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Page 2018 Medication use to manage comorbidities for people with dementia a systematic review.pdf

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  R E V I E W Medication use to manage comorbidities for people with dementia:a systematic review Amy Page, MClinPharm, GradCertHPEd, BPharm, BHSci, AdvPracPharm, Phd, Christopher Etherton-Beer, MBBS, GradCertHPEd, PhD, FRACP, Liza J. Seubert, BPharm, Vaughan Clark, BSc, MPharm, XaysjaHill, BSc, MPharm, Stephanie King, BSc, MPharm, Rhonda M. Clifford, PhD School of Medicine and Pharmacology, University of Western Australia, Perth, Australia Abstract Aim:  People with dementia commonly live with multiple comorbidities. This review aimed to review medications to manage chronicconditions in people who also have a diagnosis of dementia. The secondary aim was to determine whether drug utilisation for otherconditions change as a result of dementia diagnosis. Methods:  Data source: We included experimental and observational studies where participants with dementia were diagnosed andtreated for one or more comorbid conditions that reported health outcomes or drug utilisation. Study selection: MedLine andEmbase databases were searched from inception to March 2016 (updated September 2016). Three researchers screened titles,abstracts and full-text articles, then extracted data using a data extraction sheet. Results:  Six studies met inclusion criteria with 51 696 participants (mean age 81.1    2.0 years, 78% female). One experimental studycompared bisphosphonate use with placebo in people with mid-stage dementia and found reduced risk of non-vertebral fractures(OR  =  0.27, 95% CI 0.12  –  0.61) in the bisphosphonate group. Five observational studies reported drug utilisation for people withdementia to treat comorbidities, namely depression, osteoporosis, diabetes and cardiovascular disease. Drug utilisation was found to be similar for depression, diabetes and cardiovascular disease for people with and without dementia, although bisphosphonate usewas signi 󿬁 cantly reduced. Conclusion:  Evidence on medication use for comorbidities in people with dementia is currently limited to drug utilisation patternsand treatment of one comorbidity: osteoporosis. Comorbidities for people with dementia appear to be managed pharmacologicallyuntil the late stages of disease without considering time to bene 󿬁 t or that it is a life-limiting condition. Keywords : drug utilisation, dementia, comorbidity, multimorbidity, medication optimisation. INTRODUCTION Older age is a risk factor for many chronic conditionsand as such many older people live with multiplechronic morbidities. 1 These chronic conditions are oftenmanaged with medications that aim to control diseaseprogression or to prevent a future serious event. 2 Alter-natively, conditions can be managed with medicationsto provide symptomatic relief. As such, optimal medica-tion management for older people aims to improvehealth outcomes. 3 Dementia is one such chronic condition that isstrongly associated with older age. 4 One in 25 peoplehave a diagnosis of dementia by age 65 years, but thisrises to one in four people by age 80 years. 5 Dementiacan be de 󿬁 ned as the  ‘ signi 󿬁 cant cognitive decline froma previous level of performance in one or more cogni-tive domains (complex attention, executive function,learning and memory, language, perceptual-motor, orsocial cognition) ’  that interferes with the ability to inde-pendently partake in everyday activities. 6 Dementia is aprogressive and life-limiting condition. 7,8 Many people with dementia live with other chronicconditions. 9 Compared to cognitively intact people of the same age, people with dementia live with just asmany if not more chronic conditions, such as diabetes,heart disease and respiratory conditions. 10  –  12 The extentof chronic conditions experienced by people withdementia may be underestimated, as it can be a chal-lenge to identify other conditions when they cannot Address for correspondence:  Amy Page, School of Medicine andPharmacology, University of Western Australia, Perth, Western Aus-tralia, Australia.E-mail: ©  2018 The Society of Hospital Pharmacists of Australia  Journal of Pharmacy Practice and Research  (2018)  48,  356 – 367doi: 10.1002/jppr.1403 Official Journal of   the Society of Hospital Pharmacists of Australia  reliably report signs and symptoms. 13,14 Both healthprofessionals and people with dementia often perceiveone condition to take precedence over the others ratherthan considering all conditions equally. 15,16 Chronic health conditions can affect the manifestationand progression of dementia. 17 Medications used todelay cognitive decline or the behavioural and psycho-logical symptoms of dementia may negatively impacton the control of comorbidities. 18  –  20 An example is theintroduction of anticholinesterase inhibitors leading todeteriorating bladder symptoms or increasing gastroin-testinal symptoms. 