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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):  

 

Hearing Impairment In Childhood Bacterial Meningitis Is Little Relieved By Dexamethasone Or Glycerol -- Peltola Et Al. 125 (1): E1 -- Pediatrics

Published online December 14, 2009

 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, â‰¥60 dB, and â‰¥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.



Abstract

Background

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.

Objectives

We conducted a systematic review examining the efficacy and safety of adjuvant corticosteroid therapy in acute bacterial meningitis.

Search strategy

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.

Selection criteria

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.

Data collection and analysis

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.

Main results

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.

Authors' conclusions

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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