Transcript Cell-Free Hemoglobin-Based Blood Substitutes and Risk of

Cell-Free Hemoglobin-Based
Blood Substitutes and Risk of
Myocardial Infarction and Death
Natason et al., JAMA, Prepublished online April 28, 2008 at
http://jama.ama-assn.org/cgi/content/full/299.19.jrv80007
Journal Club
Yulia Lin, Transfusion Medicine Resident
University of Toronto
May 16, 2008
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How to critically appraise a metaanalysis?
Guyatt G, Rennie D (ed). User’s guide to the medical
literature: a manual for evidence-based clinical practice.
Chicago, IL: AMA Press. 2002. Chapter 1E: Summarizing the
evidence.
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Definitions
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Overview
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Systematic review
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Using methods designed to reduce the
likelihood of bias
Meta-analysis
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Summary of the medical literature that
attempts to address a focused clinical
question
Review that uses quantitative methods to
summarize the results
Steps to a Meta-analysis
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Question
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Literature search
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Select and critically appraise
Data abstraction
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Identify all relevant studies
Inclusion and exclusion criteria
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Population, Intervention, Control, Outcome
Collect relevant information
Analysis
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Guyatt G, Rennie D. User’s Guide to the Medical Literature (2002) ch 1E
How to critically appraise a metaanalysis?
1.
2.
3.
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Are the results of the study valid?
What are the results?
Will the results help me in caring for my
patients?
Are the results of the study valid?
Question

Literature
search

Selection &
appraisal

Data
abstraction

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Did the overview address a focused clinical
question?
Was the search for relevant studies detailed and
exhaustive?
Were the primary studies of high methodologic
quality?
Were assessments of studies reproducible?
What are the results?

Analysis
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Were the results similar from study to
study?
What are the overall results of the
review?
How precise were the results?
Will the results help me in caring
for my patients?
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External
validity
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Are the results generalizable and can
they be applied to my patients?
Were all clinically important outcomes
considered?
Are the benefits worth the harms and
cost?
Cell-Free Hemoglobin-Based
Blood Substitutes and Risk of
Myocardial Infarction and Death
Natason et al., JAMA, Prepublished online April 28, 2008 at
http://jama.ama-assn.org/cgi/content/full/299.19.jrv80007
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Hemoglobin-based blood
substitutes (HBBS)
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Ideally
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But the challenge = free hemoglobin
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Universally available
Eliminate need for refrigeration
Long shelf-life
Decreased risk of iatrogenic infection
Scavenges nitric oxide --> vascular thrombosis
Possible solutions?
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Chemically alter Hb to create larger,
more stable HBBS molecule
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Cross-link
Polymerize
Pegylate
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Copyright restrictions may apply.
Question

