Abstract
Aims
Deprescribing is a suggested intervention to reverse the potential iatrogenic harms of inappropriate polypharmacy. The review aimed to determine whether or not deprescribing is a safe, effective and feasible intervention to modify mortality and health outcomes in older adults.
Methods
Specified databases were searched from inception to February 2015. Two researchers independently screened all retrieved articles for inclusion, assessed study quality and extracted data. Data were pooled using RevMan v5.3. Eligible studies included those where older adults had at least one medication deprescribed. The primary outcome was mortality. Secondary outcomes were adverse drug withdrawal events, psychological and physical health outcomes, quality of life, and medication usage (e.g. successful deprescribing, number of medications prescribed, potentially inappropriate medication use).
Results
A total of 132 papers met the inclusion criteria, which included 34 143 participants aged 73.8 ± 5.4 years. In nonrandomized studies, deprescribing polypharmacy was shown to significantly decrease mortality (OR 0.32, 95% CI: 0.17–0.60). However, this was not statistically significant in the randomized studies (OR 0.82, 95% CI 0.61–1.11). Subgroup analysis revealed patient‐specific interventions to deprescribe demonstrated a significant reduction in mortality (OR 0.62, 95% CI 0.43–0.88). However, generalized educational programmes did not change mortality (OR 1.21, 95% CI 0.86–1.69).
Conclusions
Although nonrandomized data suggested that deprescribing reduces mortality, deprescribing was not shown to alter mortality in randomized studies. Mortality was significantly reduced when applying patient‐specific interventions to deprescribe in randomized studies.
Keywords: deprescribing, meta‐analysis, older adults, systematic review, polypharmacy, medication discontinuation
What is Already Known about this Subject
Polypharmacy in older adults is correlated to poor health outcomes.
Deprescribing is one proposed intervention to reduce the harm associated with polypharmacy.
Limited evidence is available to support deprescribing as an intervention.
What this Study Adds
Deprescribing appears to be a feasible intervention.
Deprescribing may not affect mortality.
Evidence exists to guide deprescribing individual medications in carefully defined scenarios.
Introduction
People are living longer than ever before, but many older adults live with multiple chronic diseases 1. Efficacious medications modify the risk of future serious events such as myocardial infarction or stroke 2. Medications alleviate symptoms such as pain, anxiety and reflux. Additionally, there is increased evidence for combination therapies for conditions such as hypertension, diabetes and benign prostatic hypertrophy 3, 4, 5. Consequently, the daily routine of taking many medications is now the norm rather than the exception for many older adults. By age 70, three out of four people take five or more medications every day 6. The potential problem of polypharmacy continues to grow with the average 70‐year‐old taking an additional two tablets every day than the average 70‐year‐old did just ten years ago 7, 8, 9. Therefore, the ‘cure’ may have become the ‘disease’. Polypharmacy among older people is associated with poorer health outcomes such as increased rates of impaired cognition, frailty, falls, morbidity and disability 10, 11, 12. It is independently associated with increased mortality 13. It remains unclear whether polypharmacy is merely an indicator, or cause, of poorer health outcomes.
To reverse the harms of polypharmacy appears simple. The number of medications older adults use should be reduced by ‘deprescribing’ 14. Deprescribing is defined as the ‘the process of withdrawal of inappropriate medication, supervised by a health care professional with the goal of managing polypharmacy and improving outcomes’ 15. This process can be applied in practice using a five‐step approach: (1) consider all medications currently taken and the indication for each medication, (2) evaluate the overall risk of medication‐induced harm in an individual person, (3) assess each medication for its potential to be deprescribed, (4) sort medications by the order of priority to deprescribe, (5) implement and monitor deprescribing regimen 14. A useful mnemonic for this process is CEASE 16. Yet the evidence base to support deprescribing interventions remains relatively scant, and it is unknown if deprescribing can ameliorate the correlated harms of polypharmacy. Recent systematic reviews have investigated the barriers and enablers for both consumers and prescribers, as well as the definition of deprescribing 15, 17, 18. Existing systematic reviews have explored deprescribing specific classes (including cardiovascular, psychotropic and hypnotic medications) 19, 20, 21 as well as specific scenarios, such as oncology, palliative care and deprescribing to prevent or modify the risk of falls 22, 23. This systematic review is the first to compile evidence for deprescribing in older adults across all settings and medications. The review aims to determine whether deprescribing is a safe, effective and feasible intervention to modify mortality and health outcomes in older adults. More specifically, the primary aim is to establish the safety of deprescribing by assessing its effects on mortality. The secondary aims include exploring the safety of deprescribing by investigating adverse drug withdrawal events. Further, we explore the efficacy of deprescribing interventions by investigating health outcomes and quality of life. Additionally, we review whether deprescribing interventions are achievable.
Methods
The protocol was prospectively published and registered with Prospero Database of Systematic Reviews (CRD42014009887) 24, 25. This review was conducted and reported in adherence to the PRISMA statement of quality for reporting systematic reviews and meta‐analyses 26.
Selection criteria
The selection criteria were described in detail previously and are briefly described here 24.
Types of participants
This review considered studies that included people aged 65 years and older who were prescribed one or more regular medications at the beginning of the study. Studies that included only moribund, terminal or palliative participants were excluded. No limitation was placed on the setting.
Types of interventions
This review considered studies that evaluated deprescribing by a health care professional of one or more regular prescription medications. Studies were included where the stated aim or effect was to deprescribe one or more medications.
For the study to be eligible for inclusion, the deprescribing intervention needed to target a medication available in 2015 in at least one of the following countries: Australia, New Zealand, United Kingdom, Canada or the United States. This focused the review on medications currently available today, rather than those withdrawn from the market.
These could be compared to either no comparator or usual care, namely the continuation of the prescribed medication.
Types of outcome measures
Outcomes were included where reported as either an outcome or an effect of the intervention in the original paper. Mortality was the primary outcome measure for this review. Secondary outcome measures considered were any reported adverse drug withdrawal events. Health outcomes were considered where there were clinically‐relevant physical health, cognitive function and psychological health parameters or events.
Quality of life measured using any standardized tool was considered. The effect on the medication regimen was included if reported using a standard measure, such as any implicit or explicit prescribing tools, success of deprescribing or total number of medications.
Types of studies
This review considered for inclusion both experimental and observational studies of deprescribing of one or more prescription medications in older people. These were defined as studies where the stated aim or effect of the intervention was to reduce medication. The review included experimental study designs (randomized controlled studies (RCTs), quasi‐randomized controlled studies, and nonrandomized controlled studies) as well as observational study designs with concurrent controls (prospective and retrospective cohort studies, case‐control studies), and observational studies without concurrent controls (historical cohort studies, two or more single arm studies, and before and after studies).
Studies available in English at any time up to the commencement of the search on 11 February 2015 were considered for inclusion in this review.
Search strategy
The search strategy aimed to identify both published and unpublished studies, and has previously been described in detail 24. Briefly, databases were searched from inception to February 2015. EbscoHost (CINAHL Plus, Health Source: Nursing/Academic Edition, Academic Search Premier), Ovid (Medline, DARE), Scopus, Web of Science, Elsevier (Embase) and ProQuest (Dissertations and Theses Global) were searched to identify published papers and grey literature. National Institutes of Health Trials Register, Australian New Zealand Clinical Trials Registry and European Union Clinical Trials Register were searched for ongoing trials. The search terms used were:
prescribing, prescription, drug, medication, polypharmacy, individual generic drug names, drug classes and therapeutic classes
deprescrib*, inappropriate, reduc*, stop*, withdraw*, cessation, ceas*,discontinu*
aged OR ageing OR 65 years OR geriatric OR older adult OR older OR elderly OR veteran
1 AND 2 AND 3
The detailed Medline database search is available in the supplementary file. The reference lists of all identified papers were scanned for relevant studies.
Data collection and analysis
Selection of studies
Two researchers independently screened the titles and abstracts of all records retrieved. Full texts of all articles were retrieved that appeared to meet the selection criteria and for those that could not be adequately assessed from the information given. Two researchers independently assessed the full‐text articles for eligibility. They resolved any differences through consensus, and where consensus was not achieved, a third researcher made the final decision.
Data extraction and management
An electronic data extraction form was designed using DistillerSR online application 27. One researcher independently extracted details of included articles, which were verified by a second researcher. Information extracted included the study design and size, intervention dates, setting, participants' age, sex, whether participants were living with dementia, the inclusion and exclusion criteria, medication targeted for deprescribing, withdrawal schedule, reported outcomes, follow‐up duration and funding source.
For studies where the stated aim or effect of the intervention was to deprescribe polypharmacy, we extracted additional information about the method used to identify target medication. We extracted data on whether the intervention was patient‐specific or educational. Deprescribing interventions were defined as patient‐specific when (i) the investigators identified target medications to deprescribe and implemented the process (investigator‐led interventions), and (ii) the investigators undertook medication reviews to identify target medications to deprescribe, and then recommended to the prescribing doctors that they deprescribe the medications (medication reviews). Education interventions were defined as those where health care professionals were provided with education sessions with the intention to reduce medication use through modified behaviours.
Missing data
The original authors were contacted to obtain missing information or clarify unclear data. Where this was not successful, we conducted the analysis with only the available data.
Assessment of risk of bias
Two reviewers independently assessed the risk of bias 27. The second reviewer was blinded to author, year and place of publication. The Cochrane Collaboration's ‘Risk of Bias’ tool was used to assess the risk of bias for each included RCT 28, 29. For studies other than RCTs, we modified the standard tool using the recommendations from the Cochrane Handbook and combined it with the Newcastle‐Ottawa tool 29.
Assessment of reporting biases
Risk of reporting bias was assessed using funnel plot asymmetry, where data from more than ten similar studies were pooled 29.
Unit‐of‐analysis issues
Included studies reported in two or more papers were combined into a single study. We extracted data from each report separately, and then combined information across the multiple data collection forms.
For multi‐arm studies, the authors used their judgement to identify the most relevant intervention and control group to enter into the meta‐analysis. If three or more groups were relevant to the review, then we combined the groups from multiple arms studies into a single group in RevMan v5.3 30. This was done to avoid the possibility of introducing bias caused by using one control group for multiple statistical comparisons. Where studies reported an outcome at multiple time points, we used the data from the last time point 29.
For crossover studies and factorial study designs, the analysis techniques used intended to avoid potential unit‐of‐analysis issues. For crossover studies, we used only data from the first phase of crossover studies. For studies that used a factorial design, the group that received only the deprescribing intervention were selected and compared to the group that received neither intervention.
Data synthesis
Where possible, quantitative data from studies were pooled for statistical meta‐analysis using RevMan v5.3 30. Data were pooled based on the medication(s) deprescribed regardless of the intervention technique. Studies were pooled as ‘polypharmacy’ where the stated aim or effect of the intervention was to reduce medications across three or more medications or classes. Data from RCTs were not combined with data from other study designs. We further separated comparative studies with and without concurrent control groups.
Forest plots were produced where three or more studies were included in a meta‐analysis.
Data in tables are presented in order of polypharmacy and then by therapeutic class based on the Anatomical Therapeutic Classification (ATC) codes.
Randomized studies
The Mantel‐Haenszel method using the fixed effects model was used to pool RCTs. If heterogeneity was detected, we chose the random effects model. Where one or more of the original studies used a cluster‐randomization method, we used the generic inverse‐variance method rather than the Mantel‐Haenszel method.
Nonrandomized studies with concurrent control groups
The generic inverse‐variance method with a fixed effects model was used to pool data 29. If heterogeneity was detected, we chose the random effects model.
Nonrandomized studies without a concurrent control group
The data were reported narratively for these studies 29.
Dichotomous data
Effect sizes and their 95% confidence intervals were expressed as odds ratios (OR). Where a study reported zero events in both arms, the study was excluded from the meta‐analysis 29.
Continuous data
Effect sizes and their 95% confidence intervals were expressed as weighted mean differences (MD). Where studies reported the mean but not the standard deviation, we have looked for other reports of variance for continuous data. If other measures of variance have been given, such as standard error or 95% confidence interval and P‐values, we have entered these data into RevMan 5.3 to calculate the standard deviation 30. We chose the larger of the two values where the significant decimal places in a measure of variance had been rounded and resulted in an uneven spread. We sought the standard deviation from the study author where insufficient detail of variance was provided in the paper to calculate the standard deviation. Where the detail of variance was still unavailable, the study was excluded from the meta‐analysis.
Assessment of heterogeneity
Heterogeneity was assessed visually with forest plots where applicable. Heterogeneity was quantitatively assessed using the standard Chi‐square and defined as either I 2 ≤ 50% or P > 0.1 29.
Subgroup analysis
Subgroup analyses were undertaken when ten or more studies investigating the same deprescribing target medication(s) reported an outcome. The subgroup analyses were based on age (participants aged under 80 years and those aged 80 years and over), cognitive function (participants living with dementia and cognitively intact participants) and intervention method (patient‐specific interventions and educational programmes). The subgroups based on age and cognitive function, which were prespecified in the protocol as the old‐old and people living with dementia, are demographic groups where there is often sparse clinical evidence to support medication use, and often have greater or specific health care needs.
Results
Description of studies
Results of the search
The initial search identified 27 086 records, and 1378 were identified through other methods (Figure 1). A total of 497 full papers were retrieved for further examination, and 132 papers reported 116 studies that met the inclusion criteria (Figure 1) 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162. Additional information was sought from the authors of 18 studies 41, 43, 48, 49, 50, 57, 59, 65, 77, 84, 88, 92, 99, 104, 105, 109, 119, 160. Five authors responded to this request for further information 84, 88, 92, 99, 109.
Figure 1.
Selection process for included papers
Included studies
A detailed summary of all included studies is presented in Table 1 for deprescribing polypharmacy (three or more medications or classes) and Table 2 for deprescribing individual targets, and a description of each included study is presented in Results S1. These included studies are summarized in tables based on study design and sorted by deprescribing target (Table 3, Tables S2 and S3).
Table 1.
