The Carer Assessment of MedicaTion Management GuidanCe for People With Dementia at Hospital Discharge (CATCH) Tool: Exploratory Factor Analysis.

PURPOSE: The Carer Assessment of medicaTion management guidanCe for people with dementia at Hospital discharge (CATCH) tool was developed to examine the carer's experiences of medication management guidance delivery at discharge. This study explored its factor structure, characterized carers' experiences at discharge, and identified predictors of carer preparedness to manage medications at discharge. METHODS: A cross-sectional survey of carers across Australia was distributed. Survey responses were analyzed descriptively, and exploratory factor and regression analyses were performed. RESULTS: A total of 185 survey responses were completed. Exploratory factor analysis revealed 2 factors in the CATCH tool: (1) shared and supported decision-making in medication management (16 items loading 0.47 to 0.93); 2) provision of medication management guidance that is easy to understand (4 items loading (0.48 to 0.82). Internal consistency was acceptable (Cronbach alpha >0.8). Almost 18% of participants stated that they were not included in decisions about medications for people with dementia. The carer reported that the measure of how guidance is provided was positively related to their confidence in the management of medications postdischarge and satisfaction ( P < 0.05 for both). CONCLUSIONS: The CATCH tool can give the patient and carer an opportunity to provide feedback on key elements of medication management guidance delivered at discharge.

Cost-Consequence Analysis of Deprescribing to Optimize Health Outcomes for Frail Older People: A Within-Trial Analysis.

OBJECTIVES: The structured, clinically supervised withdrawal of medicines, known as deprescribing, is one strategy to address inappropriate polypharmacy. This study aimed to evaluate the costs and consequences of deprescribing in frail older people living in residential aged care facilities (RACFs) in Australia. DESIGN: A within-trial cost-consequence analysis of a deprescribing intervention-Opti-Med. The Opti-Med double-blind randomized controlled trial of deprescribing included 3 groups: blinded control, blinded intervention, and an open intervention group. SETTING AND PARTICIPANTS: Seventeen RACFs in Western Australia and New South Wales. Participants were 303 older people living in participating RACFs from March 2014 to February 2019. METHODS: Analysis was conducted from the health sector perspective. Health economic outcomes assessed include cost saved from deprescribed medicines and the incremental quality-adjusted life-years. Costs were presented in 2022 Australian dollars. RESULTS: The total cost of the Opti-Med intervention was $239.13 per participant. The costs saved through deprescribed medicines over 12 months after adjusting for mortality within the trial period was $328.90 per participant in the blinded intervention group and $164.00 per participant in the open intervention group. On average, the cost of the intervention was more than offset by the cost saved from deprescribed medicines. Extrapolating these findings to the Australian population suggests a potential net cost saving of about $1 to $16 million per annum for the health system nationally. The incremental quality-adjusted life-years were very similar across the 3 groups within the trial period. CONCLUSIONS AND IMPLICATIONS: Deprescribing for frail older people living in RACFs can be a cost-saving intervention without reducing the quality of life. Systemwide implementation of deprescribing across RACFs in Australia has the potential to improve health care delivery through the cost savings, which could be reapplied to further optimize care within RACFs.

The Drug Burden Index and Level of Frailty as Determinants of Healthcare Costs in a Cohort of Older Frail Adults in New Zealand.

OBJECTIVES: Frailty is common in older people and is associated with increased use of healthcare services and ongoing use of multiple medications. This study provides insights into the healthcare cost structure of a frail group of older adults in Aotearoa, New Zealand. Furthermore, we investigated the relationship between participants' anticholinergic and sedative medication burden and their total healthcare costs to explore the viability of deprescribing interventions within this cohort. METHODS: Healthcare cost analysis was conducted using data collected during a randomized controlled trial within a frail, older cohort. The collected information included participant demographics, medications used, frailty, cost of service use of aged residential care and outpatient hospital services, hospital admissions, and dispensed medications. RESULTS: Data from 338 study participants recruited between 25 September 2018 and 30 October 2020 with a mean age of 80 years were analyzed. The total cost of healthcare per participant ranged from New Zealand $15 (US dollar $10) to New Zealand $270 681 (US dollar $175 943) over 6 months postrecruitment into the study. Four individuals accounted for 26% of this cohort's total healthcare cost. We found frailty to be associated with increased healthcare costs, whereas the drug burden was only associated with increased pharmaceutical costs, not overall healthcare costs. CONCLUSIONS: With no relationship found between a patient's anticholinergic and sedative medication burden and their total healthcare costs, more research is required to understand how and where to unlock healthcare cost savings within frail, older populations.

Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand.

AIMS: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students. METHODS: This study used a mixed-method approach involving student data (n = 6440) for 2017-2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted. RESULTS: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. CONCLUSION: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.

Development of a tool to evaluate medication management guidance provided to carers of people living with dementia at hospital discharge: a mixed methods study.

OBJECTIVE: Medication management guidance for carers of people with dementia at hospital discharge is important to prevent medication-related harm during transitions of care. This study aimed to develop a tool to evaluate medication management guidance provided to carers of people with dementia at hospital discharge. DESIGN: The tool was developed using mixed methods involving two stages. Stage 1 involved item generation and content validation. Items were based on a previous qualitative study and systematic review. Content validation involved experts and consumers with knowledge or experience of medication management guidance in the acute care setting, and rating each item on importance and relevance. Stage 2 involved conducting cognitive interviews with carers of people with dementia to pretest the tool. SETTING: For stage 1, experts and consumers from Australia, USA and New Zealand were included. For stage 2, carers of people with dementia were recruited across Australia. PARTICIPANTS: 18 experts and consumers participated in round 1 of content validation, and 13 experts and consumers completed round 2. Five carers of people with dementia participated in cognitive interviews. RESULTS: The final tool contained 30 items capturing information across five domains: (1) provision of medication management guidance at hospital discharge; (2) carer understanding of medication management guidance provided at discharge; (3) carer engagement in discussing the safe use of medications at discharge; (4) carer preparedness to conduct medication management activities after discharge; and (5) co-ordination of medication management guidance after discharge. CONCLUSIONS: We developed the first tool to assess medication management guidance provided for carers of people with dementia at hospital discharge. The tool may be useful to inform future research strategies to improve the delivery of medication management guidance at discharge.

Geriatric medicine and health care for older people in Australia.

Aged care coverage in Australia is universal but fragmented and has been challenged by government policy to deregulate aged care and open it up to market forces. A recent inquiry into aged care (Royal Commission into Aged Care Quality and Safety) documented the outcome of this policy-substandard care at most levels. The provision of services to older Aboriginal and Torres Strait Islander peoples, who have high prevalence of frailty and cognitive impairment, was also identified as inadequate. The effects of yet to be implemented changes in policy and funding in response to this report remain to be seen. Despite this policy backdrop, geriatricians have contributed to a steady growth in medical services and interventions focussed on specific geriatric issues such as dementia, falls, polypharmacy and orthogeriatrics. These are often driven by, or in collaboration with researchers, and aim to generate research data as well as provide patient care. The numbers of academic geriatricians and other aged care health professionals is increasing, and the training of specialist geriatricians now includes a significant research component.

Caregivers' experiences of medication management advice for people living with dementia at discharge.

RATIONALE, AIMS, AND OBJECTIVES: Caregivers of people living with dementia play an essential role in managing medications across transitions of care. Adequate caregiver medication management guidance at hospital discharge is important to ensure optimal outcomes from medication use. This qualitative study explores the experiences and perspectives of caregivers about the medication management guidance provided at hospital discharge. METHODS: A qualitative approach using semi-structured, telephone interviews was conducted with 31 caregivers of people with dementia across Australia. Purposive sampling was used to ensure maximum variation of diverse experiences and perspectives. RESULTS: Caregivers' experiences of medication guidance for people with dementia at discharge were described in three themes including: (a) inadequate information about medication management at discharge; (b) limited caregiver engagement in medication management decisions; and (c) difficulties ensuring medication supply post discharge. Most participants indicated they would like to be included in discussions at discharge. However, participation was influenced by caregivers being overwhelmed by discharge processes; proactively seeking information on medication-related harm; and belief in advocacy as part of their caregiver role. Caregivers reported they would like to receive a tailored medication list for people with dementia which included information on medications that may impact on the patient's cognition, and for hospital staff to communicate with both the community pharmacist and primary care physician, to improve co-ordination post transition. DISCUSSION: In our study of caregivers of people with dementia, we identified key recommendations to facilitate regular participation of people living with dementia and their caregiver around medication guidance at discharge.