The association between HBBSs and the
risk of myocardial infarction and death
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Additional purpose
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Examine regulatory process that permitted
repeated trials with theses agents despite
safety concerns
Literature Search
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Search Strategy
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Internet
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PubMed, EMBASE, Cochrane
Human RCT in English
1980 to March 25, 2008
“blood substitutes” and “hemoglobin”
FDA advisory committee meeting
Press releases from companies
Study Criteria
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Inclusion
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Exclusion
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RCT
Outcome variable: Death or MI
Did not involve a HBBS
All patients were healthy volunteers or
younger than 19 years
Results included in a subsequent report
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Copyright restrictions may apply.
Methods
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Standard data collection form
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Outcomes: mortality and MI
Descriptive data
Intention-to-treat analysis used when
reported
Missing data (1 treatment, 4 control)
analyzed both as survivors and nonsurvivors
Independent review by 2 authors with a
3rd author resolving discrepancies
Statistics
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“We assessed the homogeneity using
Breslow-Day test and an associated I2
statistic”
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To pool or not to pool?
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Tests of heterogeneity determine whether
the degree of variability in treatment effects
between studies is greater than that
expected by chance
I2 measures the extent of variation
• 0% indicates no observed heterogeneity
• Heterogeneity increases as I2 increases
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To pool or not to pool?
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Forest plots
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Pool if all point estimates are on the same
side of the line or if confidence intervals
overlap
Statistics
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“Risks estimated using Cochran-MantelHaenszel test with 95% CI”
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How to pool the results?
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Results typically weighted based on study
size (occasionally can be weighted based on
quality of study)
Statistics
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“A fixed effects model was required
because of the null values for the
estimates of between-study variance”
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Models for pooling data in meta-analysis
Fixed effects model
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Assumes there is a single true value
underlying all study results such that if all
studies were infinitely large, they would yield
identical estimates of the effect
Error comes only from within study variation
Models for pooling in
meta-analysis
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Random effects model
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Assumes that studies are a random sample
of a population of studies where each study
estimates a different underlying true effect
and the distribution of these effects is
assumed normal around a mean value
Error comes from both within study variation
and between study heterogeneity
Random effects model usually has a wider
confidence interval
If little heterogeneity, compared to withinstudy variance, approximates fixed effects
model
Results
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16 trials of 5 HBBSs met inclusion
criteria
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Type: 4 double-blind, 7 single-blind, 4 openlabel, 1 uninformative
Patients: 5 trauma, 10 surgical, 1 stroke
Outcomes: 12 used death, 10 used MI
Median time from completion of trial to
publication 4 years (1 to 6 years)
Trials described in Table 2
NNH 62
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NNH 50
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Subgroup analyses
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Results consistent regardless of
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Patient population
Control: non-blood vs. blood product
Product removed
Type of product
• Low vs. High tetramer content
• Low vs. High P50 content
Unpublished vs. published
Cumulative Mortality and MI
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By 2000, 11 studies completed
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Mortality RR 1.27; 95% CI 0.99-1.63
MI RR 2.77; 95% CI 1.49-5.15
The regulatory process
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Sponsors are required by law to report
their results to the FDA after studies are
completed (whether or not published)
Data are not made public unless product
is approved or an advisory committee is
convened
Article outlines pitfalls of this system
including that 5 trials are ongoing and 1
is being planned
Are the results of the study valid?
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Did the overview address a focused clinical
question?
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Was the search for relevant studies detailed and
exhaustive?
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PIO  Intervention and outcome
Population was varied and one might expect that this
might lead to variations in the absolute risk of
mortality/MI but not necessarily the relative risk
Control varied but no difference in sub-group analysis
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Yes, included unpublished studies and attempts to
contact the companies for more complete data
Assumed? Hand searching the reference lists of the
articles or consulting experts in the area
No change when unpublished studies excluded
Are the results of the study valid?
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Were the primary studies of high methodologic
quality?
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Were assessments of studies reproducible?
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Restricted to RCT but all RCTs included
Did not comment on validity of primary studies
Yes
2 investigators reviewed the studies with a 3rd author
resolving any discrepancies
What are the results?
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Were the results similar from study to
study?
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What are the overall results of the review
and how precise were the results?
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Yes, both by I2 statistic and forest plot
HBBS associated with increased death/MI
Death: RR 1.30; 95% CI, 1.06-1.61
MI: RR 2.71; 95% CI, 1.67-4.40
Will the results help me in caring
for my patients?
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Are the results generalizable and can they be
applied to my patients?
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Were all clinically important outcomes
considered?
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The study considered the adverse effects of therapy
It did not report on the treatment effect though the
endpoints in Table 2 listed avoidance of allogeneic
transfusion and in one case, disability score
Are the benefits worth the harms and cost?
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Yes – covers a variety of conditions and settings
Weighing the risk of increased mortality and MI
against the risks of avoidance of allogeneic
transfusion
No
Conclusion
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Agree with authors’ conclusions
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“In the analysis of available data from clinical
trials, HBBSs was associated with a
significantly increased risk of death and MI”
Questions?