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Department of Geriatric and Palliative Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DenmarkDepartment of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DenmarkDepartment of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DenmarkDepartment of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkCenter for Translational Research, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DenmarkCenter for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
To map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients.
Design
Scoping review with systematic search of PubMed, Embase, and Cochrane Library.
Setting and Participants
Randomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65 years.
Methods
We extracted trial characteristics including study design and assessed bias. As proxies for the “feasibility of discontinuation,” we extracted the “dropout rate” and “disease recurrence rate.”
Results
We identified 40 trials investigating discontinuation of symptomatic (n = 26), preventive (n = 6), or both preventive and symptomatic medicines (n = 8) against psychiatric (n = 10), neurologic (n = 9), musculoskeletal (n = 8), cardiovascular (n = 5), respiratory (n = 4), and urologic diseases (n = 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n = 3), alendronate for osteoporosis (n = 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain.
Conclusions and Implications
We identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing.
As all medications carry a risk of adverse drug reactions, polypharmacy is associated with an increased risk of adverse drug reactions but also with increased risk of inappropriate medicine use and adverse health outcomes in general.
To deprescribe inappropriate medicines (ie, reducing the use of medicines with a negative risk-benefit profile in a particular patient), it is necessary to know which medicines can be safely continued or discontinued. Unfortunately, few randomized controlled trials investigate the efficacy and safety of medicines in older adults
The objective of this scoping review is to map the “evidence-landscape” of medication discontinuation in older patients. We aim to provide an overview of the existing randomized controlled trials and, based on the evidence, describe the feasibility of discontinuation of investigated medicines in older patients.
Methods
This article is structured according to the PRISMA extension for Scoping Reviews (PRISMA-ScR) (Supplementary Material 1).
We systematically searched PubMed (coverage 1966 to present), Embase (coverage 1947 to present), and the Cochrane Library (coverage 1992 to present) for publications on randomized discontinuation trials in older patients defined as patients aged ≥65 years. The search was last updated on the 11th of June 2021. The search strings are available in Supplementary Material 2.
where 2 authors (J.K. and C.B./A.M.S.S.) independently screened abstracts and full texts and included studies according to the eligibility criteria. Consensus was reached through discussion or through judgment of a third author (M.B.C.).
The eligibility criteria were as follows:
•
Randomized controlled trials investigating the discontinuation of a single medicine or a single medicine class, where medicine class was defined as medicines having a similar pharmacologic effect as judged by the authors
•
Mean age ≥ 65 years in total or in 1 or more arms
The exclusion criteria were as follows:
•
No randomized discontinuation intervention
•
Full text not in English
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More than 1 medicine or medicine class discontinued
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Discontinued medicines targeting cancer, transplant complications, or infections, because these treatments are highly specialized or of limited duration
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Not published as full-length, peer-reviewed manuscript (eg, poster publications or clinical trial registrations)
•
Temporary discontinuation, that is, pausing of medicines
We limited the studies to discontinuation of a single medicine or a single medicine class with similar pharmacologic effect for ease of interpretability. As an example, antihypertensives cover a diverse range of pharmacologic effects and the choice of antihypertensive medicine for older patients may be influenced by the patient's comorbidities, other concurrent medication, frailty and fall risk,
The extracted data items included author, publication year, number of patients, discontinued medicine or medicine class, population, setting and treatment indication, study design including blinding, “feasibility of discontinuation,” other relevant results such as particular treatment-related efficacy/harms, and comments (eg, limitations to the study).