Process, impact and outcomes of medication review in Australian residential aged care facilities: A systematic review.

OBJECTIVE: To systematically review literature reporting processes, impact and outcomes of medication review and reconciliation in Australian residential aged care facilities (RACFs). METHODS: PubMed/MEDLINE, EMBASE, CINAHL, Informit Health and grey literature were searched from 1995 to July 2018. Studies reporting outcomes of a stand-alone medication review or reconciliation interventions in Australian RACFs were included. RESULTS: Thirteen studies investigated medication review, eight of which studied Residential Medication Management Reviews (RMMRs). Five studies reported that medication reviews identified an average of 2.7-3.9 medication-related problems (MRPs) per resident. One study reported medication reviews had no impact on quality of life, hospitalisation or mortality, but was not powered to assess these. Three studies reported general practitioners' acceptance of pharmacists' recommendations to resolve MRPs, ranging between 45 and 84%. CONCLUSIONS: Medication review may be a useful strategy to identify and prompt resolution of MRPs. However, the impact on clinical and resident-centred outcomes remains unclear.

Protocol for a non-randomised pilot and feasibility study evaluating a multicomponent intervention to simplify medication regimens for people receiving community-based home care services.

INTRODUCTION: Managing medication regimens is one of the most complex and burdensome tasks performed by older people, and can be prone to errors. People living with dementia may require medication administration assistance from formal and informal caregivers. Simplified medication regimens maintain the same therapeutic intent, but have less complex instructions and administration schedules. This protocol paper outlines a study to determine the feasibility of a multicomponent intervention to simplify medication regimens for people receiving community-based home care services. METHODS AND ANALYSIS: This is a non-randomised pilot and feasibility study. Research nurses will recruit 50 people receiving community-based home care services. All participants will receive the intervention from a clinical pharmacist, who will undertake medication reconciliation, assess each participant's capacity to self-manage their medication regimen and apply a structured tool to identify opportunities for medication simplification. The pharmacist will communicate recommendations regarding medication simplification to registered nurses at the community-based home care provider organisation. The primary outcome will be a description of study feasibility (recruitment and retention rates, protocol adherence and stakeholder acceptability). Secondary outcomes include the change in number of medication administration times per day, medication adherence, quality of life, participant satisfaction, medication incidents, falls and healthcare utilisation at 4 months. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Monash University Human Research Ethics Committee and the community-based home care provider organisation's ethical review panel. Research findings will be disseminated to consumers and caregivers, health professionals, researchers and healthcare providers through the National Health and Medical Research Council Cognitive Decline Partnership Centre and through conference presentations, lay summaries and peer-reviewed publications. This study will enable an improved understanding of medication management and administration among people receiving community-based home care services. This study will inform the decision to proceed with a randomised controlled trial to assess the effect of this intervention. TRIAL REGISTRATION NUMBER: ACTRN12618001130257; Pre-results.

Geriatric medicine services for older surgical patients in acute hospitals: Results from a binational survey.

OBJECTIVE: To describe perioperative geriatric medicine services in Australia and New Zealand, and to explore geriatricians' views on the need for and challenges in providing perioperative care. METHOD: An electronic questionnaire was sent to heads of geriatric medicine departments. RESULTS: Sixty-seven (83%) of 81 identified geriatric medicine departments responded. Twelve (18%) departments provide a proactive surgical-geriatric medicine service. Their most common features were regular geriatric medicine ward rounds (100%), medication review (92%) and attendance at multidisciplinary meetings (83%). All respondents thought there was a need for geriatric medicine to provide greater input into the care of older surgical patients. Lack of funding (88%) and not enough geriatricians (58%) were the major perceived barriers. CONCLUSIONS: Although geriatricians believe they should provide proactive collaborative care for older surgical patients, only a few hospitals currently provide these services. Funding streams for these services and further research to determine the best models of care are needed.

Integration of an electronic Drug Burden Index risk assessment tool into Home Medicines Reviews: deprescribing anticholinergic and sedative medications.

