JAMDA xxx (2014) 1e10

JAMDA

journal homepage: www.jamda.com

Review

Antihypertensive Treatment in People With Dementia

Veronika van der Wardt PhD a,*, Pip Logan PhD a, Simon Conroy PhD b,Rowan Harwood MDc, John Gladman MDa

aDivision of Rehabilitation and Ageing, School of Medicine, University of Nottingham, Nottingham, United KingdombGeriatric Medicine, University Hospitals of Leicester, Leicester, United KingdomcUniversity of Nottingham, Nottingham, United Kingdom

Keywords:Hypertensiondementiaantihypertensive drugs

The authors declare no conflicts of interest.* Address correspondence to Veronika van der War

itation and Ageing, School of Medicine, University of N2UH, United Kingdom.

E-mail address: v.vanderwardt@nottingham.ac.uk

1525-8610/$ - see front matter � 2014 - American Mhttp://dx.doi.org/10.1016/j.jamda.2014.03.005

a b s t r a c t

Background: The range and magnitude of potential benefits and harms of antihypertensive treatment inpeople with dementia has not been previously established.Methods: A scoping review to identify potential domains of benefits and harms of antihypertensivetherapy in people with dementia was undertaken. Systematic reviews of these domains were undertakento examine the magnitude of the benefits or harms.Results: Potential outcome domains identified in the 155 papers in the scoping review were cardiovas-cular events, falls, fractures and syncope, depression, orthostatic hypotension, behavioral disturbances,polypharmacy risks, kidney problems, sleep problems, interactions with cholinesterase inhibitors, andpain. The systematic reviews across these domains identified relatively few studies done in people withdementia, and no convincing evidence of safety, benefit, or harm across any of them.Discussion: Given the lack of firm evidence of benefits or harm from antihypertensive therapy in peoplewith dementia and the weak evidence for benefits in people over 80 years of age, the current pre-sumption that the favorable evidence drawn from the treatment of nondemented people should beextrapolated to those with dementia is contentious. There is sufficient evidence to warrant particularcaution and further research into treatment in this group of patients.

� 2014 - American Medical Directors Association, Inc. All rights reserved.

The World Health Organization 2012 report “Dementia: A PublicHealth Priority” estimated that there are 35.6 million people withdementia living at the present time worldwide.1 About one-half ofpeople over 50 years of age have hypertension.2 Although theprotective effects of antihypertensive treatment against cardio-vascular events have been established in numerous clinical trialsfor different age groups,3,4 people with dementia have beenconsistently excluded from these studies. Dementia is usually acondition of very old people, yet the evidence from randomizedcontrolled trials of hypertensive therapy in people over 80 years ofage shows no significant reduction in total mortality (relative risk0.98, 95% confidence intervals 0.87e1.10).5 Furthermore, evidencefrom randomized controlled trials of antihypertensive therapy innondemented people aged over 60 shows a markedly increasedrate of withdrawal from treatment because of the adverse effects of

dt, PhD, Division of Rehabil-ottingham, Nottingham NG7

(V. van der Wardt).

edical Directors Association, Inc. A

treatment (relative risk 1.71, 95% confidence intervals 1.45e2.00).5

This vulnerability to the adverse effects of treatment might beexpected to be even higher in people with dementia, furtherthreatening the benefit to risk ratio of antihypertensive treatment.Given these concerns, it may be that the management of hyper-tension in people with dementia should be different from in thosewith normal cognition.6 However, current guidelines for thetreatment of hypertension do not provide specific advice for peoplewith dementia.

There have been no reviews to comprehensively examine studiesinvestigating the range of outcomes (including harmful effects) ofantihypertensive treatment in people with dementia. Such work isimportant to clarify whether there is a case for altered guidance forthe management of hypertension in people with dementia.

Methods

A 2-stage process was undertaken. In the first stage, a scopingreview7 was undertaken to identify the range of outcomesof antihypertensive treatment in people with dementia. In the secondstage, systematic reviews were undertaken for each of the main areasof harmful or adverse outcomes identified in the first stage.

ll rights reserved.

V. van der Wardt et al. / JAMDA xxx (2014) 1e102

Stage 1: Scoping Review

ProtocolThe scoping review was based on a predefined protocol to search

and identify relevant research articles.

EligibilityInclusion. All articles reporting original research regarding thetreatment of hypertension in people with dementia were included.No publication date limit was applied.