Characteristics of included studies deprescribing polypharmacy (three or more drugs or drug classes). Presented in order of study design (highest level of evidence to lower levels of evidence) and then chronological order
| Reference | Intervention type | Tool to identify targets | Study design | Country | Setting | Follow‐up duration (months) | Number of participants enrolled | Gender male (Percentage) | Mean age of participants in years | Includes participants with dementia | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Potter et al. 123 | Investigator‐initiated deprescribing – doctor led (patient‐specific) | Modified Good Palliation‐Good Practice tool | Randomized controlled study | Australia | Residential care | 12 | 95 | 48 | 84.3 | Yes | Median number of regular medicines |
| Cognitive function | |||||||||||
| Independence in activities of daily living | |||||||||||
| Falls | |||||||||||
| Fractures | |||||||||||
| Sleep quality | |||||||||||
| Bowel function | |||||||||||
| Quality of life | |||||||||||
| Mortality | |||||||||||
| Dalleur et al. 55 | Medication‐review by multidisciplinary team to recommend deprescribing targets (patient‐specific) | STOPP criteria | Randomized controlled study | Belgium | Hospital | 12 | 158 | 34 | Not stated ‐ median: 84 years | Unclear ‐ 26 participants are described as having a ‘cognitive disorder’ | Proportion of potentially inappropriate medicines ceased between hospital admission and discharge |
| Characteristics associated with discontinuation of potentially inappropriate medicines at discharge | |||||||||||
| Proportion of potentially inappropriate medicines that were still discontinued 1 year after discharge | |||||||||||
| Clinical significance of the STOPP‐related recommendations | |||||||||||
| Mortality | |||||||||||
| García‐Gollarte et al. 78 | Education to nursing home physicians | STOPP/START criteria | Randomized controlled study | Spain | Residential care | 6 | 1018 | 73 | 84.4 | Yes, 1010 (99%) | STOPP/START criteria – participants with at least one item Falls |
| Delirium, number of episodes | |||||||||||
| Mortality | |||||||||||
| Physician visits | |||||||||||
| Emergency department visits | |||||||||||
| Hospital in‐patient days | |||||||||||
| Pitkala et al. 120 | Education to nursing staff at aged care facilities | Beers Criteria | Randomized controlled study | Finland | Residential care | 12 | 227 | 29 | 82.9 | Yes | Proportion of persons using inappropriate, anticholinergic or more than two psychotropic drugs |
| Change in the mean number of inappropriate, anticholinergic and psychotropic drugs | |||||||||||
| Number of hospitalizations | |||||||||||
| Ambulatory service utilization | |||||||||||
| 15D HRQOL measure | |||||||||||
| Mortality | |||||||||||
| Beer et al. 38 | Investigator‐initiated deprescribing – doctor led (patient‐specific) | Pre‐specified list of target medications | Randomized controlled study | Australia | Residential care Community | 3 | 44 | 32 | 81 | Unclear – mean MMSE 27 ± 2 so may include participants with mild dementia | Short‐form 36 health survey |
| EuroQol 5‐D visual analog scale | |||||||||||
| Sleep quality | |||||||||||
| MMSE | |||||||||||
| Medication Adherence | |||||||||||
| Mortality | |||||||||||
| Gallagher et al. 77 | Medication‐review by doctors to recommend deprescribing targets (patient‐specific) | STOPP/START criteria | Randomized controlled study | Ireland | Hospital | 6 | 400 | 45 | Unstated (median 74.5) | Yes | Medicine Appropriateness Index |
| Assessment of Underutilization indexSTOPP/START criteria – participants with at least one item | |||||||||||
| Falls | |||||||||||
| All cause mortality | |||||||||||
| Duration of initial hospital stay | |||||||||||
| Hospital readmission | |||||||||||
| General practitioner visits | |||||||||||
| Gnjidic et al. 84 | Medication‐review to recommend deprescribing targets (patient‐specific) | Drug Burden Index | Randomized controlled study | Australia | Community | 3 | 115 | 73 | 80.4 | No | Frequency of use of Drug Burden Index regularly scheduled and/or as‐needed drugs across different drug classes at baseline and prescribing change at follow‐up |
| Impact of study intervention on prescribing change | |||||||||||
| Barriers to reducing regularly scheduled Drug Burden Index drugs | |||||||||||
| Mortality | |||||||||||
| Weber et al. 159 | Medication‐review by pharmacist or doctor to recommend deprescribing targets (patient‐specific) | No identification method tool specified | Randomized controlled study | USA | Community | 15 | 620 | 21 | 76.9 | Yes | Medication use |
| Falls, percentage of participants who reported at least one fall | |||||||||||
| Mortality | |||||||||||
| Allard et al. 32 | Medication‐review to recommend deprescribing targets (patient‐specific) | List of potentially inappropriate medications list developed by the Quebec Committee on Drug Use in the Elderly | Randomized controlled study | Canada | Community | 12 | 503 | 17 | 80.4 | No | Total number of potentially inappropriate medicines per person |
| Total number of medicines prescribed per person | |||||||||||
| Number of subjects with at least one potentially inappropriate medicine | |||||||||||
| Mortality | |||||||||||
| Campbell et al. 47 | General Practitioner to identify participants, investigator‐led intervention – doctor led (patient‐specific) | Pre‐specified list of target medications (benzodiazepine, any other hypnotic or any antidepressant or major tranquilizer) | Randomized controlled study | New Zealand | Community | 10 | 93 | 24 | 74.6 | No | Falls |
| Tabloski et al. 142 | Investigator‐initiated deprescribing – nurse‐led (patient‐specific) | Pre‐specified list of target medications (sedative‐hypnotic medications) | Randomized controlled study | USA | Community | 1.25 | 20 | 0 | 77.5 | No | Sleep complaints |
| Time in bed (minutes) | |||||||||||
| Sleep latency (minutes) | |||||||||||
| Total sleep time (minutes) | |||||||||||
| Sleep (minutes) | |||||||||||
| Sleep efficiency (score) | |||||||||||
| Longest Sleep Period (minutes) | |||||||||||
| Number of wakes | |||||||||||
| Wake After Sleep Onset (minutes) | |||||||||||
| Hanlon et al. 88 | Investigator‐initiated deprescribing – pharmacist led (patient‐specific) | Medicines Appropriateness Index | Randomized controlled studyAND Before‐and‐after study (2 papers) | USA | Community | 12 | 207 | 61 | Unstated (median 69 years) | No | Medicine Appropriateness Index |
| Health‐related quality of life using Short‐form 36 health survey | |||||||||||
| Adverse drug reactions | |||||||||||
| Patient medication compliance and knowledge | |||||||||||
| Adverse drug withdrawal effects | |||||||||||
| Medicines associated with adverse drug withdrawal effects | |||||||||||
| Predictive factors of adverse drug withdrawal effects | |||||||||||
| Mortality | |||||||||||
| Pitkala et al. 122 | Investigator‐initiated deprescribing – doctor‐led (patient‐specific) | Health professional judgment (no list, criteria, or tool used) | Pseudo‐ Randomized controlled study | Finland | Community | Unstated | 174 | 34 | 77 | Yes | Drug utilization |
| Salonoja et al. 132 | Investigator‐initiated deprescribing – doctor‐led (patient‐specific) | Three pre‐specified lists of target medications based on falls‐risk increasing medications and psychotropic medications | Nonrandomized controlled study | Finland | Community | 48 | 591 | 11 | Unstated (minimum age 65) | No | Number of falls in total (i.e. one person may have had one or more falls, so can contribute more than once) |
| Number of people falling (i.e. just if the person has fallen at least once) | |||||||||||
| Risk of a fall that required medical treatment (regression – deprescribing group is reference group) | |||||||||||
| Muir et al. 111 | Medication‐review by doctor after provided with medication reconciliation and medicine list (patient‐specific) | Health professional judgment (no list, criteria, or tool used) | Nonrandomized controlled study | USA | Hospital | 1.25 to 1.75 | 836 | 99 | 65.2 | No | Change in medications and doses |
| Number of admission and discharge medications by drug class | |||||||||||
| Proportions of patients taking individual medications | |||||||||||
| Van Der Velde et al. 150, 151 | Investigator‐initiated deprescribing – doctor‐led (patient‐specific) | Pre‐specified list of target medications (falls‐risk increasing medications) | Case‐control Study | The Netherlands | Community | 2 | 141 | 26 | 78.4 | Unclear | Risk of a fall during follow‐up |
| Mobility testing | |||||||||||
| Yeh et al. 162 | Education to primary care physicians at nursing homes via mail (education) | Clinician‐Rated Anticholinergic Score (CR‐ACHS) and pre‐specified list of target medications (Beta‐blockers, benzodiazepines, antidepressants, atypical antipsychotics) | Prospective cohort study | Taiwan | Residential care | 3 | 67 | 100 | 83.4 | Yes | Clinician‐Rated Anticholinergic Score |
| MMSE | |||||||||||
| Modified Bartel Index | |||||||||||
| Hospital admissions | |||||||||||
| Mortality | |||||||||||
| Garfinkel et al. 80 | Investigator‐initiated deprescribing – doctor led (patient‐specific) | Good Palliation‐Good Practice tool | Prospective cohort study | Israel | Hospital | 12 | 190 | 31 | 81.2 | Yes | Successful deprescribing |
| Mortality | |||||||||||
| Admitted to acute care facility | |||||||||||
| Medicine cost | |||||||||||
| Kroenke et al. 101 | Medication‐review by doctors to recommend deprescribing targets (patient‐specific) | Health professional judgment (no list, criteria, or tool used) | Prospective cohort study | USA | Hospital | 6 | 79 | 59 | 72.3 | No | Mean number of medicines |
| Daily dose | |||||||||||
| Garfinkel et al. 79 | Investigator‐initiated deprescribing – doctor led (patient‐specific) | Good Palliation‐Good Practice tool | Before‐and‐after study | Israel | Community | 19.2 | 70 | 39 | 82.8 | Yes | Symptom recurrence after discontinuation |
| Successful deprescribing rate | |||||||||||
| Global assessment scale | |||||||||||
| Cognitive function ‐ MMSE | |||||||||||
| Hospital admission | |||||||||||
| Commenced recommended new medicine | |||||||||||
| Gerety et al. 83 | Medication review by pharmacists to recommend deprescribing targets (patient‐specific) | Health professional judgment (no list, criteria, or tool used) | Before‐and‐after study | USA | Residential care | 6 | 132 | Unstated | 70.1 | No | Incidence and severity of adverse drug events |
| Incidence and severity of adverse drug withdrawal events | |||||||||||
| Demographic factors associated with risk of adverse drug events and adverse drug withdrawal events. | |||||||||||
| Change in medicine use |
Table 2.
Characteristics of included studies for individual deprescribing targets (one or two drug or therapeutic classes). Presented in order of drug class (by Anatomical Therapeutic Classification codes), then by study design (highest level of evidence to lower levels of evidence), and then in chronological order
| Reference | Deprescribing target | Study design | Country | Setting | Follow‐up duration (months) | Number of participants enrolled | Gender male (percentage) | Mean age of participants in years | Includes participants with dementia | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|
| Reeve et al. 126 | Proton pump inhibitors | Before‐and‐after study | Australia | Community | 6 | 6 | 33 | 70 | No | Proton pump inhibitor use Adverse drug withdrawal effects |
| Sjöblom et al. 137 | Insulin, oral antiglycaemic | Prospective cohort study | Sweden | Residential care | 6 | 98 | 42 | 84.4 | No | Glycaemic control
HbA1C Clinical outcomes All cause mortality |
| Henschke et al. 93 | Potassium supplementation | Before‐and‐after study | Canada | Residential care | 3 | 33 | 100 | 70 | No | Potassium levels Distributions of erythrocyte K values |
| Yedidya et al. 161 | Clopidogrel | Randomized controlled study | Israel | Community | 24 | 20.00 | 75 | 65.9 | No | Hematological endpoints (surrogate endpoints) e.g. platelet aggregation Clinical events (bleeding or Ischemic) |
| Sambu et al. 134 | Clopidogrel | Before‐and‐after study | England | Community | 1 | 38 | 82 | 65.9 | No | Clinical events
Concomitant medical treatment and platelet reactivityThromboxane B2 levelsAdenosine diphosphate (ADP)‐induced platelet aggregation Arachidonic acid‐induced platelet aggregation Inflammatory biomarkers |
| Derogar et al. 60 | Aspirin | Retrospective cohort study | Sweden | Hospital | 24 | 118 | 60 | unstated (median 79) | No | Death
Acute cardiovascular events Hospitalization due to endoscopically verified Recurrent peptic ulcer bleeding |
| Patel et al. 118 | Rivaroxaban | Randomized controlled study | International | Community | 0.1 to 1 | 5882 | unstated | Unstated (median 73) | No | Stroke, noncentral nervous system, embolism, myocardial infarction, or vascular death Major bleeding |
| Dawson et al. 57 | Cilostazol, pentoxifylline | Randomized controlled study | USA | Community | 7 | 60 | 65 | 66.4 | No | Maximal walking distance
Pain‐free walking distance Resting Doppler limb pressures Safety and tolerability of the study medications were assessed for all subjects with clinical laboratory monitoring, electrocardiography, physical examination, vital signs, and adverse event reporting |
| Moonen et al. 110 | Antihypertensives | Randomized controlled study | Netherlands | Community | 4 | 385 | 46 | 81.1 | Yes | Systolic blood pressure
Diastolic blood pressure Cognition Depression Functional status Quality of life |
| Jondeau et al. 99 | Antihypertensives (Beta‐blocker) | Randomized controlled study | France | Hospital | 3 | 169 | 57 | 72.3 | No | Dyspnea and general well‐being
BNP plasma levels Duration of hospitalizations Re‐hospitalization rate Death rate Successful deprescribing |
| Hearing et al. 92 | Antihypertensives (atenolol) | Randomized controlled study | England | Community | 0.5 | 37 | 38 | 72.3 | No | Cognitive Drug Research Computerized Cognitive Assessment System |
| Espeland et al. 68; Kostis et al. 100 | Antihypertensive | Randomized controlled study | USA | Community | 26.7 | 975 | 48 | 65.8 | No | Predictors of successful deprescribing
Cardiovascular events Reported rates of cardiovascular events The probability of remaining normotensive without receiving antihypertensive medication |
| Nelson et al. 114 | Antihypertensive | Case‐control study AND Before‐and‐after study (2 papers) | Australia | Community | 12 | 6833 | 44 | 71.9 | No | Remaining normotensive Characteristics predictive of remaining normotensive |
| Lernfelt et al. 105 | Antihypertensive | Historical cohort study | Sweden | Community | 48 | 25 | 40 | Unstated (inclusion criteria mean that participants were all over 70 years) | No | Blood pressure
Successful deprescribing Left ventricular function and other surrogate measures |
| Hajjar et al. 87 | Antihypertensive | Before‐and‐after study | USA | Community | 0.75 | 53 | 36 | 71 | No | Adverse drug withdrawal effects Blood pressure (systolic and diastolic) |
| Jimenez‐Candil et al. 98 | Antihypertensive (ACEI) | Before‐and‐after study | Spain | Community | 3 | 22 | 59 | 71.6 | No | Exercise‐induced blood pressure response (fall or failure to rise)
Exercise duration Haemodynamic response |
| Alsop et al. 33 | Antihypertensive | Before‐and‐after study | England | Community | 30 | 338 | 25 | 80 | No | Symptom improvement Successful deprescribing |
| Ekbom et al. 66 | Antihypertensive | Before‐and‐after study | Sweden | Community | 60 | 333 | 32 | 75.2 | No | Probability of restarting antihypertensive therapy
Total mortality Cardiovascular events Comparison of death hazard between the three states and that of the normal Swedish population, matched for age and sex Major reasons for restarting treatment |
| Fotherby et al. 75 | Antihypertensive | Before‐and‐after study | England | Community Hospital | 12 | 78 | 63 | 76 | No | Successful deprescribing |
| Nadal et al. 113 | Antihypertensive | Before‐and‐after study | Sweden | Community | 36 | 86 | 38 | 74 | No | Reverted to hypertensive during the one month washout period
Successful deprescribing from one month to 36 months Differences in those that restarted and those who were deprescribed successfully Serious adverse events |
| Hansen et al. 89 | Antihypertensive | Before‐and‐after study | Denmark | Community | 12 | 169 | unstated | 75 | No | Successful deprescribing Screening normotensive |
| Fair 71 | Digoxin | Before‐and‐after study | Scotland | Community | 4‐ 11 | 32 | 28 | 74.2 | No | Successful deprescribing
Adverse drug withdrawal events Digoxin dose when reinstated |
| Macarthur 108 | Digoxin | Before‐and‐after study | Canada | Residential care | 16 | 14 | 0 | 82.5 | No | Successful deprescribing Clinical outcomes |
| Wilkins 160 | Digoxin | Before‐and‐after study | USA | Residential care | Unstated | 19 | 16 | 84.9 | Unclear | Clinical outcomes after deprescribing
Pulse Weight |
| Daly and Edwards 56 | Digoxin | Before‐and‐after study | Scotland | Community | 1 | 15 | 40 | 74.7 | No | Successful deprescribing
New incidences of heart failure New or increase prescription of diuretics |
| Sommers et al. 140 | Digoxin | Before‐and‐after study | South Africa | Community | 15 | 20 | 30 | 73 | No | Clinical evaluation Successful deprescribing |
| Fonrose et al. 74 | Digoxin | Before‐and‐after study | USA | Residential care | Unstated | 31 | 10 | 83 | Unclear | Successful deprescribing
Adverse events Death |
| van Kraaij et al. 152 | Diuretic | Randomized controlled study | The Netherlands | Community | Unstated | 32 | 47 | 75 | No | Successful deprescribing
Changes at three months Blood pressure Temporary difference |
| Walma et al. 157 | Diuretic | Randomized controlled study | The Netherlands | Community | 6 | 202 | 25 | 76 | No | Successful deprescribing Changes in systolic and diastolic blood pressures |
| De Jonge et al. 59 | Diuretic | Randomized controlled study | The Netherlands | Community | 1.5 | 63 | 13 | unstated (minimum age 65) | No | Ankle oedema
Successful deprescribing Determinants of oedema after deprescribing |
