The review method will be based on the Cochrane Handbook for Systematic Reviews of Interventions (31) and the Methods for the development of public health guidance of the National Institute for Health and Care Excellence (32). The following key words and terms will be combined to identify deprescribing intervention studies:
polypharmacy, deprescribing, Beers’s criteria, potentially inappropriate
withdraw*, withhold, withheld, stop*, cease*, discontinu*, reduc*
aged, geriatri*, frai*
KU will advise on relevant key papers to inform the development of search strategies by two scientific librarians in consultation with the review authors. These strategies will be adapted for each database. References will be searched using key international databases such as MEDLINE, EMBASE, CINAHL, Ageline and PsycInfo without date limitation. When available, limits will be set to restrict the search to humans aged 60 and over and publications in English, French or German but without time limits. The search strategy is featured in Appendix 1.
Reference lists of relevant review articles and of included studies will be checked manually for additional relevant articles. Authors will make a special effort to identify relevant grey literature. See Appendix 2 for the probable, but not exhaustive, list of databases and websites.
Study selection will be performed by two independent reviewers according to the following inclusion and exclusion criteria (PICOS):
Population studied: Study groups with participants aged 60 years and older will be considered for this review. Study groups with a mean age ≥ 60 years, for which at least 80% of participants were ≥ 60 years old, or offering the possibility to extract data related to a subgroup of participants aged ≥ 60 years. In addition, the participants will have at least one medication prescribed for a chronic condition.
Interventions: Deprescribing interventions, regardless of the intervention target (patients, caregivers or health professionals) in any intervention setting (hospital, nursing home, etc.) will be selected.
Comparison: Only the comparison of deprescribing interventions with usual care or different head-to-head interventions will be considered for this review.
Outcome: For interventions having affected the participants’ medication regimen all health outcomes will be considered, including withdrawal symptoms, adverse medication reactions, clinical outcomes, cognition, behavior, falls, use of health services, quality of life, mortality or survival.
Study design: All robust study designs will be included (RCT, non-RCT; controlled before-after studies; interrupted time series studies; repeated measures).
All included studies will be primary studies, therefore reviews, editorials, letters to the editor, commentaries, and other similar publications will be excluded.
All identified references will be combined into an EndNote® library (https://endnote.com/) and multiple copies will be eliminated. The systematic review software DistillerSR® (www.evidencepartners.com/) will be used for the subsequent steps. Two reviewers will independently determine the eligibility of the retrieved studies by comparing their titles and abstracts to the inclusion criteria. Subsequently, the full texts of the retained articles will be screened to confirm their relevance. The process will be similar for all types of literature sources. The study selection form can be found in Appendix 3.
The extraction of data will be completed using DistillerSR® and pre-established forms regarding
Study characteristics (design, date, and location)
Population selection and participants’ characteristics (age, sex, residency)
Intervention description (providers, targets, duration, follow-up)
Outcomes (medication regimen, health, quality of life)
An example of a data extraction form is featured in Appendix 4.
The Cochrane Collaboration’s tool GRADE system for grading the quality of evidence will be used to evaluate the quality of the evidence. The risk of bias of eligible studies will be assessed using the SIGN tool for RCTs (33) and the Research Triangle Institute (RTI) instrument for non-randomized studies (34). The process will be carried out by one reviewer and reviewed by a second one.
A meeting between researchers and stakeholders allowed to prioritize medication classes with specific indications (for example bisphosphonates against osteoporosis) over a specific health outcome (as for example mortality reduction as in the review by Page et al) (35). If methodologically feasible, meta-analyses will be performed for intervention studies reporting on deprescribing interventions for similar medications or a specific medication class, used for similar or identical indications and reporting on similar outcomes (for example benzodiazepines against insomnia, reporting on sleep quality). If meta-analyses are impossible, the study results will be summarized in a transparent and reproducible narrative synthesis, based on the methods published by Popay et al. (36) and by Rodgers et al. (37) (Objectives 1). Descriptive numerical summary tables will also be completed. In order to answer objective 2, we will identify the most effective interventions or intervention components in regard, but not limited to the following patient characteristics:
Comparative qualitative analysis will be used to analyze the causal contribution of different intervention components towards health outcomes (38). The sets of characteristics associated with the specific outcome will be charted. Afterwards, they will be subjected to a minimization procedure to identify a simpler set of conditions accounting for observed health outcomes. This will result in a matrix of intervention characteristics and related outcomes.
If outcomes or medications are sufficiently similar, the results of deprescribing interventions will be subjected to meta-analyses using RevMan 5.3.5 or SAS 9.4. Comparisons between interventions will be performed on one outcome at a time. A risk ratio will be estimated for the studies comparing an intervention group with a usual care or control group. For studies with more than one intervention group, the usual care or a control group is appropriately split for each intervention, and a sensitivity analysis will evaluate the impact of this split (39, 40). Any heterogeneity indicated by χ2 test of heterogeneity and the I2 statistic with its 95% confidence interval (41) will be investigated through subgroup analyses and the use of a random effects model, when publication bias seems low, according to a funnel plot analysis (42). If interventions have different durations, the effect of the interventions has to be comparable at different times. In such a case, a meta-regression model may be used to investigate the potential effect of intervention duration on the results (43).
Integrated Knowledge Exchange
The participation of experts in the fields of deprescribing and geriatrics is crucial in order to make the review useful for health professionals and applicable to the Canadian setting. Hence, researchers and KU will meet after the study selection and again before submission of publications of results. Each of these meetings will follow a rigorous and transparent methodology and be documented in detail. They will aim at identifying relevant grey literature and ongoing trials, discussing the selection of studies and answering specific methodological questions. Members will also contribute to the interpretation of review results, giving their own perspective as clinicians, patients and decision makers.
Deriving conclusions and recommendations
To respond to the first research questions, bottom-line statements based on the evidence gathered or on the results from meta-analyses will be formulated. For the second research question, a matrix will summarize the effective deprescribing interventions, or their components. The results will then be interpreted by the KU team in order to determine knowledge gaps and the need for additional research to validate the identified deprescribing interventions. They will also assist the team in determining which results can be generalized for certain medication groups, and which need further, specific research. Review results will then be modified and finalized through email exchanges.