Exclusion. All studies investigating hypertension as a risk factor fordementia; effects on carers; specific nondementia diseases (eg,cancer), and rarer forms of dementia (Korsakoff’s syndrome, de-mentia because of HIV, normal pressure hydrocephalus, CerebralAutosomal-Dominant Arteriopathy with Subcortical Infarcts andLeukoencephalopathy); and animal studies and non-English lan-guage articles were excluded. As effects of antihypertensive drugson the progression of dementia have been reviewed elsewhere,8,9

they were excluded from the literature analysis.

Information sourcesPubMed, Embase, Web of Science, and Cochrane library databases

were searched.

SearchThe search for articles took place from July 2012 and was updated

in February 2013. Searches were limited to English language humanresearch articles. Search terms included combinations of ‘hyperten-sion,’ ‘antihypertensive drug,’ ‘antihypertensive treatment,’ or ‘bloodpressure’ in combination with ‘dementia’ or ‘Alzheimer’s disease.’

SelectionDuplicates were removed, titles and abstracts were examined by 1

person (V.vdW.), and inclusion and exclusion criteria applied. Full textversions of the remaining papers were obtained and assessed againbased on inclusion and exclusion criteria. The remaining relevantarticles were used to identify the range of outcomes examined inscientific articles.

Data collectionMain outcome variables were recorded and categorized into

topics.

AnalysisThe number of papers examining each outcome was tabulated.

Stage 2: Systematic Reviews

ProtocolThe systematic reviews were based on a predefined protocol to

search and identify relevant research papers.

EligibilityInclusion. All articles reporting original research regarding antihy-pertensive treatment in people with dementia and the topic iden-tified in stage 1were included. Nopublication date limitwas applied.

Exclusion. As in stage 1. Studies, which did not include antihy-pertensive treatment in any form in the analysis (as compositevariable or individual medication classes), were also excluded.

Information sourcesPubMed, Embase, Web of Science, and Cochrane library databases

were searched.

SearchArticles were searched until June 2013 publication dates. Searches

were limited to English language and, where possible, humanresearch articles. Search terms for stage 2 included ‘antihypertensive’or antihypertensive drug classes (‘diuretics,’ ‘beta-blockers,’ ‘calciumchannel blockers,’ ‘angiotensin receptor blockers,’ and ‘ACEinhibitors’) in combination with ‘dementia’ or ‘Alzheimer’s disease’and the topics identified in stage 1 (Figure 1).

SelectionDuplicates were removed, titles and abstracts were examined by 1

person (V.vdW.), and inclusion and exclusion criteria applied. Full textversions of the remaining papers were obtained and assessed basedon inclusion and exclusion criteria. The remaining relevant articleswere included and the number of papers examining each topic wasrecorded.

Data collectionMethods and results were extracted to record purpose of the

study, design, sample size, main measurements, and results of eachstudy.

AnalysisMethod sections of papers were examined to determine level of

evidence. Results were compared and analyzed regarding the effect ofantihypertensive treatment on the topic in question.

Results

Stage 1: Scoping Review

Figure 1 shows that 155 papers entered this review. Ten mainoutcome themes of effects of antihypertensive treatment in peoplewith dementia emerged from the 155 papers in the scoping review(Figure 1); cardiovascular events, falls, fractures and syncope,depression, hypotension, behavioral disturbances, polypharmacy,kidney problems, sleep problems, cholinesterase inhibitors and pain.The articles identified in the last stage of the scoping review werealso included into the stage 2 analysis.

Stage 2: Systematic Reviews

Table 1 shows a summary of the findings of the searches under-taken in the systematic reviews of the topics identified in the scopingreview.

Cardio- and Cerebrovascular Events

In total, 4 studies examined the effects of antihypertensivemedication on cardio- and cerebrovascular events in people withdementia (Table 2), with antihypertensives either as main indepen-dent variable (3 studies) or as control variable (1 study).

No randomized controlled placebo trials have been conducted inthis area. In people with dementia, 2 randomized controlled trialsinvestigated the effects of calcium channel blockers (CCBs) in anintention-to-treat, an efficacy and a safety analysis.10e12 For bothtrials, main outcome was cognition but the safety analysis includedcardio- and cerebrovascular events, which were reported as adverseevents. The studies compared a control group against a treatmentgroup using CCBs. Both groups were allowed to continue withunspecified antihypertensive treatment as prescribed before thebeginning of the study except alpha methyldopa. The results showedthat the control group had significantly more adverse (cerebrovas-cular) events than the treatment group.11,12 For cardiovascular events,the trend was similar but reached significance in only one of the

Fig. 1. Scoping review.

