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Neurology Journal Club

Neurology Journal Club. McGill University April 8, 2009. Appetizers. Which Statement is False?. Regarding Randomized Control Trials: Blinding means that an investigator cannot predict the order in which subjects will be randomized to treatment or placebo

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Neurology Journal Club

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  1. NeurologyJournalClub McGill University April 8, 2009

  2. Appetizers

  3. Which Statement is False? Regarding Randomized Control Trials: • Blinding means that an investigator cannot predict the order in which subjects will be randomized to treatment or placebo • “Double-blind” trials are ones in which neither the investigator nor the patient knows if they are receiving active drug or placebo • An intention-to-treat analysis means that all subjects initially assigned to either the treatment or placebo group will be analyzed with their assigned group, even if they changed groups during the trial • RCTs are generally considered to provide better evidence of a therapeutic effect than observational studies

  4. Regarding Galantamine for Severe Alzheimer’s Disease, the SERAD Trial: • demonstrated that galantamine can improve severely demented nursing home patients’ ability to perform activities of daily living • is the only trial of acetylcholinesterase inhibitors in patients with advanced Alzheimer’s • demonstrated that galantamine therapy improved global cognition compared to placebo • would only apply to severely demented patients who are not yet in a nursing home

  5. Regarding Cholinesterase Inhibitors, The SERAD Authors Claim: • They should never be discontinued, once started, because they are neuroprotective • They can be safely prescribed with some effect in patients with severe dementia • That since patients who received galantamine died less, cholinesterase inhibitors may provide more than just symptomatic treatment • They should only be prescribed to severely demented patients who have already been taking choliesterase inhibitors at earlier stages of their disease

  6. Clinical Scenario

  7. Clinical Scenario • 80 year-old woman living in nursing home in rural village • Diagnosis of “senile dementia” • Daughter moves patient to nursing home closer to her in the city • Requests neurology consultation because she has read about treatments for advanced dementia on the internet

  8. Past History • Married French-Canadian with 5 children • Devout Catholic • lifelong homemaker, grade 8 education • PMHx: HTN, hyperlipidaemia, osteoporosis • PpsychHx: none • PSHx: appendectomy,TAH (fibroids)

  9. History • 9 years ago: first noticed forgetfulness • worsened, along with depressed mood when husband died one year later • 6 years ago: difficulty making meals, doing grocery • can no longer pay bills • family friend and daughter assumer Power of Attorney over financial affairs • “Meals on Wheels” • student volunteer visits 2x / week • MD prescribes antidepressant

  10. History • 5 years ago: • CLSC now involved for cleaning • patient’s cognitive status nadirs a bit • 3 years ago: patient moved into Seniors’ Residence • cleaning service, cafeteria • further short-term memory loss and executive dysfunction (MMSE 20) • 18 mos. ago: fall on icy sidewalk - hip fracture • Surgery complicated by delirium, prolonged recovery • Geriatrician removes unnecessary medication • Patient stabilizes at MMSE 14 • Paranoid ideation, agitated at night • placed in nursing home

  11. History • In nursing home • slow, steady deterioration in behaviour • patient now totally disoriented at baseline but can have non-specific conversation • dependant for most ADLs • MMSE 12 • Family friend dies • Patient moves to city nursing home • On admission, MMSE 10 • Patient still recognizes her daughter

  12. Question • Does this patient have Alzheimer’s Disease? • How do you diagnose definite AD? • How do you diagnose probable AD?

  13. DSM-IV: Alzheimer’s Dementia • Memory impairment AND one of • aphasia (language disturbance) • apraxia (impaired ability to carry out motor activities despite intact motor function) • agnosia (failure to recognize or identify objects despite intact sensory function) • disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting) • Significant impairment in and decline from previous social or occupational functioning • Gradual onset and continuing cognitive decline. • Cognitive deficits are not due to: • (1) other central nervous system conditions that cause progressive deficits in memory and cognition • (2) systemic conditions that are known to cause dementia • (3) substance-induced conditions • The deficits do not occur exclusively during a delirium. • Not better accounted for by another Axis I disorder

  14. NINDS Criteria • Dementia established by clinical examination and confirmed by cognitive screening (e.g., MMSE) • Deficits in ≥ 2 areas of cognition • Progressive worsening of memory • No disturbance of consciousness • Onset > 40 yrs (typically > 65) • Absence of systemic disorders or other diseases that could account for deficits and progression

  15. Stages of Alzheimer’s Disease • What defines mild / moderate / severe AD?

  16. Scenario • Daughter has brought this patient from nursing home to your general neurology practice and is requesting prescription of an “Alzheimer’s drug” for her mother. • Is there evidence to support this?

