Many thanks. We will have to wait for the updated Cochrane
Review to see if the conclusion is affected by the new RCT.
This is the third example with corticosteroids (head trauma, sepsis
and meningitis). I wonder whether instability of evidence is not due to lack
of funding for larger trials (since corticosteroids are generic). New
medications appear to achieve faster homogeneity of information (real or
apparent?). Paradoxically older drugs may leave us with less clear evidence in
some important areas where public funding is not sufficient.
Thanks for all the inputs.
Mayer
Mayer Brezis, MD MPH
Professor of Medicine
Director, Center for Clinical Quality & Safety
Hadassah Hebrew University Medical Center
Jerusalem, Israel
Office phone 02-6777110
Cellular 050-787-4596
Fax 02-643-9730
www.hadassah.org.il/departments/quality
From: Jean Levasseur
[mailto:[log in to unmask]]
Sent: Wednesday, January 27, 2010 5:07 AM
To: [log in to unmask]
Cc: Mayer Brezis
Subject: Re: meta-analysis vs. RCT contradictory conclusion
Hello,
From a recent PEDIATRICS article (free at pediatrics.org):
PEDIATRICS Vol. 125 No. 1
January 2010, pp. e1-e8 (doi:10.1542/peds.2009-0395)
OBJECTIVE. Several studies have evaluated
dexamethasone for prevention of hearing loss in childhood
bacterial meningitis, but results have varied. We compared
dexamethasone and/or glycerol recipients with placebo
recipients, and measured hearing at 3 threshold levels.
METHODS. Children aged 2 months to 16
years with meningitis were treated with ceftriaxone but were
double-blindly randomly assigned to receive adjuvant
dexamethasone intravenously, glycerol orally, both agents, or
neither agent. We used the Glasgow coma scale to grade the
presenting status. The end points were the better ear's ability
to detect sounds of >40 dB, 60 dB, and 80 dB, with these thresholds
indicating any, moderate-to-severe, or severe impairment,
respectively. All tests were interpreted by an external
audiologist. Influence of covariates in the treatment groups
was examined by binary logistic regression.
RESULTS: Of the 383 children, mostly with
meningitis caused by Haemophilus influenzae type
b orStreptococcus pneumoniae, 101 received
dexamethasone, 95 received dexamethasone and glycerol,92 received glycerol, and
95 received placebo. Only the presenting condition and young
age predicted impairment independently through all threshold
levels. Each lowering point in the Glasgow scale increased the
risk by 15% to 21% (odds ratio: 1.20, 1.21, and 1.15 [95%
confidence interval: 1.06–1.35, 1.07–1.37, and
1.01–1.31]; P = .005, .003, and .039) for any,
moderate-to-severe, or severe impairment, respectively. Each
increasing month of age decreased the risk by 2% to 6% (P =
.0001, .0007, and .041, respectively). Neither dexamethasone
nor glycerol prevented hearing loss at these levels regardless
of the causative agent or timing of antimicrobial agent.
CONCLUSIONS: With bacterial
meningitis, the child's presenting status and young age are the
most important predictors of hearing impairment. Little relief
is obtained from current adjuvant medications.
With
reference to the 2007 cochrane review : van
de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial
meningitis. Cochrane Database of Systematic Reviews2007, Issue 1.
Art. No.: CD004405. DOI: 10.1002/14651858.CD004405.pub2.
In
experimental studies, the clinical outcome of acute bacterial meningitis has
been related to the severity of the inflammatory process in the subarachnoidal
space. Treatment with corticosteroids can reduce this inflammatory response and
thereby may improve outcome. We conducted a meta-analysis of randomised
controlled trials (RCTs) of adjuvant corticosteroids in the treatment of acute
bacterial meningitis.
We
conducted a systematic review examining the efficacy and safety of adjuvant
corticosteroid therapy in acute bacterial meningitis.