To describe the “feasibility of discontinuation,” we extracted 2 measures: (1) the “dropout” rate defined as the proportion of patients who did not complete the entire study per protocol in the discontinuation and continuation groups; and (2) the “disease recurrence” rate defined as the proportion of patients with disease appearance for preventive treatments (eg, fractures after discontinuation of bisphosphonate treatment) or clinical worsening of the treated disease only for primarily symptomatic treatments (eg, pain after opioid treatment withdrawal) in the discontinuation and continuation group. Although adverse drug withdrawal events (ADWEs) can be due to either disease recurrence or physiological reactions to the discontinuation of medicines,
this measure focused on disease recurrence as the dropout rate should capture serious ADWEs due to physiological reactions. Thus, if beta-blockers are used to treat congestive heart failure and a patient experiences worsening in heart failure, then it would be considered disease recurrence. In contrast, if the patient experiences tachycardia then it is not, but it may be captured in the dropout rate if the patient exits the study because of the ADWE. To identify disease recurrence, we categorized treatment as primarily “symptomatic” if used to alleviate symptoms present (eg, fentanyl for pain), “preventive” if primarily used to prevent future events in a condition that is asymptomatic (eg, statins for prevention of cardiovascular events), or both “symptomatic and preventive” (eg, selective serotonin reuptake inhibitors for depression) as judged by the authors. We defined a difference as less than 10% in both dropout and disease recurrence rate as “small.” For trials with more treatment groups than just randomized discontinuation and continuation, we only extracted and present data from the randomized discontinuation and continuation groups.
Critical Appraisal of Evidence
Existing risk of bias evaluation tools were not suitable in their entirety. We used the first domain from Cochrane Risk of Bias tool 2
to assess the risk of bias arising from the randomization process. In addition, we assessed the comparator bias that could lead to a differential dropout rate by answering the following 4 questions: (1) Were the discontinued medicine(s) primarily symptomatic, preventive or both? Our hypothesis was that symptomatic treatments are more prone to differential dropout rates because of poor blinding. (2) Was tapering needed and if so, was the tapering strategy adequate to avoid withdrawal symptoms? (3) Was the study adequately blinded? and (4) Any other design choices which may result in differential dropout rates? Two authors (J.K. and A.M.S.S.) independently answered these questions for each trial and assessed the risk of bias as “low risk,” “some concern,” or “high risk.” In general, nonblinded studies were classified as high risk for symptomatic medicines and some concern for preventive medicines, studies with inadequate tapering were high risk, and studies where tapering was needed and mentioned, but not described in detail, were classified as some concern. Consensus was reached through discussion or via the judgment of a third author (M.B.C.).
Synthesis of the Results
To identify disease areas and medicines where discontinuation trials exist, we aggregated the data on medical specialty, indication for the treatment, and the medicine(s) discontinued. To provide an overview of the feasibility of discontinuation of the individual medicines, we plotted the dropout rates and disease recurrence rates in the discontinuation and continuation group, the size of the studies, and the risk of bias. To identify treatment areas where discontinuation may not be feasible, we compared the difference between the discontinuation and the continuation group for both the dropout and disease recurrence rate. A priori, the dropout and disease recurrence rates were expected to be greater in the discontinuation group compared with the continuation group. Therefore, the differences in these rates were compared using a 1-sided Fisher exact test in R version 3.6.3,
and a 1-sided P < .05 was considered statistically significant. To identify treatment areas where discontinuation may be feasible, we extracted the trials where the above-mentioned differences were both statistically insignificant and where the absolute difference between groups for both rates was less than or equal to 10%, corresponding to a number to discontinue of 10 for 1 additional dropout and/or 1 additional disease recurrence. Other relevant outcomes could not be readily synthesized and are presented narratively or in tables.
Results
Selection of Studies
In total, we screened 3304 records and included 41 publications comprising 40 unique trials.
Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
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.
A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
An overview of the included trials is presented in Figure 2, where the medical specialty, indication for the treatment, and the discontinued medicine(s) are visualized. Additional information on the included trials is available in Supplementary Table 1. Of the included trials, 65% (26/40) of the discontinued medicines were primarily symptomatic, 15% (6/40) were primarily preventive, and 20% (8/40) were both preventive and symptomatic. The setting of the patient recruitment was outpatient clinics (20/40 = 50%); nursing homes (5/40 = 12.5%); the community, for example, using advertisements (5/40 = 12.5%); general practitioners (4/10 = 10%); unknown, that is, multicenter studies with no description of the setting (4/40 = 10%); hospital admissions (1/40 = 2.5%); and palliative care (1/40 = 2.5%).
