

long-term survival was found between patients with BPSD with and

without APD treatment.4 This lack of association was further

sup-ported by recent studies with a long follow-up period19as well as in

meta-analyses of RCTs.20

Furthemore, it is not clear whether APD treatment significantly

contributes to improvement of BPSD in patients with dementia. An RCT of patients with AD showed a clear positive effect of olanzapine and risperidone in treating patients with neuropsychiatric symptoms

compared with placebo and quetiapine.21However, the benefits were

observed only among those patients who tolerated the medications. Studies suggest that whether advantages of APDs can offset their

adverse effects may depend on the individual profile of a patient

including the specific BPSD manifestations and dementia severity.22

Therefore, it is important to identify factors associated with sur-vival and mortality of patients with APD treatment. Previous studies have either concentrated on patients with AD or made no distinction between different types of dementia. To our knowledge, there is only 1

study including exclusively patients with vascular dementia (VAD).23

If the effect of APDs varies in less common diagnoses, conclusions may be impeded by a lack of research on the subject. Moreover, to our knowledge, little research exists on the mixed-pathology dementia

and unspecified (UNS) dementia diagnoses with no studies

consid-ering antipsychotic treatment. To help address these questions, we used data on patients with dementia registered in Swedish Dementia

Registry (SveDem).24The large size of the database used in the current

study enables an extensive description of the effects of typical and atypical APD treatment on mortality in patients with different de-mentia diagnoses and, therefore, enables us to develop a more comprehensive picture of the risk of death associated with APDs.

In this study, we report the risk of long-term mortality of patients with different dementia diagnoses associated with being treated with

typical and atypical APDs. Adjustments were made for the most relevant clinical and sociodemographic factors that may have an impact on the survival of patients with dementia.

Methods

We studied patients diagnosed with dementia and registered at

the time of diagnosis in the SveDem.24SveDem was established in

May 2007 with the goal to improve the quality of care of patients with dementia disorders in Sweden and contains information about the diagnostic work-up, medical treatment, and community support. Dementia was categorized into 8 diagnoses: AD, VAD, mixed de-mentia, dementia with Lewy bodies (DLB), frontotemporal dementia

(FTD), Parkinson’s disease dementia, UNS dementia (used when

spe-cific dementia diagnosis was not recognized), and other dementia

types (including various dementia disorders eg, Corticobasal degen-eration and alcohol related dementias). Patients are diagnosed and followed-up yearly in specialist units, primary care centers, or in nursing homes. Clinicians were instructed to diagnose the type of dementia according to the 10th revision of the International Statistical

Classification of Diseases and Related Health Problems, 10th Revision.25In

addition, the McKeith criteria26 for DLB, the Lund-Manchester

criteria27 for FTD, and the Movement Disorder Society Task Force

criteria28for PDD are recommended for diagnosis purposes.

We used the following Anatomical Therapeutic Chemical Classi

fica-tion System codes (see: http://www.whocc.no/atc_ddd_index) for

antipsychotics classes: typical: N05AA phenothiazines with aliphatic side-chain, N05AB phenothiazines with piperazine structure, N05AD phenothiazines with piperidine structure, N05AF thioxanthene de-rivatives; atypical: N05AE indole derivatives, N05AH diazepines,

oxazepines, thiazepines, and oxepines, and N05AX other

antipsychotics.

The study population consisted of 58,412 patients registered at the time of dementia diagnosis in SveDem between 2007 and 2015. After removing duplicates (258) from SveDem and patients with missing data on dementia diagnosis (117), we obtained a study population of

58,037 patients. The file was merged with the Swedish Prescribed

Drug Register, Swedish Cause of Death Register, and patients

regis-tered in The National Board of Health and Welfare (http://www.

socialstyrelsen.se). To decrease the risk of survival bias, we

restricted the analysis of patients who had APD prescriptions after and

within thefirst year after the dementia diagnosis was established and

patients not taking APDs. Thefinal sample contained 56,048 patients.