BACKGROUND: Our aim in this research was to establish whether integrating an electronically generated calculation and report on the Drug Burden Index (DBI) in the Home Medicines Review (HMR) setting is an accurate, feasible and useful risk assessment tool to assess risk of anticholinergic and sedative medications; and to establish whether the intervention of DBI together with HMR is associated with a reduced use of anticholinergic and sedative medications in older community-dwelling adults in Australia. METHODS: An interventional feasibility study was conducted. Accredited clinical pharmacists (APs) were recruited to participate. Each AP was educated on implementation of the DBI into HMR practice and given access to the DBI Calculator© web-based software to generate the DBI report for inclusion in HMR reports for general practitioners (GPs). APs recruited patients (⩾65 years) who were referred to them for HMRs. Patients were sent a letter about their DBI exposure, and a prompt to visit their GP to discuss their medication management options. GPs, APs and patients were asked to evaluate the feasibility and utility of the DBI report. A medication inventory was collected from patients at the time of the HMR and at 3 months to determine whether the intervention affected deprescribing of medications with anticholinergic and sedative effects. RESULTS: Regarding the feasibility of the DBI report as a risk assessment tool within HMR, 89% of APs and 67% of GPs agreed that it would be feasible. The DBI Calculator© was potentially inaccurate, as 26% of DBI scores were underestimated and 7% were overestimated (at baseline). At 3 months, the median (interquartile range) DBI for patients (n = 100) significantly decreased from 0.82 (0-1.33) to 0.67 (0-1.29) (p = 0.014). Additionally, of patients with a DBI > 0 (n = 66), 36.4% had their DBI score decrease, and 6.1% had a score increase. CONCLUSION: This study demonstrated that integration of the DBI Calculator© into HMR is a feasible and useful method to prompt deprescribing of anticholinergic and sedative medications in older adults. There is potential for the accuracy of the web-based platform to be improved. REGISTRATION OF TRIAL: Name: Feasibility study of the Drug Burden Index with Home Medicines Review.Website: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368523Trial ID: ACTRN 12615000539538.

Drug Burden Index and Its Association With Hip Fracture Among Older Adults: A National Population-Based Study.

BACKGROUND: The Drug Burden Index (DBI) calculates the total sedative and anticholinergic load of prescribed medications and is associated with functional decline and hip fractures in older adults. However, it is unknown if confounding factors influence the relationship between the DBI and hip fractures. The objective of this study was to evaluate the association between the DBI and hip fractures, after correcting for mortality and multiple potential confounding factors. METHODS: A competing-risks regression analysis conducted on a prospectively recruited New Zealand community-dwelling older population who had a standardized (International Resident Assessment Instrument) assessment between September 1, 2012, and October 31, 2015, the study's end date. Outcome measures were survival status and hip fracture, with time-varying DBI exposure derived from 90-day time intervals. The multivariable competing-risks regression model was adjusted for a large number of medical comorbidities and activities of daily living. RESULTS: Among 70,553 adults assessed, 2,249 (3.2%) experienced at least one hip fracture, 20,194 (28.6%) died without experiencing a fracture, and 48,110 (68.2%) survived without a fracture. The mean follow-up time was 14.9 months (range: 1 day, 37.9 months). The overall DBI distribution was highly skewed, with median time-varying DBI exposure ranging from 0.93 (Q1 = 0.0, Q3 = 1.84) to 0.96 (Q1 = 0.0, Q3 = 1.90). DBI was significantly related to fracture incidence in unadjusted (p < .001) and adjusted (p < .001) analyses. The estimated subhazard ratio was 1.52 (95% confidence interval: 1.28-1.81) for those with DBI > 3 compared with those with DBI = 0 in the adjusted analysis. CONCLUSIONS: In this study, increasing DBI was associated with a higher likelihood of fractures after accounting for the competing risk of mortality and adjusting for confounders. The results of this unique study are important in validating the DBI as a guide for medication management and it could help reduce the risk of hip fractures in older adults.

Assessment of Attitudes Toward Deprescribing in Older Medicare Beneficiaries in the United States.

