Abstract
Objectives
Design
Setting and Participants
Methods
Results
Conclusions and Implications
Keywords
Methods
Information Sources and Search Strategy
Selection of Sources of Evidence
Covidence Systematic Review Software.
- •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
- •No randomized discontinuation intervention
- •Full text not in English
- •More than 1 medicine or medicine class discontinued
- •Discontinued medicines targeting cancer, transplant complications, or infections, because these treatments are highly specialized or of limited duration
- •Not published as full-length, peer-reviewed manuscript (eg, poster publications or clinical trial registrations)
- •Temporary discontinuation, that is, pausing of medicines
Data Charting Process
Data Items
Critical Appraisal of Evidence
Synthesis of the Results
Results
Selection of Studies
- Greenspan S.L.
- Emkey R.D.
- Bone H.G.
- et al.
- Matsukawa Y.
- Takai S.
- Funahashi Y.
- et al.

Characteristics of Sources of Evidence


Critical Appraisal of Sources of Evidence
Results and Synthesis of Results of Sources of Evidence
Dropout rate

Disease Recurrence Rate

Dropout and Disease Recurrence Rate
Discussion
Findings
Diseases Where Discontinuation Trials Are Lacking
- Greenspan S.L.
- Emkey R.D.
- Bone H.G.
- et al.
Considerations for Discontinuation Trial Design
Strengths and Limitations
Conclusions and Implications
Supplementary Data
- PRISMA_checklist
Supplementary Material 1. Search strings
- 1.deprescriptions/
- 2.(inappropriat∗ or unnecessar∗ or discontinu∗ or deprescrib∗ or deprescrip∗ or withdraw∗ or stop∗ or cessation).ti.
- 3.1 or 2
- 4.exp Aged/
- 5.(elder∗ or “65” or frail or geriatric∗).ti,ab,kw,kf.
- 6.(“nursing home” or “long-term care” or “residential aged care” or “skilled nursing facility” or “aged care facility” or “aged care facilities”).ti,ab,kw.
- 7.nursing home/
- 8.4 or 5 or 6 or 7
- 9.random∗.ti,ab,kw.
- 10.3 and 8 and 9
- 1.“Deprescriptions”[Mesh]
- 2.(inappropriat∗[Title] OR unnecessar∗[Title] OR discontinu∗[Title] OR deprescrib∗[Title] OR deprescrip∗[Title] OR withdraw∗[Title] OR stop∗[Title] OR cessation[Title])
- 3.(#1 or #2)
- 4.“Aged”[Mesh]
- 5.(elder∗[Title/Abstract] OR “65”[Title/Abstract] OR frail[Title/Abstract] OR geriatric∗[Title/Abstract])
- 6.(“nursing home”[Title/Abstract] OR “long-term care”[Title/Abstract] OR “residential aged care”[Title/Abstract] OR “skilled nursing facility”[Title/Abstract] OR “aged care facility”[Title/Abstract] OR “aged care facilities”[Title/Abstract])
- 7.“Nursing Homes”[Mesh]
- 8.(#4 OR #5 OR #6 OR #7)
- 9.random∗[Title/Abstract]
- 10.(#3 AND #8 AND #9)
- 1.MeSH descriptor: [Deprescriptions] explode all trees
- 2.inappropriat∗ or unnecessar∗ or discontinu∗ or deprescrib∗ or deprescrip∗ or withdraw∗ or stop∗ or cessation:ti (Word variations have been searched)
- 3.#1 or #2
- 4.MeSH descriptor: [Aged] explode all trees
- 5.elder∗ or “65” or frail or geriatric∗:ti,ab,kw (Word variations have been searched)
- 6.“nursing home” or “long-term care” or “residential aged care” or “skilled nursing facility” or “aged care facility” or “aged care facilities”:ti,ab,kw (Word variations have been searched)
- 7.MeSH descriptor: [Nursing Homes] explode all trees
- 8.#4 or #5 or #6 or #7
- 9.random∗:ti,ab,kw (Word variations have been searched)
- 10.#3 and #8 and #9
Author (Year) | Medicine Discontinued | Indication | Population | Design (See Figure 3) | Follow-Up Duration | Dropouts | Disease Recurrence | Other Relevant Results and Comments |
---|---|---|---|---|---|---|---|---|
George et al (2003) 1 | Nitrates | Symptomatic treatment of angina pectoris | 120 nitrate-treated patients without angina or heart failure who were hemodynamically stable for the last 3 mo | Design A. Unblinded without a run-in period and with 2:1 discontinuation | 3 mo | Discontinuation: 8/80 = 10% Continuation: 0/40 = 0% | Discontinuation: 8/80 = 10% Continuation: 1/40 = 2.5% | All subjects with angina after discontinuation experienced symptoms within the first month |