Survival time was calculated individually for all patients from de-mentia diagnosis to date of death or end of follow-up as of August 28, 2016.

Statistical Analyses

Baseline characteristics were described with frequencies and per-centages for categorical variables and means and standard deviations (SDs) for continuous variables. To analyze differences between

pa-tients, t tests for independent samples or analysis of variance and

c

2

tests were performed for continuous and categorical variables, respectively. We used Kaplan-Meier method to estimate median sur-vival time and reverse Kaplan-Meier method to calculate median time

of follow-up.29To test the proportional hazard assumption for main

predictors, we plotted the Schoenfeld residuals as a function of time

E. Schwertner et al. / JAMDA 20 (2019) 323e329 324

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and tested the hypothesis of a zero slope. Next, we ran separate Cox multivariate regression models to estimate the risk of death associated with APD use compared with nonuse for the entire cohort and

strat-ified by dementia type. From these models, we derived crude and

adjusted estimates of hazard ratio (HR) and corresponding 95% con-fidence intervals (CIs). Final models were adjusted for age at dementia diagnosis, sex, and form of residency (living alone in ordinary housing, with a family member in ordinary housing, or in a nursing home), Mini-Mental State Examination (MMSE) used to assess severity of

dementia and Charlson comorbidity index (CCI) for comorbidity.30

Subsequently, we repeated analyses to compare users of typical and atypical APDs. Previous studies suggest that PDD and DLB may pertain

to the same disease spectrum31and consequently, we merged the 2

diagnoses into 1 group called LBD. The assumption for proportional hazard was violated in the VAD group, therefore, interactions with time were used to model the association in this diagnosis. Subse-quently, we inspected residual plots and divided data into 2 epochs of

thefirst 360 days and greater than that. Separate hazard functions

were fit for each time-band. Data were analyzed with the Survival

Package for R statistical software (the R Foundation for Statistical

Computing, Vienna, Austria).32,33

Results

Description of the Study Population

The results are presented as means (standard deviation) for

continuous variables (age, MMSE, CCI, number of drugs) or number of patients, and percentage for categorical variables (dementia type, sex, form of residency). The study sample contained 59% women and 41% men. The mean age was 79.7 (7.9) years and mean MMSE score was 20.9 (5.0) points. AD (31%) was the most common dementia diagnosis

followed by UNS dementia (25%), VAD (19%), and mixed dementia (18%). LBD (4%), other types of dementia (3%), and FTD (2%) together

accounted for less than 8% of all dementia diagnoses (Table 1). In the

sample, 4% (n¼ 2526) of the patients had an APD prescription: 602

had only typical APDs and 1833 had only atypical APDs. Ninety-one patients had both typical and atypical APDs prescribed. There were differences in APD use between the different dementia diagnoses. Among patients receiving APDs, typical APD use was lowest in pa-tients with LBD (13%), followed by other (23%), VAD (24%), FTD (24%), UNS dementia (25%), AD (26%), and mixed dementia (32%). Atypical use was lowest in mixed dementia (68%), followed by AD (74%), UNS dementia (75%), VAD (76%), FTD (76%), other (77%), and LBD (87%). A description of patients with and without APD treatment is provided in

Table 2.

Mortality in Patients Receiving APDs

Kaplan-Meier survival estimates for the median (95% CI) survival time after diagnosis was 1793 (range 1773e1812) days. Median (95% CI) time of follow-up was 1469 (range 1458e1495) days. Of patients treated with APDs, 61% died at the end of the study, and of patients not receiving APDs, 41% died. Among deceased patients with APD use, 63% had received typical and 58% atypical APDs. Use of typical and atypical APDs was associated with increased mortality risk compared with no APD use in the entire cohort [HR (95% CI): typical APDs: 1.4 (1.2e1.5), atypical APDs: 1.4 (1.3e1.5) (adjusted for sex, age, MMSE, CCI, and form of residency)].

