Ballard C, Hanney ML, Theodoulou M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurology 2009;8:151-57.
PubMed link: https://www.ncbi.nlm.nih.gov/pubmed/19138567
Ballard C, Margallo Lana M, Theodoulou M, et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (The DART-AD Trial). PLoS Medicine 2008;5:e76-e76.
PubMed link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276521/?report=classic
Full text article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276521/pdf/pmed.0050076.pdf
| Methods | Study design: Randomized double-blind, placebo-controlled study with a parallel-design
Number of groups: Two groups |
| Participants | Number of participants randomized: 165 participants
· Intervention deprescribing group: 82 randomized, 51 completed · Control group: 83 randomized, 52 completed Age: 84.8 ± 7.0 years Sex: 126 female, 39 male Participants with dementia: Yes MMSE: 11 ±5 MMSE > 6: n=14 (17.1%) Inclusion criteria: · Prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol, trifluoperazine or risperidone for behavioral or psychiatric disturbances in dementia for at least three months · Lived in a nursing or residential home · Met NINCDS/ADRDA criteria for possible or probable Alzheimer’s Disease · Either: · MMSE score higher than 6, or · Severe Battery Impairment scores greater than 30 · Taking at least: · 10 mg chlorpromazine equivalents of typicalneuroleptics; or · 0.5 mg daily of risperidone Exclusion criteria: · Unable to complete primary outcome measures at baseline assessment · Clinician responsible for care or study clinician considered that the patient suffered from any physical condition— including marked extrapyramidal disorder—that would have made participation in the trial distressing or likely to increase suffering · Currently taking thioridazine and showing a prolonged QTc on electrocardiogram · Likely to be unable to take capsule Concurrent medicines: cholinesterase inhibitor n=3 (3.7%%) Country: England and Scotland Setting: Residential aged care facility four area of the United Kingdom |
| Interventions | Medicine: Risperidone, or chlorpromazine, or trifluoperazine, or haloperidol
Withdrawal Schedule: Not described Comparator: Placebo compared to continued medicine |
| Outcomes | Ballard 2009:
Survival Successful deprescribing Ballard 2008: Total Severe Impairment Battery score (change from baseline to 6 months) Standardized MMSE Functional assessment scale test of verbal fluency Bristol Activities of Daily Living Scale Sheffield Test for Acquired Language Disorders Neuropsychiatric Index Modified Unified Parkinson’s Disease Rating Scale Clinician’s Global Impression of Change Post-Hoc Additional Exploratory Sensitivity Analysis |
| Dates | Dates: Between October 2001, and December 2004
Follow-up duration: 54 months |
| Funding sources | “The Alzheimer’s Research Trust, Cambridge, UK (http://www.alzheimers-research.org.uk) to Profs Ballard and Jacoby and to RM. The peer-review process undertaken by the funder did result in some modifications to the study design. The funder has no other role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript.” |
| Notes | Report details combined for Ballard 2008 and Ballard 2009 as they report the same study.
Authors declared: “Conflicts of interest: Within the past 5 years, CB has received honoraria from Novartis, Pfizer, Shire, Lundbeck, Myriad, Servier, and Arcadia, and research grants from Novartis and Lundbeck; and honoraria and research grants from AstraZeneca and Janssen more than 5 years ago. None of the other authors has any conflicts of interest.” |
Risk of bias table
| Bias | Authors’ judgment | Support for judgment |
| Random sequence generation (selection bias) | Low risk | “Randomization was performed centrally at the Center for Statistics in Medicine in Oxford, using dedicated computer software (MINIM)…. The statistician directly communicated the allocation to the relevant trial pharmacy, ensuring concealment.” |
| Allocation concealment (selection bias) | Low risk | Computerized randomization –
“Initial randomizationwas done centrally at the Center for Statistics in Medicine in Oxford, by use of dedicated computer software (MINIM, version 1.5 [a randomization program for allocating patients to treatment in clinical trials])…To avoid predictability, the first 22 patients were allocated randomly without the minimization factors. The minimization algorithm was applied to subsequentpatients with an allocation ratio that was not fullydeterministic. The statistician who did the randomization had no direct contact with patients; therefore, the allocation was totallyindependent of patient recruitment.” |
| Blinding of participants and personnel (performance bias) | Low risk | Placebo used.
Quote. “Each of the neuroleptics was over-encapsulated to conceal the identity of the contents. Placebo capsules were identical to the over-encapsulated neuroleptics, but contained only inert filler.” |
| Blinding of outcome assessment (detection bias) | Low risk | This was probably done. |
| Incomplete outcome data (attrition bias) | Unclear risk | The attrition and exclusions were reported, and it was combined with additional analysis for sensitivity and posthoc to assess if the attrition affected the outcomes. However, the high level of attrition means that it cannot be entirely clear how this affected the study.
“Over the full 12 months of the study, 47 people did not complete follow-up. Of these individuals 21 died and a further 26 (55%) stopped the allocated treatment.” This was similar across both arms of the study. |
| Selective reporting (reporting bias) | Low risk | The pre-specified primary and secondary outcomes described in the paper were reported. A study protocol was not available. |
| Other bias | Unclear risk | Participants used both typical and atypical antipsychotics, yet these were grouped together for the analysis. It is unclear if these two classes may both show the same effects. |
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