van Kraaij et al (1999) 2 and van Kraaij et al (2000)3 | Furosemide | Symptomatic treatment of heart failure with preserved ejection fraction (HFpEF) | 32 furosemide-treated patients with a history of HFpEF and left ventricular ejection fraction >40% | Design A. Blinded without a run-in period and with 2:1 discontinuation | 3 mo | Discontinuation: 5/21 = 24% Continuation: 1/11 = 9% | Discontinuation: 2/21 = 10% Continuation: 1/11 = 9% | There were no significant differences regarding heart failure score, blood pressure, heart rate, spirometry values, or functional status scores (per-protocol analysis) |
Kutner et al (2015) 4 | Statins | 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 | 1 y | Discontinuation: 94/189 = 50% Continuation: 101/192 = 53% | Discontinuation: 13/189 = 7% Continuation: 11/192 = 6% | Total quality of life was better for the group discontinuing statin therapy (mean McGill QOL score, 7.11 vs 6.85; P = .04) |
Sheppard et al (2021) 5 | Antihypertensives | Symptomatic and preventive treatment of hypertension | 569 patients aged ≥80 y with controlled systolic blood pressure, receiving ≥2 antihypertensive medications | Design C. Unblinded with 1:1 discontinuation. Post hoc subgroup analyses | 12 wk | Not reported per medicine | Not reported per medicine | Post hoc analyses and details of dropout and disease recurrence are not reported per medicine |
Nijst et al (2020) 6 | Beta-blockers | 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 | 24 mo | Discontinuation: 12/20 = 60% Continuation: 4/20 = 20% | Discontinuation: 1/20 = 5% Continuation: 2/20 = 10% | 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 |
Greenspan et al (2002) 7
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. Ann Intern Med. 2002; 137: 875-883 | Alendronate | Preventive treatment of fractures | 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. | Design B + C. Blinded with 1:1 discontinuation | 1 y | Discontinuation: 6/41 = 15% Continuation: 7/44 = 16% | Not reported | Four-armed study with a different focus and no additional relevant outcomes were reported for the 2 arms included in this review |
Michalská et al (2006) 8 | Alendronate | Preventive treatment of fractures | 66 women with postmenopausal osteoporosis and at least 3 y of treatment with alendronate | Design A. Unblinded without a run-in period and with 1:1 discontinuation | 2 y | Discontinuation: 0/33 = 0% Continuation: 2/33 = 6% | Discontinuation: 2/33 = 6% Continuation: 1/33 = 3% | 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) |
Black et al (2006) 9 | Alendronate | Preventive treatment of fractures | 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 10 ,Veritas Health Innovation Covidence Systematic Review Software. www.covidence.org Date accessed: July 17, 2022 11 | Design B. Blinded with 4:10 discontinuation | 5 y | Discontinuation: 36/437 = 8% Continuation: 68/662 = 10% | Discontinuation: 93/437 = 21% Continuation: 132/662 = 20% | 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% |
Wright et al (2017) 12 | Alendronate | Preventive treatment of fractures | 27 women older than 65 y with at least 3 y of treatment with alendronate | Design A. Unblinded without a run-in period and with 1:1 discontinuation | 6 mo | Discontinuation: 2/14 = 14% Continuation: 4/13 = 31% | Discontinuation: 0/14 = 0% Continuation: 0/13 = 0% | Pilot study and mostly administrative outcome measures were reported |
Black et al (2012) 13 | Zoledronic acid | Preventive treatment of fractures | 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 14 | Design B. Blinded with 1:1 discontinuation | 3 y | Discontinuation: 146/616 = 24% Continuation: 165/613 = 27% | Not reported | 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. |
Cibere et al (2004) 15 | Glucosamine | Symptomatic treatment of pain | 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 | 24 wk | Discontinuation: 0/66 = 0% Continuation: 3/71 = 4% | Discontinuation: 28/66 = 42% Continuation: 32/71 = 45% | Excluded patients on narcotic analgesics |