After stratifying for dementia diagnoses, statistically significant

as-sociations between APD use and increased risk of mortality compared with non-APD use were found in AD [atypical: 1.5 (1.3e1.8), mixed dementia (typical: 1.3 (1.1e1.6); atypical: 1.3 (1.1e1.6))], and UNS de-mentia [atypical: 1.3 (1.2e1.5)]. In VAD after including interactions with

Table 1

Description of Patients Included in the Study

N¼ 56,048 Total Missing AD (17 315) Mixed Dementia (10,336)

VAD (10,512) LBD (1127) FTD (816) UNS Dementia (13,813) Other (1 398) P Age mean, y (SD) 79.72 (7.87) 0 (0) 77.93 (8.19) 81.26 (6.59) 80.67 (7.25) 76.38 (7.20) 70.34 (9.28) 81.44 (7.43) 76.14 (9.84) <.001 Female sex n (%) 32996 (59) 0 (0) 11 133 (64) 6 096 (59) 5 481 (52) 705 (37) 431 (53) 8 436 (61) 714 (51) <.001 MMSE mean (SD) 20.88 (5.03) 3 975 (7) 21.28 (4.98) 20.71 (4.97) 20.87 (4.98) 21.25 (4.81) 23.14 (5.37) 20.26 (5.08) 21.28 (5.18) <.001 CCI mean (SD) 2.36 (1.77) 0 (0) 1.94 (1.49) 2.52 (1.82) 3.03 (2.05) 2.10 (1.62) 1.88 (1.48) 2.31 (1.71) 2.29 (1.65) <.001 TND mean (SD) 5.54 (3.34) 6 520 (12) 4.85 (3.07) 5.78 (3.31) 6.3 (3.51) 5.87 (3.35) 4.66 (3.28) 5.59 (3.34) 5.34 (3.50) <.001 Living arrangement: <.001 Alone, ordinary housing n (%) 23 063 (41) 469 (1) 6 928 (40) 4 697 (46) 4 294 (41) 451 (24) 255 (31) 5 894 (43) 544 (40) Ordinary housing n (%) 26 606 (48) 9 288 (54) 4 747 (46) 4 703 (45) 1 150 (62) 505 (62) 5 619 (41) 594 (43) Special residency n (%) 5 910 (11) 998 (6) 864 (8) 1 436 (14) 255 (14) 56 (7) 2 063 (15) 238 (17)

TND, total number of drugs.

Table 2

Differences Between Patients Without APDs, With APDs, and With Typical and Atypical APDs

No APDs (n¼ 53, 522) APDs (n¼ 2526) P* Typical (n¼ 601) Atypical (n¼ 1833) Py Age, mean (SD), y 79.7 (7.9) 80.5 (8.07) <.001 81.16 (7.8) 80.32 (8.2) .03 Female sex, n (%) 31 495 (59) 1501 (59) .58 370 (62) 1075 (59) .22 MMSE, mean (SD) 20.96 (5.0) 19.08 (5.5) <.001 18.74 (5.7) 19.27 (5.4) .06 CCI, mean (SD) 2.35 (1.8) 2.48 (1.8) <.001 2.64 (2.0) 2.42 (1.8) .52

Living arrangement: <.001 <.001

Ordinary housing, living alone, n (%) 22,175 (42) 888 (35) 200 (34) 661 (36) Ordinary housing, n (%) 25,752 (49) 854 (34) 177 (30) 652 (36) Nursing home, n (%) 5144 (10) 766 (31) 200 (37) 506 (28)

Deaths, n (%) 21,765 (41) 1510 (60) <.001 379 (63) 1072 (58) .05 *Comparison between APDs and no APDs.

yComparison between typical and atypical APDs.