| Myers et al. 112 | Diuretic | Randomized controlled study | Canada | Residential care | 12 | 77 | 78 | Females: 84.5 Males: 79.1 | Yes | Hypertension
Congestive heart failure Biochemical abnormalities Weight Ankle oedema Events |
| Burr et al. 46 | Diuretics & potassium supplementation | Randomized controlled study | USA | Hospital | 3 | 106 | 12 | 80.5 | No | Blood pressure and pulse
Distribution of plasma potassium levels Distribution of plasma urea levels Changes in ankle oedema |
| Straand et al. 141 | Diuretic | Before‐and‐after study | Norway | Community | 6 | 33 | 24 | 82 | No | Successful deprescribing |
| Walma et al. 156 | Diuretic | Before‐and‐after study | The Netherlands | Community | 6 | 15 | 27 | 78 | No | Successful deprescribing
Blood pressure Heart failure score Weight Ankle circumference |
| George et al. 82 | Nitrates | Randomized controlled study | Israel | Community | 3 | 120 | 55 | 65.5 | No | Successful deprescribing
Relapse Characteristics of participants who relapsed Cardiovascular events Death |
| Jackson et al. 95 | Nitrates | Before‐and‐after study | England | Community | 3 | 55 | unstated | 65.2 | No | Successful deprescribing
Exacerbation of angina Five‐item Sexual Health Inventory for Men |
| Kutner et al. 102 | Statin | Randomized controlled study | USA | Community | 12 | 381 | 55 | 74.8 | Yes | Survival at 60 days
Time to death Time to first cardiovascular‐related event Cost savings Quality of life Symptoms Number of nonstatin medications Likelihood to receive the recommended care |
| Lin et al. 106 | Benign prostatic hypertrophy treatment (alpha‐blocker and 5‐alpha–reductase inhibitor therapy) | Randomized controlled study | Taiwan | Community | 12 | 240 | 0 | 78.3 and 74.3 | No | Successful deprescribing
Progression of benign prostatic hypertrophy symptoms Progression of lower urinary tract symptoms Maximum flow rate (Q max) Volume International Prostate Symptom Score –Storage subscore International Prostate Symptom Score – Voiding subscore International Prostate Symptom Score – Total score Quality of life Postvoid residual urine Total prostate volume Transition zone index Serum prostate‐specific antigen |
| Coll and Abourizk 51 | Levothyroxine | Before‐and‐after study | USA | Residential care | 3 | 22 | 9 | 78 | No | Successful deprescribing Adverse effects |
| Cibere et al. 49 | Glucosamine | Randomized controlled study | Canada | Community | 6 | 137 | 44 | 65 | No | Disease flare
Function measured using Western Ontario and McMaster Universities Osteoarthritis Index Quality of life measured using EuroQol 5‐D utility and visual analog scale |
| Esselinckx et al. 69 | Prednisolone | Before‐and‐after study | England | Community | Unstated | 18 | 39 | 69 | No | Successful deprescribing after abrupt discontinuation
Laboratory results after gradual discontinuation Laboratory outcomes after abrupt discontinuation Successful deprescribing after titrated withdrawal Adverse effects |
| Black et al. 41 | Bisphosphonates (zoledronic acid) | Randomized controlled study | International | Community | 60 | 1099 | 0 | 73.7 | No | Bone mass density in femoral neck – percentage changebone mass density of spine and total hip
Changes from pretreatment levels over 6 years (baseline to 6 years) Biochemical bone turnover markers Fractures (clinical, nonvertebral, clinical spine, and morphometric vertebral) Adverse events |
| Black et al. 42 | Bisphosphonates (alendronate) | Randomized controlled study | USA | Community | 36 | 1233 | 0 | 75.5 | No | Change in bone mineral density for duration of deprescribing
Biochemical markers of bone turnover Incidence of fracture Histomorphometry/Micro–computed tomography Histomorphometric findings from iliac crest biopsies Adverse events Antifracture efficacy of continued alendronate in subgroups defined by femoral neck T‐score and vertebral fracture status |
| Watts et al. 158 | Bisphosphonate (risedronate) | Nonrandomized controlled study | USA | Community | 12 | 759 | 0 | 68.5 | No | Bone mass density of the femoral neck
Bone mass density of the lumbar spine Urine NTX Serum bone‐specific alkaline phosphatase New vertebral fractures New nonvertebral fractures |
| da Silva et al. 54 | Bisphosphonates (alendronate) | Prospective cohort study | Brazil | Community | 12 | 90 | 0 | 71.0 | No | Bone mass density
Fractures Bone turnover markers Parathyroid and calcium and vitamin D levels |
| Eastell et al. 65 | Bisphosphonates (risedronate) | Prospective cohort study | 80 European and Australian centers | Community | 12 | 61 | 0 | 66.9 | No | Adverse events
Bone mass density change from baseline Bone markers change from baseline |
| OrrWalker et al. 117 | Bisphosphonates (Pamidronate) | Before‐and‐after study | New Zealand | Community | 48 | 22 | 0 | 65.9 | No | Change in bone mass density |
| Leder et al. 104 | Teriparatide | Two single arm studies (without concurrent control group) | USA | Community | 42 | 65 | 54 | 65 | No | Bone mass density (PA spine, femoral neck, total hip, and trabecular spine) Biochemical markers of bone turnover |
| Radford et al. 125 | Calcium supplement | Nonrandomized controlled study | New Zealand | Community | 60 | 1408 | 100 | 74.1 | No | Death
Any fracture Osteoporotic fracture Forearm fracture Vertebral fracture Hip fracture Myocardial infarction Stroke Bone mass density |
| Dawson‐Hughes et al. 58 | Calcium, vitamin D | Randomized controlled study | USA | Community | 60 | 325 | 39 | 74 | No | Vertebral fractures
Nonvertebral fracturesbone mass density testing Laboratory measurements |
| Gallagher et al. 76 | Calcitriol and/or hormone replacement therapy | Randomized controlled study | USA | Community | 6 | 489 | 0 | 71.8 | No | Mean bone mass density for spine, total body, total femur, total hip, trochanter
Urinary N‐telopeptides Serum osteocalcin Serum parathyroid hormone Serum 25OHOD levels |
| Tariot et al. 144 | Carbamazepine | Randomized controlled study | USA | Community | 0.75 | 51 | unstated | 86 | Yes | Brief Psychiatric Rating Scale
Physical Self‐Maintenance Scale Clinical Global Impressions scale MMSE Adverse effects |
| Drimer et al. 64 | Anticholinergic medicine (biperiden) | Before‐and‐after study | Israel | Hospital | 0.3 | 27 | 48 | 65.7 | No | Adverse drug withdrawal effects
Mental status Alzheimer's disease Assessment scale – cognitive sub‐scale results |
| Tse et al. 147 | Levodopa | Randomized controlled study | USA | Residential care | 1 | 11 | 36 | 82 | Yes | MMSE
Unified Parkinson's Disease Rating Scale Nursing assistant Behavioural detection form Hoehn and Yahr staging scale Motor and behavioural deterioration as assessed by the blinded floor physician |
| Cunnington et al. 52 | Dopamine agonist | Case‐control study | Scotland | Community | Unstated | 46 | 67 | 70 | No | Presence of dopamine agonist withdrawal syndrome |
| Hauser et al. 91 | Levodopa/carbidopa and bromocriptine | Before‐and‐after study | USA | Community | 0.5 | 31 | unstated | 69.2 | No | Adverse drug withdrawal effects Unified Parkinson's disease rating scale |
| Hardy et al. 90 | Lithium | Randomized controlled study | Canada | Community | 24 | 12 | 17 | 79 | No | Serum creatinine
Serum thyroid‐stimulating hormone Mean composite side effect symptom scores Depression |
| Fahy and Lawlor 70 | Lithium | Case‐control study | Ireland | Community | 19.5 | 21 | 5 | 77.6 | No | Time to relapse or follow‐up time Response to reintroduction of therapy |
| Flint and Rifat 73 | Lithium, antidepressants | Before‐and‐after study | Canada | Community | 24 | 21 | unstated | 74.4 | No | Depression recurrence
Predictors of recurrence Response to reintroduction of therapy |
| Bergh et al. 40 | Antidepressants | Randomized controlled study | Norway | Residential care | 6 | 128 | 25 | 85.3 | Yes | Cornell scale
Neuropsychiatric Index Quality of life – Alzheimer's disease scale Unified Parkinson's disease rating scale Severe impairment battery Lawton and Brody's physical self‐maintenance scale Weight Change in number of psychotropic drugs taken Oxazepam (mg)/day in last 21 days Change in number of falls per day in the last 21 days Clinical dementia rating Death |
| Ulfvarson et al. 149 | Antidepressants | Randomized controlled study | Sweden | Residential care | 12 | 70 | 33 | 84.1 | No | Montgomery Asberg depression rating scale
Global assessment of functioning Health index Symptom assessment form Symptoms of side effects of Selective Serotonin Reuptake Inhibitor (SSRI) drug treatment Death at one year |
| Bergh and Engedal 39 | Antipsychotics and antidepressants | Before‐and‐after study | Norway | Residential care | 6 | 23 | 8 | 84.1 | No | Neuropsychiatric Index
Cornell's Depression Score Severe impairment battery Unified Parkinson Disease Rating Scale |
| Lindström et al. 107 | Antidepressants | Before‐and‐after study | Sweden | Residential care | Unclear, perhaps up to 28 weeks | 119 | unstated | Unstated (age group 65–74 years: 9 participants; age group 75–84 years: 45 participants; age group 85 years and over: 65 participants) | Yes | Successful deprescribing Predictors of successful deprescribing assessed using the Montgomery Asberg Depression Rating Scale |
| Devanand et al. 62 | Antipsychotic (risperidone) | Randomized controlled study | USA | Community and Residential care | 11 | 110 | 40 | 80.3 | Yes | Adverse events
Relapse Simpson–Angus Abnormal Involuntary Movement Scale Treatment Emergent Symptoms Scale Alzheimer's Disease Assessment Scale – cognitive Physical Self‐Maintenance Scale MMSE scores Increases in body weight |
| Devanand et al. 63 | Typical antipsychotic | Randomized controlled study | USA | Community | 10 | 44 | 43 | 75.0 | Yes | Relapse measured by Clinical Global Impression‐Change
Behavior measured by MMSE, modified Blessed Functional Activity Scale Death Brief Psychiatric Rating Scale Unified Parkinson's Disease Rating Scale |
| Ballard et al. 35, 36 | Antipsychotics | Randomized controlled study | England and Scotland | Residential care | 3 | 100 | 19 | 83.6 | Yes | Survival
Successful deprescribing Total Severe Impairment Battery score (change from baseline to 6 mo) Standardized MMSE FAS test of Verbal Fluency Bristol Activities of Daily Living Scale Sheffield Test for Acquired Language Disorders Neuropsychiatric Index Modified Unified Parkinson's Disease Rating Scale Clinician's Global Impression of Change Post‐Hoc Additional Exploratory Sensitivity Analysis |
| Ballard et al. 37 | Antipsychotics | Randomized controlled study | England | Residential care | 12 | 165 | 24 | 84.8 | Yes | Quality of life (measured as differences in change in behavioral symptoms) Change in Neuropsychiatric Inventory |
| Ruths et al. 131 | Antipsychotic | Randomized controlled study | Norway | Residential care | 1 | 30 | 20 | 83.4 | Yes | Medication useSleep/wake activity
Neuropsychiatric inventory Successful deprescribing Deaths |
| Van Reekum et al. 155 | Antipsychotic | Randomized controlled study | Canada | Residential care | 6 | 34 | 50 | 84.4 | Yes | Behaviour assessed by the Behavioral Pathology in Alzheimer's Disease Rating Scale, Neuropsychiatric Inventory, Retrospective Overt Aggression Scale
Cognitive Function assessed by the MMSE and Mattis Dementia Rating Scale Functional level assessed by the Blessed Dementia Scale – activities of daily living and motivational behavior sub‐scale Extrapyramidal symptoms assessed by the Extrapyramidal Symptom Rating Scale Clinical global impression scale Behavioural deteriorations leading to study withdrawal Lorazepam use as required |
| Bridges‐Parlet et al. 45 | Antipsychotic | Randomized controlled study | USA | Residential care | 1 | 36 | 19 | 81.7 | Yes | Episodes of physically aggressive behaviour Adverse drug withdrawal events |
| Somani 139 | Typical antipsychotic | Nonrandomized controlled study | USA | Residential care | 8 | 57 | 25 | 85 | Yes | Presence of dyskinesias
Severity withdrawal dyskinesias Reversible of withdrawal dyskinesias Behavioural relapse Falls Adverse drug withdrawal events Successful deprescribing |
| Thapa et al. 146 | Typical antipsychotic | Nonrandomized controlled study | USA | Residential care | 6 | 334 | 22 | 82.6 | Yes | Psychotropic medicine use
Behavioural problems assessed using the nursing home Behaviour Problem Scale Psychiatric symptoms assessed using the Brief Psychiatric Rating Scale Function Activities of Daily Living assessed using Lawton's Physical Self‐Maintenance Scale Cognition assessed using MMSE Geriatric Depression Scale Abnormal Involuntary Movement Scale |
| Horwitz et al. 94 | Typical antipsychotic | Comparative study with two single arms | USA | Hospital | 12 | 53 | 17 | 82.7 | Yes | Discontinued antipsychotic
MMSE Sandoz Clinical Assessment Geriatric scale Overt Aggression Scale Functional status measured by the Minimum Data Set Plus of the New York State Department of Health Psychotic symptoms as judged by a psychiatric nurse‐specialist Quantified Neurological Exam Abnormal Involuntary Movement Scale |
| Azermai et al. 34 | Antipsychotics | Before‐and‐after study | Belgium | Hospital | 1 | 40 | 53 | 84 | Yes | Successful deprescribing
Neuropsychiatric Index Possible adverse drug withdrawal effects |
| Fernandez et al. 72 | Atypical antipsychotic | Before‐and‐after study | USA | Community | Unstated | 6 | 67 | 78 | No | Relapse |
| Cohen‐Mansfield et al. 50 | Benzodiazepine, typical antipsychotics | Randomized controlled study | USA | Residential care | 5 | 58 | 26 | 86 | Yes | Brief Psychiatric Rating Scale
Mansfield Agitation Inventory FunctionAdverse effects Global Impression Accuracy of staff prediction as to whether the withdrawal would be successful |
| Tannenbaum et al. 143 | Benzodiazepine | Randomized controlled study | Canada | Community | 6 | 303 | 31 | 75.0 | No | Successful deprescribing Adverse drug withdrawal effects |
| Curran et al. 53 | Benzodiazepine | Randomized controlled study | England | Community | 12 | 138 | 29 | 77 | No | Successfully deprescribing
Cognitive and psychomotor tests Benzodiazepine withdrawal scale visual analog scalesGeriatric Depression Scale Mood factors Health‐related quality of life ‐ sub‐scales of the Medical Outcomes Study Short‐form 36 questionnaire |
| Petrovic et al. 119 | Benzodiazepine | Randomized controlled study | Belgium | Hospital | 12 | 40 | 33 | 81 | No | Successful deprescribing
Pittsburgh Sleep Quality Index score Benzodiazepine Withdrawal Symptom Questionnaire |
| Habraken et al. 86 | Benzodiazepine | Randomized controlled study | Belgium | Residential care | 12 | 55 | 18 | 84 | No | Level of daily functioning Adverse drug withdrawal effects |
| Tham et al. 145 | Benzodiazepine | Randomized controlled study | Ireland | Hospital | Unstated | 36 | 14 | 81.7 | Unclear | Hours of sleep Number of times awake |
| Salzman et al. 133 | Benzodiazepine | Prospective cohort study | USA | Residential care | 12 | 25 | 20 | 83 | Yes | Memory
Dementia Mood Assessment Scale to measure changes in sleep and affect (depression and anxiety) Successful deprescribing |
| Puustinen et al. 124 | Benzodiazepine | Historical cohort study | Finland | Community | 6 | 89 | 34 | 66.7 | No | Cognitive performance using the computerized test battery of attention, vigilance and controlled psychomotor processing |
| Tsunoda et al. 148 | Benzodiazepine | Before‐and‐after study | Japan | Residential care | 2 | 30 | 57 | 79.1 | Yes | Stability of body
Neuropsychological status Critical Flicker Fusion Test Leeds Sleep Evaluation Questionnaire |
| Gaudig et al. 81 | Anticholinesterase inhibitors (Galantamine) | Randomized controlled study | USA | Community | 1.5 | 798 | 11 | 77.9 | Yes | Alzheimer's Disease Assessment Scale using the 11‐item cognitive sub‐scale
Safety and tolerability assessments included adverse event monitoring Physical examinations and laboratory testing |
| Scarpini et al. 135 | Anticholinesterase inhibitors (galantamine) | Randomized controlled study | Italy | Community | 36 | 139 | 40 | 74.5 | Yes | Drop outs Adverse drug events |
| Minett et al. 109 | Anticholinesterase inhibitors (donepezil) | Comparative study with two single arms | England | Community | 7.5 | 24 | unstated | 81.0 | Yes | Clinical outcomes |
| Rice et al. 129 | Prednisolone | Randomized controlled study | USA | Community | 6 | 38 | 100 | 72 | No | Average number of chronic obstructive pulmonary disease exacerbations
Average daily systemic corticosteroid dose Dyspnea index Health‐related quality of life Spirometric results Changes in body weight Adverse drug withdrawal effects ‐ symptoms of steroid withdrawal |
| Adams et al. 31 | Tiotropium, inhaled | Nonrandomized controlled study | International | Community | 12 | 921 | 65 | 65 | No | Medicine use at three weeks after deprescribing
Dyspnea Peak Expiratory Flow Rate (morning and evening) Health‐related quality of life measured using the St George's Respiratory Questionnaire |
| Borrill et al. 43 | Fluticasone and salmeterol, inhaled | Randomized controlled study | England | Community | 1.5 | 14 | unstated | 65.0 | No | Exacerbations causing dropouts
Forced expiratory volume in one second Sputum neutrophil percentage |
| Choudhury et al. 48 | Inhaled corticosteroids | Randomized controlled study | England | Community | 12 | 260 | 52 | 67.6 | No | chronic obstructive pulmonary disease exacerbation frequency
Time to first exacerbation Reported symptoms Peak expiratory flow rate Reliever inhaler use Return to usual steroid inhaler Lung function Health‐related quality of life– St George's respiratory questionnaire– EuroQol 5‐D total and visual analog scale Adverse effects |
| O'Brien et al. 116 | Inhaled corticosteroids | Randomized controlled study | USA | Community | 3 | 24 | 100 | 66.9 | No | Exacerbations Chronic Respiratory Disease Questionnaire |
| Jarad et al. 97 | Inhaled corticosteroids | Prospective cohort study | England | Community | 2 | 272 | 15 | 66 | No | Exacerbations |
| Jampel et al. 96 | Intraocular pressure‐lowering medicine | Nonrandomized study | USA | Community | 0.2 to 1 | 603 | 55 | 70.3 | No | Intraocular pressure percentage increase Intraocular pressure percentage decrease |
Table 3.
