Download - Paul Moayyedi Grigorios Leontiadis
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Paul Moayyedi & Grigorios Leontiadis
• McMaster University
• Upper Gastrointestinal and Pancreatic Diseases Cochrane Group
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Financial Interest Disclosure(over the past 24 months)
No relevant financial relationships with any commercial interests
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CDDW/CASL Meeting Session: Network meta-analysis
Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.)
Communicator (as Communicators, physicians effectively facilitate the doctor-patient relationship and the dynamic exchanges that occur before, during, and after the medical encounter.)
Collaborator (as Collaborators, physicians effectively work within a healthcare team to achieve optimal patient care.)
Manager (as Managers, physicians are integral participants in healthcare organizations, organizing sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.)
Health Advocate (as Health Advocates, physicians responsibly use their expertise and influence to advance the health and well-being of individual patients, communities, and populations.)
Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning, as well as the creation, dissemination, application and translation of medical knowledge.)
Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of behaviour.)
CanMEDS Roles Covered in this Session:
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Outline
Network meta‐analysis (NMA):
Basic concepts
How does it differ from a conventional pairwise meta‐analysis
What are the advantages and limitations?
How does it work?
What are the underlying assumptions/conditions?
How can you critically assess and interpret a NMA paper?
How can you get trained to conduct one?
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Case: 40 year old female with a history of idiopathic recurrent pancreatitis
undergoing ERCP; difficult cannulation, normal findings
High risk for post‐ERCP pancreatitis
Question: Should we administer rectal indomethacin or not?
What is the evidence?
Why bother doing /reading a NMA?
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Why bother doing /reading a NMA?
We need to do (or read) an systematic review and meta‐analysis of RCTs that had compared rectal indomethacin with placebo
Yaghoobi et al. Aliment Pharmacol Ther 2013
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Why bother doing /reading a NMA?
We need to do (or read) an systematic review and meta‐analysis of RCTs that had compared rectal indomethacin with placebo
Yaghoobi et al. Aliment Pharmacol Ther 2013
So, we decide to administer rectal indomethacin
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Why bother doing /reading a NMA?
What if I ask if allopurinol is better than placebo for the prevention of PEP?‐ I would need another pairwise SR&MA
How about allopurinol vs. rectal indomethacin?‐ Again, I would need another pairwise SR&MA
36 pharmacological interventions have been assessed in RCTs for prevention of PERAlso, several technical interventions have been assessed in other RCTs
How many pairwise SR&MA do we have to do/read to find out which treatment is the best of all? How can we process all these results in our head?
Is there a way to compare two of the above treatments if these have never been assessed in head‐to‐head trials?
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NMA: definition
A procedure that permits inferences into the comparative effectiveness of interventions that may or may not have been evaluated directly against each other
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NMA synonyms
Multiple-treatments meta-analysis
Indirect-treatment meta-analysis
Mixed-treatment comparison
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Indirect comparison
B
placebo
C
placebo vs. B
placebo vs. C
But we need to compare B vs. C(indirect comparison)
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CB
A
Indirect evidence from A vs. B and A vs. B trials
Direct evidence Direct and indirect evidence can be combined when appropriate
Indirect Comparison and Network Meta‐analysis Framework
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Network graphs
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Mills et al JAMA 2012
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Nodes and edges: size can be proportional to number of studies, number of patients, mean age of participant in studies, price of the drug etc.