  17. Main Course

  18. What Kinds of Broad Questions do We Want to Ask About the Paper?

  19. What Kinds of Questions do We Want to Ask About the Paper? • Are the results of the study valid? • What were the results? • Are they applicable to my patient?

  20. Are the Results of the Study Valid?

  21. Are the Results of the Study Valid? • Was the assignment of patients to treatment randomized? • Were all patients who entered the trial properly accounted for and attributed at its conclusion? • Was follow-up complete? • Were patients analyzed in the groups to which they had been randomized? • Were patients, clinicians, and study personnel blind? • Were groups similar at the start of the trial? • Were groups treated equally (aside from the experimental intervention)?

  22. Patient Selection Criteria • Inclusion criteria: • Alzheimer's • AD - DSM-IV • probable - NINDS • possible AD/VaD - NINDS • if AD component is likely contributing to decline • Ambulatory, sufficient vision • no AChEI or memantine x 3 mo • Nursing home x 3 mo • Consent • from patients ?! • authenticated by the investigator • written consent from patient's proxy • Exclusion criteria: • Other causes of dementia • primarily VaD • neurodegenerative disease (PD, Huntington's) • Disturbance of consciousness, delirium, psychosis • Major sensorimotor impairment precluding neuropsych testing • Co-morbid conditions affecting cognition • trauma • hypoxia • vitamin defeciency • metabolic disorder • Other comorbid conditions • Cardiovascular disease precluding 6-month life expectancy • epilepsy • drug abuse • severe drug allergy • peptic ulcer • clinically sig psych, hepatic, renal, pulmonary, metabolic/endocrine disease • urinary outflow obstruction

  23. Are the Results of the Study Valid?

  24. What Were the Results?

  25. What Were the Results? • What was measured? • How large was the treatment effect? • How precise was the treatment effect?

  26. Adverse Events?

  27. Adverse Events? • About evenly distributed in both groups • Less death in galantamine group • No major infections

  28. Will the Results Help Me Care for My Patient?

  29. Will the Results Help Me Care for My Patient? • Can they be applied to my patient? • Were all clinically important outcomes considered? • Are the likely outcomes worth the potential harm and costs associated with the intervention?

  30. Can the Results be Applied to My Patient? • Easy "yes" if the patient would have fulfilled all enrolment criteria • If not, is there some compelling reason why the study doesn't apply? • What if the patient fits a subgroup about which a different outcome was reported?

  31. is there some compelling reason why the study doesn't apply? • GOAL: Balance between "unjustifiably broad generalizations" and "being too conservative” in applying results to the patient • Must consider: • biologic issues • social issues • epidemiological issues

  32. is there some compelling reason why the study doesn't apply? • Biologic Issues Impacting on Applicability: • Are there pathophysiologic differences in the illness under study that may lead to a diminished treatment response? • A single nosological entity may represent different diseases… • Are there patient differences that may alter response to treatment? • drug metabolism • immune responses • environmental factors

  33. is there some compelling reason why the study doesn't apply? • Socioeconomic Issues Impacting on Applicability: • Patient compliance factors: • Limitations due to a particular setting • behavioural idiosyncrasies • Health care provider compliance factors: • financial considerations / organization of health care team • Access to equipment • availability / skill of required care workers • technological expertise

  34. is there some compelling reason why the study doesn't apply? • Epidemiological Issues Impacting on Applicability: • Does my patient have comorbid conditions that alters the potential risks and benefits of treatment? • could cause a competing diagnostic possibility • could interfere with the desired outcome • antagonism • synergy • Are there important difference in the outcomes in untreated patients, compared to my patient?

  35. Subgroup Analyses • Only consider subgroup analyses when the reported difference is: • large in magnitude • very unlikely to occur by chance (very low p) • resulted from a pre-specified analysis • was only part of a small number of subgroup analyses (vs "data dredging") • is replicated in other studies

  36. Will the Results Help Me Care for My Patient? • Can they be applied to my patient?

  37. Will the Results Help Me Care for My Patient? • Were all clinically important outcomes considered?

  38. Will the Results Help Me Care for My Patient? • Are the likely outcomes worth the potential harm and costs associated with the intervention?

  39. Coffee

  40. Authors’ Discussion

  41. Authors’ Discussion • Extend use of galantamine to severe AD • Effective on cognitive function • SIB more sensitive scale in advanced dementia • Efficacy does not change across range of MMSE scores • NICE guidelines suggest stopping AChEI when MMSE < 10 but don’t talk about starting them • No effect on ADLs • “It’s because of the scale we used” • Adverse events mild-mod • No excess medication discontinuations • Fewer deaths on galantamine • Because of increased locomotion

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