Table 1Search Terms ‘Dementia’ or ‘Alzheimer’s’ in Combination With Antihypertensive,Diuretics, Beta-Blockers, Calcium Channel Blockers, Angiotensin Receptor Blockers,or ACE Inhibitors

Search Terms No. of Articlesfor Which FullTexts WereObtained

No. of Articles InvestigatingEffects of AntihypertensiveTreatment in People WithDementia

Stroke, cardiovascular 107 5Falls, fractures, syncope 58 4Behavioral problems,aggression, agitation, apathy

13 5

Depression 18 2Sleep, insomnia, pain, kidney,renal problems, incontinence

39 2

Eyes, retinal, glaucoma 15 0Cholinesterase inhibitors 15 4Polypharmacy 23 2Hypotension 20 2

ACE, angiotensin-converting-enzyme.

V. van der Wardt et al. / JAMDA xxx (2014) 1e10 3

studies.12 In a subgroup analysis of participants with subcorticalvascular dementia,13 no significant differences in these adverseevents were found, although again the same trend was observed(fewer events in the treatment group). One study was a non-randomized 6-week open label trial including people with dementiainto the safety of nilvadipine (CCB).14 There was no significantdifference in adverse events, but this was a very short period offollow-up.

In addition, a prognostic cohort study including a large group ofpeople diagnosed with dementia investigated the effects of angio-tensin receptor blockers and angiotensin-converting-enzyme (ACE)inhibitors on the risk of hospitalization and mortality while con-trolling for cerebro- and cardiovascular events.10 The results showedthat while there was no significant association between angiotensinreceptor blockers and risk for hospitalization or mortality, ACEinhibitors (but not angiotensin receptor blockers) significantlyincreased the risk for mortality but not for hospitalization. Thisassociation remained significant after controlling for coronary heartdisease, stroke, and congestive heart failure.

Falls, Fractures, and Syncope

The risk of falls and fractures is higher in people with dementiacompared with those without.15e17 In addition, some antihyperten-sive treatments have been shown to increase the risk for falls andfractures in older people.18,19 However, our review found no evidencefrom randomized controlled trials for the risk of falls because ofantihypertensive medication in people with dementia. This review

identified 4 prospective cohort studies, 2 of those investigating theassociation between falls risk and antihypertensive medication inpeople with dementia,20e22 and a further 2 examining the associationof falls risk with cardiovascular medication23,24 (Table 2). Cardiovas-cular medication included antihypertensive drugs as well as antico-agulants and antiplatelet agents.

The findings showed conflicting results in people with dementia.Examining risk factors for falls in people with and without dementia,

Table 2Articles Included in the Analysis

Area Author and Year Research Question Design Sample Size Main Measurements Results

Cardio- and cerebro-vascular events

Kehoe, Davies, Martin(2013)10

How do ACE-Is and ARBsaffect the risk forhospitalization andmortality in people withdementia?

Prognostic cohort studybased on primary caredatabase

N ¼ 6290 (all with dementiadiagnosis and using AHT)

HealthDeathHospitalization

ACE-Is: sig associated withmortality in patients withAD (HR 1.19; CI* 1.07e1.33)and combined dementiagroup (HR 1.20; CI 1.10e1.30)after adjustments but noassociation with hospitalization;ARBs: no significant associations

Kennelly et al (2011)14 Is nilvadipine save andtolerable for peoplewith AD?

Nonrandomized openlabel trial (6 weeks)

Treatment group n¼56;control group n ¼ 30 allused other AHTs as well

Inappropriate reduction in BPAEsFalls (self report)Orthostatic symptoms

No sig. effect on BP after adjustments;no change in OH in either group;no significant difference in reportedAEs between groups but more AEsin treatment group 39.0% vs 23.3in control group).

Pantoni Bianchi, al.(2000)11

Is nimodipine efficient inimproving cognition andslowing deterioration aswell as save for people withmulti-infarct dementia?

Double blind RCTintention-to-treat (itt),safety and efficacyanalyses

Treatment n ¼ 128; controln ¼ 131; safety analysisn ¼ 259;itt n ¼ 251, efficacy n ¼ 209,all multi-infarct dementia,controls used other AHTs

Functional rating scaleADLRapid Disability Scale, CDRClinical Global ImpressionCognitionAEs and SAEs

AEs and SAEs analysis showed thatonly cerebrovascular events weresig. more in placebo group (AE: 6in treatment vs 17 in placebogroup; SAE: 16 in treatment vs 22in placebo group, Other resultsconcerning cognition or functioningare all nonsignificant.

Pantoni, Rossi, et al(2000)13

Is nimodipine efficient inimproving cognition andslowing deterioration aswell as save for peoplewith subcortical vasculardementia?