Fig. 2Sunburst chart displaying the distribution of randomized discontinuation trials in older adults on medical specialty, the indication for the discontinued medicine(s), and medicine(s) discontinued. BPSD, behavioral and psychological symptoms of dementia; LUTS, lower urinary tract symptoms; HFpEF, heart failure with preserved ejection fraction; COPD, chronic obstructive pulmonary disease.
The designs of the 40 included trials are presented in Figure 3 (designs A-E) along with the designs of the 64 excluded trials (designs F-J). Most of the included trials (20/40 = 50%) randomized patients already on the study medicine (design A), 10% (4/40) were an extension to a parent trial with randomized discontinuation for patients on the study medicine (design B), 15% (6/40) were randomized discontinuation of 1 medicine after combination therapy with 2 medicines (design C), 23% (9/40) were randomized discontinuation of the study medicine for patients with initial effect of the study medicine during a run-in phase (design D), and 1 trial (3%) was a crossover trial for patients already on the study medicine (design E). Of the included trials, 25% (10/40) were nonblinded and 75% (30/40) were placebo-controlled.
Fig. 3Overview of study designs containing an element of medicine discontinuation. The number of arms can vary and are not limited to those visualized in the figure. The discontinuation can be blinded (ie, continued placebo treatment) or nonblinded (no medicine taken in the discontinuation group).
The bias assessments are presented in Supplementary Table 2. In summary, 5% of the trials (2/40) had high risk of bias regarding randomization whereas 45% (18/35) had “some concern” (most of them due to an inadequate description of the randomization process). Regarding differential dropout rates, 48% (19/40) of the trials had bias disfavoring the discontinuation group. Of these 19 trials, 53% (10/19) had high risk of bias, while 47% (9/19) had “some concern.” There was low risk of bias across both domains in 25% of the trials (10/40).
Results and Synthesis of Results of Sources of Evidence
Dropout rate
The dropout rate in the discontinuation group compared with the continuation group is presented in Figure 4 for all the included trials, except for 2 trials where this information was not reported.
Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
The difference in dropout rates was statistically significantly greater in the discontinuation group compared with the continuation group in 21% of the trials (8/38). These 8 trials investigated discontinuation of amantadine for levodopa-induced dyskinesia in Parkinson's disease,
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.
Fig. 4Proportion of dropouts per group per medicine for the included discontinuation trials. The size of the circle symbolizes the number of patients in the trials. The colors symbolize the risk of bias regarding differential dropout rates. Crossover trials are not included in this graph. The gray line shows when the proportion of dropouts are equal in the 2 groups; if trials are below the gray line, then there were more dropouts in the continuation group compared with the discontinuation group and vice versa. SSRI, selective serotonin reuptake inhibitors.
The disease recurrence rate was reported in 80% (32/40) of the included trials, and disease recurrence in the discontinuation group compared with the continuation group is presented in Figure 5. The disease recurrence rate varied from 0% in both groups
6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
The difference in disease recurrence rates was statistically significantly greater in the discontinuation group compared with the continuation group in 28% of the trials (9/32). Of these 9 trials, 5 trials also had greater dropout rates in the discontinuation groups and were described above, that is, amantadine,
Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
Fig. 5Proportion of patients with disease recurrence or worsening per group per medicine for the included discontinuation trials. The size of the circle symbolizes the number of patients in the trials. The colors symbolize the risk of bias. The gray line shows when the proportion with recurrence are equal in the 2 groups; if trials are below the gray line, then there were more disease recurrences in the continuation group compared with the discontinuation group and vice versa. SSRI, selective serotonin reuptake inhibitors.