19,21 People with dementia may bemore sensitive to medication side effects, although theymay not be able to reliably report them. 22,23 The common co-existence of dementia with otherchronic conditions poses a challenge for health profes-sionals to optimise medication use. 4 Limited evidenceexists to guide the challenges of managing otherchronic conditions in the presence of dementia. 24  –  26 Research often focuses on whether the chronic condi-tion alters the risk of developing dementia, 27  –  32 orwhether the chronic condition alters the progression of dementia. 33 Evidence suggests that some medicationsmay cause the dementia signs and symptoms to deteri-orate. 34  –  36 Medication management becomes morechallenging as the dementia progresses, 4 and the caregoals may change, meaning that optimal medicationmanagement in the mild phase of dementia is not thesame as in the severe stages. 37 Optimal medication management for chronic condi-tions in people who also have dementia is not well doc-umented. 24  –  26 Older people are under-represented inresearch, and this applies even more so to older peoplewith dementia. 38 Evidence for medication use oncedementia is established tends to focus on medicationuse for cognitive or psychological symptoms. 9,39 This lit-erature review aimed to review the ef  󿬁 cacy of medica-tions used to manage chronic conditions in people whoalso have a diagnosis of dementia. The secondary aimwas to review drug utilisation patterns to gauge if adementia diagnosis alters drug utilisation. METHODS Selection Criteria Types of Participants This review considered studies that included peoplewith a diagnosis of dementia in conjunction with one ormore comorbidities.Age and gender were not considered. Papers wereincluded regardless of setting (e.g. hospital, residentialcare or community). Types of Interventions This review considered quantitative studies that investi-gated pharmacological interventions for chronic condi-tions (comorbidities) in people with dementia.Pharmacological interventions (de 󿬁 ned as medicinesprescribed by a doctor to prevent or treat disease) could becompared to placebo, no comparator, and people withoutdementia or people with dementia continuing usual care.Medication use was de 󿬁 ned as the use of speci 󿬁 c medica-tions, medication classes or therapeutic classes.We excluded studies where the medication use wasintended to treat the dementia or symptoms of thedementia such as behavioural and psychological symp-toms of dementia. Outcome Measures The primary outcome measure for this review wasclinically-relevant health outcomes and quality of lifemeasured with any standardised tool. Clinically-relevanthealth outcomes were de 󿬁 ned as an outcome that theperson would be aware of such as falls, fractures andevents leading to hospital admissions. Clinically-relevanthealth outcomes included surrogate end-points that arecommonly measured in practice and reported to thepatient (e.g. blood pressure and blood sugar). Reportedadverse drug events were considered.The secondary outcome was to assess drug utilisa-tion patterns for comorbidities in people with demen-tia. Drug utilisation was de 󿬁 ned as reported patientuse. Drug utilisation was also considered to includeprescribing, dispensing or charting a medication foruse. We were interested in drug utilisation as wewanted to investigate if there is any association between dementia and altered patterns of medicationuse in practice.Speci 󿬁 c medications, medication classes or therapeu-tic classes had to be reported using an unambiguoustherapeutic or pharmacological class or individual medi-cation. We did not place limits on the drug classi 󿬁 cationsystem used.We excluded studies where the outcomes were onlycognitive or psychological health outcomes and studiesthat reported the risk or rate of developing dementia.We excluded studies where the outcome reported wasonly the number of medications used or the prevalenceof potentially inappropriate medications. Types of Studies Quantitative studies that used experimental and obser-vational methods were considered for inclusion. Experi-mental study designs included in this review wererandomised controlled trials (RCTs) or non-randomisedcontrolled trials. The observational studies had to ©  2018 The Society of Hospital Pharmacists of Australia  Journal of Pharmacy Practice and Research  (2018)  48,  356 – 367Medications for comorbidities for people with dementia  357  include a concurrent control group, such as cohort stud-ies, cross-sectional studies and case  –  control studies. Nolimitation was placed on the length of follow-up. Search Strategy The search strategy aimed to identify published studies by searching the Ovid (MEDLINE and EMBASE) fromcommencement to March 2016, and updated in Septem- ber 2016. The MEDLINE search strategy is presented inTable 1. Reference lists of included studies were scannedfor relevant studies. Data Collection and Analysis Selection of Studies Electronic search results were downloaded andimported into Endnote X7.7 bibliographic software. 