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time, adjusted HR in the first epoch for typical APDs comparing non-APD use was 1.8 (1.1e2.8), and in the second epoch 1.6 (1.2e2.1); for atypical APDs 1.5 (1.2e2.0) in the first epoch and 1.2 (1.0e1.4), in the

second epoch (Supplemental Table 1). Assuming proportional hazards:

typical: 1.6 (1.3e2.1); atypical: 1.3 (1.1e1.5), P < .001.

Additionally, in patients with AD, typical APD use was associated with lower risk of death compared with atypical APDs [0.7 (0.5e0.9)]. In patients with LBD, there was a nonsignificant trend of

increased risk of death with typical APD use compared with non-APD use: 1.4 (0.9e2.1), P ¼ .13; and atypical non-APD use 1.4 (0.9e2.2),

P¼ .19. In patients with VAD, typical APD use showed a

nonsignif-icant trend of increasing death risk compared with atypical APD use in the second epoch (1.3 (0.9e1.8), P ¼ .54) but not in the first one [1.2 (0.7e2.0), P ¼ .11]. A nonsignificant trend toward higher risk of death with typical APD use compared with atypical APD use was also

found assuming proportional hazards 1.3 (1.0-1.7), P¼ .08 (Figure 1,

Fig. 1. Cox multivariate analyses assessing all-cause mortality risk associated with APD for different dementia diagnoses. VAD: Assuming proportional hazard; Typical and atypical compared with no APDs; Typical1compared with atypical APDs; Total (typicalþ atypical) compared with no APDs.

E. Schwertner et al. / JAMDA 20 (2019) 323e329 326

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crude model:Supplemental Table 2; survival curvesSupplemental

Figure 1).

Discussion

In our study, 4% of patients with newly established dementia diagnosis used APDs. Use of APDs was associated with risk for death, and these results are in line with previous studies showing higher

death risk with APD use in patients with dementia.13,14 However,

when each specific dementia diagnosis was considered, we found

differences in survival for patients with different diagnoses. More

specifically, in patients with AD, a reduced death risk for typical APDs

treatment compared with atypical APD treatment was found. More-over, typical APDs were associated with similar mortality risk as lack of APD treatment and only atypical APDs were increasing risk of death. To our knowledge, this has not been previously described. Similar to patients with AD, the increased mortality in patients with UNS de-mentia was found only with atypical APD use. It is, therefore, possible

that this group includes a number of patients with AD,24which may

contribute to this effect. Both atypical and typical APDs were associ-ated with the increased risk of death in patients with VAD and mixed

dementia. We also identified nonsignificant trends indicating

increased risk of death for typical APD use compared to atypical APD use in patients with VAD and for typical APD use compared with atypical use and no APDs in patients with LBD.

Although part of the effect of APDs could be explained by the condition of patients with APDs, the association persists even after adjusting for differences between patients with and without APD treatment. Our data show that patients with APD treatment were slightly older, had a poorer cognition, more often lived in nursing home, and had higher total amount of drugs and comorbidity index at the time of dementia diagnosis.

It has been known that patients with LBD are particularly vulner-able for severe neuroleptic sensitivity reaction (NSR), even with low

doses or atypical APDs.34 NSR usually includes increase in

Parkin-sonism, confusion, rigidity, immobility, and,finally, increased risk of

mortality.34,35Dysfunctions in dopamine D2 receptors were suggested

as a main mechanism predisposing patients with LBD for NSR.36

However, it has been shown that frequency of severe NSR differs with different atypical APDs (the highest olanzapine and the lowest with thioridazine and clozapine), which may indicate that there may

be also other mechanisms involved.34

In patients with AD and VAD, the high degree of heterogeneity of

studies leads to contradictoryfindings and as a result, conclusions are

not easily drawn (eg, a meta-analysis of observational studies indicated

no association between APDs use and mortality of patients with AD).37

However, after excluding key contributors to the heterogeneity, the pooled relative risk of a systematic meta-analysis showed 2.08 (95% CI 1.39e3.13) higher risk of death with APDs. In another study of a cohort of 45,894 patients with AD with a 12-year follow-up, APD use showed an increase of mortality rate [2.28 (2.20e2.35)] compared with no