In total, 31 trials reported both dropout rates and disease recurrence rates. In 13 of these 31 trials, the difference in both dropout rate and disease recurrence rate were statistically insignificant and less than 10% for the discontinuation group compared with the continuation group. These 13 trials investigated discontinuation of glucosamine for osteoarthritis,
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
We identified 40 unique discontinuation trials with inclusion of older patients. Of these trials, 12 trials had dropout rates and/or disease recurrence rates that were statistically significantly higher in the discontinuation group compared with the continuation group, suggesting that discontinuation may not be feasible for these medicines in these populations. Further, we identified 13 trials where the difference in both dropout rates and disease recurrence rates were small (≤10%) and statistically insignificant, suggesting that discontinuation may be feasible. Interestingly, one study investigating discontinuation of nitrates for angina pectoris in stable patients
resulted in a statistically significantly higher risk of disease recurrence (8/80 = 10% vs 0/40 = 0%), but with an absolute difference in disease recurrence of 10%. This highlights the complexity of the interpretation of these studies where statistical significance does not always equate clinically relevant differences and underlines why the results presented in this review must be interpreted in the context of the diseases studied. In addition, this example shows that for some of the therapeutic areas where there was a statistically significant difference in dropout rate or disease recurrence, discontinuation attempts may still be feasible in clinical practice, that is, in this study 90% of the attempts were successful and the few disease recurrences were successfully treated with reinstated therapy.
Another complexity highlighted in the present review is the relatively high proportion of patients with disease recurrence in certain therapeutic areas, also in continuation groups (Figure 5); for example, 41% (13/32) of the trials reported disease recurrence rates ≥20% in both groups. A high baseline recurrence risk complicates discontinuation in clinical practice because patients may experience disease recurrence during discontinuation attempts that may in fact be unrelated to the discontinuation attempt, but this is in practice impossible to know and may lead to reinitiation of treatment. This underlines the importance of randomized discontinuation trials as the baseline risk of disease recurrence cannot be estimated from single-arm discontinuation trials.
Diseases Where Discontinuation Trials Are Lacking
The identified discontinuation trials covered many of the most prevalent diseases in older patients.
discontinuation trials were lacking for proton pump inhibitors and platelet inhibitors. Trials on discontinuation of treatment for common diseases such as type 2 diabetes and cardiovascular diseases such as atrial fibrillation were also lacking. In general, trials with discontinuation of purely preventive treatments were not very common (6/40 = 15%). We identified 5 trials with discontinuation of bisphosphonates for the treatment of osteoporosis (5/6 = 83%)
Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
This is probably due to the difficulty of conducting these trials as they require a long follow-up period. Trials with discontinuation of purely symptomatic medicines are simpler to conduct. Here, any recurrence of symptoms should be reversible with reinstated treatment of the discontinued medicines. It is therefore remarkable that we only identified 2 studies
Further studies regarding discontinuation of analgesics in older patients seem warranted.
Considerations for Discontinuation Trial Design
As expected, the included trials were clinically and methodologically diverse with regard to therapeutic area, setting, study design, sample size, reporting of dropouts, harms, and risk of bias. Recently, the need to standardize and optimize the reporting of results from discontinuation trials was highlighted.
Based on this scoping review, identified trials can be divided into 10 different trial designs with an element of discontinuation (Figure 3). The numerous different designs of the included trials are a challenge for the external validity and renders it almost impossible to summarize and meta-analyze the findings. The design that most resembles the clinical situation is where patients are already receiving a given medicine (design A without a run-in period; Figure 3) or a combination of medicines (design C without a run-in period; Figure 3), but changes in prescription patterns over time (eg, new guidelines) or differences in prescription patterns across geographical regions (eg, countries) can limit the external validity of the findings, because the success of discontinuation will depend on how good those who have prescribed the medicine have been to prescribe to the right patients. Compared to these designs, trials where the medicine is started as part of the discontinuation trial (design A and C with a run-in period or design B; Figure 3) may have a more precisely defined population, but also a higher concentration of responders and are thereby more prone to showing lower feasibility of discontinuation. This feature is exacerbated in trials that only include patients who, in the short term, both tolerate the medicine and has apparent effect of the medicine (design D; Figure 3). Lastly, crossover trials with discontinuation (design E; Figure 3) may have problems with carryover effect and the high dropout rate in many discontinuation trials is problematic when analyzing data from these trials.