Importance: Use of harmful and/or unnecessary medications in older adults is prevalent. This can lead to avoidable harms such as adverse drug reactions, falls, hospitalization, and mortality. Primary care physicians report that patient resistance to discontinuing medication use is a significant barrier to deprescribing. Objective: To describe the attitudes of older adults toward deprescribing and to determine whether individual characteristics are associated with these attitudes. Design, Setting, and Participants: For this population-based survey study of US Medicare beneficiaries 65 years and older, data were obtained from the Medication Attitudes module fielded through in-person interviews in round 6 of the National Health and Aging Trends Study (weighted response rate of round 6 was 88.5%). The questions in this module were drawn from the Patients' Attitudes Towards Deprescribing questionnaire and its revised version. The Medication Attitudes module was fielded to a random one-third (n = 2124) of the National Health and Aging Trends Study participants (weighted response rate of this module was 94.8%). Main Outcomes and Measures: Responses to 2 statements ("If my doctor said it was possible, I would be willing to stop one or more of my regular medicines" and "I would like to reduce the number of medicines I am taking") were the main outcomes of interest. Results: Of the 1981 Medicare beneficiaries included in the study, 1149 (55.2%, weighted) were women, and the majority (n = 715 [54.6%, weighted]) were 65 to 74 years old. A total of 1752 (92.0%, weighted) older adults reported being willing to stop taking 1 or more of their medicines if their physician said it was possible, and 1241 (66.6%, weighted) older adults wanted to reduce the number of medicines that they were taking. Older adults taking 6 or more medications had greater odds than those taking fewer than 6 medications of being willing to stop taking 1 or more of their medicines (adjusted odds ratio, 2.90; 95% CI, 1.74-4.82) and wanting to reduce the number of medicines that they were taking (adjusted odds ratio, 2.31; 95% CI, 1.71-3.13). Conclusions and Relevance: Physicians considering deprescribing as part of comprehensive, patient-centered care should be reassured that a majority of older Americans are open to having 1 or more of their medicines deprescribed if their physician says it is possible, and more than two-thirds want to reduce the number of medicines that they are taking.

Development and validation of the Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE).

BACKGROUND: Residents of aged care facilities use increasingly complex medication regimens. Reducing unnecessary medication regimen complexity (eg, by consolidating the number of administration times or using alternative formulations) may benefit residents and staff. OBJECTIVE: To develop and validate an implicit tool to facilitate medication regimen simplification in aged care facilities. METHOD: A purposively selected multidisciplinary expert panel used modified nominal group technique to identify and prioritize factors important in determining whether a medication regimen can be simplified. The five prioritized factors were formulated as questions, pilot-tested using non-identifiable medication charts and refined by panel members. The final tool was validated by two clinical pharmacists who independently applied the tool to a random sample of 50 residents of aged care facilities to identify opportunities for medication regimen simplification. Inter-rater agreement was calculated using Cohen's kappa. RESULTS: The Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE) was developed as an implicit tool comprising of five questions about 1) the resident; 2) regulatory and safety requirements; 3) drug interactions; 4) formulation; and 5) facility and follow-up considerations. Using MRS GRACE, two pharmacists independently simplified medication regimens for 29/50 and 30/50 residents (Cohen's kappa=0.38, 95% CI 0.12-0.64), respectively. Simplification was possible for all residents with five or more administration times. Changing an administration time comprised 75% of the two pharmacists' recommendations. CONCLUSIONS: Using MRS GRACE, two clinical pharmacists independently simplified over half of residents' medication regimens with fair agreement. MRS GRACE is a promising new tool to guide medication regimen simplification in aged care.

Development and validation of an instrument for measuring the burden of medicine on functioning and well-being: the Medication-Related Burden Quality of Life (MRB-QoL) tool.

OBJECTIVE: Medication-related burden (MRB) is a negative experience with medicine, which may impact on psychological, social, physical and financial well-being of an individual. This study describes the development and initial validation of an instrument specifically designed to measure MRB on functioning and well-being-the Medication-Related Burden Quality of Life (MRB-QoL) tool. METHODS: An initial pool of 76-items for MRB-QoL was generated. The link to MRB-QoL survey was sent to a sample of consumers living with at least one chronic medical condition and taking ≥3 prescription medicines on a regular basis. Exploratory factor analysis (EFA) was used to determine the underlining factor structure. Internal consistency (Cronbach's α) and construct validity were examined. The latter was examined through correlation with Medication Regimen Complexity Index (MRCI), Drug Burden Index (DBI) and Charlson's Comorbidity Index (CCI). RESULTS: 367 consumers completed the survey (51.2% male). EFA resulted in a 31-item, five-factor solution explaining 72% of the total variance. The five subscales were labelled as 'Routine and Regimen Complexity' (11 items), 'Psychological Burden' (six items), 'Functional and Role Limitation' (seven items), 'Therapeutic Relationship' (three items) and 'Social Burden' (four items). All subscales showed good internal consistency (Cronbach's α 0.87 to 0.95). Discriminant validity of MRB-QoL was demonstrated via its correlations with MRCI (Spearman's r -0.16 to 0.08), DBI (r 0.12 to 0.28) and CCI (r -0.23 to -0.15). Correlation between DBI and 'Functional and Role Limitation' subscale (r 0.36) indicated some evidence of convergent validity. Patients with polypharmacy, multiple morbidity and DBI >0 had higher median scores of MRB-QoL providing evidence for known group validity. CONCLUSIONS: The MRB-QoL V.1 has good construct validity and internal consistency. The MRB-QoL may be a useful humanistic measure for evaluating the impact of pharmaceutical care interventions on patients' quality of life. Future research is warranted to further examine additional psychometric properties of MRB-QoL V.1 and its utility in patient care.

