|Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation
|Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, Payne E, Cuthbertson B H
This review concluded that drotrecogin alfa (activated) is likely to be clinically effective and cost-effective for the treatment of patients with severe sepsis within the UK National Health Service. The review was well conducted and the conclusions are likely to be reliable, although evidence of the treatment's effectiveness came primarily from one large clinical trial.
To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of adults with severe sepsis in the setting of the UK National Health Service (NHS).
The authors searched the Cochrane Database of Systematic Reviews, DARE, HTA, NHS EED, MEDLINE and PubMed, EMBASE, BIOSIS Previews, TOXLINE, the Cochrane Controlled Trials Register, the Science Citation Index, BioMed Central and EconLit. The search strategy used for MEDLINE was reported. The following sources were searched for unpublished research or research in progress: the National Research Register, an Early Warning System database, Index to Scientific and Technical Proceedings, Conference Papers Index (from CSA), Current Controlled Trials, Clinical Trials.gov, Zetoc, SIGLE (grey literature), and the websites of the Food and Drug Administration and European Agency for the Evaluation of Medicinal Products. Further information was retrieved by scanning the reference lists of retrieved studies and checking sponsor submissions, and through contact with experts.
Study designs of evaluations included in the review
Only RCTs were eligible for inclusion in the effectiveness evaluation. All studies conducted in relevant participants were eligible for inclusion in the safety assessment.
Specific interventions included in the review
Studies that compared drotrecogin alfa (activated) plus conventional care with conventional care alone were eligible for inclusion. One of the included randomised controlled trials (RCTs) used seven different dosage regimens of drotrecogin alfa (activated). The second RCT and subsequent open-label studies used a continuous intravenous infusion for 96 hours at a dose of 24 microg/kg per hour. Both RCTs used intravenous saline infusion as a placebo.
Participants included in the review
Eligible participants were hospitalised adult patients with severe sepsis (defined according to the 1992 guidelines of the American College of Chest Physicians and the Society of Critical Care Medicine) or septic shock acquired in either the community or hospital. Studies in children were excluded from the effectiveness evaluation. The majority of the participants in the included studies (56 to 66%) were male and their mean age was about 60 years. In the larger study, 75% of the participants had two or more organ failures while 43% had three or more.
Outcomes assessed in the review
The primary outcome was all-cause mortality at the end of the study follow-up. The adverse effect profile of drotrecogin alfa (activated) was also assessed. The secondary outcomes were death from septic shock, length of hospital and/or intensive care unit stay, functional status (quality of life), APACHE II (Acute Physiology, Age and Chronic Health Evaluation) score, the number of organ failures, organ dysfunction, the duration of assisted ventilation, and nosocomial infection. Data on these outcomes were included in the review.
How were decisions on the relevance of primary studies made?
Two reviewers independently assessed studies for relevance. Any disagreements were resolved by discussion, with referral to a third reviewer if necessary.
Assessment of study quality
The validity of the primary studies was assessed by evaluating adequacy of allocation concealment and randomisation, blinding and adequacy of intention-to-treat analysis. The generalisability of studies to the UK context was also assessed, based on the definition of sepsis and severe sepsis, admission diagnoses and patient characteristics, and the regimen of standard care. Two independent reviewers made judgements of validity. Any disagreements were resolved by discussion, with referral to a third reviewer if necessary.
Two reviewers independently extracted the data using pre-designed forms. Any disagreements were resolved by discussion, with referral to a third reviewer if necessary. The mortality rates in RCTs were used to calculate relative risks (RRs) and 95% confidence intervals (95% CIs). For continuous outcomes, the mean and standard deviation for each group were extracted. All available data on adverse events associated with the use of drotrecogin alfa (activated) in patients with severe sepsis were extracted for the safety assessment.
Methods of synthesis
How were the studies combined?
The studies were combined in a narrative that covered overall mortality, subgroup analyses of mortality (by severity of disease at baseline, number of organ failures, and source and site of infection), secondary outcomes and safety. A combined result for 28-day mortality from the two included RCTs was derived by calculating the mean of the mortality rates from the two studies. The authors did not report any attempt to assess publication bias.
How were differences between studies investigated?
The main evaluation included only two RCTs. Differences between the two studies were discussed in the text, and detailed baseline characteristics of the participants were tabulated.
Results of the review
Two RCTs with 1,821 participants were included in the effectiveness evaluation. Additional data from one open-label study (1,578 participants) and two compassionate use studies (268 participants) were used for the safety evaluation.