Arai et al (2015) 16 | Fentanyl patch | Symptomatic treatment of pain | 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 | 12 wk | Discontinuation: 38/77 = 49% Continuation: 36/73 = 49% | Discontinuation: 29/77 = 38% Continuation: 21/73 = 29% | 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. |
Arai et al (2015) 16 | Fentanyl patch | Symptomatic treatment of pain | 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 | 12 weeks | Discontinuation: 51/79 = 65% Continuation: 37/84 = 44% | Discontinuation: 35/79 = 44% Continuation: 18/84 = 21% | 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. |
Holmes et al (2004) 17 | Donepezil | Symptomatic treatment of Alzheimer's disease | 134 treatment-naïve patients with mild to moderate Alzheimer's disease and marked neuropsychiatric symptoms; Neuropsychiatric Inventory (NPI > 11) | Design A. Blinded with 12 wk run-in period and 3:2 discontinuation | 12 wk | Discontinuation: 10/55 = 18% Continuation: 6/41 = 15% | Discontinuation: 6/55 = 11% Continuation: 2/41 = 5% | 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 |
Johannsen et al (2006) 18 | Donepezil | Symptomatic treatment of Alzheimer's disease | 202 treatment-naïve patients with mild to moderate, probable, or possible Alzheimer's disease with uncertain benefit on donepezil in the run-in phase | Design A. Blinded with 12- to 24-wk run-in period and 1:1 discontinuation | 12 wk | Discontinuation: 20/103 = 19% Continuation: 11/99 = 11% | Discontinuation: 0/103 = 0% Continuation: 2/99 = 2% | 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 |
Howard et al (2012) 19 | Donepezil | Symptomatic treatment of Alzheimer's disease | 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 | 52 wk | Discontinuation: 43/72 = 60% Continuation: 23/73 = 32% | Discontinuation: 11/72 = 15% Continuation: 7/73 = 10% | 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 |
Gaudig et al (2011) 20 | Galantamine | Symptomatic treatment of Alzheimer's disease | 72 patients who had completed treatment with galantamine for 3 months in the parent trial. 34 Patients in the parent trial had mild to moderate Alzheimer's disease21 | Design B. Blinded with 1:1 discontinuation. Only study 2 and only those on galantamine in the parent trial is relevant for this review | 6 wk | Discontinuation: 0/39 = 0% Continuation: 1/32 = 3% | Not reported | There was no statistically significant difference in cognitive function between the discontinuation and continuation group |
Scarpini et al (2011) 22 | Galantamine | Symptomatic treatment of Alzheimer's disease | 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 | 2 y | Discontinuation: 44/63 = 70% Continuation: 40/76 = 53% | Discontinuation: 26/63 = 41% Continuation: 23/76 = 30% | 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 |
Herrmann et al (2016) 23 | Donepezil, galantamine, rivastigmine | Symptomatic treatment of Alzheimer's disease | 40 institutionalized patients with moderate to severe Alzheimer's disease | Design A. Blinded without a run-in period and with 1:1 discontinuation | 8 wk | Discontinuation: 4/19 = 21% Continuation: 3/21 = 14% | Discontinuation: 7/19 = 37% Continuation: 6/21 = 29% | Multiple different cholinesterase inhibitors discontinued |
Ory-Magne et al (2014) 24 | Amantadine | Symptomatic treatment of levodopa-induced dyskinesia | 56 amantadine-treated patients with Parkinson's disease and levodopa-induced dyskinesia | Design A. Blinded without a run-in period and 1:1 discontinuation | 3 mo | Discontinuation: 24/29 = 83% Continuation: 5/27 = 19% | Discontinuation: 18/29 = 62% Continuation: 3/27 = 11% | 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 |
Biaggioni et al (2015) 25 | Droxidopa | 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 | 14 d | Discontinuation: 8/51 = 16% Continuation: 6/50 = 12% | Discontinuation: 2/51 = 4% Continuation: 1/50 = 2% | 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. |