Sub analysis of double blindRCT; intention eto-treat(itt), safety and efficacyanalyses

Treatment n ¼ 45; controln ¼ 47; safety analysisn ¼ 92;itt n ¼ 87, efficacy n ¼ 77,all subcortical VaD, controlsuse other AHTs

Functional rating scaleADLRapid Disability Scale, CDRClinical Global ImpressionCognitionAEs and SAEs

Because of low numbers, nostatistical significance couldbe established but more controlsthan people in treatment grouphad SAEs and total AEs. Morepeople in treatment group hadBP values indicating hypotension

Pantoni et al (2005)12 Is nimodipine efficient inimproving cognition andslowing deterioration aswell as save for peoplewith subcortical vasculardementia?

Double blind RCTintention-to-treat (itt),safety and efficacyanalyses

Treatment n ¼ 124 (baseline)/94 (endpoint); controln ¼ 118 (baseline)/55(endpoint); safety analysisn ¼ 239;itt n ¼ 230, efficacy n ¼ 149,all subcortical VaD, controlsuse other AHTs

Sandoz Clinical AssessmentGeriatric ScaleGlobal Deterioration ScoreGait performance testNurses Observation ScaleClinical Global Impressiondepression

Cognitive decline in some aspectsless in treatment group; AEs andSAE reported sig. more in placebothan treatment group (AE: RR1.29, CI 1.03e1.61; SAE: RR 1.58,CI 1.03e2.42) in particularcardiovascular andcerebrovascular events e 9in treatment group vs 28 inplacebo group); no sig. effectsblood pressure levels.

Falls Allan et al (2009)23 What are the modifiablerisk factors for falls inpeople with dementia?

Prospective cohort study(12 months)

Total n ¼ 179, Controlsn ¼ 39, AD n ¼ 38, VDn ¼ 32, DLB n ¼ 30, PDDn ¼ 40

Medical history, CAMCOG,physical activity scale,BMI, mobility, PD ratingscale, ADL, depression,behavioral symptoms,autonomic assessment(OH), falls

Cardiovascular medication only:sig. predictor in univariateanalysis for all dementia (HR 2.08;CI 1.15e3.75) and when stratifiedper diagnosis (HR 1.91; CI 1.03e3.54); Trend sig. in multivariateanalysis when stratified bydiagnosis (HR 1.98; CI 0.994e3.96)

Asada et al (1996)24 What are the predictorsof fall-related injuries inpeople with dementia?

Prospective cohort study(12 months)

Total n ¼ 18498 controls, 86 peoplewith dementia

Cognition, behavioralproblems, ADL, medication,history of falls, visual &hearing acuity, falls

Cardiovascular medication only:nonsignificant contributor tofalls-related injuries (OR 0.9;CI 0.6e1.5)

Eriksson et al 200720

(incl. erratum21)What are the risk factorsfor falls in people withand without dementia?

Prospective cohort study(6 months)

Total n ¼ 186,83 without dementia;103 with dementia

Cognition, vision, hearing,walking ability, ADL,medication, falls

In Erratum: In people with dementiain univariate analysis, takingdiuretics was a significant riskfactor (IRR 1.86; CI 1.07e3.23).

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Not significant in multivariateanalysis.

Pellfolk, Gustafsson(2009)22

What are the risk factorsfor falls in people withdementia?

Prospective study cohort(6 months)

Total n ¼ 160 people withdementia; of those n ¼ 64fallers and n ¼ 96 nonfallers

Cognition, vision, hearing,ADL, behavioral andpsychiatric symptoms,use of medication, falls

No sig. difference in AHT(beta-blockers, CCB, ACE inhibitors,diuretics) between fallers andnonfallers. No effect sizes reported.

Behavioral problems Herrmann et al (2004)25 What is the relation betweenaggression and BB use inAD patients?

RCT (cross-over design);total duration 15 weeks

Total n ¼ 11 Aggression (retrospectiveOvert Aggression Scale),MMSE, Depression,

Sig. decrease in verbal aggressionin treatment group but not intotal aggression score; higherbaseline aggression, higher MMSEand lower growth hormoneresponse to clonidine challengepredicted improvement inaggression. No effect size reported.

Peskind, Tsuang,Bonner (2005)26

Does propranolol (BB) reducedisruptive behavior?

RCT (6 weeks) Total n ¼ 31 with probableor possible AD; n ¼ 17on BB, n ¼ 14 placebo

NPI change,Clinical Global Impressionof Change

Overall score of NPI but no individualsubscore sig. improved intreatment group compared withplacebo group. However, withintreatment group, results showedsig. reductions in agitation/aggression scores and anxiety scoresfrom baseline to follow-up. No effectsize reported.