Validity and generalisability.
Both RCTs were double-blind and reported an intention-to-treat analysis. The methods of randomisation and allocation treatment were adequate for the larger pivotal RCT, but were not reported for the other. The pivotal RCT applied a stricter definition of severe sepsis than that used in practice in the UK, and the RCTs only included patients who developed severe sepsis during the first 24 hours of screening.
The combined overall 28-day mortality rate was 25.1% in patients treated with drotrecogin alfa (activated) and 31.0% in those treated with placebo (RR 0.81, 95% CI: 0.70, 0.94), suggesting that treatment with drotrecogin alfa (activated) was associated with a statistically significant reduction in mortality. Data from the larger RCT also suggested a significant reduction in 28-day mortality rates with drotrecogin alfa (activated) compared with placebo (24.8% versus 31.3%; RR 0.79, 95% CI: 0.68, 0.92); the benefit was maintained to 90 days but by 9 months the difference was not statistically significant. Across the two RCTs, drotrecogin alfa (activated) did not reduce the risk of death from sepsis-induced multiple organ dysfunction, but there was a trend towards a reduced risk of death from refractory septic shock (RR 0.71, 95% CI: 0.49, 1.01). Further analyses (based on subgroup analyses of the larger RCT) were reported in the review.
There were no significant differences in the incidence of serious adverse events between the drotrecogin alfa (activated) and placebo groups in the two RCTs. Based on data from all available clinical studies, 2.3% of patients on placebo experienced a serious bleeding event, compared with 5.3% of those who had received drotrecogin alfa (activated). The pooled safety data indicated that 0.6% of drotrecogin alfa (activated)-treated patients experienced an intracranial haemorrhage compared with none of the placebo group.
The mean additional cost per patient treated with drotrecogin alfa (activated) in the UK was estimated to be £5,106 by the manufacturer and £6,661 by the Southampton Health Technology Assessments Centre (SHTAC). The manufacturer estimated the cost-effectiveness of drotrecogin alfa (activated) in patients with severe sepsis and multiple organ dysfunction to be £6,637 per quality-adjusted life-year (QALY) based on 28-day effectiveness data, and £10,397 when based on longer term follow-up data. SHTAC estimated a base-case cost per QALY of £8,228 based on 28-day survival data.
Drotrecogin alfa (activated) plus best supportive care appears clinically and cost-effective compared with best supportive care alone for patients with severe sepsis in the UK. The same conclusion applies to the subgroup of patients with severe sepsis and multiple organ failure.
This review addressed a clear question and the inclusion and exclusion criteria were clear. The authors searched a wide range of sources, including several of unpublished research and research in progress, but it was unclear whether any language restrictions were applied. The authors did not formally assess publication bias but, as this was a review of a new technology and in view of the wide range of sources searched, the risk of publication bias is likely to be low. Two reviewers independently selected the studies, assessed validity and extracted the data, thus minimising the risk of bias or errors affecting the review process. Validity was assessed using standard criteria. In line with their objectives, the authors considered generalisability to the UK setting as an aspect of validity.
Extensive details of the included studies were provided in the text and tables. The results were presented as a narrative synthesis and the authors based their conclusions mainly on the best available evidence. A combined result for 28-day mortality in the two RCTs was presented without a statistical test of heterogeneity, although differences between the studies were discussed in the text. Overall, the authors' conclusions are likely to be reliable, but it should be borne in mind that the effectiveness conclusions are largely based on the results of a single large RCT.
Implications of the review for practice and research
Practice: The authors stated that up to 16,570 patients per year could be eligible for treatment with drotrecogin alfa (activated) in England and Wales, with an estimated annual drug acquisition cost of over 80 million.
Research: The authors stated that research is required on the longer term impact of drotrecogin alfa (activated) on mortality and morbidity, on its clinical and cost-effectiveness in children with severe sepsis, and on the effect of timing and duration of treatment.
NHS R&D Health Technology Assessment (HTA) Programme, project number 03/18/01.
Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, Payne E, Cuthbertson B H. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation Health Technology Assessment 2005; 9(11): 1-140
Subject indexing assigned by NLM
Acute Disease; Adolescent; Adult; Cost-Benefit Analysis; Evidence-Based Medicine; Female; Great Britain; Humans; Male; Placebos; Protein C /economics /therapeutic use; Randomized Controlled Trials as Topic; Recombinant Proteins /economics /therapeutic use; Sepsis /drug therapy; Treatment Outcome
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.