Tse et al (2008) 26 | Levodopa | Symptomatic treatment of Parkinson's disease | 11 levodopa-treated, institutionalized patients with Parkinson's disease and dementia | Design A without a run-in period and 1:1 discontinuation blinded | 4 wk | Discontinuation: 1/6 = 17% Continuation: 0/5 = 0% | Discontinuation: 1/6 = 17% Continuation: 0/5 = 0% | There were no statistically significant changes in cognitive, behavioral, or motor function between the discontinuation and continuation groups. |
Psychiatry | ||||||||
Findlay et al (1989) 27 | Thioridazine | Symptomatic treatment of behavioral and psychological symptoms of dementia (BPSD) | 36 thioridazine-treated women with Alzheimer's disease and BPSD who were admitted to a long-stay psychogeriatric ward | Design A. Blinded without a run-in period and 1:1 discontinuation | 4 wk | Discontinuation: 0/18 = 0% Continuation: 0/18 = 0% | Not reported | There were no statistically significant differences between the 2 groups regarding mental function, mobility, balance, or orthostatic blood pressure |
Devanand et al (2011) 28 | Haloperidol | Symptomatic treatment of BPSD | 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 | 6 mo | Discontinuation: 8/10 = 80% Continuation: 4/10 = 40% | Discontinuation: 8/10 = 80% Continuation: 4/10 = 40% | 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 |
Devanand et al (2012) 29 | Risperidone | Symptomatic treatment of BPSD | 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 | 16 wk (staggered) | Discontinuation: 27/40 = 68% Continuation: 30/70 = 43% | Discontinuation: 23/40 = 58% Continuation: 22/70 = 31% | 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) 30 |
Bergh et al (2012) 31 | Escitalopram, citalopram, sertraline, paroxetine | Symptomatic treatment of BPSD | 128 SSRI-treated nursing home residents without depressive disorders with Alzheimer's disease, vascular dementia, or mixed dementia | Design A. Blinded without a run-in period and 1:1 discontinuation | 25 wk | Discontinuation: 28/63 = 44% Continuation: 19/65 = 29% | Discontinuation: 13/63 = 21% Continuation: 4/65 = 6% | 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 |
Hardy et al (1997) 32 | Lithium | 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 | 2 y | Discontinuation: 3/6 = 50% Continuation: 4/6 = 67% | Discontinuation: 3/6 = 33% Continuation: 4/6 = 33% | 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 |
Klysner et al (2002) 33 | Citalopram | 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 | 48 wk | Discontinuation: 49/61 = 80% Continuation: 34/60 = 57% | Discontinuation: 38/61 = 62% Continuation: 18/60 = 30% | 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 |
Wilson et al (2003) 34 | Sertraline | 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 | 100 wk | Discontinuation: 43/57 = 75% Continuation: 39/56 = 70% | Discontinuation: 30/57 = 53% Continuation: 25/56 = 45% | During run-in, 26% (66/254) discontinued treatment because of AEs and 11% (29/254) were not eligible for discontinuation because of lack of efficacy. |
Ulfvarson et al (2003) 35 | Citalopram, sertraline | Symptomatic and preventive treatment of depression | 70 SSRI-treated nursing home residents without a history of depression, anxiety, or dementia | Design A. Blinded without a run-in period and 1:1 discontinuation | 6 mo | Discontinuation: 10/35 = 29% Continuation: 8/35 = 23% | Discontinuation: 7/35 = 20% Continuation: 0/35 = 0% | 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. |
Habraken et al (1997) 36 | Lorazepam | Symptomatic treatment of insomnia | 55 nursing home residents without dementia or other serious medical diseases and with at least 1 y of stable benzodiazepine treatment | Design A. Blinded with a run-in period and 1:1 discontinuation | 1 y | Discontinuation: 10/27 = 37% Continuation: 9/28 = 32% | Discontinuation: 5/27 = 19% Continuation: 2/28 = 7% | 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. |
Curran et al (2003) 37 | Temazepam, nitrazepam, loprazolam | Symptomatic treatment of insomnia | 104 patients without dementia or other diseases associated with cognitive impairment and with at least 6 mo use of benzodiazepines | Design A (at 12 weeks). Blinded without a run-in period and 1:1 discontinuation | 12 wk | Discontinuation: 7/55 = 13% Continuation: 6/49 = 12% | Not reported | 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 |