Included study characteristics by deprescribing target (randomized studies)
| References | Deprescribing target | Setting | Follow‐up duration in months (weighted mean ± standard deviation (SD)) | Number of participants randomized | Gender | Age of participants in years (weighted mean ± SD) | Participants with dementia | Withdrawal schedule |
|---|---|---|---|---|---|---|---|---|
| Allard et al. 32 ; Beer et al. 38 ; Campbell et al. 47 ; Dalleur et al. 55 ; Gallagher et al. 77 ; García‐Gollarte et al. 78 ; Gnjidic et al. 84 ; Hanlon et al. 88 ; Pitkala et al. 120 ; Potter et al. 123 ; Tabloski et al. 142 ; Weber et al. 159 . | Polypharmacy | Hospital (participants = 558, studies = 2)
Community (participants = 1568, studies = 7) Residential aged care (participants = 1365; studies = 4) |
9.6 ± 3.8 | 3500 | 1961 female, 1539 male | 80.3 ± 3.1 | Yes (Participants; = 1535; studies = 6) | One study described dose reductions occurring at approximately two‐weekly intervals (participants = 95; studies = 1).
The withdrawal schedule in two studies as dose reduction at approximately two‐weekly intervals (participants = 44; studies = 1) Half dose of psychotropic medicines for one week before ceasing the medicine (participants = 20; studies = 1)STD‐Tabloski‐1998 Not described (participants = 3341; studies = 9) |
| Yedidya et al. 161 | Clopidogrel | Community | 24 | 20 | 5 female, 15 male | 65.9 ± 5.0 | No | Abrupt cessation in one group was compared with tapered withdrawal where the dose was changed to 75mg alternate days for four weeks before it was ceased |
| Patel et al. 118 | Rivaroxaban | Community | Not given (range 3 to 30 days) | 14,143 | 5590 female, 8553 male | Not given (Median age of 73) | No | Not described |
| Dawson et al. 57 | Cilostazol 100mg twice‐daily and pentoxifylline 400mg three times daily | Community | 1.5 | 60 | 6 female, 39 male | 66.4 ± 7.3 | No | Not described |
| Hearing et al. 92 Jondeau et al. 99 | Beta‐blockers | Community (participants = 37; studies = 1) Hospital (participants = 169; studies = 1) | 2.6 ± 1.0 | 206 | 88 female, 110 male, 8 not stated | 72.3 ± 0.0 | No | Titrated over one week (participants = 37; studies = 1), Abruptly ceased the beta‐blocker (participants = 169; studies = 1). |
| Moonen et al. 110 | Antihypertensive | Community | 4 | 385 | 208 female, 177 male | 81.1 ± 4.3 | Yes | Tapered over six weeks until a maximum increase of 20mm Hg in systolic blood pressure |
| Burr et al. 46 ; Myers et al. 112 ; van Kraaij et al. 152 ; Walma et al. 157 De Jonge et al. 59 | Diuretics | Community (participants = 297; studies = 3)
Hospital (participants =1 06; studies = 1) Residential aged care (participants = 77; studies = 1) |
5.7 ± 3.3 | 480 | 425 female, 147 male | 77.6 ± 2.1 | Yes (participants = 77; studies = 1) | Dose halved for one week then placebo, though in one study participants who were on 80mg frusemide had the daily dose halved for two weeks (participants 234 =; studies = 2) Not described (participants = 246; studies = 3) |
| George et al. 82 | Nitrates | Community | 3 | 102 | 54 female, 66 male | 65.5 ± 11 | No | Not described |
| Kutner et al. 102 | Statins | Community | 12 | 381 | 171 female, 210 male | 74.8 | Yes (participants =84) | Not described |
| Lin et al. 106 | Alpha‐blocker (doxazosin 4 mg) and 5‐Alphaereductase Inhibitor Therapy (dutasteride 0.5 mg) | Community | 12 | 240 | 0 female, 240 male | 78.3 ± 8.19 | No | Not described |
| Cibere et al. 49 | Glucosamine | Community | 6 | 137 | 77 female, 60 male | 65 | No | Not described |
| Black et al. 41, 42 | Bisphosphonates | Community | 47 ± 12 | 2,332 | 2,332 female, 0 male | 74.7 ± 0.9 | No | Not described |
| Dawson‐Hughes et al. 58 | Calcium 500mg and vitamin D 17.5 mcg | Community | 60 | 295 | 167 female, 128 male | 74 ± 5 | No | Not described |
| Gallagher et al. 76 | Individually and together:
Calcitriol 0.25 mcg twice‐daily Conjugated equine estrogens 0.625 mg daily (Premarin®) (combined with medroxyprogesterone acetate 2.5 mg daily in the woman had a uterus) |
Community | 24 | 487 | 487 female, 0 male | 71.8 ± 0.31 | No | Not described |
| Tariot et al. 144 | Carbamazepine | Community | 0.75 | 51 | Not stated | 86 ± 6.4 | Yes severe dementia with a mean (SD) mini‐mental‐state‐examination (MMSE) score of 6 ± 7 | Not described |
| Tse et al. 147 | Levodopa | Residential aged care facilities | 1 | 11 | 7 females, 4 males | 82.0 ± 10.1 | Yes all 11 participants | Not described |
| Hardy et al. 90 | Lithium | Community | 24 | 12 | 10 females, 2 males | 79 ± 6 | No | Titrated by reducing the daily dose by 150mg each week in the withdrawal group until completely replaced with a placebo |
| Bergh et al. 40 | Antidepressants | Residential aged care facilities | 6 | 198 | 143 female, 55 male | 85.3 ± 8.2 | Yes (participants = 128; studies = 1) | Not described |
| Ballard et al. 36, 37 Bridges‐Parlet et al. 45 Devanand et al. 62, 63 Ruths et al. 131 Van Reekum et al. 155 | Antipsychotics | Community (participants = 99; studies = 2) Residential aged care facilities (participants = 420; studies = 6) | 21.3 ± 22.6 | 519 | 367 female, 151 male | 82.5 ± 2.8 | Yes all 519 participants | Abrupt discontinuation of their antipsychotic (participants = 30; studies = 1)
Abrupt only if the dose was less than 50mg daily of chlorpromazine equivalence, and dose equivalent to 50mg chlorpromazine daily or above, the dose was reduced by half in week one and ceased in week two (participants = 36; studies = 1) titrated over 1 to 3 weeks depending on the original antipsychotic dose (participants = 44; studies = 1) Reduce the regular daily dose by half in week one, a quarter of the regular daily dose in week three and cease in week three (participants = 34; studies = 1) Not described (participants = 375; studies = 3) |
| Curran et al. 53 , Habraken et al. 86 Petrovic et al. 119 Tham et al. 145 Tannenbaum et al. 143 | Benzodiazepine | community (participants = 441; studies = 2)
Residential aged care facilities (participants = 55; studies = 1) hospital (participants = 76; studies = 2) |
8.6 ± 3.0 | 572 | 406 female, 161 male | 77.2 ± 3.1 | Unclear Mild to moderate confusion (participants = 25; studies = 1) | Individually tailored dose titration schedule with regard to the original dose and specific benzodiazepine (participants = 138; studies = 1)
Titrated over five weeks with a 25% reduction weekly for three weeks then 12.5% dose reduction for two weeks before ceasing the benzodiazepine (participants = 55; studies = 1) Titrated using one week of 1mg lormetazepam (which was less than half the average daily benzodiazepine dose in the group) before ceasing the benzodiazepine (participants = 40; studies = 1). Abrupt withdrawal (switched straight to a placebo for 10 days) compared to gradual withdrawal (5mg temazepam for 4 days, 2mg temazepam for 4 days, placebo for 2 days) (participants = 36; studies = 1). Titrated over 21 weeks. Dose reduction from full dose to half a dose to quarter dose before it was ceased (participants = 303; studies = 1). STD‐Tannenbaum‐2014 |
| Cohen‐Mansfield et al. 50 | Antipsychotic Benzodiazepines | Residential aged care facilities | 5 | 58 | 43 female, 15 male | 86 | Yes Yes ‐ mean MMSE was 7.90 | Tapered during a 3‐week period, and then ceased |
| Gaudig et al. 81 ; Scarpini et al. 135 | Anticholinesterase inhibitors | Community | 14.4 ± 10.5 | 257 | 152 female, 105 male | 75.4 ± 1.0 | Yes All 257 participants | Not described |
| Rice et al. 129 | Prednisolone, oral | Community | 6 | 38 | 0 female, 38 male | 72 ± 6 | No | Reduce the daily maintenance dose by 5mg per week |
| Choudhury et al. 48 ; O'Brien et al. 116 | Corticosteroids, inhaled | Community | 11.2 ± 2.5 | 284 | 124 female, 160 male | 67.4 ± 0.2 | No | Abrupt (participants = 260, studies = 1) Not described (participants = 24; studies = 1) |
| Borrill et al. 43 | Corticosteroids and beta‐2 receptor agonist, inhaled | Community | 1.5 | 14 | Gender not stated | 65 | No | Not described |
Study design
Included studies were RCTs (participants = 17 428; studies = 56) 32, 36, 37, 38, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 53, 55, 57, 58, 59, 62, 63, 68, 76, 77, 78, 81, 82, 84, 86, 88, 90, 92, 99, 102, 106, 112, 116, 118, 119, 120, 123, 129, 135, 142, 143, 144, 145, 147, 149, 152, 157, 159, 161, comparative studies with a concurrent control group (participants = 14 522; studies = 22) 31, 33, 34, 39, 44, 51, 52, 54, 56, 60, 64, 66, 69, 70, 71, 72, 73, 74, 75, 79, 80, 81, 83, 87, 88, 89, 91, 93, 94, 95, 96, 97, 98, 101, 104, 105, 107, 108, 109, 111, 113, 114, 117, 122, 124, 125, 126, 132, 133, 134, 137, 139, 140, 141, 146, 148, 150, 156, 158, 160, 162, and comparative studies without a concurrent control group (participants = 2207; studies = 37) 33, 34, 39, 44, 51, 56, 64, 66, 69, 71, 72, 73, 74, 75, 79, 83, 87, 88, 89, 91, 93, 94, 95, 96, 98, 104, 105, 107, 108, 109, 113, 117, 124, 126, 134, 140, 141, 148, 156, 160. Follow‐up was for a weighted mean (SD) of 15.5 ± 17.4 months.
Participants
The 34 143 participants had a mean age of 73.8 ± 5.4 years, and 51.8% were male. The mean age was over 80 years in 38 studies (4833 participants) 33, 34, 35, 37, 38, 39, 40, 44, 45, 46, 50, 62, 74, 78, 79, 80, 84, 86, 94, 108, 109, 110, 112, 119, 120, 123. Thirty‐three studies included people living with dementia (6090 participants) 34, 36, 37, 40, 45, 50, 62, 63, 77, 78, 79, 80, 81, 94, 102, 107, 109, 110, 112, 120, 123, 131, 133, and another six studies were unclear whether they included participants living with dementia (429 participants) 38, 55, 74, 145, 150, 160.