40 Duplicates were removed where possible. Threeresearchers (XH, VC, SK) independently screened thetitles, then the abstracts of all records retrieved. Allarticles that appeared to meet the selection criteria fromthe title and abstract were retrieved and considered asfull-text articles. Articles that could not be adequatelyassessed from the information given in the title andabstract were also considered as full text. Threeresearchers (XH, VC, SK) then independently assessedthe full-text articles to deem them eligible or ineligiblefor inclusion. A fourth researcher (AP) acted as a mod-erator and repeated the screening process. Discrepan-cies were resolved by discussion. The reference lists of identi 󿬁 ed papers were scanned for relevant studies. Data Extraction and Management Three researchers equally divided eligible papers andindependently extracted details. The informationextracted from each paper was: study design andmethodology, sample size, setting, follow-up duration,participant gender and age, inclusion and exclusion cri-teria, comorbidity targeted, intervention dates, reportedoutcomes, relevant outcome data and, where relevant,the intervention details. Any additional material consid-ered to be relevant to the review was also extracted atthe researcher ’ s discretion.  Assessment of Risk of Bias Two reviewers critically analysed and assessed eachpaper for risk of bias. The Cochrane Collaboration  ‘ Riskof Bias ’  tool was used for RCTs. 41,42 The non-rando-mised studies were assessed with the modi 󿬁 edCochrane Collaboration risk of bias tool and the New-castle  –  Ottawa tool as a recommendation from theCochrane Handbook. 42 The modi 󿬁 ed Cochrane Collabo-ration risk of bias tool had an additional item to assessthe risk of bias from confounding. Subsequently, eachstudy was assigned either a high, moderate or low risk.Of the papers each individual critically analysed, anassessed risk of bias was also made. Data Synthesis The data were grouped according to the reportedcomorbidity. Where data were available for both groups,the dichotomous outcomes were reported as odds ratios(ORs), and continuous outcomes were reported as meandifference. Where the data were reported as ORs andmean difference with the measure of variance, wereported the values as given in the original paper.Where the data were available but not reported in thisformat, the authors used Review Manager (RevMan) 5.3software 43 to calculate the ORs and mean differencewith the 95% con 󿬁 dence interval (CI) for the data. Datawere not pooled to undertake a meta-analysis. Table 1  Search strategy MEDLINE1 Dementia.ti.ab2 Alzheimer$.ti.ab3 Frontotemporal.ti.ab4 Lewy ADJ1 body.ti.ab5 Cognitive ADJ3 (impair$ OR declin$ OR deteriorat$).ti.ab6 Exp Dementia/ 7 OR/1  –  68 Diabetes.ti.ab9 Chronic ADJ3 (disease OR condition OR syndrome).ti.ab10 Stroke.ti.ab11 Cardiovascular.ti.ab12 COPD OR COAD.ti.ab13 Asthma.ti.ab14 Lungs.ti.ab15 Pulmonary.ti.ab16 Osteoarthritis.ti.ab17 Osteoporosis.ti.ab.18 Heart.ti.ab19 Exp Respiratory tract disease/ 20 Exp Musculoskeletal diseases/ 21 Exp Endocrine system diseases/ 22 Exp Cardiovascular diseases/ 23 OR/8  –  2224 Comorbidity.ti.ab25 exp comorbidity/ 26 Multimorbidity.ti.ab27 OR/24  –  2628 7 AND 23 AND 2729 exp Drug therapy/ 30 medicine$.ti.ab.31 medication$.ti.ab32 pharmacotherapy.ti.ab33 OR/30  –  3234 28 AND 33  Journal of Pharmacy Practice and Research  (2018)  48,  356 – 367  ©  2018 The Society of Hospital Pharmacists of Australia 358  A. Page  et al.  Results were not included if it could not be ascer-tained if the person did or did not have both dementiaand the comorbidity. RESULTS Results of the Search The initial search returned 2246 studies and a further 49papers were identi 󿬁 ed by screening the reference lists of articles considered for inclusion (Figure 1). A total of 25full-text papers were retrieved for further consideration.Of these, six papers met the inclusion criteria. Included Studies The review included six studies with a total of 51 696participants, who were 78% female with a weightedmean age across all studies of 81.1    2.0 years. Thestudy characteristics are presented in Table 2. Records identifiedRecords after duplicatesRecords screened ( n  = 2029)Records excluded ( n  = 2003)19 full-text articlesFull-text articlesassessed for eligibility ( n  = 25)6 studies includedin qualitativesynthesisexcluded, withreasons- ineligible study- no relevant- no relevant- full-text not- no particular design ( n  = 6)intervention ( n  = 3)comorbidity ( n  = 1)outcomes ( n  = 8)available(conferenceabstract) ( n  = 1)Records removed as duplicates n  = 266removed ( n  = 2029) Additional recordsidentified throughother sources( n  = 49)through databasesearching( n  = 2246) Figure 1  Prisma  󿬂 ow chart. ©  2018 The Society of Hospital Pharmacists of Australia  Journal of Pharmacy Practice and Research  (2018)  48,  356 – 367Medications for comorbidities for people with dementia  359  Risk of Bias The assessment of risk of bias for  󿬁 ve out of sixincluded studies incorporated a measure of confoundingand assessment with both the Cochrane Collaborationand the Newcastle  –  Ottawa risk of bias tools as theywere observational studies rather than experimentalstudies (Figure 2). 