O'Brien et al (2001) 38 | Beclomethasone dipropionate | Symptomatic and preventive treatment of chronic obstructive pulmonary disease (COPD) | 24 outpatients with severe irreversible airway obstruction (mean forced expiratory volume in 1 second [FEV1] 47% of predicted) | Design E. Blinded crossover trial | 6 weeks per phase | Crossover trial with randomized order of discontinuation and continuation. Dropout per phase not reported. Dropout during the entire study: 9/24 = 38% | Discontinuation phase: 3/18 = 17% Continuation phase: 0/16 = 0% | There were no statistically significant differences in lung function or walking distance between the discontinuation phase and the continuation phase. |
Choudhury et al (2007) 39 | Fluticasone propionate | Symptomatic and preventive treatment of chronic obstructive pulmonary disease (COPD) | 260 patients with COPD with irreversible airway obstruction and no other chronic active lung diseases treated with inhaled corticosteroids | Design A. Blinded with a run-in period and 1:1 discontinuation | 1 y | Discontinuation: 78/132 = 59% Continuation: 56/128 = 44% | Discontinuation: 61/132 = 46% Continuation: 34/128 = 27% | 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. |
Borrill et al (2009) 40 | 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. |
Rice et al (2000) 41 | Prednisone | Symptomatic and preventive treatment of chronic obstructive pulmonary disease (COPD) | 38 patients with steroid-dependent COPD | Design C. Blinded with a run-in period with addition of ICS and with 1:1 discontinuation | 6 mo | Discontinuation: 10/18 = 56% Continuation: 8/20 = 40% | Discontinuation: 14/18 = 78% Continuation: 14/20 = 70% | 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. |
Fabricius et al (1990) 42 | Terazosin | 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 | 12 wk | Discontinuation: 0/15 = 0% Continuation: 0/15 = 0% | Not reported | During run-in, 47% (27/57) were not eligible for discontinuation because of lack of efficacy and 30% (17/57) experienced adverse events. |
Barkin et al (2003) 43 | Tamsulosin | Symptomatic treatment of LUTS | 305 men with moderate to severe urinary symptoms due to BPH | Design C. Blinded with a run-in period with dutasteride and tamsulosin and with 1:1 discontinuation | 6 wk | Discontinuation: 2/151 = 1% Continuation: 1/154 = 1% | Discontinuation: 35/151 = 23% Continuation: 14/154 = 9% | 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. |
Lee et al (2012) 44 | Tamsulosin | Symptomatic treatment of LUTS | 86 treatment-naïve men with moderate urinary symptoms due to BPH | Design C. Nonblinded with a run-in period with dutasteride and tamsulosin and with 1:1 discontinuation | 24 wk | Discontinuation: 10/43 = 23% Continuation: 7/43 = 16% | Discontinuation: 6/43 = 14% Continuation: 4/43 = 9% | There was no statistically significant differences between groups in voiding symptoms and related measures, quality of life, adverse effects, or blood pressure. |
Matsukawa et al (2017) 45
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. J Urol. 2017; 198: 905-912 | Silodosin | Symptomatic treatment of LUTS | 132 treatment-naïve men with moderate to severe urinary symptoms due to BPH | Design C. Nonblinded with a run-in period with dutasteride and silodosin and with 1:1 discontinuation | 12 mo | Discontinuation: 6/66 = 9% Continuation: 9/66 = 14% | Discontinuation: 23/66 = 35% Continuation: 15/66 = 23% | There was no statistically significant differences between groups in subjective symptoms or bladder outlet obstruction. |
Author (year) | Medicine(s) Discontinued | Risk of Bias Assessment | |
---|---|---|---|
Randomization Process | Differential Dropout Rate: Blinding, Tapering, etc | ||
George et al (2003) 1 | Nitrates | Some concern | High risk |
van Kraaij et al (1999 and 2000) 2 ,3 | Furosemide | Some concern | Low risk |
Kutner et al (2015) 4 | Statins | Low risk | Some concern |