Our risk of bias assessment revealed that adequate tapering, blinding, and randomization are key when designing future discontinuation studies, and that high dropout rates seem unavoidable even in studies with low risk of bias; for example, overall 45% (17/38) had dropout rates ≥20% in both groups (Figure 4). Therefore, study outcomes that are less affected by high dropout rates should be considered such as time-to-event analyses as seen in Arai et al.
Limitations to this study include the exclusion of trials with patients with a mean age <65 years and the exclusion of trials investigating discontinuation of more than 1 medicine. Another limitation is that the proxies for feasibility of discontinuation we used, that is, disease recurrence rate and dropout rate, only imperfectly describe the feasibility of discontinuation. Disease recurrence, although easy to interpret, is not reported by all trials, and will generally favor continuation because no treatment-related harms (eg, adverse effects) are captured. In contrast, the dropout rate is more difficult to interpret, but this measure is reported univariately and should reflect a conservative estimate of the proportion of patients, where discontinuation is not feasible in clinical practice. As an example of the sometimes conflicting and complementary information these measures convey, a trial with discontinuation of beta-blockers for heart failure in patients with normalized ejection fraction following cardiac resynchronization therapy reported a similar low disease recurrence rate in the continuation and discontinuation groups, but a much higher dropout rate in the discontinuation group (because of withdrawal tachycardia).
Thus, although a combination of the 2 measures provide some reassurance for the feasibility of discontinuation, a good measure of the feasibility of discontinuation is lacking.
Conclusions and Implications
We identified 40 trials with randomized discontinuation of single medicines or similar medicines in older adults. Based on disease recurrence and trial dropout rates, 13 trials were in therapeutic areas where discontinuation of medicines on average are feasible, and 12 trials were in therapeutic areas where discontinuation may not be feasible. The trials were clinically and methodologically diverse in terms of design, therapeutic areas, and reporting of outcomes and harms. Identified therapeutic areas lacking discontinuation trials in older adults include type 2 diabetes and atrial fibrillation. The identified randomized trial evidence may guide deprescribing in clinical practice as well as future clinical trials to avoid overtreatment of older patients.
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Supplementary Table 1Characteristics of Included Studies
There were no significant differences regarding heart failure score, blood pressure, heart rate, spirometry values, or functional status scores (per-protocol analysis)
Primary or secondary prevention of cardiovascular disease, and no recent active cardiovascular disease
381 adults with advanced, life-limiting illness with an estimated life expectancy of between 1 mo and 1 y and recent deterioration in functional status taking statins for 3 mo or more
Design A. Unblinded without a run-in period and with 1:1 discontinuation
Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
Symptomatic and preventive treatment of heart failure
40 patients with heart failure with normalized ejection fractions after cardiac resynchronization therapy (CRT) and no symptoms of heart failure for the past 6 mo on optimal pharmacologic therapy
Design A. Part of 2 × 2 design with discontinuation of RAAS and/or beta blockers. Unblinded with 1:1 discontinuation. Only discontinuation of beta-blockers is eligible for inclusion in this review
Prompt reinitiation of therapy led to recovery of ejection fraction in 100% of subjects within 6 mo. 58% (7/12) dropouts in the discontinuation group were due to tachycardia
Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
85 women who had completed 2 y of treatment with alendronate and conjugated estrogen in the parent trial. Patients in the parent trial were hysterectomized postmenopausal women with lumbar BMD T score < −1.65.
The change in BMD from baseline was higher in the continuation group compared with the discontinuation group at multiple sites, eg, for total body BMD; difference in change from baseline ≈ 2%, P < .05 (read from Figure 2 in the publication)
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
1099 patients with total hip bone mineral density (BMD) T score > −3.5 and without declining BMD during at least 3 y of treatment with alendronate in the parent trial. Patients in the parent trial were postmenopausal women aged 55-80 y with femoral neck BMD T score < −1.6
Disease recurrence is all clinical fractures. The decline in BMD from baseline was lower in the continuation group compared with the discontinuation group at multiple sites, eg, for total hip BMD the decline was −1.02% vs −3.38%; difference in decline = 2.36%, 95% CI: 1.81%-2.90%
1233 women who had completed 3 y of treatment in the parent trial. Patients in the parent trial were women aged >65 y with BMD T score < −2.5 or T score < −1.5 with osteoporotic vertebral fractures
BMD increased in the continuation group and decreased in the discontinuation group; the mean difference in change ranged from 1.04% to 2.03% depending on site (max P = .002). There was no statistically significant difference in incidence of clinical fractures at any site.