Setting
Fourteen studies were set in hospital 34, 46, 55, 60, 64, 77, 80, 94, 99, 101, 111, 119, 145, 29 in residential aged care facilities 36, 37, 39, 40, 44, 45, 50, 51, 74, 78, 83, 86, 93, 107, 108, 112, 120, 123, 131, 133, 137, 139, 146, 147, 149, 155, 160, 162, and 73 were community based, which included outpatient facilities, general practice and retirement villages 31, 32, 33, 41, 42, 43, 47, 48, 49, 52, 53, 54, 56, 57, 58, 59, 62, 63, 65, 66, 68, 69, 70, 71, 72, 73, 76, 79, 81, 82, 84, 87, 88, 89, 90, 91, 92, 95, 96, 97, 98, 102, 104, 105, 106, 109, 110, 113, 114, 116, 117, 118, 122, 124, 125, 126, 129, 132, 134, 135, 140, 141, 142, 143, 144, 150, 152, 156, 157, 158, 159, 161. One study included participants based in the community and residential aged care 38, and another was based in community and hospital 75.
Interventions
Deprescribing single medications was the most common type of intervention investigated. These included deprescribing (i) a single medication (e.g. atenolol) 31, 41, 42, 49, 51, 54, 56, 60, 62, 63, 64, 65, 69, 70, 71, 74, 81, 90, 92, 104, 106, 108, 109, 117, 118, 129, 134, 135, 140, 144, 147, 158, 160, 161; (ii) a single pharmacological class (e.g. beta‐blockers) 52, 53, 59, 82, 95, 98, 99, 102, 110, 116, 119, 124, 126, 133, 141, 143, 145, 148, 152, 156, 157; or (iii) a single therapeutic category (e.g. antihypertensives) 33, 34, 36, 37, 39, 45, 46, 63, 66, 68, 72, 75, 87, 89, 93, 94, 105, 107, 112, 113, 114, 131, 137, 139, 146, 149, 155. Eleven studies investigated withdrawing two medications 39, 43, 44, 50, 57, 58, 73, 76, 91, 97, 106.
Twenty‐one studies investigated deprescribing polypharmacy 32, 38, 47, 55, 77, 78, 79, 80, 83, 84, 88, 101, 111, 120, 123, 132, 142, 150, 159, 162. Of these studies, 18 were patient‐specific interventions 32, 38, 47, 55, 77, 79, 80, 83, 84, 88, 101, 111, 122, 123, 132, 142, 150, 159. These patient‐specific interventions were led by doctors in 11 studies 38, 47, 77, 79, 80, 101, 111, 122, 123, 132, 150, pharmacists in two studies 83, 88, nurses in one study 142, and multidisciplinary teams in four studies 32, 55, 84, 159. These were investigator‐led deprescribing interventions in 10 studies 38, 47, 79, 80, 88, 122, 123, 132, 142, 150, and used medication reviews with recommendations to the prescriber in eight studies 32, 55, 77, 83, 84, 101, 111, 159. Three studies were educational programmes delivered at residential aged care facilities to nurses 120 and to the prescribing doctors 78, 162.
Excluded studies
Citations for excluded full‐text papers are shown in the supplementary file 2 along with the rationale for exclusion. Only a published protocol or trial registration was found for seven studies (supplementary file 2) 123, 163, 164, 165, 166, 167. Six of these studies were excluded as no results were available 163, 164, 165, 166. Results were available for one unpublished study, so the unpublished data has been included 123. This paper has since been published.
Risk of bias in included studies
Details of the risk of bias for RCTs are presented in Figure 2. The risk of bias assessment for each study is presented in Results S1. The risk of bias was rated low in at least four of the seven parameters assessed in 32% (18 of the 56) of RCTs 36, 40, 45, 47, 48, 49, 53, 62, 77, 90, 102, 110, 112, 116, 123, 129, 131, 135, 143, 157. The remaining 68% of studies all had unclear or high risk of bias. Industry funded ten studies that were included in this review, which was declared in the paper in each case 31, 41, 42, 57, 66, 81, 97, 114, 118, 135.
Figure 2.
Risk of bias graph for all included randomized studies. 
Low risk of bias, 
unclear risk of bias, 
high risk of bias
Heterogeneity in included studies
Quantitative heterogeneity assessments are presented in Tables S3 and S4. Forest plots are presented in Figures 3, 4, 5, 6, and Figures S1–S9.
Figure 3.
Mortality associated with deprescribing interventions to reduce polypharmacy (randomized studies)
Figure 4.
Mortality associated with deprescribing interventions to reduce polypharmacy for subgroup analysis based on intervention technique (randomized studies)
Figure 5.
Mortality associated with deprescribing interventions to reduce polypharmacy for subgroup analysis based on age (randomized studies)
Figure 6.
Mortality associated with deprescribing interventions to reduce polypharmacy for subgroup analysis for participants living with dementia and cognitively intact participants (randomized studies)
Effects of interventions for deprescribing: primary outcome (mortality)
Polypharmacy: randomized studies
Ten studies that investigated deprescribing to reduce polypharmacy reported mortality (eTable 3) 32, 38, 55, 77, 78, 84, 88, 120, 123, 159. The follow‐up duration was a weighted mean (SD) of 9.6 ± 3.9 months. They were set in the community 32, 38, 84, 88, 159, hospital 55, 77 and residential care 38, 78, 120, 123. Across these studies, deprescribing did not significantly modify mortality (OR 0.82, 95% CI 0.61–1.11; participants = 3151, studies = 10) (Figure 3) 32, 38, 55, 77, 78, 84, 88, 120, 123, 159.
The sub‐group analysis based on intervention technique demonstrated differences in mortality. Mortality was significantly reduced when patient‐specific interventions were applied (OR 0.62, 95% CI 0.43–0.88; participants = 1906; studies = 8) (Figure 4) 32, 38, 55, 77, 84, 88, 123, 159. In contrast, educational programmes demonstrated no change in mortality (OR 1.21, 95% CI 0.86–1.69; participants = 1245; studies = 2) 78, 120.
Participant sub‐group analysis: age
The sub‐group analysis based on age demonstrated no change in mortality (Figure 5) for people aged over 80 years (OR 0.98, 95% CI 0.74–1.31; participants = 1923; studies = 7) 32, 38, 55, 78, 84, 120, 123. People aged under 80 years showed a trend to reduced mortality (OR 0.64, 95% CI 0.40–1.04; participants = 1228; studies = 3) 47, 77, 142.
Participant sub‐group analysis: dementia
Subgroup analysis indicated dementia did not show altered mortality outcomes associated with deprescribing (Figure 6) 77, 78, 120, 123, 159.
Polypharmacy: nonrandomized studies
Two studies assessed the effect of deprescribing polypharmacy on mortality (Table S4). They indicated a significant decrease in mortality (OR 0.32, 95% CI 0.17–0.60; participants = 257; studies = 2) 80, 162.
Single medications/classes: randomized studies
Deprescribing of single medications/classes in RCTs (eTable 3) was not associated with a statistically significant difference in mortality. For example, deprescribing antipsychotics did not significantly reduced mortality (OR 0.59, 95% CI 0.33–1.07; participants = 453; studies = 5) (eFigure 1) 35, 36, 37, 62, 131, 155.
Single medications/classes: nonrandomized studies
Deprescribing of single medications/classes in nonrandomized studies (eTable 4) was also not associated with a statistically significant difference in mortality 60, 125.
Effects of interventions for deprescribing: secondary outcomes
Deprescribing polypharmacy
Adverse drug withdrawal events, health outcomes, quality of life and the effect on the medication regime in RCTs to reduce polypharmacy are reported in Table S3, Figures S2 and S3. For nonrandomized studies, the results are reported in Tables S4 and S5 and Figure S9. They are briefly summarized below.
Adverse drug withdrawal events
Deprescribing to reduce polypharmacy was not associated with a significant increase in adverse drug withdrawal events 88.
Health outcomes
Deprescribing to reduce polypharmacy did not change the incidence of adverse drug events 88. Cognitive function did not significantly change (Table S3) 38, 123. Deprescribing did not significantly improve the risk of experiencing at least one fall (OR 0.65, 95% CI 0.40–1.05; participants = 2173; studies = 5) (Figure S2) 47, 77, 78, 123, 159. However, participants who did fall had significantly fewer falls overall in the deprescribing group compared to those in the control group (MD −0.11, 95% CI −0.21–−0.02; participants = 844; studies = 3) (Figure S3) 78, 123, 168.
Quality of life
Deprescribing to reduce polypharmacy was not associated with significant changes in quality of life using standardized measures (Table S3). The exception was one study where deprescribing produced a significant yet modest positive finding that it slows the decline in quality of life (MD 0.03, 95% CI 0.01–0.06; participants = 189; studies = 1) 120.
Effect on the medication regime
Deprescribing reduced both the total number of medications (MD −0.99, 95% CI −1.83–−0.14; participants = 451; studies = 2) 78, 123 and number of potentially inappropriate medications taken (MD −0.49, 95% CI −0.70–−0.28; participants = 839; studies = 3) 32, 78, 120.
Deprescribing single medications/classes
The secondary outcomes for studies where a single medication was deprescribed are reported in Table S3, Figures S4–S8. They are briefly summarized below.
Adverse drug withdrawal effects
Adverse drug withdrawal effects (Tables S3) were most frequently exacerbations of the underlying condition or known withdrawal effects. There was no statistical difference in exacerbations of the underlying condition after deprescribing glucosamine, carbamazepine and corticosteroids 48, 49, 129, 144, or in reported adverse drug withdrawal effects in response to deprescribing benzodiazepines, antipsychotics and antidepressants (Table S3, Figure S4) 45, 53, 62, 131, 149.
Health outcomes
Health outcomes of deprescribing (Table S3; eFigure S5–S7) were related to the signs, symptoms or disease state that the medication(s) were intended to manage, or improvement of suspected adverse effects. For example, the effect of deprescribing antihypertensives on blood pressure control was investigated. This produced an increased systolic (MD 7.40, 95% CI 3.10–11.70; participants = 385 studies = 1) 110 and diastolic blood pressure (MD 2.60, 95% CI 0.24–4.96 participants = 385 studies = 1) 110. Similar changes in the systolic (MD 9.73, 95% CI 8.13–11.33; participants = 368; studies = 3) 46, 112, 157 and diastolic blood pressure (MD 3.99, 95% CI 3.04–4.94; participants = 367; studies = 3) 46, 112, 157 were observed when diuretics were deprescribed (Figure S6 and S7).
Quality of life
Deprescribing single medications was not associated with significant changes in quality of life using standardized measures (Table S3).
Effect on the medication regime
Effect on the medication regimen varied according to the medication (Table S3; Figure S8).
Discussion
This paper reports the first comprehensive systematic review of deprescribing interventions intended to reduce one or more medications. Deprescribing to reduce polypharmacy was not shown to modify mortality in RCTs although nonrandomized data suggested that it reduced mortality. Mortality was significantly reduced when patient‐specific deprescribing interventions were applied in RCTs. Deprescribing appears to be feasible and generally safe.
Deprescribing to reduce polypharmacy appears to have some health benefits. The number of people who fell did not change, but it reduced the number of falls they experienced. This finding is consistent with a previous review on interventions to reduce falls 22. Deprescribing does not appear to modify mortality in people aged over 80 years despite epidemiological and animal evidence that associates polypharmacy to poorer health outcomes in older adults 10, 11, 12. Nonetheless, a trend to decreased mortality was noted in the 65–80‐year‐old age group. This hints that the susceptibility to the effects from deprescribing may vary across the lifespan.
The health outcomes from deprescribing varied with the target medication. This is unsurprising as the evidence to support treatment, the risk to benefit profile, and rationale for both prescribing and deprescribing varies between medications. For example, the rationale for deprescribing bisphosphonates after 3–5 years of treatment is that the therapeutic benefit persists after drug withdrawal 169. In contrast, antihypertensives rapidly cease to exert an effect. Deprescribing antihypertensives resulted in modest increases in blood pressure. The rationale for deprescribing antihypertensives would need to be individualized to consider actual adverse effects experienced, blood pressure controlled too tightly, or to consider the less stringent blood pressure targets that may be appropriate for older adults 14, 170. Another consideration for these preventative treatments is whether the treatment is appropriate late in life with a limited life expectancy 171. However, deprescribing single medications did not always significantly alter health outcomes and quality of life. The available data suggests some medications can be deprescribed without adverse changes in the specific health outcomes the medications were intended to treat, which was consistent with the findings of previous systematic reviews that assessed deprescribing of specific medications 19, 20.
Deprescribing is difficult to implement, though this review suggests that deprescribing is feasible 21, 172. It reinforces the importance of individualized approaches to medication use for older adults. Identifying deprescribing targets is not an exact science, and health care professionals can vary in their assessment on which medications are inappropriate 173, 174. Evidence of feasibility supports the existing body of research including previous systematic reviews on the intervention techniques, barriers and enablers 17, 18, 175. These combined works can be integrated to inform the design and implementation of future deprescribing interventions and contribute to the growing discussion about deprescribing 14, 176, 177, 178.
There are several limitations to this review. Language bias may have also been introduced as we included only English‐language studies though applied no other limits. The review had broad inclusion criteria and a comprehensive search strategy, and we detected many relevant studies for inclusion. Despite this, there may be studies that were not identified, as the area of deprescribing has been poorly indexed historically. The review included many studies that were nonrandomized and many small RCTs of low quality. The limited methodological rigour was signified by an uncertain or high risk of bias assessment for most studies. Many of these studies aimed to assess the feasibility of the deprescribing intervention rather than the health or mortality outcomes, which was reflected in the included studies with limited well‐powered RCTs to assess health outcomes. The follow‐up durations, settings, age and health status of participants were variable. These limitations make it difficult to generalize the findings broadly in practice, though together they suggest that deprescribing in older adults is a field that warrants further attention.
This review collates the growing body of research in the field of deprescribing for older adults. However, as previously discussed, there are substantial limitations to the available study data. Rigorous large clinical trial data that implement patient‐specific deprescribing interventions are needed to confirm the outcomes suggested in this review. Further research is needed to understand which medications should be deprescribed in which patients and at what time.
This study suggests that deprescribing needs to be considered for older people as a routine component of the ongoing medication review process. Clinicians would benefit from deprescribing guidelines to support the implementation of deprescribing in practice. In the meantime, clinicians can use the data synthesized in this paper to inform decisions about deprescribing in conjunction with practical algorithms such as the CEASE acronym 16.
Conclusion
The available data suggest that patient‐specific deprescribing interventions to reduce polypharmacy may improve longevity. Deprescribing is often achieved without adverse changes in quality of life or health outcomes, which is helpful for older adults. Though more research is needed, the current evidence suggests that individualized interventions to reduce inappropriate polypharmacy appear safe and feasible.
Competing Interests
All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: AP had support from a University Postgraduate Award from the University of Western Australia, Australia and KP had support from a National Health and Medical Research Council (NHMRC) Early Career Fellowship for the submitted work. CEB and RC had no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
We would like to thank Michael Phillips and Sally Burrows, biostatisticians with the Royal Perth Hospital and the University of Western Australia for their advice on the statistical analysis. We thank Hanan Khalil of Monash University for her contribution and advice for the protocol for this systematic review and screening the articles. We thank the authors of included articles who responded to our requests for further information and researchers who offered suggestions of relevant articles to consider for inclusion.
