Transcript Neurology Journal Club

NEUROLOGY
JOURNAL
CLUB
McGill 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.
B.
C.
D.
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
REGARDING CHOLINESTERASE INHIBITORS,
THE SERAD AUTHORS CLAIM:
A.
B.
C.
D.
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
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 DEMENTIA
Memory impairment AND one of
A.
a)
b)
c)
d)
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:
B.
C.
D.
(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.
F.
The deficits do not occur exclusively during a delirium.
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 ?!







Exclusion criteria:
 Other causes of dementia





written consent from patient's
proxy
Disturbance of consciousness, delirium,
psychosis
Major sensorimotor impairment
precluding neuropsych testing
Co-morbid conditions affecting
cognition



authenticated by the investigator


primarily VaD
neurodegenerative disease (PD, Huntington's)
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
 very
in magnitude
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



Adverse events mild-mod


“It’s because of the scale we used”
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.
B.
C.
D.
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
REGARDING CHOLINESTERASE INHIBITORS,
THE SERAD AUTHORS CLAIM:
A.
B.
C.
D.
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
THE INTERROBANG – A TWENTY-FIRST
CENTURY PUNCTUATION MARK