137 patients with pain due to osteoarthritis who were not taking any opioid analgesics and had improvement in pain after at least 1 month of treatment with glucosamine
Design A. Blinded without a run-in period and with 1:1 discontinuation
150 opioid-naïve patients with low back pain or pain due to osteoarthritis. Only patients without AEs and with sufficient pain relief on fentanyl during a 20-d run-in period were included
Design D. Blinded with 20 days run-in period and with 1:1 discontinuation
During run-in, 15% (33/218) discontinued treatment because of AEs and 9% (20/218) were not eligible for discontinuation because of lack of pain relief. The change in pain scores favored continuation; change −6.9 mm on the visual analog scale (VAS) vs 0.2 mm, adjusted mean difference = 7.3 mm, 95% CI: 1.1-13.5.
163 opioid-naïve patients with pain due to post-herpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain. Only patients without AEs and with sufficient pain relief on fentanyl during a 20-days run-in period were included
Design D. Blinded with 20 days run-in period and with 1:1 discontinuation
During run-in, 12% (33/280) discontinued treatment due to AEs and 18% (50/280) were not eligible for discontinuation due to lack of pain relief. The change in pain scores favored continuation; change in VAS -9.6 mm vs 0.3 mm, adjusted mean difference = 8.7 mm, 95% CI: 2.4 to 15.0 mm.
There were differences in cognition, neuropsychiatric symptoms, and caregiver's distress in favor of continuation; change in Mini Mental State Examination (MMSE) scores of −0.1 vs −1.8, P = .02; change in NPI of −2.9 vs 3.3, P = .02; and change in NPI distress score of −2.0 vs 1.0, P = .01
There were differences in cognition and neuropsychiatric symptoms in favor of continuation: difference in MMSE scores = 1.13, P = .02; difference in NPI scores = 2.87, P = .02. There was no statistically significant difference in activities of daily living between the 2 groups
145 donepezil-treated, community-dwelling patients with moderate to severe Alzheimer's disease
Design A. Blinded without a run-in period and 1:1 discontinuation. Part of a 2 × 2 factorial design where discontinuation of donepezil only involves arm 1 and 3
There were differences in cognition and activities of daily living in favor of continuation; average difference in MMSE = 2.4, 95% CI: 1.5-3.2; average difference in Bristol Activities of Daily Living Scale = −4.1, 95% CI: −5.8 to −2.4
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.
139 treatment-naïve patients with mild to moderate Alzheimer's disease. Only patients without AEs and with sufficient effect of the treatment during a 1-year run-in period were included
Design D. Blinded with a 1-y run-in period and 1:1 discontinuation
During run-in, 15% (38/254) discontinued treatment because of AEs, 0.4% died (1/254), and 12% (30/254) were not eligible for discontinuation because of lack of effect
A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
The change in dyskinesia (measured with the Unified Parkinson's Disease Rating Scale dyskinesia subscore) was worse in the discontinuation group (1.7) compared with the continuation group (0.2), P = .003
Symptomatic treatment of neurogenic orthostatic hypotension
101 patients with symptomatic neurogenic orthostatic hypotension due to Parkinson's disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy. Only patients without AEs and with sufficient effect of the treatment during a 14-d run-in period were included
Design D. Blinded with 14-d run-in period and 1:1 discontinuation
During run-in, 24% (43/181) discontinued treatment because of AEs and 13% (24/181) were not eligible for discontinuation because of lack of effect. There was no statistically significant difference in the change from baseline in symptoms of dizziness and lightheadedness or systolic standing blood pressure between the discontinuation group and the continuation group.