expo-sure.38Similarly, results from a double-blind randomized clinical trial

suggested a persistent risk of increased mortality with the long-term use

of antipsychotics in patients with AD.6Contradicting our results,

sys-tematic meta-analysis37 found no difference in mortality among

pa-tients with AD between typical and atypical APD use. However, evidence from broader studies corroborates our results. A recent publication

including participants with APD use of all ages39indicates higher

mor-tality with atypical antipsychotics compared with typical. In addition, authors also found differences among individual atypical APD use. To our knowledge, there is only 1 study including only patients with VAD, and it reports no increase in mortality risk with atypical APD use

(compared with no APD treatment).23However, when stratified for

in-dividual agents, there was a trend showing that patients exposed to

quetiapine had a 1.13 times higher risk of mortality (95% CI 0.92e1.37) compared with nonexposed patients with VAD.

Several mechanisms have been discussed in conjunction with increased mortality with antipsychotic treatment. However, studies exploring potential mechanisms underpinning higher mortality for APD treatment among patients with AD and VAD are scarce. Generally, atypical APDs, which occupy dopamine D2 receptors only transiently, are thought to be associated with lower risk of extrapyramidal

symp-toms.40However, it is complicated by the fact that with increasing doses

the risk of extrapyramidal symptoms equals the risk caused by typical APDs. When the dose of APDs is considered, atypical APDs are not safer than typical antipsychotics in relation to the development of

parkin-sonism.41 Despite this, a misconception that atypical APDs are less

harmful than typical APDs is still common. Morevoer, patients with AD in our sample were younger and had lower comorbidity and MMSE score at the time of dementia diagnosis compared with patients with

VAD and mixed dementia. It is possible that it could influence a decision

to prescribe higher doses of atypical APDs to patients with AD and thereby contribute to obtained results.

Moreover, cardio- and cerebrovascular events have previously

been reported to be a serious side effect of APD treatment.42High rates

of ventricular arrhythmias and cardiac arrest have been shown to be

associated with typical APDs43 and high rates of venous

thrombo-embolism with atypical APDs.44Both typical and atypical APDs have

been associated with QT prolongation.45Because of coexisting cardiac

disease, patients with VAD and mixed dementia may be particularly

susceptible for both types of APDs. Further, Moretti et al46did notfind

any difference in the risk of stroke or myocardial infarction between atypical and typical APDs in patients with VAD. In patients with AD, only 1 study reported higher incidence of cerebrovascular adverse events (an increased risk of transient ischemic attack) associated with

atypical APDs but not typical APDs.47

Moreover, BPSD may lead to risk-taking behavior48 that adds

additional burden to the ongoing neurodegeneration. Thus, BPSDs, which motivate both typical and atypical APD use, are also a major reason for poor functioning in patients with dementia, contribute to

faster functional and cognitive decline,49 and increase the risk of

death.16However, typical APDs and atypical APDs are usually

pre-scribed for the same symptoms. We may, thus, expect that when comparing patients with different APD differences in survival may be more due to effects of drugs than symptoms they are prescribed for.

It should be emphasized that this is an observation study using registry data. Therefore, we cannot assume causal relationship be-tween APDs and mortality or obtain a conclusive and unambiguous result. Designs of this type, however, may lead to generation of new hypotheses and give solid foundation for further studies. Our study

contributes to research aiming at defining predictors of mortality of

dementia patients with antipsychotic treatment. Strength of the study is a large sample size and long follow-up time. It is, therefore, possible that sample sizes included in previous studies on individual diagnosis were underpowered to detect associations. Moreover, contrary to other studies, we studied both inpatients and outpatients. It is important to note that in our sample almost every third person with APDs was living in a special residency at the time of dementia compared with 10% of patients without APD treatment. We found that form of residency (living alone in ordinary housing, with a family member in ordinary housing, or in a special residency) was an important confounder, with special residency increasing the risk of death in all dementia diagnoses. What is more, rate of APD prescrip-tion in our study is lower compared with rates previously reported in

different countries.50 We indeed observed a decrease in APD

pre-scriptions between 2007 and 2015 in Sweden (unpublished results). SveDem was established in 2007 with the main aim to increase the quality of care. At the same time, it is a useful tool for physicians to monitor and control their own activity. This could contribute to the