Aripiprazole
Asenapine
Carbamazpine
DivalproexHaloperidol
Lamotrigine
Lithium
Olanzapine
Placebo
Quetipaine
Ripseridone Topiramate
Ziprasidone
Paliperidone
Network graphs
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Aripiprazole
Asenapine
Carbamazpine
DivalproexHaloperidol
Lamotrigine
Lithium
Olanzapine
Placebo
Quetipaine
Ripseridone Topiramate
Ziprasidone
Paliperidone
Nodes and edges color can be used to present risk of bias characteristics
Network graphs
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Numerical presentation of NMA results
paroxetine
sertraline
citalopram
fluoxetine
fluvoxamine
milnacipran
venlafaxine
reboxetine
bupropion
mirtazapine
duloxetine
escitalopram
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OR>1 means the treatment in top-left is better
Numerical presentation of NMA results
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Ranking of treatments
% probability A B C D
Best 0.25 0.50 0.25 0.00
Second 0.50 0.75 0.75 0.00
Third 0.75 1.00 1.00 0.25
Last 1.00 1.00 1.00 1.00
Rank of A
Cumulative Probability 1.0 1.5 2.0 2.5 3.0 3.5 4.0
0.00.2
0.40.6
0.81.0
Rank of B1.0 1.5 2.0 2.5 3.0 3.5 4.0
0.00.2
0.40.6
0.81.0
Rank of C
Cumulative Probability 1.0 1.5 2.0 2.5 3.0 3.5 4.0
0.00.2
0.40.6
0.81.0
Rank of D1.0 1.5 2.0 2.5 3.0 3.5 4.0
0.00.2
0.40.6
0.81.0
Surface Under the Cumulative RAnkingcurve (SUCRA):
• A=0.5• B=0.75• C=0.67• D=0.08
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Ranking of treatments
Akshintala et al. Aliment Pharmacol Ther 2013
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OLZ
HAL
RIS
QTP
CBZ
ARI
DVPZIP
ASE
PBO
LIT
LAM
TOP
GBT
Effi
cacy
1st
3rd
5th
7th
9th
11th
13th
Acceptability1st3rd5th7th9th11th13th
Cipriani et al Lancet 2011
Ranking of treatments for two outcomes
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Advantages of NMAs
Provide answers to clinically relevant questions that cannot be addressed in a practical fashion by conventional pairwise meta-analyses– All treatments of interest compared among each other – Provide the “full picture”
Improve precision – by considering both direct and indirect evidence the 95%
CI for the pooled estimate of pairwise comparions is further narrowed
Rank treatments
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Ciapponi et al. Cochrane Colloquium 2013
Exponential trend in NMA publications
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Assumptions/conditions underlying indirect/mixed comparisons
A NMA is not valid unless these 3 assumptions/conditions are met:
1. Homogeneity
2. Similarity (transitivity)
3. Consistency
Mills et al JAMA 2012
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Assumptions/conditions underlying indirect/mixed comparisons
Within each pairwise comparison there should be:
low clinical heterogeneity/ diversity: the characteristics of the studies should be sufficiently similar
low statistical heterogeneity: the results of the studies should be sufficiently similar, i.e. there should not be variation in effect estimates beyond chance
1. Homogeneity
Drug A Drug B
placebo
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Assumptions/conditions underlying indirect/mixed comparisons
low clinical heterogeneity/ diversity
Compare whether the PICOT components are sufficiently similar among studies
Population
Intervention
Comparator
Outcomes
Timeline
1. Homogeneity
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Assumptions/conditions underlying indirect/mixed comparisons1. Homogeneity
Study Population
1 Canada, primary care, adults with FD
2 Germany, primary care, adults with FD
3 US, secondary care, male veterans with epigastric pain and negative endoscopy
4 US, tertiary care (Mayo Clinic), adults with FD
5 France, primary care, teenagers (age 15‐18) with FD
H pylori eradication treatment for patients with functional dyspepsia
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Assumptions/conditions underlying indirect/mixed comparisons1. Homogeneity
Study Population
1 Canada, primary care, adults with FD
2 Taiwan, primary care, adults with FD
3 US, secondary care, male veterans with epigastric pain and negative endoscopy
4 US, tertiary care (Mayo Clinic), adults with idiopathic gastroparesis
5 France, primary care, children (age 4‐12) with FD
H pylori eradication treatment for patients with functional dyspepsia
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Assumptions/conditions underlying indirect/mixed comparisons1. Homogeneity
Study Outcome Timeline
1 Proportion of patients with complete resolution of symptoms 12 months
2 Proportion of patients with 25% improvement in epigastric pain 3 month
3 Proportion of patients with 50% improvement on global dyspepsia score 1 months
4 Proportion of patients with 50% improvement on global dyspepsia score 12 months
5 Proportion of patients with any improvement in the main symptom 6 months