6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
20 outpatients with Alzheimer's disease and BPSD. Only patients without AEs and with sufficient effect of haloperidol during a 20-wk run-in period were included
Design D. Blinded with a 20-wk run-in period and 1:1 discontinuation
During run-in, 14% (6/44) discontinued treatment because of AEs and 20% (9/44) were not eligible for discontinuation because of lack of effect. The time to relapse was shorter in the discontinuation group (mean = 5.8 wk) compared with the continuation group (mean = 8.0 wk); log rank test, P = .04
110 patients with Alzheimer's disease and BPSD. Only patients without AEs and with sufficient effect of risperidone during a 16-wk run-in period were included
Design D. Blinded with a 16-wk run-in period and with 1:1:1 staggered discontinuation; 2 arms with discontinuation
During run-in, 9% (17/180) discontinued treatment because of AEs, 2% (3/180) died, and 20% (36/180) were not eligible for discontinuation because of lack of effect. Severe hallucinations were a predictor for relapse (HR = 2.70, 95% CI: 1.19-6.12)
Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
Depressive symptoms increased more in the discontinuation group than the continuation group; Cornell scale 6.03 vs 4.42, mean difference adjusted for baseline values = 2.89, 95% CI: 1.02-4.76
Symptomatic and preventive treatment of depression
12 patients treated with lithium as adjunct to other antidepressive medicine(s) for refractory major unipolar depression with at least 1 y of remission
Design C. Blinded without run-in and 1:1 discontinuation
The discontinuation group experienced less AEs, especially urinary urgency at night, urination of more than usual volumes, urinary incontinence, and neurotoxicity (ie, hand tremor, lightheadedness, dizziness, and unsteady gait); lower mean composite side-effect symptom score (no estimates reported), P < .05
Symptomatic and preventive treatment of depression
121 patients with unipolar major depressive episode of at least moderate severity without antidepressive treatment. Only patients without AEs and with sufficient effect of citalopram during a 24-wk run-in period were included
Design D. Blinded with a 24-wk run-in phase and 1:1 discontinuation
During run-in, 17% (39/230) discontinued treatment because of AEs and 6% (14/230) were not eligible for discontinuation because of lack of efficacy. The time to recurrence differed significantly between the treatment groups in favor of continuation; HR = 0.32, 95% CI: 0.19-0.56, log-rank test P < .001
Symptomatic and preventive treatment of depression
113 patients with major depressive episode of at least moderate severity without antidepressive treatment. Only patients without AEs and with sufficient effect of sertraline during a 24- to 28-wk run-in period were included
Design D. Blinded with a 24- to 28-wk run-in period and 1:1 discontinuation
There were no statistically significant differences in depression rating scale, global assessment of functioning, health-related quality of life, symptoms of depression or side effects of SSRIs between the discontinuation and continuation group.
All benzodiazepines were switched to lorazepam before randomization. The discontinuation group was tapered over 5 wk. There was no statistically significant difference in the level of daily functioning between the discontinuation and continuation group.
The discontinuation group was tapered over 4-6 wk. There were no statistically significant differences in sleep quality and several cognitive tests between the discontinuation group and the continuation group
In the per-protocol analysis, there was an increased risk of exacerbations in the discontinuation group compared with the continuation group; 279 exacerbations during a mean study duration of 179 d vs 293 exacerbations during a mean study duration of 235 d, RR = 1.48, 95% CI: 1.17-1.86. Time to first exacerbation was shorter in the discontinuation group (median 44 d) compared with the continuation group (median 63 d); log-rank test, P = .05, adjusted Cox regression analysis OR = 1.43, 95% CI: 1.08-1.96. The discontinuation group had an increase in wheeze (OR = 1.83, 95% CI: 1.06-3.18), an increase in shortness of breath (OR = 2.11, 95% CI: 1.25-3.57) and cough (during the first 3 mo; OR = 1.95, 95% CI: 1.16-3.29). There were no statistically significant differences in sputum production, lung function, or quality of life between the 2 groups.