Shankle, Nielson,Cotman, (1995)28

Does low-dose propranolol(BB) reduce aggressionand agitation in peoplewith dementia?

Case series, meanfollow-up 6 months

Total n ¼ 12 Aggression (by proxy;caregiver rating, CMAI,CBQ), propranolol givenuntil aggression stopped

Sig. improvement compared withpretreatment aggression levels(proxy rating); CMAI showed sig.reduction in physical and verbalaggression and wandering inresponders (n ¼8) only. CBQshowed sig improvements in allsubscales for resp. and non-resp.except wandering; lower MMSEcorrelated with treatment efficacy.No effect size reported.

Wang et al (2009)27 How effective and tolerable isprazosin (alpha-adrenergicblocker) for behavioralsymptoms in AD patients?

Double-blind RCT;duration 8 weeks

Total n ¼ 24 (n ¼ 11 intreatment group; n ¼ 11in control group at baseline,n ¼ 7 in treatment groupand n ¼ 6 in placebo groupat follow-up)

Clinical Global Impression ofChange and change frombaseline in NPI and BPRS;side effects, changes in BP,functional status

Sig. improvement in all behavioraloutcome measures in treatmentgroup compared with placebo.Similar side effects, BP levels andfunctional status. No effect sizereported.

Weiler, Mungas, Bernick(1988)29

Does propranolol (BB)improve disruptivebehavior?

6 case studies N ¼ 6 with dementia By-proxy observations Improvements in behaviorobserved

Depression Ban et al (1990)34 What effects has nimodipine(CCB) in dementiatreatment?

RCT N ¼ 178 with dementia;n ¼ 89 treatment (CCB);n ¼ 89 control

Depression Sig. more improvement regardingdepression in treatment thanplacebo group. No effect sizereported.

Newman (1999)35 What is the relationship ofAD and VaD to depression?

Cohort study n ¼ 2341, n ¼ 749 AD;n ¼ 208 VaD; n ¼ 175 otherdementia; of total n ¼ 29diagnosed with depression

MMSE; cognitive andphysical assessments,depression, BB use

BB use was not a sig. covariatein the relationship betweendementia and depression(OR not reported)

Sleep problems, pain,kidney problems,incontinence

Suzuki Meguro, Meguro(2011)39

Is there an associationbetween sleep disturbance,decreased daily activityand impaired nocturnalreduction in BP in peoplewith dementia?

Prospective cohort study(14 days)

N ¼ 107 with dementia ADL, ABPM, evaluation ofsleep/wake pattern

No sig. differences in use of AHTbetween dippers and non-dippersor low and high ADL (no effectsizes reported)

Ridgeway et al (2008)44 Which comorbidities andmedicines are associated

Retrospective cohort study N ¼ 67 female residents Medications, comorbidities Dementia was associated withurinary (OR 4.3, CI 1.3e17.4) and

(continued on next page)

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Table 2 (continued )

Area Author and Year Research Question Design Sample Size Main Measurements Results

with urinary and fecalincontinence in a long-termcare population?

fecal (OR 6.8, CI 1.8e47.2)incontinence in a multivariateanalysis. AHT was not associatedwith UI or FI (no effect sizesreported).

Cholinesteraseinhibitors

Grossberg et al (2000)46 Are there any adversepharmaco-dynamic druginteractions withrivastigmine and otherclasses of medications?

Prospective cohort studyover 6 months

N ¼ 2459; n ¼ 1696 usingrivastigmine; n ¼ 763controls

22 types of adverse events No significant pattern of increasein AEs was found for users of AHTas one group and beta-blockersas well as alpha-blockers asindividual medication types.However, for diuretics, a significantdifference was found betweenpeople with and withoutrivastigmine.

Pariente et al (2010)47 What are factors associatedwith serious adverse drugreactions in patients treatedwith cholinesteraseinhibitors?

Population study- basedon the French pharmaco-vigilance database fromdrug launching up to 2007

773 reports aboutcholinesterase inhibitorsmentioning a total of1044 ADRs

ADRs leading to death,hospitalization orprolongation ofhospitalization

Factors associated with seriousADRs were age, use of atypicalantipsychotics, use of conventionalantipsychotics and use of AHT(OR 2.11, CI 1.47e3.02); Morepatients with serious ADRs(33.8% of all patients) thannonserious ADRs (19.7% of allpatients) when using AHTalongside cholinesterase inhibitors.

Rozzini et al (2005)45 What is the relationshipbetween AHT andcholinesterase inhibitors?

