Evidence Based Rheumatology
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Transcript Evidence Based Rheumatology
Evidence-Based Medicine and
the Cochrane Collaboration
Clinical Research Methodology Course
Thursday, December 11, 2008
NYU HOSPITAL FOR JOINT DISEASES
NEW YORK, NY
Peter Tugwell
On behalf of Cochrane Musculoskeletal Review Group,
Editors and Authors of Evidence Based Rheumatology.
What is Evidence-Based Medicine?
What is Evidence-Based Medicine?
Evidence-Based Medicine is the conscientious, explicit,
and judicious use of current best evidence in making
decisions about the care of individual patients.
The practice of evidence-based medicine means
integrating individual clinical expertise with the best
available external clinical evidence from systematic
research and patient’s values and expectations.
Sackett et al 1996
Practicing Evidence-Based Medicine
The five steps of practicing evidence-based
medicine:
1. Formulating a clinical question
2. Searching for the best evidence
3. Critical appraisal of the evidence
4. Applying evidence to patients
5. Evaluating your performance
Evidence Based Rheumatology
Using coxibs and biologics lets look at
some issues in evidence based
rheumatology/medicine
1. Formulating a clinical question
The question takes into consideration:
P = population
I = intervention (treatment)
C = comparison (placebo or active control)
O = outcome
Should patients with early RA be treated with a biologic
agent?
What is the evidence that a biologic reduces joint damage
whereas NSAIDS including coxibs don’t?
2. Searching for the best evidence
Improved Strategies for searching
How many ways of searching do you know
to find best evidence on
eg
Etanercept in RA ?
Coxibs in RA?
Identifying best studies – primary literature
Google
MEDLINE
EMBASE
Handsearching
Reference lists
Drug companies
Grey literature
Personal communication
Identifying pre-appraised sources –
secondary literature
Who has heard of the Cochrane
Library?
www.thecochranelibrary.com
Identifying pre-appraised sources –
secondary literature
Who has heard of the Cochrane
Library?
www.thecochranelibrary.com
Who has used the Cochrane Library?
Who/what is Cochrane?
The Cochrane Collaboration is an international
not-for-profit and independent organization,
dedicated to making up-to-date, accurate
information about the effects of health care readily
available worldwide.
It produces and disseminates systematic reviews
of healthcare interventions and promotes the
search for evidence in the form of clinical trials and
other studies of interventions.
The Cochrane Collaboration was founded in 1993
and named after the British epidemiologist, Archie
Cochrane.
Archie Cochrane
Obstetrician in United Kingdom
‘Effectiveness and Efficiency’
You should consider Archie Cochrane’s book
‘Effectiveness and Efficiency’ for your ‘Desert
Island Texts’ of the top 10 books that have made
an enormous impact!
100 pages long
The basis for his parading before the UK
Parliament when they were designing the National
Health Service - he ‘wore’ a ‘Sandwich Board’
stating:
‘All Effective Health Care should be free’
What
does the logo represent?
www.Cochrane.org
What does the logo represent?
The circle formed by the 'C' of Cochrane and the mirror
image 'C' of Collaboration reflects the international
collaboration that makes our work relevant globally.
The inner part of the logo illustrates the results of a
systematic review of seven RCTs of a short, inexpensive
course of a corticosteroid given to women about to give birth
too early.
The diagram summarises the evidence that would have been
revealed had the available RCTs been reviewed
systematically. A decade later it indicates strongly that
corticosteroids reduce the risk of babies dying from the
complications of immaturity.
What does the logo represent?
Each horizontal line represents the results of one trial (the
shorter the line, the more certain the result); and the
diamond represents their combined results. The vertical line
indicates the position around which the horizontal lines
would cluster if the two treatments compared in the trials had
similar effects; if a horizontal line touches the vertical line, it
means that that particular trial found no clear difference
between the treatments. The position of the diamond to the
left of the vertical line indicates that the treatment studied is
beneficial. Horizontal lines or a diamond to the right of the
line would show that the treatment did more harm than good.