Fluticasone propionate and salmeterol, fixed dose combination
Symptomatic and preventive treatment of chronic obstructive pulmonary disease (COPD)
14 patients with stable, moderate COPD (GOLD stage-II)
Design A. Nonblinded without a run-in period and 3:2 discontinuation
6 wk
Discontinuation: 4/9 = 44% Continuation: 0/5 = 0%
Discontinuation: 4/9 = 44% Continuation: 0/5 = 0%
There was a decrease in lung function in the discontinuation group compared with the continuation group; difference in change in FEV1 = 0.35, P = .017. The percentage of sputum neutrophil increased more in the continuation group compared with the continuation group; difference in change from baseline = 16.5%, P = .03.
There were no statistically significant differences regarding exacerbations, lung function, or quality of life between the 2 groups. There was a difference in change in weight from baseline between the discontinuation group (−4.8 kg) and the continuation group (0.5 kg); P = .007.
Symptomatic treatment of lower urinary tract symptoms (LUTS)
30 men with moderate obstructive symptoms due to benign prostatic hyperplasia (BPH). Only patients with sufficient effect of terazosin during a 24-wk run-in period were included.
Design D. Blinded with a 24-week run-in period and 1:1 discontinuation
Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
There was a difference in urinary symptoms with more patients feeling the same or better in the continuation group (91%) compared with the discontinuation group (77%); difference = 14%, 95% CI: 4%-18%; P = .001.
Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
There was no statistically significant differences between groups in voiding symptoms and related measures, quality of life, adverse effects, or blood pressure.
Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
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.
A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
AEs not described for the individual groups. Overall, no difference in AEs between the discontinuation and continuation group, including no difference in gastrointestinal AEs
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
Total patients with any AE = 552; total patients with any SAE = 168; total patients discontinuing because of AE = 11; renal events = 26; any of the most common postdose symptoms (pyrexia, myalgia, influenza-like illness, headache og arthralgia): First year = 29, second year = 14, third year = 7; cardiovascular AEs: 52 arrhythmia, 13 atrial fibrillation, 9 stroke, 4 myocardial infarction, 93 hypertension, 3 death from cardiovascular causes
Total patients with any AE = 552; total patients with any SAE = 191; total patients discontinuing because of AE = 14; renal events = 48; any of the most common postdose symptoms (pyrexia, myalgia, influenza-like illness, headache og arthralgia): First year = 36, second year = 24, third year = 14; cardiovascular AEs: 60 arrythmia, 21 atrial fibrillation, 19 stroke, 6 myocardial infarction, 48 hypertension, 8 death from cardiovascular causes
Total patients with any AE = 16; total patients with any SAE = 1; total patients discontinuing because of AE = 0; AEs occurring in at least 2.5% of patients: 3 headache, 1 confusion, 0 dizziness, 0 agitation, 1 tremor, 0 vomiting
Total patients with any AE = 17; total patients with any SAE = 1; total patients discontinuing because of AE = 0; AEs occurring in at least 2.5% of patients: 0 headache, 2 confusion, 2 dizziness, 1 agitation, 1 tremor, 2 vomiting
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.
A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
AEs not systematically described; AEs were registered using a composite side-effect symptom score; at all clinic visits, the mean score was less in the discontinuation group compared with the continuation group (P < .05)
There was no significant difference in reporting of skin bruising, thinning of skin, sore throat, oral thrush, or hoarseness of voice between fluticasone and placebo groups during the study; there were 3 COPD-related deaths in the continuation group
Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial.
Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
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.
A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease.
6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer’s disease.
Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial.
Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride.
Effect of discontinuation of tamsulosin in Korean men with benign prostatic hyperplasia taking tamsulosin and dutasteride: an open-label, prospective, randomized pilot study.
Effects of withdrawing α1-blocker from combination therapy with α1-blocker and 5α-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a prospective and comparative trial using urodynamics.
Funding: Jonatan Kornholt reports grants from the Velux Foundation (grant number 00025835) and the Capital Region of Denmark (E-12825-01-12-01) during the conduct of the study. Anne Mette S. Sørensen reports grants from Tværspuljen, Helsefonden, Copenhagen University Hospital Bispebjerg and Frederiksberg, and Aase and Ejnar Foundation during the conduct of the study.
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