address = administration of drotrecogin alfa ( activated ) in early stage severe sepsis ; apache = acute physiology and chronic health evaluation ; drotaa = drotrecogin alfa ( activated ) ; prowess = recombinant human activated protein c worldwide evaluation of severe sepsis .
jf was involved with the conception and design of the study , acquisition , analysis and interpretation of data , and wrote the first draft of the manuscript .
na was involved with the conception and design of the study , analysis and interpretation of data , and critical revision of the manuscript for important intellectual content .
mm was involved with the interpretation of data and critical revision of the manuscript for important intellectual content .
relative risk ( rr ) and 95% confidence intervals ( 95% ci ) for 28-day mortality in each study .
n / n = number of deaths at 28 days divided by the total number of patients randomly assigned to drotrecogin alfa ( activated ) or placebo .
for the phase ii trial , only patients who were randomized to the same dose and duration of drotrecogin alfa ( activated ) used in the recombinant human activated protein c worldwide evaluation of severe sepsis ( prowess ) and administration of drotrecogin alfa ( activated ) in early stage severe sepsis ( address ) trials are included .
results are classified by low - risk and high - risk subgroups from the recombinant human activated protein c worldwide evaluation of severe sepsis ( prowess ) and administration of drotrecogin alfa ( activated ) in early stage severe sepsis ( address ) trials , defined by either acute physiology and chronic health evaluation ( apache ii ) score ( less than 25 , and 25 or more ) or organ failure ( single and multiple ) .
weight refers to the contribution of each study to the overall pooled estimate of treatment effect for each low - risk and high - risk subgroup .
the weight of each study is calculated as the inverse of the variance of the natural logarithm of its relative risk .
the size of the symbol denoting each point estimate approximates the weighting of each study to each pooled effect measure .
each pooled effect measure is calculated with the use of a random - effects model .
n / n = number of deaths at 28 days divided by the total number of patients in each particular subgroup randomly assigned to drotrecogin alfa ( activated ) or placebo .
the numbers of patients and deaths at 28 days in each subgroup were estimated from data provided in references ,   and   for the prowess trial , and in references   and   for the address trial .
 two international multicentre randomised controlled trials of drotrecogin alfa ( activated ) ( drotaa ) , the recombinant human activated protein c worldwide evaluation of severe sepsis ( prowess ) and administration of drotrecogin alfa ( activated ) in early stage severe sepsis ( address ) trials , have produced inconsistent results . when 28-day mortality data from these trials for patients with severe sepsis and at high risk of death are pooled using a standard random - effects meta - analysis technique , there is no statistically significant survival benefit ( for patients with acute physiology and chronic health evaluation ( apache ii ) scores of 25 or more ) , or a borderline significant benefit ( for patients with multi - organ failure ) . 
 we argue that two important methodological issues might explain the disparate results between the two trials . 
 these issues centre on early trial stopping , which exaggerates treatment effects , and reliance on subgroup analyses , which for drotaa yields inconsistent results across different definitions of high risk . 
 these concerns call into question the effectiveness of drotaa in any patients with severe sepsis . 
 consequently , further randomised trials of this agent in prospectively defined high - risk patients are required to clarify its role in the management of severe sepsis . 
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