To help people make well informed decisions
by preparing, maintaining and promoting
access to systematic reviews of studies on
the effects of health and health care practices
and policies.
www.Cochrane.org
Recent events in Cochrane
Recent update of the Cochrane Handbook for Systematic
Reviews of Interventions (the Handbook) with new
improvements to Cochrane review methodology especially
regarding assessing risk of bias in systematic reviews and
presenting and interpretation of results – using ‘Risk of bias’
and ‘Summary of findings’ tables, and the GRADE approach
for grading of evidence.
The handbook provides guidance to authors for the
preparation of Cochrane intervention reviews.
The Cochrane Database of Systematic Reviews obtained its
first impact factor in 2007 – 4.654 and ranked 14 out of 100
journals in the ISI category Medicine, General & Internal.
What is special about the Cochrane
Library?
ww
What is special about the Cochrane
Library?
The Cochrane Library provides fast access to the most
reliable, independent evidence on which to base clinical
treatment decisions.
Cochrane reviews are produced to the highest
methodological standard.
Cochrane reviews are done in a variety of health care
diseases and conditions, including musculoskeletal
conditions.
A systematic review uses a predefined, explicit methodology.
The methods used include steps to minimize bias in all parts
of the process: identifying relevant studies, selecting them
for inclusion, and collecting and combining their data.
Studies should be sought regardless of their results.
111 Rheumatology Cochrane Reviews
Summarize the best evidence for therapy
Gout
Legg Calve Perthes
Lupus erythematosus
OA
Osteoporosis
Pediatric rheumatology
RA
Soft tissue conditions
i. Fibromyalgia
ii. Upper limb conditions
iii. Lower limb conditions
Spondyloarthropathies
Systemic sclerosis
Vasculitis
www.cochrane.org
Evidenced
Based
Rheumatology
BMJ Books 2004
Tugwell,Shea,Boers,
Brooks,Simon,Strand,
Wells
BMJ Books
All use Cochrane as basis
Clinical Evidence
Evidence Based Cardiology
Evidence Based Dermatology
Evidence Based Gastroenterology and Hepatology
Evidence Based Hypertension
Evidence Based Infectious Diseases
Evidence Based Pediatrics and Child Health
Evidence Based Practice in Primary Health Care
Evidence Based Sports Medicine
Evidence-based Oncology
Evidence-Based Ophthalmology
Evidence Based Rheumatology
Summarises
the Rheumatology
Cochrane Reviews.
Summarises
therapy.
the best evidence for
Rheumatoid Arthritis chapter
Chapter presents a summary of recent
systematic reviews and meta-analyses of
interventions for RA, including
Education
Ultrasound, thermotherapy, dynamic exercise
NSAIDs including coxibs
DMARDs
Biologic agents
Corticosteroids
3. Critical appraisal of the evidence
Main issues to consider…
Is the review valid?
What are the results?
Are the results valid?
Is the review valid?
PICO(S):
Were there clearly defined groups of patients, similar in all
important ways other than exposure to the treatment or other
cause?
Were treatments/exposures and clinical outcomes measured
in the same ways in both groups? (Was the assessment of
outcomes either objective or blinded to exposure?)
Was the follow-up of the study patients sufficiently long (for
the outcome to occur and complete)?
What study designs were included?
Is the review valid?
1.
2.
3.
4.
5.
6.
METHODS: Assessment of risk of bias in
included studies
Was the allocation sequence adequately generated?
Was allocation adequately concealed?
Was knowledge of the allocated interventions adequately
prevented during the study?
Were incomplete outcome data adequately addressed?
Are reports of the study free of suggestion of selective
outcome reporting?
Was the study apparently free of other problems that could
put it at a risk of bias?
What are the results?
Overall findings – presented as:
1. Summary of findings (SoF) table - new
Cochrane approach
2. Clinical relevance table – old Cochrane
Musculoskeletal Group approach
Summary of findings table – Etanercept
compared to control for the treatment of RA
Are the results valid?