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changes in pharmacologic management of psychiatric symptoms in people in geriatric care. Moreover, in Sweden Selective, serotonin

reuptake inhibitors are recommended as afirst-line treatment for

ir-ritability, agitation, and anxiety. Consequently, the use of antide-pressants is common in Sweden with every second person in special

residency being treated with antidepressants.51 It is, therefore,

possible that to some extent the APD use was replaced by the antidepressant treatment.

Limitations

Our study has several limitations. It is also possible that physicians

in our cohort prescribed typical APDs more frequently“as needed” for

acute symptoms and atypical medication was used in smaller doses but for a continous period. Furthermore, we cannot rule out a scenario in which atypical APDs were prescribed in higher doses than typical APDs in patients with AD. Our study may also be subject to other

uncon-trolled confounding and indication bias. Moreover, stratification for

dementia type and class of APDs together may have led to a sample size that was too small to detect the association in some of the categories. Conclusions and Implications

Although we cannot rule out the influence of residual confounding

(eg BPSD), these results would seem to support studies that suggest cautious APD prescribing for patients with dementia.

Acknowledgments

The authors are grateful to (SveDem,www.svedem.se). We thank

all patients, caregivers, reporting units, and coordinators in SveDem as well as SveDem steering committee. Special thanks to Johan Fastbom for extracting the data from the prescribed drug registry. We also

thank the Margaretha af Ugglas’ Foundation.

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Supplemental Table 1

Cox Multivariate Analyses Assessing All-Cause Mortality Risk HR (95% CI) Associated With APD in VAD in the First/After 1 Year After Diagnosis: Total (Typicalþ Atypical), Typical, and Atypical

Crude Adjusted*

>1 y

Total 2.02 (1.65e2.46) 1.61 (1.28e2.04)y Typical* 2.21 (1.50e3.26) 1.79 (1.14e2.82)y Atypical* 1.98 (1.57e2.50) 1.54 (1.17e2.02)y Typicalz 1.12 (0.71e1.74) 1.18 (0.70e1.99) <1 y

Total 1.45 (1.27e1.65) 1.24 (1.07e1.44)x Typical* 1.78 (1.38e2.29) 1.59 (1.19e2.11)y Atypical* 1.39 (1.20e1.62) 1.20 (1.01e1.42)x Typicalz 1.26 (0.94e1.69) 1.31 (0.94e1.83) *Adjusted for age, sex, MMSE, CCI, and living arrangement and Ref: No APD.

yP< .001. zRef: Atypical. xP< .005.

Supplemental Table 2

Cox Multivariate Analyses Assessing All-Cause Mortality Risk HR (95%CI) Associated With APD in VAD in the First/After 1 Year After Diagnosis: Total (Typicalþ Atypical), Typical, and Atypical

Crude Adjusted*

Total

Total* 1.68 (1.6e1.77)y 1.38 (1.30e1.46)y Typical* 1.73 (1.56e1.91)y 1.35 (1.20e1.51)y Atypical* 1.65 (1.55e1.75)y 1.39 (1.29e1.48)y Typicalz 1.05 (0.93e1.18) 0.97 (0.85e1.11) AD

Total* 1.72 (1.53e1.94)y 1.35 (1.19e1.54)y Typical* 1.47 (1.16e1.86)y 1.05 (0.81e1.36) Atypical* 1.78 (1.54e2.05)y 1.51 (1.29e1.76)*