In
this updated review, we searched the Cochrane Central Register of Controlled
Trials (CENTRAL) (The Cochrane Library 2006, Issue 2); MEDLINE
(1966 to July 2006); EMBASE (1974 to June 2006); Current Contents (2001 to June
2006); and reference lists of all articles. We also contacted manufacturers and
researchers in the field.
Eligible
published and non-published RCTs on corticosteroids as adjuvant therapy in
acute bacterial meningitis. Patients of any age and in any clinical condition,
treated with antibacterial agents and randomised to corticosteroid therapy (or
placebo) of any type, could be included. At least case fatality rate or hearing
loss had to be recorded for inclusion.
Two
review authors independently assessed trial quality and extracted data. Adverse
effects were collected from the trials. Additional analyses were performed for
children and adults, causative organisms, and low-income and developed
countries.
Eighteen
studies involving 2750 people were included. Overall, adjuvant corticosteroids
were associated with lower case fatality (relative risk (RR) 0.83, 95% CI 0.71
to 0.99), lower rates of severe hearing loss (RR 0.65, 95% CI 0.47 to 0.91) and
long-term neurological sequelae (RR 0.67, 95% CI 0.45 to 1.00). In children,
corticosteroids reduced severe hearing loss (RR 0.61, 95% CI 0.44 to 0.86). In
adults, corticosteroids gave significant protection against death (RR 0.57, 95%
CI 0.40 to 0.81) and short-term neurological sequelae (RR 0.42, 95% CI 0.22 to
0.87). Subgroup analysis for causative organisms showed that corticosteroids
reduced mortality in patients with meningitis due to Streptococcus
pneumoniae (RR 0.59, 95% CI 0.45 to 0.77) and reduced severe hearing
loss in children with meningitis due to Haemophilus influenzae (RR
0.37, 95% CI 0.20 to 0.68); subgroup analysis for patients with meningococcal
showed a nonsignificant favourable trend in mortality (RR 0.71, 95% CI 0.31 to
1.62). Sub analyses for high-income and low-income countries of the effect of
corticosteroids on mortality showed RRs of 0.83 (95% CI 0.52 to 1.05) and 0.87
(95% CI 0.72 to 1.05), respectively. Corticosteroids were protective against
short-term neurological sequelae in patients with bacterial meningitis in high-income
countries (RR 0.56, 95% CI 0.3 to 0.84); in low-income countries this RR was
1.09 (95% CI 0.83 to 1.45). For children with
bacterial meningitis admitted in high-income countries, corticosteroids showed
a protective effect against severe hearing loss (RR 0.61, 95% CI 0.41 to 0.90)
and favourable point estimates for severe hearing loss associated with non-Haemophilus
influenzae meningitis (RR 0.51, 95% CI 0.23 to 1.13) and short-term
neurological sequelae (RR 0.72, 95% CI 0.39 to 1.33). For children in
low-income countries, the use of corticosteroids was neither associated with
benefit nor with harmful effects. Overall, adverse events were not increased
significantly with the use of corticosteroids.
Overall,
corticosteroids significantly reduced rates of mortality, severe hearing loss
and neurological sequelae. In adults with community-acquired bacterial
meningitis, corticosteroid therapy should be administered in conjunction with
the first antibiotic dose. In children, data support the use of adjunctive
corticosteroids in children in high-income countries. We found no beneficial
effect of corticosteroids for children in low-income countries.
I still have to go through the cochrane review, having only
read the abstract, but promises to be interesting!
Jean Levasseur MD, MSc
Joliette, QC, Canada
Le 10-01-26 à 15:57, Mayer Brezis a écrit :
Excellent example! Many thanks for your input and for you
nice Cochrane review. A possible explanation for the discrepancy, as you indicate
in your discussion, might be publication bias (non publication of negative
studies).
I have copied the links below for anyone interested from our EBM
group.