H pylori eradication treatment for patients with functional dyspepsia
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Assumptions/conditions underlying indirect/mixed comparisons
low statistical heterogeneity
1. Homogeneity
high statistical heterogeneity
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Assumptions/conditions underlying indirect/mixed comparisons
Studies across comparisons are similar in characteristics that are effect modifiers
2. Similarity (transitivity)
Drug A Drug B
Drug C
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Assumptions/conditions underlying indirect/mixed comparisons
The “anchor” treatment should be transitive
We can evaluate clinically and epidemiologically its plausibility
2. Similarity (transitivity)
Drug A Drug B
Drug C
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Assumptions/conditions underlying indirect/mixed comparisons
The “anchor” treatment should be transitive
We can evaluate clinically and epidemiologically its plausibility
2. Similarity (transitivity)
Panto Esome
Lanso
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Assumptions/conditions underlying indirect/mixed comparisons
The “anchor” treatment should be transitive
We can evaluate clinically and epidemiologically its plausibility
– The “anchor” treatment (Lanso) should be similarly defined in both sets of pairwise comparisons
2. Similarity (transitivity)
Panto Esome
Lanso
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Assumptions/conditions underlying indirect/mixed comparisons
The “anchor” treatment should be transitive
We can evaluate clinically and epidemiologically its plausibility
– The “anchor” treatment (Lanso) should be similarly defined in both sets of pairwise comparisons
– What if Panto 40 mg was compared to Lanso 15 mgand Esome 40 mg was compared to Lanso 30 mg
2. Similarity (transitivity)
Panto Esome
Lanso
Panto Esome
Lanso15 mg
Lanso30 mg
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Assumptions/conditions underlying indirect/mixed comparisons2. Similarity (transitivity)
Fluoride toothpaste
Fluoride rinse
placebo
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Assumptions/conditions underlying indirect/mixed comparisons2. Similarity (transitivity)
Fluoride toothpaste
Fluoride rinse
placebo
Fluoride toothpaste
Fluoride rinse
Placebo toothpaste
Placebo rinse
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AC and BC trials should not differ with respect to the distribution of effect modifiers
variable(e.g. age)
Effe
ctiv
enes
sAssumptions/conditions underlying indirect/mixed comparisons2. Similarity (transitivity)
Drug A Drug B
Drug C
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AC and BC trials should not differ with respect to the distribution of effect modifiers
variable(e.g. age)
Effe
ctiv
enes
s
AB
C
Assumptions/conditions underlying indirect/mixed comparisons2. Similarity (transitivity)
Drug A Drug B
Drug C
C
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Assumptions/conditions underlying indirect/mixed comparisons
All treatments should be “jointly randomizable” meaning that a trial including all treatments would be clinically reasonable.The assumption of transitivity could be violated if interventions have different indications. Treatments need to be competing or alternative treatments for the condition of interest
Example: treatment A is a chemotherapy regimen administered as a second line treatment, whereas treatments B and C can be either as first or second line- we cannot assume that participants in a BC trial could have been randomized in an AC trial
2. Similarity (transitivity)
Drug A Drug B
Drug C
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Assumptions/conditions underlying indirect/mixed comparisons
Direct and indirect evidence should be in agreement
Inconsistency factor
3. Consistency
Drug A Drug B
Drug C
Indirect evidence
Direct evidence
In 112 trial networks‐ Incoherence was statistically significant in 16 cases ‐ The direction of treatment effects only differed in 2 cases
Song et al BMJ 2011
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Statistics
Bayesian approach
Probabilistic approach
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Useful reading
International Society for Pharmacoeconomics and Outcomes Research (ISPOR) task force on indirect comparisons http://www.ispor.org/taskforces/ITC.asp
Mills et al. JAMA. 2012;308(12):1246-1253
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Conclusions
NMA is a new powerful tool for evidence synthesis
If not conducted properly, a NMA can generate spurious and misleading results
If conducted properly, a NMA may provide long-waited answers on the comparative effectiveness of interventions that have not been evaluated directly against each other
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Thank you!
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