Supporting information
Results S1 Summary of included studies (reference, summary, and risk of bias assessment for each included study)
Results S2 Reasons for study exclusion and references
Results S3 Characteristics of ongoing studies
Results S4 Medline search strategy
Table S1 Included study characteristics by deprescribing target
Table S2 Included study characteristics by deprescribing target
Table S3 Results from randomized studies
Table S4 Results from nonrandomized studies with concurrent control groups
Table S5 Results from nonrandomized studies without concurrent control groups
Figure S1 Mortality associated with deprescribing interventions to reduce antipsychotic medications in randomized studies
Figure S2 Number of participants who experienced at least one fall associated with deprescribing interventions to reduce polypharmacy in randomized studies
Figure S3 Number of falls per participant associated with deprescribing interventions to reduce polypharmacy in randomized studies
Figure S4 Adverse drug withdrawal effects associated with deprescribing interventions to reduce antipsychotic medications in randomized studies
Figure S5 Change in the Neuropsychiatric Index associated with deprescribing interventions to reduce antipsychotic medications in randomized studies
Figure S6 Systolic blood pressure associated with deprescribing interventions to reduce diuretics in randomized studies
Figure S7 Diastolic blood pressure associated with deprescribing interventions to reduce diuretics in randomized studies
Figure S8 Successful withdrawal associated with deprescribing interventions to reduce benzodiazepine use in randomized studies
Figure S9 Nonvertebral fractures associated with deprescribing interventions to cease bisphosphonates in nonrandomized studies
Supporting info item
Supporting info item
Supporting info item
Supporting info item
Page, A. T. , Clifford, R. M. , Potter, K. , Schwartz, D. , and Etherton‐Beer, C. D. (2016) The feasibility and effect of deprescribing in older adults on mortality and health: a systematic review and meta‐analysis. Br J Clin Pharmacol, 82: 583–623. doi: 10.1111/bcp.12975.
References
- 1. Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A, et al. Aging with multimorbidity: a systematic review of the literature. Ageing Res Rev 2011; 10: 430–9. [DOI] [PubMed] [Google Scholar]
- 2. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta‐analysis involving more than 65,000 patients. J Am Coll Cardiol 2008; 52: 1769–81. [DOI] [PubMed] [Google Scholar]
- 3. Home PD, Pocock SJ, Beck‐Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open‐label trial. Lancet 2009; 373: 2125–35. [DOI] [PubMed] [Google Scholar]
- 4. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta‐analysis on 11,000 participants from 42 trials. Am J Med 2009; 122: 290–300. [DOI] [PubMed] [Google Scholar]
- 5. Roehrborn CG, Siami P, Barkin J, Damião R, Major‐Walker K, Nandy I, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4‐year results from the CombAT study. Eur Urol 2010; 57: 123–31. [DOI] [PubMed] [Google Scholar]
- 6. Hubbard RE, Peel NM, Scott IA, Martin JH, Smith A, Pillans PI, et al. Polypharmacy among inpatients aged 70 years or older in Australia. Med J Aust 2015; 202: 373–8. [DOI] [PubMed] [Google Scholar]
- 7. Linjakumpu T, Hartikainen S, Klaukka T, Veijola J, Kivelä SL, Isoaho R. Use of medications and polypharmacy are increasing among the elderly. J Clin Epidemiol 2002; 55: 809–17. [DOI] [PubMed] [Google Scholar]
- 8. Guthrie B, Makubate B, Hernandez‐Santiago V, Dreischulte T. The rising tide of polypharmacy and drug–drug interactions: population database analysis 1995–2010. BMC Med 2015; 13: 74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Hovstadius B, Hovstadius K, Åstrand B, Petersson G. Increasing polypharmacy – an individual‐based study of the Swedish population 2005–2008. BMC Clin Pharmacol 2010; 10: 16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Turner JP, Jamsen KM, Shakib S, Singhal N, Prowse R, Bell JS. Polypharmacy cut‐points in older people with cancer: how many medications are too many? Support Care Cancer 2016; 24: 1831–40. [DOI] [PubMed] [Google Scholar]
- 11. Gnjidic D, Hilmer SN, Blyth FM, Naganathan V, Waite L, Seibel MJ, et al. Polypharmacy cutoff and outcomes: five or more medicines were used to identify community‐dwelling older men at risk of different adverse outcomes. J Clin Epidemiol 2012; 65: 989–95. [DOI] [PubMed] [Google Scholar]
- 12. Huizer‐Pajkos A, Kane AE, Howlett SE, Mach J, Mitchell SJ, de Cabo R, et al. Adverse geriatric outcomes secondary to polypharmacy in a mouse model: the influence of aging. J Gerontol A Biol Sci Med Sci 2016; 71: 571–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Jyrkkä J, Enlund H, Korhonen MJ, Sulkava R, Hartikainen S. Polypharmacy status as an indicator of mortality in an elderly population. Drugs Aging 2009; 26: 1039–48. [DOI] [PubMed] [Google Scholar]
- 14. Scott IA, Hilmer SN, Reeve E, Potter K, Le Couteur D, Rigby D, et al. Reducing inappropriate polypharmacy: the process of deprescribing. JAMA Intern Med 2015; 175: 827–34. [DOI] [PubMed] [Google Scholar]
- 15. Reeve E, Gnjidic D, Long J, Hilmer S. A systematic review of the emerging definition of ‘deprescribing’ with network analysis: implications for future research and clinical practice. Br J Clin Pharmacol 2015; 80: 1254–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Scott IA, Le Couteur David G. Physicians need to take the lead in deprescribing. Intern Med J 2015; 45: 352–6. [DOI] [PubMed] [Google Scholar]
- 17. Anderson K, Stowasser D, Freeman C, Scott I. Prescriber barriers and enablers to minimising potentially inappropriate medications in adults: a systematic review and thematic synthesis. BMJ Open 2014; 4: e006544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Reeve E, To J, Hendrix I, Shakib S, Roberts MS, Wiese MD. Patient barriers to and enablers of deprescribing: a systematic review. Drugs Aging 2013; 30: 793–807. [DOI] [PubMed] [Google Scholar]
- 19. Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter A, van Driel ML, et al. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev 2013; 3: CD007726. [DOI] [PubMed] [Google Scholar]
- 20. Iyer S, Naganathan V, McLachlan AJ, Le Conteur DG. Medication withdrawal trials in people aged 65 years and older. Drugs Aging 2008; 25: 1021–31. [DOI] [PubMed] [Google Scholar]
- 21. Pollmann AS, Murphy AL, Bergman JC, Gardner DM. Deprescribing benzodiazepines and Z‐drugs in community‐dwelling adults: a scoping review. BMC Pharmacol Toxicol 2015; 16: 19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Gillespie LD, Robertson MC, Gillespie WJ, Lamb SE, Gates S, Cumming RG, et al. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev 2009; 2: CD007146. [DOI] [PubMed] [Google Scholar]
- 23. Lindsay J, Dooley M, Martin J, Fay M, Kearney A, Barras M. Reducing potentially inappropriate medications in palliative cancer patients: evidence to support deprescribing approaches. Support Care Cancer 2014; 22: 1113–9. [DOI] [PubMed] [Google Scholar]
- 24. Page A, Khalil H, Etherton‐Beer C, Clifford R, Potter K. The efficacy of deprescribing interventions on health outcomes in people aged over 65 years: a systematic review protocol. PROSPERO 2014; CRD42014009887 Available at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014009887 [Google Scholar]
- 25. Page AT, Khalil H, Etherton‐Beer C, Clifford R, Potter K. The efficacy of deprescribing interventions on health outcomes in people aged over 65 years: a systematic review protocol. JBI Database Syst Rev Implementation Rep 2014; 12: 124–34. [Google Scholar]
- 26. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. BMJ 2009; 339: b2700. [PMC free article] [PubMed] [Google Scholar]
- 27. Evidence Partners Inc. Distiller SR, 2010. Available at: https://distillercer.com/products/distillersr‐systematic‐review‐software/ (accessed May 3, 2016).
- 28. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Higgins J. Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration 2011; 5.
- 30. Cochrane Collaboration . Review Manager (RevMan). 5.3. Copenhagen: The Nordic Cochrane Centre, 2014. [Google Scholar]
- 31. Adams SG, Anzueto A, Briggs DD Jr, Leimer I, Kesten S. Evaluation of withdrawal of maintenance tiotropium in COPD. Respir Med 2009; 103: 1415–20. [DOI] [PubMed] [Google Scholar]
- 32. Allard J, Hebert R, Asselin J, Voyer L. Efficacy of a clinical medication review on the number of potentially inappropriate prescriptions prescribed for community‐dwelling elderly people. Can Med Assoc J 2001; 164: 1291–6. [PMC free article] [PubMed] [Google Scholar]
- 33. Alsop K, Mac Mahon M. Withdrawing cardiovascular medications at a syncope clinic. Postgrad Med J 2001; 77: 403–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Azermai M, Petrovic M, Engelborghs S, Elseviers MM, Van der Mussele S, Debruyne H, et al. The effects of abrupt antipsychotic discontinuation in cognitively impaired older persons: a pilot study. Aging Ment Health 2013; 17: 125–32. [DOI] [PubMed] [Google Scholar]
- 35. Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, et al. The dementia antipsychotic withdrawal trial (DART‐AD): long‐term follow‐up of a randomised placebo‐controlled trial. Lancet Neurol 2009; 8: 151–7. [DOI] [PubMed] [Google Scholar]
- 36. Ballard C, Margallo Lana M, Theodoulou M, Douglas S, McShane R, Jacoby R, et al. A randomised, blinded, placebo‐controlled trial in dementia patients continuing or stopping neuroleptics (the DART‐AD trial). PLoS Med 2008; 5: e76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Ballard C, Thomas A, Fossey J, Lee L, Jacoby R, Lana M, et al. A 3‐month, randomized, placebo‐controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome. J Clin Psychiatry 2004; 65: 114–9. [DOI] [PubMed] [Google Scholar]
- 38. Beer C, Potter K, Loh PK, Peng YG, Millar A. A pilot randomized controlled trial of deprescribing: Stopat (Systematic Termination of Pharmaceutical Agents Trial). Basic Clin Pharmacol Toxicol 2011; 109: 156.21426490 [Google Scholar]
- 39. Bergh S, Engedal K. The withdrawal of antipsychotics and antidepressants from patients with dementia and BPSD living in nursing homes – an open pilot study. Int J Geriatr Psychiatry 2008; 23: 877–9. [DOI] [PubMed] [Google Scholar]
- 40. Bergh S, Selbaek G, Engedal K. Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial. BMJ 2012; 344: e1566. [DOI] [PubMed] [Google Scholar]
- 41. Black DM, Reid IR, Boonen S, Bucci‐Rechtweg C, Cauley JA, Cosman F, et al. The effect of 3 versus 6 years of Zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON‐Pivotal Fracture Trial (PFT). J Bone Miner Res 2012; 27: 243–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, et al. Effects of continuing or stopping alendronate after 5 years of treatment – the Fracture Intervention Trial long‐term extension (FLEX): A randomized trial. JAMA 2006; 296: 2927–38. [DOI] [PubMed] [Google Scholar]
- 43. Borrill Z, Roy K, Kolsum U, Southworth T, Vestbo J, Singh D. Seretide withdrawal increases airway inflammation in moderate COPD patients. Eur J Clin Pharmacol 2009; 65: 1165–6. [DOI] [PubMed] [Google Scholar]
- 44. Bourgeois J, Elseviers MM, Van Bortel L, Petrovic M, Vander Stichele RH. Feasibility of discontinuing chronic benzodiazepine use in nursing home residents: a pilot study. Eur J Clin Pharmacol 2014; 70: 1251–60. [DOI] [PubMed] [Google Scholar]
- 45. Bridges‐Parlet S, Knopman D, Steffes S. Withdrawal of neuroleptic medications from institutionalized dementia patients: results of a double‐blind, baseline‐treatment‐controlled pilot study. J Geriatr Psychiatry Neurol 1997; 10: 119–26. [DOI] [PubMed] [Google Scholar]
- 46. Burr ML, King S, Davies HE, Pathy MS. The effects of discontinuing long‐term diuretic therapy in the elderly. Age Ageing 1977; 6: 38–45. [DOI] [PubMed] [Google Scholar]
- 47. Campbell AJ, Robertson MC, Gardner MM, Norton RN, Buchner DM. Psychotropic medication withdrawal and a home‐based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 1999; 47: 850–3. [DOI] [PubMed] [Google Scholar]
- 48. Choudhury AB, Dawson CM, Kilvington HE, Eldridge S, James WY, Wedzicha JA, et al. Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial. Respir Res 2007; 8: 93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. Cibere J, Kopec JA, Thorne A, Singer J, Canvin J, Robinson DB, et al. Randomized, double‐blind, placebo‐controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum 2004; 51: 738–45. [DOI] [PubMed] [Google Scholar]
- 50. Cohen‐Mansfield J, Lipson S, Werner P, Billig N, Taylor L, Woosley R. Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a controlled, double‐blind study. Arch Intern Med 1999; 159: 1733–40. [DOI] [PubMed] [Google Scholar]
- 51. Coll PP, Abourizk NN. Successful withdrawal of thyroid hormone therapy in nursing home patients. J Am Board Fam Pract 2000; 13: 403–7. [DOI] [PubMed] [Google Scholar]
- 52. Cunnington AL, White L, Hood K. Identification of possible risk factors for the development of dopamine agonist withdrawal syndrome in Parkinson's disease. Parkinsonism Relat Disord 2012; 18: 1051–2. [DOI] [PubMed] [Google Scholar]
- 53. Curran HV, Collins R, Fletcher S, Kee SCY, Woods B, Iliffe S. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med 2003; 33: 1223–37. [DOI] [PubMed] [Google Scholar]
- 54. da Silva AG, Vieira JGH, Kunii IS, de Lana JM, Lazaretti‐Castro M. The effects of discontinuing long term alendronate therapy in a clinical practice setting. Arq Bras Endocrinol Metabol 2011; 55: 272–8. [DOI] [PubMed] [Google Scholar]
- 55. Dalleur O, Boland B, Losseau C, Henrard S, Wouters D, Speybroeck N, et al. Reduction of potentially inappropriate medications using the STOPP criteria in frail older inpatients: a randomised controlled study. Drugs Aging 2014; 31: 291–8. [DOI] [PubMed] [Google Scholar]
- 56. Daly C, Edwards H. Withdrawal of digoxin in general practice in elderly patients. Ir Med J 1983; 76: 19–20. [PubMed] [Google Scholar]
- 57. Dawson DL, De Maioribus CA, Hagino RT, Light JT, Bradley DVJ, Britt KE, et al. The effect of withdrawal of drugs treating intermittent claudication. Am J Surg 1999; 178: 141–6. [DOI] [PubMed] [Google Scholar]
- 58. Dawson‐Hughes B, Harris SS, Krall EA, Dallal GE. Effect of withdrawal of calcium and vitamin D supplements on bone mass in elderly men and women. Am J Clin Nutr 2000; 72: 745–50. [DOI] [PubMed] [Google Scholar]
- 59. De Jonge JW, Knottnerus JA, Van Zutphen WM, De Bruijne GA, Struijker Boudier HAJ. Short term effect of withdrawal of diuretic drugs prescribed for ankle oedema. BMJ 1994; 308: 511–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60. Derogar M, Sandblom G, Lundell L, Orsini N, Bottai M, Lu Y, et al. Discontinuation of low‐dose aspirin therapy after peptic ulcer bleeding increases risk of death and acute cardiovascular events. Clin Gastroenterol Hepatol 2013; 11: 38–42. [DOI] [PubMed] [Google Scholar]