Quality of
evidence
High
Study design
Lower if
Higher if
Randomised trial
Study quality:
-1 Serious
limitations
-2 Very serious
limitations
Strong association:
+1 Strong, no
plausible
confounders
+2 Very strong,
no major
threats to
validity
Moderate
Low
Observational
study
Very low
Any other
evidence
-1 Important
inconsistency
Directness:
-1 Some
uncertainty
-2 Major
uncertainty
-1 Sparse or
imprecise data
-1 High probability
of reporting bias
+1 Evidence of a
Dose response
gradient
+1 All plausible
confounders
would have
reduced the
effect
PLATINUM
Systematic Review (meta-analysis) that is well-conducted and
includes 2 or more randomised controlled trials
GOLD
Randomised controlled trial (1 or more) that tests at least 50
people with a treatment and 50 people without the treatment
SILVER
Observational studies or studies that did not assign people
randomly to groups who receive or do not receive the treatment
BRONZE
Expert opinion or reports of specific cases
4. Applying evidence to patients
1.
2.
3.
4.
Will the results help my patient?
Sufficient outcomes considered
Generalizability (population, setting,
intervention)
Applicability – what are the benefits and
harms? What alternative treatments are
available?
What are my patient’s preferences, values
and situation?
Evidence Based Rheumatology Text:
best therapy evidence
Features
Improved Strategies for searching/identifying
best studies.
KTE: make the evidence more “usable”
for both clinicians and consumers in five
ways:
Knowledge Mobilisation
Anyone know what ‘FFE’ stands for?
Knowledge Mobilisation
Anyone know what ‘FFE’ stands for?
FFE= “Friendly Front End”
Features
KT FFE’s: make the evidence more
“usable” for both clinicians and
consumers in five ways:
1. Web availability,
2. Simple quality grading,
3. Getting to a ‘friendly number’
Use of percentages and NNT
FFE
1.Getting to a friendly number…
Cochrane/Campbell
Database
RR
ARR (CER – EER)
NNT
#/100
2.Develop an Evidence Based Message
EXAMPLE:
ETANERCEPT FOR TREATMENT OF RHEUMATOID ARTHRITIS
Clinicians [and patients and policy
makers] often prefer percentages!
Should they be relative or absolute?
.
GPs in UK over twice as likely to
recommend starting therapy when only
given RR information
33% vs 88%
Proportion who would prescribe
Relative RR
Absolute
NNT
0
2
4
6
8
Provision of the information in tables in a
clinically useful format.
Use of percentages and NNT
Where possible, the following data are
provided:
if a scale, the range;
baseline rates;
relative effects;
absolute effects
NNT (number needed to treat), NNH
(number needed to harm).
Clinical relevance table -Percentages
Is Relative difference enough?
Etanercept for Rheumatoid Arthritis
25 mg x 12 months
Outcome
ACR 50
Event rate in
Placebo
Group
4.5%
Event rate in
Treatment
Group
39.4%
Relative Risk
(95% CI)
8.89
(3.61, 21.89)
Absolute
Risk
Difference
(95%CI)
35%
NNT
?
Can
anyone
tell me?
Blumenauer B, Judd M, Cranney A, Burls A, Coyle D, Hochberg M, Tugwell P, Wells G. Etanercept for
the treatment of rheumatoid arthritis.. The Cochrane Database of Systematic Reviews 2003, Issue 3.
Meaningful Expression of Active Treatment Over
Control: Number Needed to Treat to Benefit (NNTB)
Number of patients that should be treated to achieve favourable outcome eg
ACR 50
NNTB=1/ARR=1/(Pc-Pi) 1/[39-4] x 100=1/35 x100 = 3
(Pi-Pc)=difference between the proportion of events in the control group (Pc)
and the proportion of events in the intervention group (Pi)
NNTs for treatment should be small – means that a favourable outcome
occurs in almost every patient who receives the treatment.
Because few treatments are 100% effective and because few controls - even
placebo or no treatment - are without some effect, NNTs for effective
treatments are usually in the range of 2 - 4
Always round NNTB to whole number
ARR = absolute risk reduction; Pc = proportion of events in control group; Pi = proportion of events in
intervention group
Tugwell P, Shea B, Boers M, Brooks P, Simon L, Strand V, Wells G. eds. Evidence Based Rheumatology.