Typicalz 0.83 (0.63e1.09) 0.7 (0.52e0.94)*

Mix

Total* 1.86 (1.65e2.09)y 1.32 (1.16e1.50)*

Typical* 1.97 (1.61e2.41)y 1.32 (1.06e1.64)*

Atypical* 1.81 (1.57e2.1)y 1.34 (1.14e1.57)*

Typicalz 1.09 (0.85e1.39) 0.98 (0.75e1.28) VADx

Total* 1.58 (1.42e1.77)y 1.33 (1.17e1.51)y Typical* 1.89 (1.53e2.33)y 1.64 (1.29e2.09)y Atypical* 1.53 (1.35e1.74)y 1.28 (1.1e1.48)y Typicalz 1.23 (0.97e1.57) 1.28 (0.97e1.70) LBD

Total* 1.12 (0.93e1.33) 1.07 (0.89e1.30) Typical* 1.48 (0.99e2.22) 1.39 (0.91e2.14) Atypical* 1.05 (0.86e1.28) 1.02 (0.83e1.26) Typicalz 1.41 (0.91e2.19) 1.37 (0.86e2.17) FTD

Total* 1.21 (0.81e1.81) 1.15 (0.69e1.94) Typical* 1.29 (0.57e2.89) 1.27 (0.52e3.11)*

Atypical* 1.04 (0.64e1.69) 1.11 (0.60e2.05) Typicalz 1.24 (0.49e3.15) 1.15 (0.40e3.33) UNS

Total* 1.59 (1.43e1.76)* 1.33 (1.17e1.50)*

Typical* 1.51 (1.23e1.86)* 1.24 (0.95e1.60) Atypical* 1.59 (1.41e1.79)* 1.33 (1.15e1.53)*

Typicalz 0.95 (0.75e1.21) 0.93 (0.7e1.24) Other

Total* 1.37 (0.98e1.92) 1.21 (0.78e1.85) Typical* 1.38 (0.69e2.78) 1.01 (0.45e2.28) Atypical* 1.36 (0.92e2.00) 1.21 (0.71e2.07) Typicalx 1.02 (0.46e2.25) 0.83 (0.32e2.19) *Adjusted for age, sex, MMSE, CCI, and living arrangemnet and Ref: No APD.

yP< .001. zRef: Atypical.

xRef: Assuming proportional hazard.

E. Schwertner et al. / JAMDA 20 (2019) 323e329 329.e1

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0.00 0.25 0.50 0.75 1.00 0 1000 2000 3000 Time in days Su rv iv a lr a te

Treatment No Typical Atypical

AD 0.00 0.25 0.50 0.75 1.00 0 1000 2000 3000 Time in days Sur vi val ra te

Treatment No Typical Atypical Mix 0.00 0.25 0.50 0.75 1.00 0 1000 2000 3000 Time in days S ur vi va lra te

Treatment No Typical Atypical VAD 0.00 0.25 0.50 0.75 1.00 0 1000 2000 3000 Time in days Su rv iv al ra te

Treatment No Typical Atypical

LBD 0.00 0.25 0.50 0.75 1.00 0 1000 2000 3000 Time in days Sur viv a lr a te

Treatment No Typical Atypical

FTD 0.00 0.25 0.50 0.75 1.00 0 1000 2000 3000 Time in days Sur viv al ra te

Treatment No Typical Atypical

UNS 0.00 0.25 0.50 0.75 1.00 0 1000 2000 3000 Time in days Su rv iv al rat e

Treatment No Typical Atypical

Other

Supplemental Fig. 1. Survival functions stratified by dementia diagnoses from Cox hazard regression adjusted for age, sex, MMSE, CCI, and form of living for patients receiving typical, atypical, and no APD treatment. Y-axis, estimated survival percentages; X-axis, number of days.

E. Schwertner et al. / JAMDA 20 (2019) 323e329 329.e2

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