- 61. Devanand DP. Relapse risk after discontinuation of risperidone in Alzheimer's disease. N Engl J Med 2012; 367: 2458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Devanand DP, Mintzer J, Schultz SK, Andrews HF, Sultzer DL, de la Pena D, et al. Relapse risk after discontinuation of risperidone in Alzheimer's disease. N Engl J Med 2012; 367: 1497–507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Devanand DP, Pelton GH, Cunqueiro K, Sackeim HA, Marder K. A 6‐month, randomized, double‐blind, placebo‐controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer's disease. Int J Geriatr Psychiatry 2011; 26: 937–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Drimer T, Shahal B, Barak Y. Effects of discontinuation of long‐term anticholinergic treatment in elderly schizophrenia patients. Int Clin Psychopharmacol 2004; 19: 27–9. [DOI] [PubMed] [Google Scholar]
- 65. Eastell R, Hannon RA, Wenderoth D, Rodriguez‐Moreno J, Sawicki A. Effect of stopping risedronate after long‐term treatment on bone turnover. J Clin Endocrinol Metab 2011; 96: 3367–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Ekbom T, Lindholm LH, Oden A, Dahlof B, Hansson L, Westers PO, et al. A 5‐year prospective, observational study of the withdrawal of antihypertensive treatment in elderly people. J Intern Med 1994; 235: 581–8. [DOI] [PubMed] [Google Scholar]
- 67. Ensrud KE, Barrett‐Connor EL, Schwartz A, Santora AC, Bauer DC, Suryawanshi S, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long‐term extension. J Bone Miner Res 2004; 19: 1259–69. [DOI] [PubMed] [Google Scholar]
- 68. Espeland MA, Whelton PK, Kostis JB, Bahnson JL, Ettinger WH, Cutler JA, et al. Predictors and mediators of successful long‐term withdrawal from antihypertensive medications. Arch Fam Med 1999; 8: 228–36. [DOI] [PubMed] [Google Scholar]
- 69. Esselinckx W, Doherty SM, Dixon ASJ. Polymyalgia rheumatica – abrupt and gradual withdrawal of prednisolone treatment, clinical and laboratory observations. Ann Rheum Dis 1977; 36: 219–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70. Fahy S, Lawlor B. Discontinuation of lithium augmentation in an elderly cohort. Int J Geriatr Psychiatry 2001; 16: 1004–9. [DOI] [PubMed] [Google Scholar]
- 71. Fair JF. Supervised withdrawal of long‐term digoxin therapy. Fam Pract 1990; 7: 56–9. [DOI] [PubMed] [Google Scholar]
- 72. Fernandez H, Trieschmann M, Okun MS. Rebound psychosis: effect of discontinuation of antipsychotics in Parkinson's disease. Mov Disord 2005; 20: 104–5. [DOI] [PubMed] [Google Scholar]
- 73. Flint AJ, Rifat SL. Recurrence of first‐episode geriatric depression after discontinuation of maintenance. Am J Psychiatry 1999; 156: 943. [DOI] [PubMed] [Google Scholar]
- 74. Fonrose HA, Ahlbaum N, Bugatch E, Cohen M, Genovese C, Kelly J. The efficacy of digitalis withdrawal in an institutional aged population. J Am Geriatr Soc 1974; 22: 208–11. [DOI] [PubMed] [Google Scholar]
- 75. Fotherby MD, Potter JF. Possibilities for antihypertensive drug therapy withdrawal in the elderly. J Hum Hypertens 1994; 8: 857–63. [PubMed] [Google Scholar]
- 76. Gallagher JC, Rapuri PB, Haynatzki G, Detter JR. Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. J Clin Endocrinol Metab 2002; 87: 4914–23. [DOI] [PubMed] [Google Scholar]
- 77. Gallagher PF, O'Connor MN, O'Mahony D. Prevention of potentially inappropriate prescribing for elderly patients: a randomized controlled trial using STOPP/START criteria. Clin Pharmacol Ther 2011; 89: 845–54. [DOI] [PubMed] [Google Scholar]
- 78. García‐Gollarte F, Baleriola‐Júlvez J, Ferrero‐López I, Cuenllas‐Díaz Á, Cruz‐Jentoft AJ. An educational intervention on drug use in nursing homes improves health outcomes resource utilization and reduces inappropriate drug prescription. J Am Med Dir Assoc 2014; 15: 885–91. [DOI] [PubMed] [Google Scholar]
- 79. Garfinkel D, Mangin D. Feasibility study of a systematic approach for discontinuation of multiple medications in older adults addressing polypharmacy. Arch Intern Med 2010; 170: 1648–54. [DOI] [PubMed] [Google Scholar]
- 80. Garfinkel D, Zur‐Gil S, Ben‐Israel J. The war against polypharmacy: a new cost‐effective geriatric‐palliative approach for improving drug therapy in disabled elderly people. Isr Med Assoc J 2007; 9: 430–4. [PubMed] [Google Scholar]
- 81. Gaudig M, Richarz U, Han J, Van Baelen B, Schauble B. Effects of galantamine in Alzheimer's disease: double‐blind withdrawal studies evaluating sustained versus interrupted treatment. Curr Alzheimer Res 2011; 8: 771–80. [DOI] [PubMed] [Google Scholar]
- 82. George J, Kitzis I, Zandorf D, Golovner M, Shapira I, Laniado S, et al. Safety of nitrate withdrawal in angina‐free and hemodynamically stable patients with coronary artery disease. Chest 2003; 124: 1652–7. [DOI] [PubMed] [Google Scholar]
- 83. Gerety MB, Cornell JE, Plichta DT, Eimer M. Adverse events related to drugs and drug withdrawal in nursing home residents. J Am Geriatr Soc 1993; 41: 1326–32. [DOI] [PubMed] [Google Scholar]
- 84. Gnjidic D, Le Couteur DG, Abernethy DR, Hilmer SN. A pilot randomized clinical trial utilizing the drug burden index to reduce exposure to anticholinergic and sedative medications in older people. Ann Pharmacother 2010; 44: 1725–32. [DOI] [PubMed] [Google Scholar]
- 85. Graves T, Hanlon JT, Schmaler KE, Landsman PB, Samsa GP, Pieper CF, et al. Adverse events after discontinuing medications in elderly outpatients. Arch Intern Med 1997; 157: 2205–10. [PubMed] [Google Scholar]
- 86. Habraken H, Soenen K, Blondeel L, Van Elsen J, Bourda J, Coppens E, et al. Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research. Eur J Clin Pharmacol 1997; 51: 355–8. [DOI] [PubMed] [Google Scholar]
- 87. Hajjar I, Hart M, Wan S‐H, Novak V. Safety and blood pressure trajectory of short‐term withdrawal of antihypertensive medications in older adults: experience from a clinical trial sample. J Am Soc Hypertens 2013; 7: 289–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88. Hanlon JT, Weinberger M, Samsa GP, Schmader KE, Uttech KM, Lewis IK, et al. A randomized controlled trial of a clinical pharmacist intervention with elderly outpatients with polypharmacy. Am J Med 1996; 100: 428–37. [DOI] [PubMed] [Google Scholar]
- 89. Hansen AG, Jensen H, Laugesen LP, Petersen A. Withdrawal of antihypertensive drugs in the elderly. Acta Med Scand 1983; 214: 178–85. [DOI] [PubMed] [Google Scholar]
- 90. Hardy BG, Shulman KI, Zucchero C. Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. J Clin Psychopharmacol 1997; 17: 22–6. [DOI] [PubMed] [Google Scholar]
- 91. Hauser RA, Koller WC, Hubble JP, Malapira T, Busenbark K, Olanow CW. Time course of loss of clinical benefit following withdrawal of levodopa/carbidopa and bromocriptine in early Parkinson's disease. Mov Disord 2000; 15: 485–9. [PubMed] [Google Scholar]
- 92. Hearing SD, Wesnes KA, Bowman CE. Beta blockers and cognitive function in elderly hypertensive patients: withdrawal and consequences of ACE inhibitor substitution. Int J Geriatr Psychopharmacol 1999; 2: 13–7. [Google Scholar]
- 93. Henschke PJ, Spence JD, Cape RDT. Diuretics and the institutional elderly – a case against routine potassium prescribing. J Am Geriatr Soc 1981; 29: 145–50. [DOI] [PubMed] [Google Scholar]
- 94. Horwitz GJ, Tariot PN, Mead K, Cox C. Discontinuation of antipsychotics in nursing home patients with dementia. Am J Geriatr Psychiatry 1995; 3: 290–9. [DOI] [PubMed] [Google Scholar]
- 95. Jackson G, Martin E, McGing E, Cooper A. Successful withdrawal of oral long‐acting nitrates to facilitate phosphodiesterase type 5 inhibitor use in stable coronary disease patients with erectile dysfunction. J Sex Med 2005; 2: 513–6. [DOI] [PubMed] [Google Scholar]
- 96. Jampel HD, Chon BH, Stamper R, Packer M, Han Y, Nguyen QH, et al. Effectiveness of intraocular pressure‐lowering medication determined by washout. JAMA Ophthalmol 2014; 132: 390–5. [DOI] [PubMed] [Google Scholar]
- 97. Jarad NA, Wedzicha JA, Burge PS, Calverley PMA. An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease. Respir Med 1999; 93: 161–6. [DOI] [PubMed] [Google Scholar]
- 98. Jiménez‐Candil J, Bermejo J, Yotti R, Cortina C, Moreno M, Cantalapiedra JL, et al. Effects of angiotensin converting enzyme inhibitors in hypertensive patients with aortic valve stenosis: a drug withdrawal study. Heart 2005; 91: 1311–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99. Jondeau G, Neuder Y, Eicher JC, Jourdain P, Fauveau E, Galinier M, et al. B‐CONVINCED: Beta‐blocker CONtinuation Vs. INterruption in patients with Congestive heart failure hospitalizED for a decompensation episode. Eur Heart J 2009; 30: 2186–92. [DOI] [PubMed] [Google Scholar]
- 100. Kostis JB, Espeland MA, Appel L, Johnson KC, Pierce J, Wofford JL. Does withdrawal of antihypertensive medication increase the risk of cardiovascular events? Trial of Nonpharmacologic Interventions in the Elderly (TONE) Cooperative Research Group. Am J Cardiol 1998; 82: 1501–8. [DOI] [PubMed] [Google Scholar]
- 101. Kroenke LTCK, Pinholt EM. Reducing polypharmacy in the elderly. a controlled trial of physician feedback. J Am Geriatr Soc 1990; 38: 31–6. [DOI] [PubMed] [Google Scholar]
- 102. Kutner JS, Blatchford P, Taylor D, Ritchie C, Bull J, Fairclough D, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life‐limiting illness: a randomized clinical trial. JAMA Intern Med 2015; 175: 691–700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103. Lähteenmäki R, Puustinen J, Vahlberg T, Lyles A, Neuvonen PJ, Partinen M, et al. Melatonin for sedative withdrawal in older patients with primary insomnia: a randomized double‐blind placebo‐controlled trial. Br J Clin Pharmacol 2014; 77: 975–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104. Leder BZ, Neer RM, Wyland JJ, Lee HW, Burnett‐Bowie S‐AM, Finkelstein JS. Effects of teriparatide treatment and discontinuation in postmenopausal women and eugonadal men with osteoporosis. J Clin Endocrinol Metabol 2009; 94: 2915–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105. Lernfelt B, Landahl S, Svanborg A, Wikstrand J. Overtreatment of hypertension in the elderly? J Hypertens 1990; 8: 483–90. [DOI] [PubMed] [Google Scholar]
- 106. Lin VC‐H, Liao C‐H, Kuo H‐C. Progression of lower urinary tract symptoms after discontinuation of 1 medication from 2‐year combined alpha‐blocker and 5‐alpha‐reductase inhibitor therapy for benign prostatic hyperplasia in men – a randomized multicenter study. Urology 2014; 83: 416–21. [DOI] [PubMed] [Google Scholar]
- 107. Lindström K, Ekedahl A, Carlsten A, Mårtensson J, Mölstad S. Can selective serotonin inhibitor drugs in elderly patients in nursing homes be reduced? Scand J Prim Health Care 2007; 25: 3–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108. Macarthur C. Withdrawal of maintenance digoxin from institutionalized elderly. Postgrad Med J 1990; 66: 940–2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109. Minett TSC, Thomas A, Wilkinson LM, Daniel SL, Sanders J, Richardson J, et al. What happens when donepezil is suddenly withdrawn? An open label trial in dementia with Lewy bodies and Parkinson's disease with dementia. Int J Geriatr Psychiatry 2003; 18: 988–93. [DOI] [PubMed] [Google Scholar]
- 110. Moonen JE, Foster‐Dingley JC, de Ruijter W, van der Grond J, Bertens AS, van Buchem MA, et al. Effect of discontinuation of antihypertensive treatment in elderly people on cognitive functioning – the DANTE Study Leiden: a randomized clinical trial. JAMA Intern Med 2015; 175: 1622–30. [DOI] [PubMed] [Google Scholar]
- 111. Muir AJ, Sanders LL, Wilkinson WE, Schmader K. Reducing medication regimen complexity – a controlled trial. J Gen Intern Med 2001; 16: 77–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112. Myers MG, Weingert ME, Fisher RH, Gryfe CI, Shulman HS. Unnecessary diuretic therapy in the elderly. Age Ageing 1982; 11: 213–21. [DOI] [PubMed] [Google Scholar]
- 113. Nadal M, Wikstrom L, Allgulander S. Once hypertensive, always hypertensive? A three year follow‐up after stopping medication. Scand J Prim Health Care 1994; 12: 62–4. [DOI] [PubMed] [Google Scholar]
- 114. Nelson MR, Reid CM, Krum H, Muir T, Ryan P, McNeil JJ. Predictors of normotension on withdrawal of antihypertensive drugs in elderly patients: prospective study in second Australian national blood pressure study cohort. BMJ 2002; 325: 815–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115. Nelson MR, Reid CM, Krum H, Ryan P, Wing LMH, McNeil JJ. Short‐term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in the Second Australian National Blood Pressure Study (ANBP2). Am J Hypertens 2003; 16: 39–45. [DOI] [PubMed] [Google Scholar]
- 116. O'Brien A, Russo‐Magno P, Karki A, Hiranniramol S, Hardin M, Kaszuba M, et al. Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction. Am J Respir Crit Care Med 2001; 164: 365–71. [DOI] [PubMed] [Google Scholar]
- 117. OrrWalker B, Wattie DJ, Evans MC, Reid IR. Effects of prolonged bisphosphonate therapy and its discontinuation on bone mineral density in post‐menopausal osteoporosis. Clin Endocrinol (Oxf) 1997; 46: 87–92. [DOI] [PubMed] [Google Scholar]
- 118. Patel MR, Hellkamp AS, Lokhnygina Y, Piccini JP, Zhang Z, Mohanty S, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: Analysis from the ROCKET AF trial (Rivaroxaban once‐daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol 2013; 61: 651–8. [DOI] [PubMed] [Google Scholar]
- 119. Petrovic M, Pevernagie D, Mariman A, Van Maele G, Afschrift M. Fast withdrawal from benzodiazepines in geriatric inpatients: a randomised double‐blind, placebo‐controlled trial. Eur J Clin Pharmacol 2002; 57: 759–64. [DOI] [PubMed] [Google Scholar]
- 120. Pitkala KH, Juola A‐L, Kautiainen H, Soini H, Finne‐Soveri UH, Bell JS, et al. Education to reduce potentially harmful medication use among residents of assisted living facilities: a randomized controlled trial. J Am Med Dir Assoc 2014; 15: 892–8. [DOI] [PubMed] [Google Scholar]
- 121. Pitkala KH, Juola A‐L, Soini H, Laakkonen M‐L, Kautiainen H, Teramura‐Gronblad M, et al. Reducing inappropriate, anticholinergic and psychotropic drugs among older residents in assisted living facilities: study protocol for a randomized controlled trial. Trials 2012; 13: 85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122. Pitkala KH, Strandberg TE, Tilvis RS. Is it possible to reduce polypharmacy in the elderly? A randomised, controlled trial. Drugs Aging 2001; 18: 143–9. [DOI] [PubMed] [Google Scholar]