Prospective cohort study;40 weeks

N ¼ 416; n ¼ 161 AHT users;n ¼ 255 not AHT users

MMSE, ADL, Sig difference between AHT user andnon-user in MMSE in favor ofusers at week 16 (T2). No sig.difference at T3 (40 weeks). Sig.higher MMSE for users in thosethat respond to cholinesteraseinhibitors, but not innonresponders. No effect sizesreported.

Tavassoli et al (2007)48 What are the druginteractions withcholinesterase inhibitors?

Analysis of spontaneousreports regarding cholin-esterase inhibitors

N ¼ 1058 spontaneousreports incl cholinesteraseinhibitors

Beta-blockers, Calciumchannel antagonists

Beta-blockers were among themost frequently encountereddrugs involved in DDI (83 cases)with cholinesterase inhibitors

Polypharmacy Giron et al (2001)50 What is the extent ofinappropriate drug usein people with and withoutdementia?

Prospective cohort study(8e10 years)

N ¼ 681; n ¼188 withdementia; n ¼ 493without dementia

Drug groups; drugduplications

People with dementia were sig.more likely to use high-ceilingdiuretics and sig. less likely touse BBs and CCBs than peoplewithout dementia;no difference in drugduplication between peoplewith and without dementia(no effect sizes reported).

Montastruc et al (2013)51 What is the prevalence ofpotentially inappropriatemedication use in peoplewith mild to moderate AD?

Prospective cohort study(4 years)

N ¼ 684 with AD ADL, MMSE, NPI, PIM use 3.1% of sample usedinappropriate centrallyacting AHT; 2.9% of sampleused inappropriate short actingcalcium channel inhibitors.

Orthostatichypotension

Anderson et al (2008)54 Is orthostatic hypotensionmore common in peoplewith dementia than inthose without cognitiveimpairment?

Cross-sectional cohort study AD n ¼ 235; DLB n ¼ 52;controls n ¼ 62

MMSE, medication, afterresting in supine position:immediately and after 1, 3,5, 10 minutes of standing

OH occurred sig. more in DLB thanin AD, and in AD sig. more thanin controls.No sig. difference in AHT betweengroups. No effect sizes reported.

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V. van der Wardt et al. / JAMDA xxx (2014) 1e10 7

Eriksson et al20,21 found that taking diuretics was a significant riskfactor for falls for people with dementia in a univariate analysis, butthis was nonsignificant when controlled for significant covariates.However, taking more than 4 drugs was a significant risk factor forfalling in people with dementia after controlling for significant cov-ariates.20,21 Pellfolk et al22 found no significant difference in the useof antihypertensive medication between fallers and nonfallers inpeople with dementia and, therefore, did not enter antihypertensivemedication in their logistic regression analysis of independent riskfactors of falls. However, Allan et al23 reported that cardiovascularmedication was a significant predictor of falls in an analysis of alltypes of dementia combined (Alzheimer’s disease, vascular dementia,dementia with Lewy bodies, and Parkinson’s with dementia), as wellas when stratified per dementia type. When significant and poten-tially modifiable predictors were entered into a multivariate analysis,which was stratified by dementia type, cardiovascular medicationremained significantly associated with falls. Asada et al,24 on theother hand, found that cardiovascular medication was not a signifi-cant contributor to falls-related injuries in people with dementia.

Behavioral Problems

Only the effects of beta- (propranolol/pindolol) and alpha-blockers (prazosin) on behavioral symptoms in people with demen-tia have been investigated in randomized controlled trials (Table 2).All 3 trials had very small sample sizes (between 6 and 31 partici-pants) but showed a significant beneficial effect of centrally activeantihypertensive medication on behavioral problems. Herrmannet al25 showed that verbal aggression was significantly reduced inpeople using beta-blockers, without a significant change in totalaggression. Peskind, Tsuang, and Bonner26 found no significantassociation between use of beta-blockers and any specific behavioralsubscale but a significant effect of beta-blocker use on the totalbehavioral score. A small randomized controlled trial to assess theeffect of alpha-blockers on behavior showed that nonsignificantlygreater improvements in the treatment group than in the controlgroup.27 A case series study to assess the effect of beta-blockers onbehavior in people with dementia28 indicated significant improve-ments for all behavioral measures (except for wandering, whichimproved on only 1 scale). Behavioral improvements after using beta-blockers were also found in another case study including people withdementia.29 Meta-analyses showed that beta-blockers have relativelylittle effect on cerebro- and cardiovascular events and mortalitycompared with other antihypertensive drugs30,31 and are more likelyto be discontinued.32 Other antihypertensive treatments have notbeen investigated for their effect on behavioral problems.