London, England: BMJ Publishing Group. Book and CD-ROM edition. June 1, 2004. Chaellier G, et al. BMJ.
1996;312:426-429. Bandolier NNT Supplement (http://www.jr2.ox.ac.uk/bandolier/band59/NNT1.html)
Clinical relevance tableNNT [ 1/ARR]
Etanercept for Rheumatoid Arthritis
25 mg x 12 months
Outcome
ACR 50
Event rate in
Placebo
Group
4.4%
Event rate in
Treatment
Group
39.4%
Relative Risk
(95% CI)
8.89
(3.61, 21.89)
Absolute
Risk
Difference
(95%CI)
35%
NNT[B]
3
Blumenauer B, Judd M, Cranney A, Burls A, Coyle D, Hochberg M, Tugwell P, Wells G. Etanercept for
the treatment of rheumatoid arthritis. The Cochrane Database of Systematic Reviews 2003, Issue 3.
Features
1.
2.
3.
4.
5.
Summarise the best evidence for therapy.
KT FFE’s: make the evidence more
“usable” for both clinicians and consumers
in five ways:
Web availability,
Simple quality grading,
Use of percentages and NNT
‘Faces’: visual aids
1,5,15,45 min Patient handouts.
FFE
1.Getting to a friendly number…
Cochrane/Campbell
Database
RR
ARR (CER – EER)
Clinical Tables
NNT
Faces
#/100
Peter and Chris Cates
Website
http://www.nntonline.net,
FACES
Graphical display of treatment effect
Etanercept for Rheumatoid Arthritis 25 mg x 12 months
ACR 50 response
Each display represents a total of 100 people with rheumatoid arthritis
Without treatment, 5 people will experience an ACR 50 response (green faces)
With treatment, 41 people will experience an ACR 50 response (green + yellow faces)
Therefore, 36 more people will benefit from the treatment (yellow faces)
Visual Rx calculates and converts data to face tables (Chris Cates www.nntonline.net)
Features
1.
2.
3.
4.
5.
Summarise the best evidence for therapy.
KT FFE’s: make the evidence more
“usable” for both clinicians and consumers
in five ways:
Web availability,
Simple quality grading,
Use of percentages and NNT
‘Faces’: visual aids
1,5,15,45 min Patient handouts.
FFE
1.Getting to a friendly number…
Cochrane/Campbell
Database
RR
ARR (CER – EER)
Clinical Tables
NNT
Faces
#/100
2.Develop Evidence Based Summaries tailored to audience
www.arthritis.ca
FFE:1,5,15,45
MINUTE FORMAT
Four versions of the same information from
systematic reviews presented in ever increasing
detail and graded according to the level of
evidence
Developed by the Cochrane Musculoskeletal Consumer
Group, Musculoskeletal Review Group and
Ottawa Health Decision Centre
Example: Infliximab for rheumatoid arthritis
1 MINUTE CONSUMER SUMMARY
(bottom line)
5 MINUTE CONSUMER SUMMARY
Number of studies
Number of pts
Dose of drug
What is rheumatoid arthritis
and infliximab?
What did the studies show?
What are the side effects?
1 minute summary
(Bottom line)
15 MINUTE CONSUMER SUMMARY
PAGE 1
What is rheumatoid
arthritis and infliximab?
How were the studies
found?
Study quality and
description
15 MINUTE CONSUMER SUMMARY
PAGE 2
What do the studies
show?
What are the side
effects?
15 MINUTE CONSUMER SUMMARY
PAGE 3
Bottom Line
45 MINUTE DECISION AID
PAGE 1
Context
What is RA
Range of Treatment
options
45 MINUTE DECISION AID
PAGE 2
6 steps in
decision making
-Understand the
decision
-Think about the
benefits and harms
45 MINUTE DECISION AID
PAGE 3
Values Clarification
Balance Sheet
and Importance
Role in decision
making process
45 MINUTE DECISION AID
PAGE 4
More information
needed
Next steps
Share answers and
questions with
doctor
45 MINUTE DECISION AID
Keeping track
of evidence
base
More on
statistical
modelling in
future
NSAID/COXIB BALANCE SHEET EXAMPLE
Evidence-based Rheumatology
NSAID BALANCE SHEET
4. Applying evidence to patients
Will the results help my patient?