- 123. Potter K, Flicker L, Page A, Etherton‐Beer CD. Deprescribing in frail older people: a randomised controlled trial. PLoS One 2016; 11: e0149984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124. Puustinen J, Lahteenmaki R, Polo‐Kantola P, Salo P, Vahlberg T, Lyles A, et al. Effect of withdrawal from long‐term use of temazepam, zopiclone or zolpidem as hypnotic agents on cognition in older adults. Eur J Clin Pharmacol 2014; 70: 319–29. [DOI] [PubMed] [Google Scholar]
- 125. Radford L, Bolland M, Mason B, Horne A, Gamble G, Grey A, et al. The Auckland calcium study: 5‐year post‐trial follow‐up. Osteoporos Int 2014; 25: 297–304. [DOI] [PubMed] [Google Scholar]
- 126. Reeve E, Andrews J, Wiese M, Hendrix I, Roberts M, Shakib S. Feasibility of a patient‐centered deprescribing process to reduce inappropriate use of proton pump inhibitors. Ann Pharmacother 2015; 49: 29–38. [DOI] [PubMed] [Google Scholar]
- 127. Reid IR, Wattie DJ, Evans MC, Gamble GD, Stapleton JP, Cornish J. Continuous therapy with pamidronate, a potent bisphosphonate, in postmenopausal osteoporosis. J Clin Endocrinol Metab 1994; 79: 1595–9. [DOI] [PubMed] [Google Scholar]
- 128. Reitz CJ. Digoxin withdrawal in patients in sinus rhythm. S Afr Med J 1981; 60: 570. [PubMed] [Google Scholar]
- 129. Rice K, Rubins J, Lebahn F, Parenti C, Duane P, Kuskowski M, et al. Withdrawal of chronic systemic corticosteroids in patients with COPD – a randomized trial. Am J Respir Crit Care Med 2000; 162: 174–8. [DOI] [PubMed] [Google Scholar]
- 130. Ruths S, Straand J, Anygaard H, Aarsland D. Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo‐controlled study – The Bergen District Nursing Home Study (BEDNURS). Int J Geriatr Psychiatry 2008; 23: 889–95. [DOI] [PubMed] [Google Scholar]
- 131. Ruths S, Straand J, Nygaard HA, Bjorvatn B, Pallesen S. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo‐controlled, double‐blinded study. The Bergen District Nursing Home Study. J Am Geriatr Soc 2004; 52: 1737–43. [DOI] [PubMed] [Google Scholar]
- 132. Salonoja M, Salminen M, Vahlberg T, Aarnio P, Kivela SL. Withdrawal of psychotropic drugs decreases the risk of falls requiring treatment. Arch Gerontol Geriatr 2012; 54: 160–7. [DOI] [PubMed] [Google Scholar]
- 133. Salzman C, Fisher J, Nobel K, Glassman R, Wolfson A, Kelley M. Cognitive improvement following benzodiazepine discontinuation in elderly nursing home residents. Int J Geriatr Psychiatry 1992; 7: 89–93. [Google Scholar]
- 134. Sambu N, Dent H, Englyst N, Warner TD, Leadbeater P, Roderick P, et al. Effect of clopidogrel withdrawal on platelet reactivity and vascular inflammatory biomarkers 1 year after drug‐eluting stent implantation: results of the prospective, single‐centre CESSATION study. Heart 2011; 97: 1661–7. [DOI] [PubMed] [Google Scholar]
- 135. Scarpini E, Bruno G, Zappala G, Adami M, Richarz U, Gaudig M, et al. Cessation versus continuation of galantamine treatment after 12 months of therapy in patients with Alzheimer's disease: a randomized, double blind, placebo controlled withdrawal trial. J Alzheimers Dis 2011; 26: 211–20. [DOI] [PubMed] [Google Scholar]
- 136. Schwartz AV, Bauer DC, Cummings SR, Cauley JA, Ensrud KE, Palermo L, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res 2010; 25: 976–82. [DOI] [PubMed] [Google Scholar]
- 137. Sjöblom P, Anders T, Löfgren UB, Lannering C, Anderberg N, Rosenqvist U, et al. Can diabetes medication be reduced in elderly patients?: An observational study of diabetes drug withdrawal in nursing home patients with tight glycaemic control. Diabetes Res Clin Pract 2008; 82: 197–202. [DOI] [PubMed] [Google Scholar]
- 138. Sjosten NM, Salonoja M, Piirtola M, Vahlberg T, Isoaho R, Hyttinen H, et al. A multifactorial fall prevention programme in home‐dwelling elderly people: a randomized‐controlled trial. Public Health 2007; 121: 308–18. [DOI] [PubMed] [Google Scholar]
- 139. Somani S. Dyskinesias secondary to gradual neuroleptic drug withdrawal in elderly nursing home residents. J Geriatr Drug Ther 1996; 11: 37–51. [Google Scholar]
- 140. Sommers DK, Reitz CJ, Koch Z, Avenant JC. Digoxin withdrawal in patients with sinus rhythm. S Afr Med J 1981; 60: 239–40. [PubMed] [Google Scholar]
- 141. Straand J, Fugelli P, Laake K. Withdrawing long‐term diuretic treatment among elderly patients in general practice. Fam Pract 1993; 10: 38–42. [DOI] [PubMed] [Google Scholar]
- 142. Tabloski PA, Cooke KM, Thoman EB. A procedure for withdrawal of sleep medication in elderly women who have been long‐term users. J Gerontol Nurs 1998; 24: 20–8 .quiz 50–1 [DOI] [PubMed] [Google Scholar]
- 143. Tannenbaum C, Martin P, Tamblyn R, Benedetti A, Ahmed S. Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern Med 2014; 174: 890–8. [DOI] [PubMed] [Google Scholar]
- 144. Tariot PN, Jakimovich LJ, Erb R, Cox C, Lanning B, Irvine C, et al. Withdrawal from controlled carbamazepine therapy followed by further carbamazepine treatment in patients with dementia. J Clin Psychiatry 1999; 60: 684–9. [DOI] [PubMed] [Google Scholar]
- 145. Tham TCK, Brown H, Taggart HM. Temazepam withdrawal in elderly hospitalized‐patients – a double‐blind randomized trial comparing abrupt versus gradual withdrawal. Ir J Med Sci 1989; 158: 294–6. [DOI] [PubMed] [Google Scholar]
- 146. Thapa PB, Meador KG, Gideon P, Fought RL, Ray WA. Effects of antipsychotic withdrawal in elderly nursing home residents. J Am Geriatr Soc 1994; 42: 280–6. [DOI] [PubMed] [Google Scholar]
- 147. Tse W, Frisina PG, Haelbit TD, Gracies JM, Liang L, Tarshish C, et al. The effects of withdrawal of dopaminergic medication in nursing home patients with advanced Parkinsonism. J Am Med Dir Assoc 2008; 9: 670–5. [DOI] [PubMed] [Google Scholar]
- 148. Tsunoda K, Uchida H, Suzuki T, Watanabe K, Yamashima T, Kashima H. Effects of discontinuing benzodiazepine‐derivative hypnotics on postural sway and cognitive functions in the elderly. Int J Geriatr Psychiatry 2010; 25: 1259–65. [DOI] [PubMed] [Google Scholar]
- 149. Ulfvarson J, Adami J, Wredling R, Kjellman B, Reilly M, Von Bahr C. Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression. Eur J Clin Pharmacol 2003; 59: 735–40. [DOI] [PubMed] [Google Scholar]
- 150. Van Der Velde N, Stricker BHC, Pols HAP, Van Der Cammen TJM. Risk of falls after withdrawal of fall‐risk‐increasing drugs: a prospective cohort study. Br J Clin Pharmacol 2007; 63: 232–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151. Van Der Velde N, Stricker BHC, Pols HAP, Van Der Cammen TJM. Withdrawal of fall‐risk‐increasing drugs in older persons: effect on mobility test outcomes. Drugs Aging 2007; 24: 691–9. [DOI] [PubMed] [Google Scholar]
- 152. van Kraaij DJW, Jansen RWMM, Bouwels LHR, Gribnau FWJ, Hoefnagels WHL. Furosemide withdrawal in elderly heart failure patients with preserved left ventricular systolic function. Am J Cardiol 2000; 85: 1461–6. [DOI] [PubMed] [Google Scholar]
- 153. van Kraaij DJW, Jansen RWMM, Bouwels LHR, Hoefnagels WHL. Furosemide withdrawal improves postprandial hypotension in elderly heart failure patients with preserved left ventricular systolic function. Arch Intern Med 1999; 159: 1599–605. [DOI] [PubMed] [Google Scholar]
- 154. van Kraaij DJW, Jansen RWMM, Sweep FCGJ, Hoefnagels WHL. Neurohormonal effects of furosemide withdrawal in elderly heart failure patients with normal systolic function. Eur J Heart Fail 2003; 5: 47–53. [DOI] [PubMed] [Google Scholar]
- 155. Van Reekum R, Clarke D, Conn D, Herrmann N, Eryavec G, Cohen T, et al. A randomized, placebo‐controlled trial of the discontinuation of long‐term antipsychotics in dementia. Int Psychogeriatr 2002; 14: 197–210. [DOI] [PubMed] [Google Scholar]
- 156. Walma EP, Hoes AW, Prins A, Boukes FS, van der Does E. Withdrawing long‐term diuretic therapy in the elderly: a study in general practice in The Netherlands. Fam Med 1993; 25: 661–4. [PubMed] [Google Scholar]
- 157. Walma EP, Hoes AW, van Dooren C, Prins A, van der Does E. Withdrawal of long term diuretic medication in elderly patients: a double blind randomised trial. BMJ 1997; 315: 464–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 158. Watts NB, Chines A, Olszynski WP, McKeever CD, McClung MR, Zhou X, et al. Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int 2008; 19: 365–72. [DOI] [PubMed] [Google Scholar]
- 159. Weber V, White A, McIlvried R. An electronic medical record (EMR)‐based intervention to reduce polypharmacy and falls in an ambulatory rural elderly population. J Gen Intern Med 2008; 23: 399–404. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 160. Wilkins CE, Khurana MS. Digitalis withdrawal in elderly nursing home patients. J Am Geriatr Soc 1985; 33: 850–1. [DOI] [PubMed] [Google Scholar]
- 161. Yedidya I, Netzer A, Vaduganathan M, Solodky A, Kornowski R, Lev Eli I. Clopidogrel tapering as a strategy to attenuate platelet rebound phenomenon in patients with bare‐metal stents. J Thromb Thrombolysis 2012; 33: 16–21. [DOI] [PubMed] [Google Scholar]
- 162. Yeh YC, Liu CL, Peng LN, Lin MH, Chen LK. Potential benefits of reducing medication‐related anticholinergic burden for demented older adults: a prospective cohort study. Geriatr Gerontol Int 2013; 13: 694–700. [DOI] [PubMed] [Google Scholar]
- 163. Brodaty H. Halting Antipsychotic use in Long‐Term Care (HALT). Sydney, Australia: Australian and New Zealand Clinical Trials Registry, 2014.
- 164. Etherton‐Beer CD, Potter K, Hilmer Sarah N, Naganathan V, McLachlan A, Comans T, et al Opti‐Med: A randomised controlled trial of deprescribing to optimise health outcomes for frail older people. Crawley, Western Australia: Australian and New Zealand Clinical Trials Registry, 2013.
- 165. Wouters H, Quik E, Boersma F, Nygard P, Bosman J, Bottger W, et al. Discontinuing inappropriate medication in nursing home residents (DIM‐NHR Study): protocol of a cluster randomised controlled trial. BMJ Open 2014; 10: e006082. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 166. Hartholt KA, Van Der Velde N, Van Lieshout EM, Polinder S, De Vries OJ, Boyé ND, et al. [Cost]effectiveness of withdrawal of fall‐risk increasing drugs versus conservative treatment in older fallers: design of a multicenter randomized controlled trial (IMPROveFALL‐study). BMC Geriatr 2011; 11: 48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 167. Hasler S, Senn ORT, Neuner‐Jehle S. Effect of a patient‐centered drug review on polypharmacy in primary care patients: study protocol for a cluster‐randomized controlled trial. Trials 2015; 16: 380. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 168. Campbell AJ, Robertson MC, Gardner MM, Norton RN, Tilyard MW, Buchner DM. Randomised controlled trial of a general practice programme of home based exercise to prevent falls in elderly women. BMJ 1997; 315: 1065–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 169. Eriksen EF, Diez‐Perez A, Boonen S. Update on long‐term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review. Bone 2014; 58: 126–35. [DOI] [PubMed] [Google Scholar]
- 170. Goeres LM, Williams CD, Eckstrom E, Lee DS. Pharmacotherapy for hypertension in older adults: a systematic review. Drugs Aging 2014; 31: 897–910. [DOI] [PubMed] [Google Scholar]
- 171. Holmes HM, Hayley DC, Alexander GC, Sachs GA. Reconsidering medication appropriateness for patients late in life. Arch Intern Med 2006; 166: 605–9. [DOI] [PubMed] [Google Scholar]
- 172. Garfinkel D, Ilhan B, Bahat G. Routine deprescribing of chronic medications to combat polypharmacy. Ther Adv Drug Saf 2015; 6: 212–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 173. Dalleur O, Boland B, De Groot A, Vaes B, Boeckxstaens P, Azermai M, et al. Detection of potentially inappropriate prescribing in the very old: cross‐sectional analysis of the data from the BELFRAIL observational cohort study. BMC Geriatr 2015; 15: 1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 174. Page AT, Etherton‐Beer CD, Clifford RM, Burrows S, Eames M, Potter K. Deprescribing in frail older people – do doctors and pharmacists agree? Res Social Adm Pharm 2016; 12: 438–49. [DOI] [PubMed] [Google Scholar]
- 175. Gnjidic D, Le Couteur DG, Kouladjian L, Hilmer SN. Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes. Clin Geriatr Med 2012; 28: 237–53. [DOI] [PubMed] [Google Scholar]
- 176. Scott IA, Gray LC, Martin JH, Pillans PI, Mitchell CA. Deciding when to stop: towards evidence‐based deprescribing of drugs in older populations. Evid Based Med 2013; 18: 121–4. [DOI] [PubMed] [Google Scholar]
- 177. Scott IA, Anderson K, Freeman CR, Stowasser DA. First do no harm: a real need to deprescribe in older patients. Med J Aust 2014; 201: 390–2. [DOI] [PubMed] [Google Scholar]
- 178. Hardy JE, Hilmer SN. Deprescribing in the last year of life. J Pharm Pract Res 2011; 41: 146–51. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Results S1 Summary of included studies (reference, summary, and risk of bias assessment for each included study)
Results S2 Reasons for study exclusion and references
Results S3 Characteristics of ongoing studies
Results S4 Medline search strategy
Table S1 Included study characteristics by deprescribing target
Table S2 Included study characteristics by deprescribing target
Table S3 Results from randomized studies
Table S4 Results from nonrandomized studies with concurrent control groups
Table S5 Results from nonrandomized studies without concurrent control groups
Figure S1 Mortality associated with deprescribing interventions to reduce antipsychotic medications in randomized studies
Figure S2 Number of participants who experienced at least one fall associated with deprescribing interventions to reduce polypharmacy in randomized studies
Figure S3 Number of falls per participant associated with deprescribing interventions to reduce polypharmacy in randomized studies
Figure S4 Adverse drug withdrawal effects associated with deprescribing interventions to reduce antipsychotic medications in randomized studies
Figure S5 Change in the Neuropsychiatric Index associated with deprescribing interventions to reduce antipsychotic medications in randomized studies
Figure S6 Systolic blood pressure associated with deprescribing interventions to reduce diuretics in randomized studies
Figure S7 Diastolic blood pressure associated with deprescribing interventions to reduce diuretics in randomized studies
Figure S8 Successful withdrawal associated with deprescribing interventions to reduce benzodiazepine use in randomized studies
Figure S9 Nonvertebral fractures associated with deprescribing interventions to cease bisphosphonates in nonrandomized studies
Supporting info item
Supporting info item
Supporting info item
Supporting info item