Post on 15-Dec-2015
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Pragmatic cohort studies and comparative effectiveness
Eric S Johnson, PhDKaiser Permanente’sCenter for Effectiveness and Safety Research
AHRQ’s Effective Healthcare Program:Scientific Resource Center
June 18, 2010 UC Davis School of Medicine
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The risk of death associated with the use of conventional versus atypical antipsychoticsamong elderly patients
Sebastian Schneeweiss, Soko Setoguchi, Alan Brookhart, Colin Dormuth, Philip S Wang
Canadian Medical Association Journal 2007;176:627-32
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BMJ’s PICO format: Study question
Do conventional antipsychotic drugs pose risks equal to orgreater than those associated with newer, atypical drugsin an elderly population?
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BMJ’s PICO format: Design, intervention and control
We conducted a retrospective cohort study of elderly patients with a diagnosis of dementia who started a conventional or an atypical antipsychotic drug.
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BMJ’s PICO format: Participants and setting
We followed 37,241 patients 65 years or older who started an antipsychotic drug between 1996 and 2004 and wereresidents of British Columbia.
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BMJ’s PICO format: Outcomes and their timing
We compared the 180-day all-cause mortality rate for patientswho started conventional versus atypical antipsychotic drugs.
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BMJ’s PICO format: Results and role of chance
Of the 24,359 (control cohort) patients who started an atypical antipsychotic drug, 9.6% died by 180 days. In adjusted analyses, patients who started a conventional drug were 32% more likely to die (hazard ratio=1.32; 95% CI, 1.23 to 1.42)—an excess of 3.5 deaths per 100 patients.
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A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers
Kevin Thorpe, Merrick Zwarenstein, Andrew Oxman, and others
J Clin Epidemiology 2009;62:464-75.
“Pragmatic trials seek to answer the question: ‘Does the intervention work under usual conditions.’ ”
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The pragmatic to explanatory trials continuum*
Flexibility of comparisonintervention
PractitionerExpertise(experimental)
Flexibility of theexperimentalintervention
Eligibilitycriteria
Primaryanalysis
Practitioneradherence
Participantcompliance
Outcomes
Follow-upintensity
Practitionerexpertise(comparison)
E
* J Clin Epidemiology 2009;62:464-75
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New atypical
antipsychotic drug
New conventional antipsychotic drug
No antipsychotic drugs filled: year-long baseline
Time
Zero
Intention-to-treat analyses to 180 days
A pragmatic cohort study: new users
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Evaluating medication effects outside of clinical trials:New-user designs
Wayne Ray
Am J Epidemiol 2003;158:915-20
“[P]revalent users can introduce two types of biases:(1) Underascertainment of events that occur early in therapy (2) Inability to control for predictors that may have been altered
by the study drugs.”
Prevalent users also preclude meaningful propensity scores.
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One class of intervention
Usual care:New or current users?Consistency of alternatives?
Any criteria for medications filled in year-long baseline?
Time
Zero
Valid comparisons with usual care?
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How might we design a score to predict the usefulness of pragmatic cohort studies?
How well does the cohort answer decision-makers’ questions?Inferiority or non-inferiority?
How closely does the cohort resemble a pragmatic trial? Design? Analysis?
How easy is the cohort for systematicreviewers to GRADE and synthesize?An unintended outcome, a harm?
.
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“[A] national CER programshould promote the professional ethos that places the interests ofpatients and the largercommunity above all otherconsiderations.”
Harold Sox and Sheldon GreenfieldAnnals of Intern Med 2009;151:203-5
Comparative effectivenessresearch: a report from theInstitute of Medicine
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“He wants to look at his plate,see a steak, and say,‘I like steak!’ ”
“Give people what they want,then later you can give themwhat you want.”
Pascal in Big Night (1996)
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Variation in the risk of suicide attempts andcompleted suicides by antidepressant agentin adults
Sebastian Schneeweiss, Amanda Patrick, Daniel Solomon, Jyotsna Mehta,Colin Dormuth, Matthew Miller, Jennifer Lee, Philip S Wang
Archives of General Psychiatry 2010;67:497-506
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Design, intervention and control:Advanced strategies for propensity scores
“After plotting and comparing the distribution of propensity scores…we truncated our study population to the area of overlap. [S]ubjects with non-overlapping propensity scores mayhave absolute clinical indications or contraindications for aparticular treatment.”
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Design, intervention and control:Advanced strategies for propensity scores
“We constructed a high-dimensional propensity score based on the top 500 identified variables in addition to the variablesidentified by us…We consider results from this analysis to be the most completely adjusted… ”
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Design, intervention and control:Advanced strategies for propensity scores
“We created adjusted Kaplan-Meier plots by weighting eachsubject by the inverse of his or her probability for treatmentas estimated in the propensity score analysis.”
Sertraline vs. fluoxetine
Time since treatment initiation (months)
0 3 6 9 12
Com
posi
te e
vent
-fre
e pr
obab
ility
0.994
0.996
0.998
1.000
SertralineFluoxetine
Probability of remaining free of suicide or suicide attempt since treatment with sertraline (36,135) or fluoxetine (22,207), weighted by the inverse probability of treatment from the propensity score.From Schneeweiss et al. Arch Gen Psychiatry 2010;67:497-506