Paul Moayyedi Grigorios Leontiadis

Paul Moayyedi & Grigorios Leontiadis

• McMaster University

• Upper Gastrointestinal and Pancreatic Diseases Cochrane Group

Financial Interest Disclosure(over the past 24 months)

No relevant financial relationships with any commercial interests

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:

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?

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?


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


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


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?

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

NMA synonyms

Multiple-treatments meta-analysis

Indirect-treatment meta-analysis

Mixed-treatment comparison

Indirect comparison

B

placebo

C

placebo vs. B

placebo vs. C

But we need to compare B vs. C(indirect comparison)

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

Network graphs

Mills et al JAMA 2012

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

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

Numerical presentation of NMA results

paroxetine

sertraline

citalopram

fluoxetine

fluvoxamine

milnacipran

venlafaxine

reboxetine

bupropion

mirtazapine

duloxetine

escitalopram

OR>1 means the treatment in top-left is better

Numerical presentation of NMA results

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

Ranking of treatments

Akshintala et al. Aliment Pharmacol Ther 2013

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

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

Ciapponi et al. Cochrane Colloquium 2013

Exponential trend in NMA publications

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


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


low clinical heterogeneity/ diversity

Compare whether the PICOT components are sufficiently similar among studies

Population

Intervention

Comparator

Outcomes

Timeline

1. Homogeneity

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


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



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



low statistical heterogeneity

1. Homogeneity

high statistical heterogeneity


Studies across comparisons are similar in characteristics that are effect modifiers


Drug A Drug B

Drug C


The “anchor” treatment should be transitive

We can evaluate clinically and epidemiologically its plausibility


Drug A Drug B

Drug C





Panto Esome

Lanso




– The “anchor” treatment (Lanso) should be similarly defined in both sets of pairwise comparisons


Panto Esome

Lanso




– 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


Panto Esome

Lanso

Panto Esome

Lanso15 mg

Lanso30 mg

Assumptions/conditions underlying indirect/mixed comparisons2. Similarity (transitivity)

Fluoride toothpaste

Fluoride rinse

placebo


Fluoride toothpaste

Fluoride rinse

placebo

Fluoride toothpaste

Fluoride rinse

Placebo toothpaste

Placebo rinse

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

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


Drug A Drug B

Drug C

C


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


Drug A Drug B

Drug C


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

Statistics

Bayesian approach

Probabilistic approach

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

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

Please visit the CAG websiteat http://www.cag-acg.org/

to complete the session evaluation and to print your certificate of attendance.

Thank you!

Evaluation and Certificate of Attendance

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Paul Moayyedi Grigorios Leontiadis