Sheppard et al (2021) 5 | Antihypertensives | Low risk | Some concern |
Nijst et al (2020) 6 | Beta-blockers | Low risk | High risk |
Greenspan et al (2002) 7
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. Ann Intern Med. 2002; 137: 875-883 | Alendronate | Low risk | Low risk |
Michalská et al (2006) 8 | Alendronate | Some concern | Some concern |
Black et al (2006) 9 | Alendronate | Low risk | Low risk |
Wright et al (2017) 12 | Alendronate | Low risk | Some concern |
Black et al (2012) 13 | Zoledronic acid | Low risk | Low risk |
Cibere et al (2004) 15 | Glucosamine | Low risk | Low risk |
Arai et al (2015), study 1 16 | Fentanyl patch | Some concern | Some concern |
Arai et al (2015), study 2 16 | Fentanyl patch | Some concern | Some concern |
Holmes et al (2004) 17 | Donepezil | Low risk | Low risk |
Johannsen et al (2006) 18 | Donepezil | Some concern | Low risk |
Howard et al (2012) 19 | Donepezil | Low risk | Low risk |
Gaudig et al (2011) 20 | Galantamine | Some concern | Low risk |
Scarpini et al (2011) 22 | Galantamine | Low risk | Low risk |
Herrmann et al (2016) 23 | Cholinesterase inhibitors | Low risk | Low risk |
Ory-Magne et al (2014) 24 | Amantadine | Low risk | High risk |
Biaggioni et al (2015) 25 | Droxidopa | Some concern | High risk |
Tse et al (2008) 26 | Levodopa | Some concern | Low risk |
Findlay et al (1989) 27 | Thioridazine | Some concern | Low risk |
Devanand et al (2011) 28 | Haloperidol | Some concern | Low risk |
Devanand et al (2012) 29 | Risperidone | Low risk | Low risk |
Bergh et al (2012) 31 | SSRIs | Low risk | Some concern |
Hardy et al (1997) 32 | Lithium | Some concern | Low risk |
Klysner et al (2002) 33 | Citalopram | Some concern | High risk |
Wilson et al (2003) 34 | Sertraline | Low risk | High risk |
Ulfvarson et al (2003) 35 | Citalopram, sertraline | Some concern | High risk |
Habraken et al (1997) 36 | Lorazepam | Some concern | Some concern |
Curran et al (2003) 37 | Benzodiazepines | Some concern | Some concern |
O'Brien et al (2001) 38 | Inhaled beclomethasone | High risk | Low risk |
Choudhury et al (2007) 39 | Inhaled fluticasone | Low risk | Low risk |
Borrill et al (2009) 40 | Inhaled fluticasone + salmeterol | Some concern | High risk |
Rice et al (2000) 41 | Prednisone | Some concern | Low risk |
Fabricius et al (1990) 42 | Terazosin | Some concern | Low risk |
Barkin et al (2003) 43 | Tamsulosin | Some concern | Low risk |
Lee et al (2012) 44 | Tamsulosin | High risk | High risk |
Matsukawa et al (2017) 45
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. J Urol. 2017; 198: 905-912 | Silodosin | Low risk | High risk |
Author (Year) | Medicine(s) Discontinued | Harms | |
---|---|---|---|
Discontinuation Group | Continuation Group | ||
George et al (2003) 1 | Nitrates | 8 with recurrent angina with prompt effect of reinstated therapy (1 of the patients hospitalized, catheterized, and underwent coronary angioplasty) | 1 patient with angina |
van Kraaij et al (1999 and 2000) 2 ,3 | Furosemide | 2 recurrence of congestive heart failure, 2 requested restart because ankle edema without heart failure, 1 hypertension | 1 recurrence of congestive heart failure |
Kutner et al (2015) 4 | Statins | Not specified per group. There were 33 AEs experienced by 19 of the patients (5.0%). No serious AEs were determined to be study related | |
Sheppard et al (2021) 5 | Antihypertensives | AEs not reported per group in this post hoc analysis | |
Nijst et al (2020) 6 | Beta-blockers | 1 death noncardiovascular cause, 1 disease recurrence, 6 supraventricular tachycardia, 1 nonsustained ventricular tachycardia | 2 disease recurrence, 1 death noncardiovascular cause |
Greenspan et al (2002) 7
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. Ann Intern Med. 2002; 137: 875-883 | Alendronate | AEs not described for the individual groups. Overall, no difference in AEs between the discontinuation and continuation group, including no difference in gastrointestinal AEs | |