Depression

Antihypertensive treatment, in particular the use of highly lipid-soluble beta-blockers, has been associated with depression.33 Onerandomized controlled trial and one cohort study investigated therelationship between antihypertensive treatment and depression inpeople with dementia. The randomized controlled trial investigatedthe effect of Nimodipine (CCB) on depression in patients with diag-nosed dementia as well as those with mild to moderate cognitivedecline on the Global Deterioration scale.34 The treatment and con-trol group were allowed to use other medication including antihy-pertensive treatment. Scores on the Hospital Anxiety and Depressionscale improved significantly more in the treatment group than in thecontrol group. In a large cohort study examining the prevalence ofdepression in people with dementia, Newman35 found that beta-blocker use was not a significant covariate in the relationship

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between dementia and diagnosis of major depression. No otherantihypertensive drugs were included in the analysis.

Sleep Problems, Pain, Kidney Problems, and Incontinence

Although these topics emerged during the first stage of thisreview, there were only a very few studies investigating the effect ofantihypertensive medication in people with dementia (Table 2).

Sleep problems are common in people with dementia,36,37 andsleep disturbances, in particular obstructive sleep apnea, have beenshown to improve with antihypertensive treatment.38 Although thereare no studies examining the effects of antihypertensive treatment onsleep quality, 1 prospective cohort study investigated the relationshipbetween sleep disturbances and nocturnal reduction of blood pres-sure in people with dementia whilst controlling for antihypertensivetreatment.39 The results showed no significant difference in use ofantihypertensive medication between dippers (hypertensive patientswho experience a nocturnal reduction in blood pressure) and non-dippers (those who do not). Other sleep disturbances have not beeninvestigated in people with dementia in relation to use of antihy-pertensive medication.

Some antihypertensive drugs such as beta-blockers, angiotensinreceptor blockers, and ACE inhibitors seem to have beneficial effectson pain in older people without dementia.40,41 For people with de-mentia, however, the association between pain and antihypertensivetreatment has not yet been investigated.

The relationship between kidney problems and antihypertensivemedication has not been assessed in people with dementia. Onecohort study including geriatric emergency patients investigated theassociation. The results showed that antihypertensive drugs maycontribute to an increased risk of a clinically relevant impairment ofrenal function.42 However, although 56% of the participants werediagnosed with dementia, and no separate analysis for this group wasconducted.

The effect of antihypertensive drugs on incontinence has beenexamined by Ruby et al43 in a large cohort study of older people. Theyreported that use of alpha-blockers was significantly associated withurinary incontinence. Ridgeway et al44 investigated the relationshipbetween incontinence and use of antihypertensive medication in along-term care population with 79% being diagnosed with dementia.The results indicated that although dementia was significantly asso-ciated with urinary and fecal incontinence, antihypertensive medi-cation was not individually related to incontinence. However, asubanalysis including only people with dementia was not reported.

Use of Cholinesterase Inhibitors

Cholinesterase inhibitors are commonly used in the mild tomoderate stages of Alzheimer’s disease. Several studies investigatedthe interaction effects between cholinesterase inhibitors and anti-hypertensive medication (Table 2), although the evidence is limited tocohort studies and population database studies, no randomizedcontrolled trials have been conducted to assess these effects.

The results of a prospective cohort study45 showed significantbetter cognition in those taking antihypertensive drugs comparedwith those not taking them. Other studies, however, demonstratedthat the joint use of antihypertensive medication and cholinesteraseinhibitors was associated with a significantly increased risk of seriousadverse drug reactions. Grossberg et al46 found no significant inter-action between rivastigmine and antihypertensive medication as agroup in their cohort study but when analyzed separately, the use ofdiuretics and rivastigmine was related to a significantly higher rate ofserious adverse events while centrally acting antihypertensives, ACEinhibitors, and calcium channel blockers were not. Furthermore, the

results of 2 database studies showed that use of antihypertensivetreatment was significantly associated with serious adverse drug re-actions in patients treated with cholinesterase inhibitors47 and beta-blockers were among the most frequently encountered drugsinvolved in drug-drug interactions with cholinesterase inhibitors.48

These studies indicate that the combination of cholinesteraseinhibitors and antihypertensive medication might result in benefits(improvement of cognition) as well as harms (serious adverse drugreactions), which might depend on drug class.