Best regards,
Mayer
LARGE RCT:
CONCLUSIONS: We set out to
determine whether ultrasound-guided embryo transfer improved clinical pregnancy
rates and live birth rates in assisted conception. We used an appropriately
powered RCT design. We did not demonstrate a difference. This outcome is at odds with the UKs
National Institute of Clinical Excellence recommendations for fertility
treatment (Fertility Assessment and Treatment for People with Fertility
Problems. London, UK: RCOG Press, 2004, 112.) which used a meta-analysis of
four smaller trials (range 362-800 patients, totalling 2051 embryo transfers)
to conclude that ultrasound should be offered. We suggest that the current
Cochrane review should be updated with data from our trial and recommend that
consideration is given to accounting for heterogeneity between the included
trials.
Conclusion of NEW COCHRANE REVIEW:
The studies are limited by their
quality with only two studies reporting details of both computerised
randomisation techniques and adequate allocation concealment. Ultrasound
guidance does appear to improve the chances of live/ongoing and clinical
pregnancies compared with clinical touch methods. The quality of future
studies should be improved with adequate reporting of randomisation, allocation
concealment, and power calculations. The primary outcome measure of future
studies should be the reporting of live births per woman randomized.
From: Ahmed
Abou-Setta, M.D. [mailto:[log in to unmask]]
Sent: Tuesday, January 26,
2010 10:09 PM
To: Mayer Brezis
Subject: Re: meta-analysis
vs. RCT contradictory conclusion
Hi Mayer,
I am at a workshop right now, but
there is a recent Cochrane review that has exactly what you are looking for.
The results are significant but the largest trial found no significant
difference in results. The trial is Drakeley et al., 2008 (or 2009) and the
Cochrane review is Brown et al., 2010. I can send you both later today if you
want.
Best wishes,
Ahmed
From: [log in to unmask]">Mayer Brezis
Sent: Tuesday, January 26, 2010 2:47 PM
Subject: Re: meta-analysis vs. RCT contradictory
conclusion
Many thanks for your prompt and interesting responses on the more
general question of discrepancies between large RCT's and meta-analysis.
My question is more specifically for a meta-analysis that includes a large RCT with results contradictory
to that of the meta-analysis.
A current example I have in mind is a RCT on corticosteroids for
sepsis (CORTICUS, NEJM 2008) showing no effect on mortality while a subsequent
meta-analysis (includingthis RCT) concluded corticosteroids reduce
mortality in sepsis (JAMA 2009).
I'm looking for another example to better understand the problem.
Sorry for not having being clear enough.
Many thanks and best,
Mayer Brezis
From: [log in to unmask] [mailto:[log in to unmask]] On Behalf Of Dr. Carlos Cuello
Sent: Tuesday, January 26,
2010 9:30 PM
To: Mayer Brezis
Cc: [log in to unmask]
Subject: Re: meta-analysis
vs. RCT contradictory conclusion
Well, not a contradictory result,
but different is the CRASH trial on corticosteroids for patients for head
trauma injury. All previous meta-analysis were not sufficient for reaching a
conclusion on whether to use or not CS, but the large RCT concluded that they
increased the risk of death
I´ll keep looking for the
contradictory ones
Cheers
2010/1/26 Mayer Brezis <[log in to unmask]>
Can
anyone give me one or more good example(s) of a well done large RCT
reaching a conclusion contradictory to a well done meta-analysis (including
this RCT) and what are the potential or likely explanations for those
discrepancies?
Thanks in advance,
Mayer Brezis, MD MPH
Professor of Medicine
Director, Center for Clinical Quality & Safety
Hadassah Hebrew University Medical Center
Jerusalem, Israel
Office phone 02-6777110
Cellular 050-787-4596
Fax 02-643-9730
www.hadassah.org.il/departments/quality
--
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Director, Centre for Evidence-Based Practice-Tecnologico de Monterrey
Cochrane-ITESM coordinator. Professor of Paediatrics and Clinical Research
Avda. Morones Prieto 3000 pte. Col. Doctores. CITES 3er. piso,Monterrey NL,
México. CP64710
Phone. +52(81)88882154 & 2141. Fax: +52(81)88882148
www.cmbe.net
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