SImplification of Medications Prescribed to Long-tErm care Residents (SIMPLER): study protocol for a cluster randomised controlled trial.

BACKGROUND: Complex medication regimens are highly prevalent in residential aged care facilities (RACFs). Strategies to reduce unnecessary complexity may be valuable because complex medication regimens can be burdensome for residents and are costly in terms of nursing time. The aim of this study is to investigate application of a structured process to simplify medication administration in RACFs. METHODS: SImplification of Medications Prescribed to Long-tErm care Residents (SIMPLER) is a non-blinded, matched-pair, cluster randomised controlled trial of a single multidisciplinary intervention to simplify medication regimens. Trained study nurses will recruit English-speaking, permanent residents from eight South Australian RACFs. Medications taken by residents in the intervention arm will be assessed once using a structured tool (the Medication Regimen Simplification Guide for Residential Aged CarE) to identify opportunities to reduce medication regimen complexity (e.g. by administering medications at the same time, or through the use of longer-acting or combination formulations). Residents in the comparison group will receive routine care. Participants will be followed for up to 36 months after study entry. The primary outcome measure will be the total number of charted medication administration times at 4 months after study entry. Secondary outcome measures will include time spent administering medications, medication incidents, resident satisfaction, quality of life, falls, hospitalisation and mortality. Individual-level analyses that account for clustering will be undertaken to determine the impact of the intervention on the study outcomes. DISCUSSION: Ethical approval has been obtained from the Monash University Human Research Ethics Committee and the aged care provider organisation. Research findings will be disseminated through conference presentations and peer-reviewed publications. SIMPLER will enable an improved understanding of the burden of medication use in RACFs and quantify the impact of regimen simplification on a range of outcomes important to residents and care providers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617001060336 . Retrospectively registered on 20 July 2017.

Efficacy and Safety of Quarter-Dose Blood Pressure-Lowering Agents: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There is a critical need for blood pressure-lowering strategies that have greater efficacy and minimal side effects. Low-dose combinations hold promise in this regard, but there are few data on very-low-dose therapy. We, therefore, conducted a systematic review and meta-analysis of randomized controlled trials with at least one quarter-dose and one placebo and standard-dose monotherapy arm. A search was conducted of Medline, Embase, Cochrane Registry, Food and Drug Administration, and European Medicinal Agency websites. Data on blood pressure and adverse events were pooled using a fixed-effect model, and bias was assessed using Cochrane risk of bias. The review included 42 trials involving 20 284 participants. Thirty-six comparisons evaluated quarter-dose with placebo and indicated a blood pressure reduction of -4.7/-2.4 mm Hg (P<0.001). Six comparisons were of dual quarter-dose therapy versus placebo, observing a -6.7/ -4.4 mm Hg (P<0.001) blood pressure reduction. There were no trials of triple quarter-dose combination versus placebo, but one quadruple quarter-dose study observed a blood pressure reduction of -22.4/-13.1 mm Hg versus placebo (P<0.001). Compared with standard-dose monotherapy, the blood pressure differences achieved by single (37 comparisons), dual (7 comparisons), and quadruple (1 trial) quarter-dose combinations were +3.7/+2.6 (P<0.001), +1.3/-0.3 (NS), and -13.1/-7.9 (P<0.001) mm Hg, respectively. In terms of adverse events, single and dual quarter-dose therapy was not significantly different from placebo and had significantly fewer adverse events compared with standard-dose monotherapy. Quarter-dose combinations could provide improvements in efficacy and tolerability of blood pressure-lowering therapy.