Michalská et al (2006) 8 | Alendronate | 1 leg cramp, 1 upper gastrointestinal symptoms | 2 upper gastrointestinal symptoms, 2 bone pain, 1 allergic skin reactions, 1 gastric pain |
Black et al (2006) 9 | Alendronate | AEs not systematically described | |
Wright et al (2017) 12 | Alendronate | No AEs were reported | |
Black et al (2012) 13 | Zoledronic acid | 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 |
Cibere et al (2004) 15 | Glucosamine | No SAEs were reported during the study, and there were no differences in AEs between the glucosamine and placebo groups | |
Arai et al (2015), study 1 16 | Fentanyl patch | 6 nervous system, 11 infections and infestations, 5 metabolism and nutrition disorders, 5 psychiatric disorders, 15 gastrointestinal disorders, 13 general disorders and administration, 1 opioid withdrawal syndrome | 5 nervous system, 12 infections and infestations, 3 metabolism and nutrition disorders, 7 psychiatric disorders, 21 gastrointestinal disorders, 13 general disorders and administration, 4 opioid withdrawal syndrome |
Arai et al (2015), study 2 16 | Fentanyl patch | 12 nervous system, 9 infections and infestations, 5 metabolism and nutrition disorders, 27 gastrointestinal disorders, 16 general disorders and administration, 8 skin and subcutaneous tissue disorders | 24 nervous system, 8 infections and infestations, 8 metabolism and nutrition disorders, 36 gastrointestinal disorders, 21 general disorders and administration, 13 skin and subcutaneous tissue disorders |
Holmes et al (2004) 17 | Donepezil | None reported | AEs: 1 rhinitis and 2 diarrhea |
Johannsen et al (2006) 18 | Donepezil | Any AE (n = 33); 10 treatment-related AEs, 6 digestive system, 8 nervous system, 10 body as a whole, 4 musculoskeletal system, 7 respiratory system, 4 cardiovascular system, 2 urogenital system | Any AE (n = 27); 8 treatment-related AEs, 7 digestive system, 14 nervous system, 4 body as a whole, 4 musculoskeletal system, 2 respiratory system, 4 cardiovascular system, 3 urogenital system |
Howard et al (2012) 19 | Donepezil | Only SAEs reported. Discontinuation group: total of 46 SAEs; 12 fall, 6 respiratory tract infection, 2 urinary tract infection, 7 deterioration of AD, 4 behavioral symptoms of AD, 2 gastrointestinal, 3 stroke, 1 cardiac, 1 dysphagia, 2 psychosis, 2 unknown (died), 1 venous embolus, 3 other | Only SAEs reported. Continuation group: Total of 46 SAEs; 9 fall, 6 respiratory tract infection, 5 urinary tract infection, 2 deterioration of AD, 5 behavioral symptoms of AD, 4 gastrointestinal, 5 stroke, 1 cardiac, 2 dysphagia, 1 unknown (died), 2 cancer, 2 syncope, 2 other |
Gaudig et al (2011) 20 | Galantamine | 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 |
Scarpini et al (2011) 22 | Galantamine | Assumed related: 1 cardiac disorder, 1 investigation, 3 psychiatric disorder; assumed not related: 1 gastrointestinal disorder, 2 general disorders and administration site conditions, 2 infections and infestations, 3 investigations, 1 metabolism and nutrition disorder, 1 musculoskeletal and connective tissue disorder, 1 neoplasm benign, malignant, and unspecified, 7 nervous system disorder, 5 psychiatric disorder, 1 renal and urinary disorder | Assumed related: 1 investigation; assumed not-related: 2 cardiac disorder, 1 gastrointestinal disorder, 3 general disorders and administration site conditions, 3 infections and infestations, 1 injury, poisoning and procedural complications, 3 investigations, 1 metabolism and nutrition disorder, 1 musculoskeletal and connective tissue disorder, 3 neoplasm benign, malignant, and unspecified, 5 nervous system disorder, 4 psychiatric disorder, 2 respiratory, thoracic and mediastinal disorder, 3 vascular disorder |
Herrmann et al (2016) 23 | Cholinesterase inhibitors | 5 unintentional weight loss, 3 falls, 1 oval thrush, 1 IV due to poor appetite, 1 respiratory tract infection, 1 cognitive decline, 3 deterioration in behavior, 1 bowel obstruction | 3 unintentional weight loss, 3 falls, 1 loss of consciousness, 2 vomiting, 1 perineum wound, 1 respiratory tract infection, 1 conjunctivitis, 1 dizziness, 1 rash, 1 acute cough, 2 deterioration in behavior, 1 bradycardia, 1 seizure, 1 atrial fibrillation |
