NEUROLOGYJOURNALCLUBMcGill University

April 8, 2009

APPETIZERS

WHICH STATEMENT IS FALSE?

Regarding Randomized Control Trials:A. Blinding means that an investigator cannot

predict the order in which subjects will be randomized to treatment or placebo

B. “Double-blind” trials are ones in which neither the investigator nor the patient knows if they are receiving active drug or placebo

C. 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

D. RCTs are generally considered to provide better evidence of a therapeutic effect than observational studies

REGARDING GALANTAMINE FOR SEVERE ALZHEIMER’S DISEASE, THE SERAD TRIAL:

A. demonstrated that galantamine can improve severely demented nursing home patients’ ability to perform activities of daily living

B. is the only trial of acetylcholinesterase inhibitors in patients with advanced Alzheimer’s

C. demonstrated that galantamine therapy improved global cognition compared to placebo

D. would only apply to severely demented patients who are not yet in a nursing home

REGARDING CHOLINESTERASE INHIBITORS, THE SERAD AUTHORS CLAIM:

A. They should never be discontinued, once started, because they are neuroprotective

B. They can be safely prescribed with some effect in patients with severe dementia

C. That since patients who received galantamine died less, cholinesterase inhibitors may provide more than just symptomatic treatment

D. They should only be prescribed to severely demented patients who have already been taking choliesterase inhibitors at earlier stages of their disease

CLINICAL SCENARIO

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

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)

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

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

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

QUESTION

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

DSM-IV: ALZHEIMER’S DEMENTIAA. Memory impairment AND one of

a) aphasia (language disturbance)b) apraxia (impaired ability to carry out motor activities despite intact

motor function)c) agnosia (failure to recognize or identify objects despite intact sensory

function)d) disturbance in executive functioning (i.e., planning, organizing,

sequencing, abstracting)

B. Significant impairment in and decline from previous social or occupational functioning

C. Gradual onset and continuing cognitive decline.D. 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

E. The deficits do not occur exclusively during a delirium.F. Not better accounted for by another Axis I disorder

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

STAGES OF ALZHEIMER’S DISEASE

What defines mild / moderate / severe AD?

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?

MAIN COURSE

WHAT KINDS OF BROAD QUESTIONS DO WE WANT TO ASK ABOUT THE PAPER?

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?

ARE THE RESULTS OF THE STUDY VALID?

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)?

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

ARE THE RESULTS OF THE STUDY VALID?

WHAT WERE THE RESULTS?

WHAT WERE THE RESULTS?

What was measured? How large was the treatment effect? How precise was the treatment effect?

Analysis SIB MDS-ADL n

Completer 4.6 (1.3,7.5, p=0.006) -0.41 (-1.3,3.9,p=0.383) 311

LOCF 5.02 (2.17,7.86, p=0.0006) -0.50 (-1.39, 0.39, p=0.394) 364

ADVERSE EVENTS?

ADVERSE EVENTS?

About evenly distributed in both groups Less death in galantamine group

No major infections

WILL THE RESULTS HELP ME CARE FOR MY PATIENT?

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?

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?

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

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

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

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?

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

WILL THE RESULTS HELP ME CARE FOR MY PATIENT?

Can they be applied to my patient?

WILL THE RESULTS HELP ME CARE FOR MY PATIENT?

Were all clinically important outcomes considered?

WILL THE RESULTS HELP ME CARE FOR MY PATIENT?

Are the likely outcomes worth the potential harm and costs associated with the intervention?

COFFEE

AUTHORS’ DISCUSSION

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

AUTHOR’S DISCUSSION

Strengths of study: Many countries used – broad applicability Good sized cohort of elderly patients

Weaknesses: No effect shown on ADLs

Due to chosen scale Does not assess continuing medication, only

starting

DESSERT

WHICH STATEMENT IS FALSE?

Regarding Randomized Control Trials:A. Blinding means that an investigator cannot

predict the order in which subjects will be randomized to treatment or placebo

B. “Double-blind” trials are ones in which neither the investigator nor the patient knows if they are receiving active drug or placebo

C. 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

D. RCTs are generally considered to provide better evidence of a therapeutic effect than observational studies

REGARDING GALANTAMINE FOR SEVERE ALZHEIMER’S DISEASE, THE SERAD TRIAL:

A. demonstrated that galantamine can improve severely demented nursing home patients’ ability to perform activities of daily living

B. is the only trial of acetylcholinesterase inhibitors in patients with advanced Alzheimer’s

C. demonstrated that galantamine therapy improved global cognition compared to placebo

D. would only apply to severely demented patients who are not yet in a nursing home

REGARDING CHOLINESTERASE INHIBITORS, THE SERAD AUTHORS CLAIM:

A. They should never be discontinued, once started, because they are neuroprotective

B. They can be safely prescribed with some effect in patients with severe dementia

C. That since patients who received galantamine died less, cholinesterase inhibitors may provide more than just symptomatic treatment

D. They should only be prescribed to severely demented patients who have already been taking choliesterase inhibitors at earlier stages of their disease

THE INTERROBANG – A TWENTY-FIRST CENTURY PUNCTUATION MARK