1. Sufficient outcomes considered
2. Generalizability (population, setting,
intervention)
3. Applicability – what are the benefits and
harms? What alternative treatments are
available?
A clinical decision is then made and applied taking
into account the patient’s preferences, values and
situation.
5. Self-evaluation
Evaluating your performance in using
the EBM methodologies
Reactions from your patient
Using PICO to orient us
P = population
I = intervention
C = comparison
O = outcome
OMERACT is linked to the Cochrane
Musculoskeletal Group, where the outcomes
endorsed by OMERACT are recommended for
use in Cochrane systematic reviews.
OMERACT 10 will be held in
Australasia from May 5 – 9, 2010.
More details to come soon!
What is OMERACT?
1.
Data driven process to define outcome measures
applicable in RCTs and LOS for each clinical indication
2.
Domains derived from the “Ds”: Discomfort
Disability
Dollar cost
Death
3.
Definition of a “minimally clinically important
improvement”
= MCID
What is OMERACT?
4.
Presentation of evidence and development of
consensus at each conference:
5.
Representatives include: Academia, Clinical
Investigators, Regulatory Agencies,
Sponsors, Clinical Rheumatologists
6.
Previous OMERACT Recommendations have
been ratified by WHO / ILAR and National
Approval Agencies in RA, OA, AS, SLE,
including HRQOL and Economic evaluations
OMERACT History
Started in 1992 as transatlantic effort to
agree on core set and response for RA trials
Expanded into
Other areas: safety, economics
Other study types: LOS
Other diseases
Became patient-inclusive
Grew from 92 participants in 1992 to >250 in
2008!
OMERACT
I:
II:
1992:
1994:
III: 1996:
IV: 1998:
5:
2000:
6:
2002:
7:
8:
9:
2004:
2006:
2008:
Rheumatoid Arthritis Clinical Trials
Adverse Events → Establishment of Registries
Health Related Quality of Life
Economic Evaluations
Osteoarthritis
Osteoporosis
Psychosocial Measures
Longitudinal Observational Studies
RA Response Criteria / Imaging
Ankylosing Spondylitis ASAS
Systemic Lupus Erythematosus
MCID
Economics: Cost Effectiveness
Imaging: Radiography and MRI
Economics
Imaging
Rheumatoid Arthritis: Low Disease Activity
Surrogate outcomes
Safety trade off with Benefit
OMERACT/ACR Outcome Core set: Benefit
Rheumatoid Arthritis
PsychoSocial QOL
biologic
markers
Joint Counts
Pain
Physical Function
Patient/MD Global
Acute Phase
Imaging (>1yr)
Stiffness,
fatigue
Toxicity
OMERACT Core set for Osteoarthritis
8%
inflammation
QoL/utility
36%
90%
biologic
markers
pain
physical function
patient global
imaging (> 1 yr)
MD global
stiffness
other
ASAS/
OMERACT
core
domains for
Ankylosing
Spondylitis
physical function
spinal stiffness
patient global assessment
spinal mobility
pain
acute
phase
reactants
hip
peripheral joints/
radiograph
entheses
spine
radiograph
fatigue
OMERACT Participants
Rheumatologists
Health professionals
Trialists
Methodologists
Scientists from industry
Regulators
Patients!
OMERACT Filter
to select measures
To be applicable in its intended setting,
a measure must be
truthful
discriminative
feasible
JRheum 1998: 25: 198-9
OMERACT Process
Data-driven, iterative
Decisions forever ‘preliminary’
Small group process aimed at making
everyone’s voice heard
Program can change if necessary
Please join us in Australasia!!
OMERACT 10
May 5 – 9, 2010
www.omeract.org