Polypharmacy and Inappropriate Medications

All antihypertensive medications contribute to polypharmacy andits harmful effects,49 but only 2 cohort studies investigated antihy-pertensive drug use in the context of polypharmacy in people withdementia (Table 2). A longitudinal cohort study compared drug usebetween people with and without dementia,50 showing that peoplewith dementia used significantly more loop diuretics than peoplewithout dementia, and significantly less beta-blockers and calciumchannel blockers. Inappropriate antihypertensive drug use (estimateddaily dose in excess of assumed average maintenance dose per day ofa drug used for its main indication in an adult) did not differ betweenpeople with and without dementia. Montastruc et al51 investigatedthe use of potentially inappropriate medication in people withdementia in a cohort study, showing that 3.1% of people with mild tomoderate Alzheimer’s disease used inappropriate centrally actingantihypertensive medication and 2.9% used inappropriate short-acting calcium-channel inhibitors.

Orthostatic Hypotension

Orthostatic hypotension is associated with poorer cognition52,53

and occurs significantly more often in people with dementia thanwithout.54 However, the role of antihypertensive medication in thiscontext is unclear. Again, no randomized controlled trials have beenconducted to examine the relationship between antihypertensivetreatment and hypotension in people with dementia. The non-randomized open label trial, which looked at safety of nilvadipine forpeople with dementia,14 found no significant difference betweentreatment and control group in the incidence of orthostatichypotension.

In a cross-sectional cohort study, Anderson et al54 found thatdifferences in incidence of orthostatic hypotension between peoplewith Alzheimer’s disease, Lewy Body dementia and without dementiawere independent of the use of antihypertensive treatment. Mehra-bian et al55 confirmed these results in a cohort study including peoplewith memory complaints including dementia when looking at use orno use of antihypertensive treatment (Table 2). Although worsecognitive function and number of different antihypertensives weresignificantly associated with orthostatic hypotension, it was notreported if the number of different antihypertensive drugs wassignificantly related to orthostatic hypotension for the dementiagroup separately.

Discussion

The first phase of this review identified several importantdomains of outcome relevant to the treatment of hypertension inpeople with dementiadnot only cardiovascular events but also falls,fractures and syncope, depression, orthostatic hypotension, behav-ioral disturbances, polypharmacy risks, kidney problems, inconti-nence, sleep problems, interactions with cholinesterase inhibitors,and pain could also be affected. The second phase examined each ofthese areas in turn and concluded that relatively little is known about

V. van der Wardt et al. / JAMDA xxx (2014) 1e10 9

the effect of antihypertensive therapy upon these outcomes in peoplewith dementia (as opposed to older people in general). Fromwhat wefound, calcium channel blockers might have a beneficial additionaleffect upon depression, beta–blockers may reduce behavior distur-bance, ACE inhibitors might increase the risk of mortality, and therewas no consistent evidence of any relationship between antihyper-tensive therapy and falls, orthostatic hypotension, or interactionswith cholinesterase inhibitors. Overall, relatively few studies ofantihypertensive therapy have been undertaken in people withdementia, and there is virtually no information specific to differentdementia subtypes.

This review could be subject to a publication bias towards positiveoutcomes and benefits, and against the reporting of adverse conse-quences of treatment, which means that the possible benefits thereview identified of antihypertensive treatment should be interpretedwith caution.

This review adds to the little that is known specifically about thetreatment of hypertension in people with dementia. Previous reviewshave proposed but not proven that such treatment might delay theonset of dementia.8,9 Another review concluded that there is noconvincing evidence of the effectiveness of antihypertensive therapyin the reduction of cardiovascular and cerebrovascular events inpeople with dementia,56 which our review has confirmed. Thisreview, however, illustrates the range of potential harms and benefitsof antihypertensive therapy in people with dementia beyond thosementioned in most trials of antihypertensive agentsdalthough itfound little firm evidence about them.

Given the lack of firm evidence of benefits or harm from antihy-pertensive therapy in people with dementia and the weak evidencefor benefits in people over 80 years of age,5 the current presumptionthat the favorable evidence drawn from the treatment of non-demented people should be extrapolated to those with dementia iscontentious.

Given such uncertainties, clinicians managing hypertension inpeople with dementia should carefully and routinely look out for theside effects of antihypertensive drugs. Our review is compatible withguidance about prescribing in general in frailty states, which wouldapply to many people in the later stages of dementia. This includeswithdrawing preventative medication in those believed to be in theirlast months of life when the potential benefits diminish in magni-tude, and confirming whether the consent to treatment made bypatients before the onset of dementia is still valid when they have lostmental capacity.57

Trials of safe withdrawal of antihypertensive therapy should beconsidered for this population (as have been done for the generalpopulation)58,59 taking the wide range of outcomes identified in thisreview into account, and more work is required to clarify the factorsthat should determine when antihypertensive therapy should bewithdrawn in the later stages of the dementia process.

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