41 Using the Cochrane tool, the risk of  bias was assessed as high in more than half of the stud-ies across four domains. 44  –  48 Using the Newcastle  –  Ottawa risk of bias tool, the risk of bias was assessed aslow for at least half the studies in six of the eightdomains. 44  –  48 Outcomes The six studies reported  󿬁 ve distinct outcomes. Clini-cally-relevant health outcomes were reported in onestudy that reported bisphosphonate treatment for osteo-porosis in people with moderate dementia. 49 Clinicalparameters were reported in one study, namely bloodpressure, haemoglobin A1C (HBA 1C ), blood glucose andcholesterol. 48 Drug utilisation patterns were evaluated in 󿬁 ve studies. 44  –  48 These are described in more detail below. Quality of Life No studies reported the effect of treating physical orpsychiatric comorbidities on quality of life in peoplewith dementia in a manner where it could be deter-mined that the participant had a diagnosis of bothdementia and the comorbidity. Health Outcomes by Comorbidity Osteoporosis Treatment:  One experimental studyinvestigated medication use for people with moderatedementia and osteoporosis. 49 Risedronate 2.5 mg dailycompared to placebo reduced the risk of a non-vertebralfracture (OR  =  0.27, 95% CI 0.12  –  0.61, partici-pants  =  500, studies  =  1) including hip fracture(OR  =  0.25, 95% CI 0.09  –  0.68, participants  =  500, stud-ies  =  1). 49 The risk of adverse drug effects was notincreased in the risedronate group compared to placebo(OR  =  2.02, 95% CI 0.50  –  8.19, participants  =  500, stud-ies  =  1). Cardiovascular and Diabetic Treatment Targets:  Onecase  –  control study investigated medication use for dia- betes, hypertension and hyperlipidaemia across peoplewith dementia at any stage compared to age-matchedpeers without dementia. 48 This study reported bloodpressure, blood glucose, HbA 1C  and cholesteroltreatment targets (Table 3). This study suggests that blood pressure may have been lower in people withdementia than without, but that serum cholesterol, blood glucose and HBA 1C  is treated to similar targets inpeople with and without dementia. Drug Utilisation Patterns for Comorbidities Five studies reported drug utilisation, which are pre-sented in Table 4. 44  –  48 Compared to people withoutdementia, people with dementia were less likely to bedispensed osteoporosis medication. Oral anticoagulationand antiplatelet agents were more likely to be pre-scribed to people with dementia who also had atrial  󿬁  b-rillation compared to those without atrial  󿬁  brillation.Other drug utilisation patterns were not found to bedifferent. DISCUSSION We identi 󿬁 ed six papers, involving a total of 51 696 par-ticipants that addressed medication use for people withdementia to manage speci 󿬁 c comorbidities, namelyosteoporosis, diabetes, depression and cardiovasculardisease. 44  –  49 We found little evidence to guide medica-tion use to manage comorbidities with only one paperthat reported clinically-relevant health outcomes. 49 Theone experimental study found treatment with a bispho-sphonate compared to placebo reduced fractures inpeople with moderate dementia and osteoporosis.However, the majority of the studies evaluated drugutilisation patterns rather than health outcomes. 44  –  48 Drug utilisation patterns for people with dementiawere evaluated in these studies using treatment targetsand standards based on existing evidence in peoplewithout dementia.Osteoporosis increases the risk of fractures and theconsequences of fractures include an increased morbid-ity and premature mortality, but can also result in dete-riorating quality of life and substantial pain. Currenttreatment for all people with osteoporosis is to providetreatment for a  󿬁 nite duration to reduce the risk of frac-ture. 50  –  52 Bisphosphonates are documented to have anonset time for bene 󿬁 t to reduce fractures; bisphospho-nates have been shown to have a reduction in fractureincidence after 2 years. 53 The experimental studyincluded in this literature review found that even inmoderate dementia, mobile people continued to receive bene 󿬁 ts from bisphosphonate treatment. Bisphosphonatetreatment compared to placebo resulted in fewer frac-tures. 49 This evidence supports the bene 󿬁 t from bisphos-phonate treatment to ambulant people with dementia.However, people with osteoporosis were less likely to  Journal of Pharmacy Practice and Research  (2018)  48,  356 – 367  ©  2018 The Society of Hospital Pharmacists of Australia 360  A. Page  et al.
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