Ory-Magne et al (2014) 24 | Amantadine | 19 worsening of dyskinesia, 8 worsening of parkinsonism, 4 pain, 2 fatigue, 1 sweat/flushing, 2 asthenia, 2 nausea/vomiting, 2 drowsiness, 1 cephalgia, 2 cough | 7 worsening of dyskinesia, 7 worsening of parkinsonism, 3 pain, 3 fatigue, 2 sweat/flushing, 2 asthenia, 2 nausea/vomiting, 2 drowsiness, 2 cephalgia, 3 falls, 1 cough |
Biaggioni et al (2015) 25 | Droxidopa | Total 19 (37%) patients experienced ≥ 1 AEs; these included 4 headache, 1 dizziness, 1 fatigue, 6 falls, 2 nausea, 1 diarrhea, 2 urinary tract infection | Total 15 (30%) patients experienced ≥ 1 AEs; these included 2 headache, 2 dizziness, 1 fall, 1 diarrhea, 1 urinary tract infection |
Tse et al (2008) 26 | Levodopa | 1 fever and worsening of mental status and parkinsonian symptoms | None described |
Findlay et al (1989) 27 | Thioridazine | None described | |
Devanand et al (2011) 28 | Haloperidol | AEs not systematically described | |
Devanand et al (2012) 29 | Risperidone | SAE: 1 died, 1 cardiovascular events, 1 neurologic event, 2 agitation-aggression, 1 pulmonary event, 2 other SAE. AE: 10 extrapyramidal signs, 10 akathisia or restlessness, 7 sedation, 2 insomnia, 8 confusion, 3 agitation-aggression, 1 falls, 3 nausea or vomiting | SAE: 2 died, 2 cardiovascular events, 1 pulmonary event, 2 other SAEs. AE: 17 extrapyramidal signs, 5 akathisia or restlessness, 8 sedation, 3 insomnia, 5 confusion, 1 agitation-aggression, 2 falls, 4 nausea or vomiting |
Bergh et al (2012) 31 | SSRIs | AEs not systematically described. 13 increased depressive or neuropsychiatric symptoms | AEs not systematically described; 4 increased depressive or neuropsychiatric symptoms |
Hardy et al (1997) 32 | Lithium | 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) | |
Klysner et al (2002) 33 | Citalopram | 2 nausea, 3 diarrhea, 4 headache, 3 increased sweating, 4 dizziness, 6 fatigue, 3 hot flushes, 1 vertigo, 2 dry mouth, 3 insomnia, 1 vomiting, 1 abdominal pain, 2 hypokalemia, 2 hypertension, 4 influenza-like symptoms, 4 traumatic injury, 1 pain, 2 back pain, 1 cystitis, 2 bronchitis | 3 diarrhea, 1 headache, 4 increased sweating, 3 tremor, 1 dizziness, 10 fatigue, 1 hot flushes, 3 abdominal pain, 2 hypokalemia, 1 hypertension, 9 influenza-like symptoms, 7 traumatic injury, 2 pain, 9 back pain, 3 dyspepsia, 3 cystitis, 3 bronchitis |
Wilson et al (2003) 34 | Sertraline | 3 unspecified AEs | 2 unspecified AEs |
Ulfvarson et al (2003) 35 | Citalopram, sertraline | AEs not systematically described | |
Habraken et al (1997) 36 | Lorazepam | AEs not systematically described | |
Curran et al (2003) 37 | Benzodiazepines | No AEs were reported | |
O'Brien et al (2001) 38 | Inhaled beclomethasone | 3 severe exacerbations during discontinuation | |
Choudhury et al (2007) 39 | Inhaled fluticasone | 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 | |
Borrill et al (2009) 40 | Inhaled fluticasone + salmeterol | No AEs were reported | |
Rice et al (2000) 41 | Prednisone | Weight loss = –4.8 ± 2.0 kg | Weight gain = 0.5 ± 3.5 kg |
Fabricius et al (1990) 42 | Terazosin | No AEs during the discontinuation phase | |
Barkin et al (2003) 43 | Tamsulosin | 2 dysuria, 2 urinary frequency, 2 urinary infections, 2 ejaculation disorders, 2 musculoskeletal pain, 2 viral respiratory tract infection | 2 dysuria, 1 urinary frequency, 1 ejaculation disorders, 2 musculoskeletal pain, 2 viral respiratory tract infection |
Lee et al (2012) 44 | Tamsulosin | AEs not specified per group; in total: 2 reduced libido, 2 ejaculatory problem | |
Matsukawa et al (2017) 45
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. J Urol. 2017; 198: 905-912 | Silodosin | 1 chest pain and 1 anthema | 1 chest pain, 1 postural hypotension, 1 dizziness |
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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.
The authors declare no conflicts of interest.
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